Structural pathology underlying neuroendocrine dysfunction in schizophrenia.
Polydipsic hyponatremic schizophrenic (PHS) patients exhibit altered neuroendocrine activity that has been linked to their life-threatening water imbalance, as well as to impaired function and reduced volume of the anterior hippocampus. Polydipsic patients without hyponatremia (polydipsic normonatremic schizophrenics: PNS) exhibit similar, albeit less marked, changes in neuroendocrine activity and anterior hippocampal function, but not reduced anterior hippocampal volume. Indeed, reduced anterior hippocampal volume is seen in patients with normal water balance (nonpolydipsic normonatremic schizophrenics: NNS) whose neuroendocrine activity and anterior hippocampal function differ markedly from those with polydipsia. In an effort to reconcile these findings we measured hippocampal, amygdala and 3rd ventricle shapes in 26 schizophrenic patients (10 PNS, 7 PHS, 9 NNS) and 12 healthy controls matched for age and gender. Bilateral inward deformations were localized to the anterior lateral hippocampal surface (part of a neurocircuit which modulates neuroendocrine responses to psychological stimuli) in PHS and to a lesser extent in PNS, while deformations in NNS were restricted to the medial surface. Proportional deformations of the right medial amygdala, a key segment of this neurocircuit, were seen in both polydipsic groups, and correlated with the volume of the 3rd ventricle, which lies adjacent to the neuroendocrine nuclei. Finally, these structural findings were most marked in those with impaired hippocampal-mediated stress responses. These results reconcile previously conflicting data, and support the view that anterior lateral hippocampal pathology disrupts neuroendocrine function in polydipsic patients with and without hyponatremia. The relationship of these findings to the underlying mental illness remains to be established.


Excision of skin tumours without wound closure.
Sixty-two patients with 67 large or poorly defined skin tumours predominantly on the head and neck (58 basal cell carcinomas) were treated by excision of the lesion and allowing the defect created to heal by second intention. Histological control of the adequacy of excision was monitored using routine vertical sections of formalin-fixed tissue. Further re-excisions were performed in 17 patients in whom tumour extended up to or within 1 high power field (approximately 0.44 mm) of the excision margin. The formalin-fixed specimens ranged from 6-60 (mean 21) mm in diameter and 2-12 (mean 5) mm in depth. After one excision the time to complete re-epithelialization was directly proportional to the surface area (r = 0.73) and ranged from 13 to 60 days (mean 33 days). Measurements of the movements of fixed reference points tattooed at the wound edges in six patients showed that movement of surrounding tissue into the defect accounted for 39-62% (mean 45%) of the reduction in surface area of the defect during healing. Post-operative complications were rare and the cosmetic results were considered good or excellent in 48 patients, fair in nine and poor, i.e. requiring corrective surgery, in three patients. Poor results were due to distortions of free margins, e.g. lower eyelid and nasal margin. The major benefit of this technique is the ease with which further excisions can be performed when histologically indicated.(ABSTRACT TRUNCATED AT 250 WORDS)


Evaluating teamwork development in combat training settings: An exploratory case study utilising the Junior Leaders' Field Gun competition.
A behaviourally-anchored observational rating scale (BAORS) of teamwork based upon the 'Big Five' teamwork model (Salas et al., 2005) was selected and adapted for use in a combat training setting - a UK military field gun competition. The teamwork development of 16 newly-formed teams training to master a historic tactical drill was evaluated over the course of a week-long residential programme. Training culminated in a timed field gun competition. Teams were trained and mentored in respects to teamwork and taskwork by experienced military instructors. Teamwork was assessed at the outset and end of training. Significant improvements were evident on all teamwork process dimensions, with the greatest improvement seen in teams' shared understanding of teamwork roles and strategies (shared mental models). The lack of an association between teamwork development and final drill performance is explored, as is the utility of the measurement protocol developed for teamwork assessment in other settings.


Biological therapy for pustular psoriasis: a systematic review.
The anecdotic evidence of the benefits from biologic agents for psoriasis is extensive. However, data on the efficacy of biologic agents for pustular psoriasis are limited. To update the data on the efficacy and safety of biologic agents for the management of pustular psoriasis. A systematic review of published data regarding biologic therapies on PubMED database, used in the management of pustular psoriasis from 2012 was undertaken. A total of 209 articles were identified, and 43 articles were selected for inclusion. TNF-α inhibitors were used in 205 patients, and 86 patients received ustekinumab, secukinumab, brodalumab, ixekizumab and IL-1 inhibitors. Overall response was favorable for most modalities. No serious adverse events were reported. Inconsistent measures of treatment response and study variability limited the overall evaluation of data. Infliximab and ustekinumab have the most evidence of efficacy and safety for the treatment of pustular psoriasis. Recent evidence supports the use of IL-17 antagonists. Prospective controlled and comparative trials are needed to further explore the efficacy and safety of biologic agents in order to establish objective recommendations for the management of this challenging condition.


[Menometrorrhagia: to whom, why, on which criteria to propose a hormonal exploration?].
The hormonal exploration of menometrorrhagia concerns only the patients throughout their reproductive life, it is not indicated outside this period. In first intention at the woman in age to procreate, will be realized a determination of hCG, an inescapable determination to eliminate a pregnancy and a measure of serum TSH in the case of personal or family history for the screening of subclinical hypothyroidism. Further investigations can be carried out in second-based signs of appeal under the differential diagnosis of polycystic ovary syndrome (PCOS), as a measure serum prolactin, 17-hydroxyprogesterone and total testosterone and not bound to its binding protein the SHBG.


Switching slow relaxation in a Mn(III)(3)Mn(IV) cluster: an example of grafting single-molecule magnets onto polyoxometalates.
Binding an established single-molecule magnet cluster of distorted cubane type [Mn(III)(3)Mn(IV)O(4)] to the lacunary site of an {alpha-P(2)W(15)} polyoxotungstate scaffold results in a surprising zero-field splitting inversion and the subsequent loss of magnetization bistability.


Competitive Memory Training for treating depression and rumination in depressed older adults: a randomized controlled trial.
Although rumination is an important mediator of depressive symptoms, there is insufficient proof that an intervention that specifically targets rumination ameliorates the clinical condition of, depressed patients. This study investigates whether a time-limited cognitive behavioral intervention (Competitive Memory Training, or COMET for depressive rumination) is an effective treatment for depression and rumination. This intervention was tested in older adult depressed outpatients. A total of 93 patients (aged ≥ 65 years with major depression and suffering from rumination) were treated in small groups according to the COMET protocol in addition to their regular treatment. Patients were randomized to two treatment conditions: 7 weeks of COMET + treatment-as-usual (TAU) versus TAU only. COMET + TAU showed a significant improvement in depression and rumination compared with TAU alone. This study shows that the transdiagnostic COMET protocol for depressive rumination might also be successful in treating depression and rumination in older adults.


Varying Flavobacterium psychrophilum shedding dynamics in three bacterial coldwater disease-susceptible salmonid (Family Salmonidae) species.
Flavobacterium psychrophilum causes bacterial coldwater disease (BCWD) and rainbow trout fry syndrome, both of which cause substantial losses in farmed and hatchery-reared salmon and trout populations worldwide. This study provides insight into F. psychrophilum shedding dynamics in rainbow trout (Oncorhynchus mykiss) and, for the first time, coho salmon (O. kisutch) and Atlantic salmon (Salmo salar). Findings revealed that live and dead fish of all fish species shed the bacterium. However, dead fish shed F. psychrophilum at higher rates than living fish, emphasizing the importance of removing dead fish in farms and hatcheries. Furthermore, shedding dynamics may differ according to F. psychrophilum genetic variant and/or fish species, a matter that may complicate BCWD management. Overall, study results provide deeper insight into F. psychrophilum shedding dynamics and will guide future BCWD management strategies.


Selenium-dependent glutathione peroxidase activity is increased in healthy post-menopausal women.
Selenium helps protect against peroxidation during aging as part of the glutathione peroxidase (GPx) antioxidant system. Selenium status, however, is often low in elderly persons who have low selenium intake, live in institutions, and have certain chronic diseases. In addition, a relationship has been observed between the female reproductive hormone, estrogen, and selenium status, with blood selenium and GPx activity coinciding with fluctuations in estrogen during the menstrual cycle. These findings suggest that the decrease in estrogen following menopause may cause a decrease in selenium status, and thus accelerate the process of aging and increase the risk of certain diseases. The current study compared selenium status in healthy premenopausal (n = 13, 21 to 43 years) and postmenopausal (n = 10, 57 to 86 years) women. Selenium intakes of both groups were similar and greater than the recommended dietary allowance (RDA) of 55 microg/day for adult women. Although neither plasma nor RBC selenium concentrations were significantly different between groups, postmenopausal women had significantly greater plasma (p < 0.02), and RBC (p < 0.05) GPx activities compared to premenopausal women possibly in response to oxidative processes associated with aging. These results indicate that the selenium status of healthy postmenopausal women did not decline with menopause and that their antioxidant capability, as measured by GPx activity, was preserved with dietary intake of selenium greater than the RDA.


Vascular calcification presenting as necrosis of penis in patient with chronic renal failure.
An unusual presentation of metastatic calcification as gangrene of the penis is reported in a patient with chronic renal failure on maintenance hemodialysis. Calcification of the vessels of the penis was documented radiographically and pathologically. Recognition of the possible occurrence of this complication becomes of great importance in younger patients on dialysis or with kidney transplants.


Epidural anesthesia for cesarean section in a primigravida woman with Ebstein's anomaly with recurrent supraventricular tachycardia.
Ebstein's anomaly is an uncommon congenital heart defect with an extremely variable natural history due to a wide spectrum of pathological features. We report on the anesthetic management of a 24-year-old primigravida woman with Ebstein's anomaly with recurrent supraventricular tachycardia for emergency cesarean section.


Association between maternal exposure to tobacco, presence of TGFA gene, and the occurrence of oral clefts. A case control study.
To determine the association between maternal tobacco use or exposure, presence of variant transforming growth factor alpha (TGFA) gene, and the occurrence of oral clefts. The present case control study was carried out for 5 months in three tertiary government hospitals in Chennai city with a sample of 100 children (50 children with non syndromic cleft and 50 control) aged 0-24 months. The details of maternal risk factors during the period of gestation were recorded from case and control parents through a pre-validated questionnaire, following which blood samples from 92 children (46 case and 46 controls) based on consent were obtained and evaluated for TGFA gene polymorphism. A significant number of case mothers (48%) were exposed to secondhand smoke during the period of gestation than their control counterparts (24%) (P = 0.01) with an odds ratio of 2.46 (95% CI = 0.99-6.08). Electrophoresis of the restriction fragment length polymorphism (RFLP) product revealed the presence of the homozygous C1C1 allele in all the tested 92 samples with no homozygous C2C2 allele or heterozygous C1C2 allele. The present study has highlighted the role of passive smoking in the causation of non syndromic oral clefts in a developing country like India; however, the involvement of TGFA in causing the same disease in an ethnically Dravidian Indian population is uncertain. The study has brought into forth the role of passive smoking in the development of oral clefts thereby warranting an effective public health policy to tackle the same.


Nilotinib as frontline therapy for patients with newly diagnosed Ph+ chronic myeloid leukemia in chronic phase: results from the Japanese subgroup of ENESTnd.
Recent results from the phase 3 ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients) study have demonstrated superiority of nilotinib over imatinib for the treatment of newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in the chronic phase (CML-CP). Here, we report results from the Japanese subset of patients in ENESTnd, and assess whether results in this subpopulation are consistent with the overall study population. Seventy-nine Japanese patients with CML-CP were randomized to receive nilotinib 300 mg twice daily (BID) (n = 30), nilotinib 400 mg BID (n = 24) or imatinib 400 mg once daily (QD) (n = 25). Major molecular response rates at 12 months, the primary endpoint, were at least twice as high for nilotinib 300 mg BID (57%) and nilotinib 400 mg BID (50%) compared with imatinib 400 mg QD (24%). No patient on nilotinib progressed, while one patient progressed on imatinib. Both drugs were generally well tolerated and discontinuations due to adverse events were comparable among treatment arms. The results in the subpopulation of Japanese patients from ENESTnd closely mirror the results of the overall population, and support the use of nilotinib at 300 mg BID in Japanese patients with newly diagnosed CML-CP.


Chickenpox party or varicella vaccine?
The most compelling rationale for introducing universal vaccination against varicella was the predicted benefits to healthy children. Current evidence from the US experience indicates that these benefits are being realized. As is true for any new vaccine, implementation of such a program necessitates disease surveillance and modifications of the vaccine regimen as needed. In the case of VZV, the epidemiology of herpes zoster must be tracked as well as varicella disease trends. The prevention of herpes zoster may be another use of live attenuated or inactivated varicella vaccines.


Metabolic profiling of seminal plasma from teratozoospermia patients.
Teratozoospermia is one of conditions that can cause male infertility. The mechanism of teratozoospermia remains unclear. The knowledge of the metabolites in human seminal plasma (HSP) is meaningful for the pathological study of teratozoospermia. Analysis of changed metabolites in HSP can help understand the cellular mechanism, find the novel biomarkers and subsequently design a diagnosis test. In this study, the analysis of samples performed by proton nuclear magnetic resonance spectroscopy (1H NMR spectroscopy) to identify the various metabolites, with the aim of finding metabolic profiles and biomarkers related to male infertility. Eighteen de-regulated metabolites were identified in fertile men compared to teratozoospermia patients. These changes illustrate the deficiencies in absorption or metabolism of these metabolites in teratozoospermia. Furthermore, metabolic profiling showed that it is not possible to classify teratozoospermia based on teratozoospermia index (TZI). To the best of our knowledge, this is the first metabolic profiling analysis of HSP described the metabolic features of teratozoospermia in a holistic view.


Cutaneous carcinoma of the head and neck: management of massive and previously uncontrolled lesions.
Cutaneous basal cell and squamous cell carcinoma is the most common of malignant neoplasms. The etiology and natural history of these cutaneous neoplasms are related to actinic exposure, age, sex, hereditary factors, previous tissue injury, and chemical ingestion and exposure. Identification of cutaneous basal cell and squamous cell carcinoma is important. There are several different histologic subtypes of basal cell carcinoma, and each behaves clinically in a different way. There are several accepted methods of treatment including cryosurgery, electrodesiccation and curettage, radiotherapy, surgical excision and Mohs' histographic surgery. Each of these methods is reviewed. The vast majority of cutaneous basal cell and squamous cell carcinomas are easily cured no matter what the treatment modality. However, about 10% of these tumors (30,000 new cases each year) are not cured. These tumors often become massive and uncontrollable. Sixty patients met the criteria of being massive and/or uncontrollable. These criteria are 1. size 3 cms or greater, 2. involvement deeper than skin and subcutaneous fat, 3. four or more previous treatments without control, or 4. proven metastatic disease. These patients with massive and/or uncontrollable tumors underwent treatment with either Mohs' histographic surgery followed by conventional surgery with total microscopic marginal control or conventional excision with total microscopic marginal control. Of the 60 patients treated in this way, 53 are free of disease; 41 of these patients have been free of disease for more than 24 months. Massive and/or previously uncontrollable tumors appear to be better controlled with total microscopic marginal control while preserving as much normal tissue as possible. This technique appears to allow preservation of important esthetic and functional tissue while excising the complete tumor with the greatest degree of certainty.


The effect of prompt local cooling on oedema formation in scalded rat paws.
A standardized, reproducible burn model on rat paw was used and the effect of prompt local cooling on the oedema formation was measured using a newly developed non-invasive method. A transient reduction in oedema formation was observed lasting for a longer period of time with decreasing temperature down to 0 degrees C and increasing cooling time up to 120 min. The decrease in oedema formation was followed by an increase towards or above the amount of oedema in untreated scald injury. This post-cooling increase in oedema formation was related to the temperature and the exposure time of the cooling fluid. The immediate effects of cooling are most likely due to local restriction of the blood flow as a result of cold-induced vasoconstriction. The increase of the oedema formation after the cooling period may be due to reactive hyperaemia.


Involvement of P2Y13 receptor in suppression of neuronal differentiation.
We examined the receptor-mediated effects of extracellular ATP on neuronal differentiation of PC12 cells, Neuro2a cells and MEB5 cells by using a series of receptor antagonists. The P2Y13 receptor antagonist MRS2211 significantly accelerated neurite outgrowth in all cases. Treatment with nerve growth factor (NGF) alone activated ERK1/2 in PC12 cells, and the activation was further increased by MRS2211. These results suggest involvement of P2Y13 receptor in suppression of neuronal differentiation. Thus, P2Y13 receptor antagonists might be candidates for treatment of neurodegenerative diseases.


Segmental composition of the porcine iliopsoas muscle and influence of the body size and posture on the composition of the iliopsoas muscle.
The iliopsoas muscle (IPM) of the pig consists of the iliacus muscle (IM) and the psoas major muscle (PMM). Due to the differences in posture and size between animal species, the musculoskeletal system is subjected to different functional demands, which affects the morphological characteristics of the musculoskeletal system. The aim of this study was to determine the muscle fiber type composition in pigs IPM, as pigs are large quadrupeds that differ in body size and posture from humans and small mammals, and to determine the influence of body size and posture on the composition of IPM. Muscle samples were collected from the Pietrain Landrace pigs, a sample from IM and a samples at four segments of the PMM. Samples were analyzed with monoclonal antibodies specific for different isoforms of the myosin heavy chain. The percentages and cross-sectional area (CSA) of type I, IIA, and IIX/IIB muscle fibers were calculated. Our studies revealed that in pigs IPM, type IIX/IIB muscle fibers were predominant with the largest CSA. A decrease in the proportion of type IIX/IIB muscle fibers, an increase in type I and IIA muscle fibers, and a decrease in the CSA of all muscle fiber types from the cranial to the caudal part of the PMM were observed. The pig IPM has primarily a dynamic function. The function of the PMM in the cranio-caudal direction changes from a dynamic to a static role. Body size and posture influence the composition of the IPM.


Plumage evolution in relation to light environment in a novel clade of Neotropical tanagers.
Molecular phylogenetic analyses have greatly changed Neotropical avian systematics in the past couple of decades. These new phylogenies provide the necessary framework to study the ecology and natural history of species in the region in an evolutionary context. This study addresses the systematics of Poospiza, Compsospiza, Hemispingus, Thlypopsis, and eight monotypic genera, which form a strongly supported and novel clade within the tanagers. We find Poospiza, Hemispingus, and Thlypopsis to be polyphyletic, confirm or reject relationships proposed based on morphology and life history, and describe novel relationships among these and the monotypic genera. The diversity of plumage, habitat, and geography throughout the clade allows us to test hypotheses of plumage evolution in relation to light environment. We find that overall plumage brightness best fits a model that includes selective regimes based on open versus closed habitats and foraging strata, while plumage measures describing color diversity and chroma best fit a model that only includes selective regimes based on open and closed habitats.


A case control study to explore the risk factors for acquisition of leptospirosis in Surat city, after flood.
Between August and November 2006, a population-based case control study was conducted to identify the probable risk factors for leptospirosis during flooding in Surat city. Sixty-two laboratory confirmed cases out of 129 suspected cases, and 253 age and sex matched fever and healthy controls were interviewed with the help of predesigned questionnaire. The association of risk factors with acquiring leptospirosis was assessed by adjusted OR with the help of logistic regression model to control confounders. By univariate analysis, factors identified were, walking barefoot (OR = 10.34, 95% CI 5.09-21.31, P <0.05). Prompt and vigilant fever surveillance activities in pre-monsoon preparedness plan, intensive IEC messages, rodent control programs and improvement of environmental sanitary conditions may help to greatly reduce the incidence of leptospirosis.


Highly enantioselective Michael addition of malonates to beta,gamma-unsaturated alpha-ketoesters catalyzed by chiral N,N'-dioxide-Yttrium(III) complexes with convenient procedure.
Highly enantioselective Michael addition of malonates to beta,gamma-unsaturated alpha-ketoesters has been promoted by chiral N,N'-dioxide-Yttrium(iii) complexes, providing the corresponding products in excellent yields with 94-99% ee values.


CDPKs: The critical decoders of calcium signal at various stages of malaria parasite development.
Calcium ions are used as important signals during various physiological processes. In malaria parasites, Plasmodium spp., calcium dependent protein kinases (CDPKs) have acquired the unique ability to sense and transduce calcium signals at various critical steps during the lifecycle, either through phosphorylation of downstream substrates or mediating formation of high molecular weight protein complexes. Calcium signaling cascades establish important crosstalk events with signaling pathways mediated by other secondary messengers such as cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). CDPKs play critical roles at various important physiological steps during parasite development in vertebrates and mosquitoes. They are also important for transmission of the parasite between the two hosts. Combined with the fact that CDPKs are not present in humans, they continue to be pursued as important targets for development of anti-malarial drugs.


Allelic variation of the Waxy gene in foxtail millet [Setaria italica (L.) P. Beauv.] by single nucleotide polymorphisms.
The Waxy (Wx) gene product controls the formation of a straight chain polymer of amylose in the starch pathway. Dominance/recessiveness of the Wx allele is associated with amylose content, leading to non-waxy/waxy phenotypes. For a total of 113 foxtail millet accessions, agronomic traits and the molecular differences of the Wx gene were surveyed to evaluate genetic diversities. Molecular types were associated with phenotypes determined by four specific primer sets (non-waxy, Type I; low amylose, Type VI; waxy, Type IV or V). Additionally, the insertion of transposable element in waxy was confirmed by ex1/TSI2R, TSI2F/ex2, ex2int2/TSI7R and TSI7F/ex4r. Seventeen single nucleotide polymorphims (SNPs) were observed from non-coding regions, while three SNPs from coding regions were non-synonymous. Interestingly, the phenotype of No. 88 was still non-waxy, although seven nucleotides (AATTGGT) insertion at 2,993 bp led to 78 amino acids shorter. The rapid decline of r (2) in the sequenced region (exon 1-intron 1-exon 2) suggested a low level of linkage disequilibrium and limited haplotype structure. K (s) values and estimation of evolutionary events indicate early divergence of S. italica among cereal crops. This study suggested the Wx gene was one of the targets in the selection process during domestication.


Spy: a new group of eukaryotic DNA transposons without target site duplications.
Class 2 or DNA transposons populate the genomes of most eukaryotes and like other mobile genetic elements have a profound impact on genome evolution. Most DNA transposons belong to the cut-and-paste types, which are relatively simple elements characterized by terminal-inverted repeats (TIRs) flanking a single gene encoding a transposase. All eukaryotic cut-and-paste transposons so far described are also characterized by target site duplications (TSDs) of host DNA generated upon chromosomal insertion. Here, we report a new group of evolutionarily related DNA transposons called Spy, which also include TIRs and DDE motif-containing transposase but surprisingly do not create TSDs upon insertion. Instead, Spy transposons appear to transpose precisely between 5'-AAA and TTT-3' host nucleotides, without duplication or modification of the AAATTT target sites. Spy transposons were identified in the genomes of diverse invertebrate species based on transposase homology searches and structure-based approaches. Phylogenetic analyses indicate that Spy transposases are distantly related to IS5, ISL2EU, and PIF/Harbinger transposases. However, Spy transposons are distinct from these and other DNA transposon superfamilies by their lack of TSD and their target site preference. Our findings expand the known diversity of DNA transposons and reveal a new group of eukaryotic DDE transposases with unusual catalytic properties.


Maxillary implant overdentures on two or four implants. A prospective randomized cross-over clinical trial of implant and denture success and survival.
To determine implant survival and success of four conventionally but initially asynchronously loaded implants in implant-supported overdentures for the edentulous maxilla, in participants with opposing mandibular two-implant overdentures. Twenty-six participants received four implants in the region of the maxillary canines and molars. After healing, 24 of these participants (mean age: 68.3 years) were randomly allocated to one of two treatment groups, and the adapted overdenture was attached to two unsplinted cylindrical attachments. The other two matrixes remained unattached to the implants for 3 months. After this period, the other two implants were loaded for 3 months (cross-over design). Then, all four implants were loaded for another 3 months. Kaplan-Meier curves were used to evaluate survival and success of implants and dentures. During the active prosthetic study phase, three participants lost one implant. Two participants lost three implants during the recall period. Implant survival after loading was 93.8% after a mean observation period of 3.1 years. Denture survival was 100%, but denture success was 95.8%, due to major prosthetic complications. Most participants preferred four implants to two. Within the limitations of the study, it can be concluded that maxillary implant overdentures on two or four implants are both recommendable treatment options. Two posterior implants are not superior to two anterior implants under overdentures retained by unsplinted cylindrical attachments. Implant and prosthetic complications and aftercare measures are common but are mostly easy to handle. However, 23 of the 24 participants preferred the 4-implant maxillary overdenture.


Predictors of prolonged guidewire manipulation time for native coronary chronic total occlusion percutaneous coronary intervention via primary antegrade approach.
This study aimed to identify the predictive factors for the guidewire manipulation time (GWMT) of ≥20 and 30 min for chronic total occlusion-percutaneous coronary intervention (CTO-PCI) via the primary antegrade approach (PAA). Selection of primary retrograde approach (PRA) and the optimal timing to switch from antegrade to retrograde approach for coronary CTO-PCI is still debatable. Using the Japanese CTO-PCI expert registry data, we selected and analyzed 4461 patients who underwent CTO-PCI via PAA alone. The considerable lesion/anatomical factors for GWMT ≥20 and 30 min were analyzed. The risks of prolonged GWMT ≥20 and 30 min were stratified as easy, intermediate, difficult, and very difficult according to the multivariate analysis. Nine lesion/anatomical characteristics (blunt stump, side branch at proximal cap, bifurcation at the exit point, calcification, tortuosity, occlusion length ≥ 20 mm, reattempt, nonleft anterior descending artery (nonleft anterior descending artery [LAD]), and tandem CTO) were independent predictors of GWMT ≥20 min (all p < 0.05). Excluding the nonLAD and tandem CTO, the same factors of GWMT ≥20 min correlated with GWMT ≥30 min (all p < 0.05). The distributions were increased in easy, intermediate, difficult, and very difficult subsets of GWMT ≥20 min (58.3%, 77.2%, 89.1%, and 100%) and GWMT ≥30 min (47.5%, 69.2%, 83.9%, and 100%). These predictive factors of prolonged GWMT should be assessed before CTO-PCI via PAA and when considering an adequate timing to switch the retrograde or PRA if clinically available.


Continuous ethanol exposure inhibits agonist-stimulated phosphorylation of p70S6 kinase and ribosomal S6 protein in cultured rat astrocytes.
The effects of ethanol exposure on agonist-stimulated phosphorylation of p70S6 kinase and ribosomal S6 protein were determined in confluent astrocyte monolayers. Basal phosphorylation of p70S6 kinase and S6 protein was either unaffected or reduced, respectively, after exposure to 50 mM ethanol for 4 days. The abilities of norepinephrine, carbachol and epidermal growth factor to phosphorylate these proteins were significantly decreased after ethanol exposure. In contrast, ethanol exposure had no effect on the protein expression of either p70S6 kinase or S6 protein. Our data suggest that continuous ethanol exposure results in a generalized decrease in agonist-activation of the p70S6 pathway.


Studies on cell adhesion and recognition. III. The occurrence of alpha-mannosidase at the fibroblast cell surface, and its possible role in cell recognition.
The occurrence of alpha-mannosidase activity at the surface of hamster embryo (NIL) fibroblasts is indicated by the following findings: (a) When NIL cells were incubated on the glass surfaces on which ovalbumin glycopeptides were covalently linked, a rapid release of free mannose from ovalbumin glycopeptides was observed as evidenced by analysis on gas chromatography/mass spectrometry. (b) Cell suspensions as well as intact cell monolayers hydrolyzed rapidly p-nitrophenyl-alpha-D-mannoside, and the time-course of the hydrolytic cleavage was linear from the moment of mixing of the substrate with the cells. The hydrolysis of the nitrophenyl glycosides of beta-D-mannose, alpha-D-galactose, beta-D-galactose, alpha-L-fucose, beta-D-glucose, beta-D-N-acetylgalactosamine and beta-D-N-acetylglucosamine was negligible or more than ten times lower as compared with the hydolysis of alpha-D-mannoside. (c) No released or secreted activity of mannosidase could be detected under the conditions used. (d) Studies using known proportions of broken cells in the incubation mixture indicated that more than 90 percent of the mannosidase activity measured was attributable to intact cells and not to broken cells or cell fragments. (e) Hydrolysis of p-nitrophenyl-alpha-D-mannoside by cell monolayers was inhibited, in the order of decreasing inhibitory activity, by yeast mannan, ovalbumin, alpha-1,4-L-mannonolactone, alpha-methylmannoside, and mannose-6-phosphate. High inhibitory activity of the mannan polysaccharide and of ovalbumin favored the presence of the mannosidase activity at the cell surface, as these substrates may not penetrate rapidly into the cells. The following findings indicated that the cell surface mannosidase is mediating the cell adhesion based on the recognition of high-mannose-type glycopeptide: (a) Ovalbumin- coated plastic surfaces strongly promoted attachment and spreading of NIL fibroblasts, whereas the same ovalbumin coat did not promote attachment and spreading of some other cell types (BALB/c 3T3 fibroblasts and freshly prepared rat liver cells). (b) Digestion of ovalbumin with alpha-mannosidase greatly reduced the adhesion-mediating activity. (c) Cell adhesion to ovalbumin-coated surfaces was strongly inhibited by mannose tetrasaccharides, moderately by alpha-1,4-L-mannonolactone, and weakly by alpha- methylmannoside and mannose-6-phosphate. This order of the inhibitory activity for cell attachment is the same as that for the inhibition of mannosidic hydrolysis. The interpretation that the cell surface mannosidase is able to mediate cell adhesion is in agreement with previous studies suggesting that polyvalent glycosidase surfaces can promote cell adhesion to a degree similar to that caused by fibronectin and several lectins by interacting with their cell surface substrate site (the accompanying papers of this series).


Overexpression of acetyl-CoA carboxylase gene of Mucor rouxii enhanced fatty acid content in Hansenula polymorpha.
Malonyl-CoA is an essential precursor for fatty acid biosynthesis that is generated from the carboxylation of acetyl-CoA. In this work, a gene coding for acetyl-CoA carboxylase (ACC) was isolated from an oleaginous fungus, Mucor rouxii. According to the amino acid sequence homology and the conserved structural organization of the biotin carboxylase, biotin carboxyl carrier protein, and carboxyl transferase domains, the cloned gene was characterized as a multi-domain ACC1 protein. Interestingly, a 40% increase in the total fatty acid content of the non-oleaginous yeast Hansenula polymorpha was achieved by overexpressing the M. rouxii ACC1. This result demonstrated a significant improvement in the production of fatty acids through genetic modification in this yeast strain.


Numerical simulation of realistic top coal caving intervals under different top coal thicknesses in longwall top coal caving working face.
In the process of longwall top coal caving, the selection of the top coal caving interval along the advancing direction of the working face has an important effect on the top coal recovery. To explore a realistic top coal caving interval of the longwall top coal caving working face, longwall top coal caving panel 8202 in the Tongxin Coal Mine is used as an example, and 30 numerical simulation models are established by using Continuum-based Distinct Element Method simulation software to study the top coal recovery with 4.0 m, 8.0 m, 12.0 m, 16.0 m, 20.0 m and 24.0 m top coal thicknesses and 0.8 m, 1.0 m, 1.2 m, 1.6 m and 2.4 m top coal caving intervals. The results show that with an increase in the top coal caving interval, the single top coal caving amount increases. The top coal recovery is the highest with a 0.8 m top coal caving interval when the thickness of the top coal is 4.0 m, and it is the highest with a 1.2 m top coal caving interval when the coal seam thickness is greater than 4.0 m. These results provide a reference for the selection of a realistic top coal caving interval in thick coal seam caving mining.


Using Quality Improvement Principles to Redesign a Cardiothoracic Surgery Fellowship Program Website.
Websites are primary sources of information for prospective trainees. However, little is known regarding the information deemed most important to cardiothoracic (CT) surgery interviewees when evaluating a program. The objectives of this study were to (1) report informational content important to CT surgery interviewees on a fellowship website and (2) improve the quality of a specific program's website. Study investigators conducted a survey of interviewees at a traditional 2-year CT surgery fellowship program. Questions were asked to elicit what information interviewees considered important to include in a program website and to identify gaps in the website's content. After administering the survey to 2018 fellowship interviewees, the website was redesigned, and the survey was readministered to 2019 fellowship interviewees. A total of 49 interviewees completed the survey (response rate, 90.7%); 45 (91.8%) of these interviewees had previously visited the program's website. Interviewees reported that the most important information they sought when accessing fellowship websites included faculty profiles (n = 47), rotation schedules (n = 33), current fellows' profiles (n = 29), and past fellows' profiles (n = 26). The website was revamped to include content across each of these domains. After website redesign, there was significant improvement in interviewees reporting that they found the information they sought (mean score, 3.56 to 4.64; P < .001) and that the website was useful (mean score, 3.67 to 4.77; P < .001) compared with the previous year. CT surgery fellowship websites are accessed by the majority of interviewees and are a critical source of program information. Optimizing website design and content on the basis of survey feedback objectively improved the usefulness of the program website to interviewees.


Cardioneuroablation for cardioinhibitory vasovagal syncope.
Cardioneuroablation (CNA) is an emerging technique being used to treat patients with cardioinhibitory vasovagal syncope (VVS). We describe a case of CNA in targeting atrial ganglionated plexi (GP) based upon anatomical landmarks and fractionated electrogram (EGM) localization in a patient with cardioinhibitory syncope. A 20-year-old healthy female presented with malignant VVS and symptomatic sinus pauses, with the longest detected at 10 s. She underwent acutely successful CNA with demonstration of vagal response (VR) noted after ablation of left sided GP, and tachycardia noted with right sided GP ablation. All GP sites were defined by anatomical landmarks and EGM analysis. By using the fractionation mapping software of Ensite Precision mapping system with high density mapping, fragmented EGMs were successfully detected in each GP site. One month after vagal denervation, there were no recurrent syncopal episodes or sinus pauses. Longer term follow-up with implantable loop recorder is planned. We performed CNA in a patient with VVS by utilizing a novel approach of combined use of high density mapping and fractionation mapping software. With this approach, we were able to detect fractionation in all GP sites and demonstrate acute VR. This workflow may allow for a new, standardized technique suitable for widespread use.


Applying Pix2pix to Translate Hyperemia in Blood Pool Image into Corresponding Increased Bone Uptake in Delayed Image in Three-Phase Bone Scintigraphy.
Delayed images may not be acquired due to severe pain, drowsiness, or worsening vital signs while waiting after blood pool imaging in three-phase bone scintigraphy. If the hyperemia in the blood pool image contains information from which increased uptake on the delayed images can be inferred, the generative adversarial network (GAN) can generate the increased uptake from the hyperemia. We attempted to apply pix2pix, a type of conditional GAN, to transform hyperemia into increased bone uptake. We enrolled 1464 patients who underwent three-phase bone scintigraphy for inflammatory arthritis, osteomyelitis, complex regional pain syndrome (CRPS), cellulitis, and recent bone injury. Blood pool images were acquired 10 min after intravenous injection of Tc-99 m hydroxymethylene diphosphonate, and delayed bone images were obtained after 3 h. The model was based on the open-source code of the pix2pix model with perceptual loss. Increased uptake in the delayed images generated by the model was evaluated using lesion-based analysis by a nuclear radiologist in areas consistent with hyperemia in the blood pool images. The model showed sensitivities of 77.8% and 87.5% for inflammatory arthritis and CRPS, respectively. In osteomyelitis and cellulitis, their sensitivities of about 44% were observed. However, in cases of recent bone injury, the sensitivity was only 6.3% in areas consistent with focal hyperemia. The model based on pix2pix generated increased uptake in delayed images matching the hyperemia in the blood pool image in inflammatory arthritis and CRPS.


Psychophysiologic predictors of weaning from mechanical ventilation in chronic bronchitis and emphysema.
This study identified psychophysiologic variables related to successful weaning in 27 ventilator-dependent patients with chronic bronchitis and emphysema (CBE) from two long-term care pulmonary-specialty hospitals in South Central Florida. Subjects were studied from admission until weaning occurred (successful weaning without mechanical ventilation) or until they were transferred without being weaned or died (unsuccessful weaning). The study subjects, 15 males and 12 females, ranged in age from 56 to 89. Baseline data on the variables (age, mastery, hope, social support, dyspnea, and rapid shallow breathing index [RSBI]) were not statistically significant by gender. The logistic regression model identified mastery and RSBI to be the best predictors of successful weaning (model chi 2 = 16.33, df = 2, and p value = .0003; prediction rate 82%).


Conserved cysteine dioxidation enhances membrane interaction of human Cl- intracellular channel 5.
The human chloride intracellular channel (hCLIC) family is thought to transition between globular and membrane-associated forms by exposure of a hydrophobic surface. However, the molecular identity of this surface, and the triggering events leading to its exposure, remain elusive. Here, by combining biochemical and structural approaches, together with mass spectrometry (MS) analyses, we show that hCLIC5 is inherently flexible. X-ray crystallography revealed the existence of a globular conformation, while small-angle X-ray scattering showed additional elongated forms consisting of exposure of the conserved hydrophobic inter-domain interface to the bulk phase. Tryptophan fluorescence measurements demonstrated that the transition to the membrane-associated form is enhanced by the presence of oxidative environment and lipids. Using MS, we identified a dose-dependent oxidation of a highly conserved cysteine residue, known to play a key role in the structurally related omega-class of glutathione-S-transferases. Hydrogen/deuterium exchange MS analysis revealed that oxidation of this cysteine facilitates the exposure of the conserved hydrophobic inter-domain interface. Together, our results pinpoint an oxidation of a specific cysteine residue as a triggering mechanism initializing the molecular commitment for membrane interaction in the CLIC family.


Population Pharmacokinetics and Pharmacodynamics of Once-Daily Growth Hormone Norditropin® in Children and Adults.
Once-daily injectable recombinant human growth hormone (GH) formulations (e.g. Norditropin®; Novo Nordisk A/S) are used to treat GH deficiency in children and adults, with much of the therapeutic effect mediated via the insulin-like growth factor-I (IGF-I) response. Despite a long history of use, there are few data on the pharmacokinetics and pharmacodynamics (serum IGF-I response) of this therapy, or of potential differences in the relationship of GH pharmacokinetic/pharmacodynamic (PK/PD) effects between children and adults. This study aimed to characterise the GH pharmacokinetics and IGF-I profile following daily subcutaneous GH in adults and children with GH deficiency. A model was developed based on a population PK/PD modelling meta-analysis of data from three phase I clinical trials (two using Norditropin® as a comparator with somapacitan, and one as a comparator with a pegylated GH product). Sequential model building was performed, first developing a model that could describe GH pharmacokinetics. A PD model of IGF-I data was then developed using PK and PD data, and where all PK parameters were kept fixed to those estimated in the PK model. The model developed accurately describes and predicts GH pharmacokinetics and IGF-I response. Body weight was shown to have an important inversely correlated influence on GH exposure (and IGF-I standard deviation score), and this largely explained differences between adults and children. The pharmacokinetics/pharmacodynamics developed here can inform expectations about the PD effects of different doses of GH in patients with GH deficiency of different body weights, regardless of their age. Pooled modelling analysis of data from ClinicalTrials.gov identifiers NCT01973244, NCT00936403 and NCT01706783. NCT01973244: 22 October, 2013; NCT00936403: 9 July, 2009; NCT01706783: 11 October, 2012.


The costs associated with adverse drug events among older adults in the ambulatory setting.
Reducing the rate of adverse drug events in the ambulatory setting may require large investments in quality improvement efforts and technologic innovations. Little evidence is available on the potential resulting savings. The objective of this study was to estimate the costs associated with adverse drug events among older adults in the ambulatory setting. This study consisted of a 1-year retrospective cohort study among Medicare enrollees of a large multispecialty group practice. The study included 1210 older adults with an adverse drug event. A matched comparison group was randomly selected from enrollees with recent healthcare encounters and medication dispenses. Difference between estimated costs for medical care utilization during the 6 weeks before and 6 weeks beginning on the day of an adverse drug event. For all adverse drug events, the increase in postevent costs over the preevent period was $1310 (95% confidence interval [CI], $625-$1995) greater for those experiencing an adverse drug event than the comparison group after controlling for age, sex, comorbidity, number of scheduled medications, and having been hospitalized during the preevent period. For preventable adverse drug events, the adjusted increase was $1983 (95% CI, $193-$3773) greater for cases. Based on rates of adverse drug events and these cost estimates, 1000 older adults would have annual costs related to adverse drug events in the ambulatory setting of $65,631 with $27,365 of this associated with preventable events. Adverse drug events in the ambulatory setting substantially increase the healthcare costs of elderly persons.


Water soluble carbon nanoparticles: hydrothermal synthesis and excellent photoluminescence properties.
Water-soluble carbon nanoparticles (CNPs) were fabricated by a facile, one step hydrothermal synthetic route using acid/alkali as additives. These CNPs emit bright photoluminescence (PL) covering the entire visible-near infrared (NIR) spectral range. PL measurements confirmed that the CNPs have up-conversion of PL properties, and that the NIR PL of the CNPs can also be observed by NIR excitation. Control experiments indicated that different additives can strongly affect the PL properties of the CNPs. With a combination of free dispersion in water and attractive PL properties, these CNPs hold promise for applications in nanotechnology.


Biomarker profiling of postmortem blood for diabetes mellitus and discussion of possible applications of metabolomics for forensic casework.
Acute metabolic disorders of diabetes mellitus (DM), such as diabetic ketoacidosis, hyperosmolar hyperglycemic state, and hypoglycemia, are life-threatening and difficult to diagnose postmortem owing to lack of macroscopic and microscopic findings, especially when the medical history of the patient is not available before autopsy. Although various biochemical tests, including ketone bodies and hemoglobin A1c, have been used to diagnose diabetes in the postmortem setting, each marker has some limitations. Consequently, it would be helpful in forensic practice to find new biomarkers reflecting the decedent's history of DM irrespective of whether the DM was being treated. Metabolomics enables the non-targeting analysis of biomarkers, and metabolomics was performed on postmortem blood from decedents with and without a DM history to determine whether a marker reflecting DM could be identified. The statistical analysis, including primary component analysis, presented a potent set of metabolites that could be used for the forensic diagnosis of DM. Qualitative analysis revealed significantly lower sphingomyelin and plasmalogen lipid levels and higher lysophospholipid levels in the DM group. Meanwhile, some discrepancies in the levels of some classes of phospholipids were noted between samples from living and deceased persons. This suggests that further metabolomics using postmortem samples rather than living persons' samples is required to identify markers that can be used for forensic diagnosis.


Contribution of the TA repeats on melting temperature (T(m)) in a double strand DNA: comparison of two methods and implications in molecular diagnostics.
The present paper is aimed to discuss and revise a not recent molecular laboratory protocol describing the behavior of UGT1A1 gene melting curves. Since some problems in the standardization of this already published molecular protocol were found, we tried to improve this method in order to correctly set up the amplification and melting profile steps. Under our standardized conditions, we were able to perfectly distinguish the three different UGT1A1 genotypes since each one showed a peculiar melting behavior, as compared with those previously published by another group. Finally, some suggestions and indications are provided for laboratory specialists interested in Gilbert syndrome diagnostics. Based on these results, we underline the need of more standardized protocols above all when they are used for clinical diagnostics.


Ultrasonic pretreatment of liquid NaK metal catalyst for side-chain alkenylation of o-xylene with 1,3-butadiene.
The effects of sonochemical treatment of a NaK eutectic mixture as catalyst on the side-chain alkenylation of o-xylene with 1,3-butadiene were studied. The parameters studied include ultrasound frequency, insonation time, sonication power as well as the reaction temperature. In addition, the effect of N,N,N',N'-tetramethylethylenediamine (TMEDA) on the reaction was also studied. The results showed that sonochemical treatment of this NaK eutectic mixture catalyst resulted in excellent conversion (up to 83.16%) under mild conditions. The introduction of TMEDA further increased the conversion to 89.4%.


Venous insufficiency in male workers with a standing profession. Part 2: diurnal volume changes of the lower legs.
Chronic venous insufficiency (CVI) occurs frequently in the occupational population but is often not recognized. To evaluate leg volume measurements in the detection of CVI. The lower leg volume was measured in 81 males with CVI and a standing occupation, at the beginning and end of 2 full working days using an optical leg volume meter. A volume increase of over 50 ml was found in 60% of the legs. The mean volume change was +2.6% in legs with minor CVI and +3.6% in legs with major CVI. A high volume change was associated with a tired feeling and pain in the legs. In the detection of CVI, the predictive value of volume measurements was 71%, and in combination with a questionnaire 83%. A volume increase of the lower legs in the course of the day was common and associated with subjective complaints of the legs. As a predictor of CVI, isolated volume measurements were ineffective because an overlap was present with the distribution of volume changes in healthy workers.


New Opioid Use after Invasive Mechanical Ventilation and Hospital Discharge.
Rationale: Patients who receive invasive mechanical ventilation (IMV) are usually exposed to opioids as part of their sedation regimen. The rates of posthospital prescribing of opioids are unknown.Objectives: To determine the frequency of persistent posthospital opioid use among patients who received IMV.Methods: We assessed opioid-naive adults who were admitted to an ICU, received IMV, and survived at least 7 days after hospital discharge in Ontario, Canada over a 26-month period (February, 2013 through March, 2015). The primary outcome was new, persistent opioid use during the year after discharge. We assessed factors associated with persistent use by multivariable logistic regression. Patients receiving IMV were also compared with matched hospitalized patients who did not receive intensive care (non-ICU).Measurements and Main Results: Among 25,085 opioid-naive patients on IMV, 5,007 (20.0%; 95% confidence interval [CI], 19.5-20.5) filled a prescription for opioids in the 7 days after hospital discharge. During the next year, 648 (2.6%; 95% CI, 2.4-2.8) of the IMV cohort met criteria for new, persistent opioid use. The patient characteristic most strongly associated with persistent use in the IMV cohort was being a surgical (vs. medical) patient (adjusted odds ratio, 3.29; 95% CI, 2.72-3.97). The rate of persistent use was slightly higher than for matched non-ICU patients (2.6% vs. 1.5%; adjusted odds ratio, 1.37 [95% CI, 1.19-1.58]).Conclusions: A total of 20% of IMV patients received a prescription for opioids after hospital discharge, and 2.6% met criteria for persistent use, an average of 300 new persistent users per year in a population of 14 million. Receipt of surgery was the factor most strongly associated with persistent use.


Immunological microenvironment in prostate cancer: high mast cell densities are associated with favorable tumor characteristics and good prognosis.
Number of intratumoral mast cells predicts survival in various cancers. The prognostic significance of such mast cells in surgically treated prostate cancer is unknown. Mast cell densities were determined in prostate cancer samples of more than 2,300 hormone-naïve patients using a tissue microarray format in correlation with clinical follow-up data. Mast cells were visualized immunohistochemically (c-kit). All patients were homogeneously treated by radical prostatectomy at a single institution. Mast cells were present in 95.9% of the tumor samples. Median mast cell number on the tissue spot was 9 (range: 0-90; median density: 31 mast cells/mm(2)). High mast cell densities were significantly associated with more favorable tumors having lower preoperative prostate-specific antigen (P = 0.0021), Gleason score (P < 0.0001) and tumor stage (P < 0.0001) than tumors with low mast cell densities. Prostate-specific antigen recurrence-free survival significantly (P = 0.0001) decreased with decline of mast cell density showing poorest outcome for patients without intratumoral mast cells. In multivariate analysis mast cell density narrowly missed to add independent prognostic information (P = 0.0815) for prostate-specific antigen recurrence. High intratumoral mast cell density is associated with favorable tumor characteristics and good prognosis in prostate cancer. This finding is consistent with a role of mast cells in the immunological host-defense reaction on prostate cancer. Triggering mast cell activity might expand immunotherapeutic strategies in prostate cancer.


Capillary-channeled polymer (C-CP) fibers for the rapid extraction of proteins from urine matrices prior to detection with MALDI-MS.
While MS is a powerful tool for biomarker determinations, the high salt content and the small molecules present in urine poses incredible challenges. Separation/extraction methods must be employed for the isolation of target species at relevant concentrations. Micropipette tips packed with capillary-channeled polymer (C-CP) fibers are employed for the SPE of proteins from a synthetic and a certified urine matrix. Extractions are performed utilizing a very simple centrifugation method to spin-down species through the C-CP fiber tips. Proteins adsorb to the hydrophobic polypropylene fibers and are eluted in a solvent suitable for MALDI-MS analysis. Figures of merit are determined for representative compounds β2-microglobulin, retinol binding protein, and transferrin. The optimum protein processing included a 100 μL aqueous rinse and an elution solvent composition was 10 μL of 55:45 ACN:water (with triflouroacetic acid). MALDI-MS responses for the target proteins are improved from nondetectable levels to eventually yield LOD ranging from 5 to 180 nM in 1 μL aliquots. C-CP fiber tips offer a plethora of advantages including low materials costs, high throughput, microvolume processing, and the determination of sub-nanogram quantities of analyte; allowing determination of biomarkers that are otherwise undetectable in urine matrices.


Cochlear modiolus and lateral semicircular canal in sudden deafness.
This study demonstrated that precise analysis shows that the inner ear shape in sudden deafness (SD) is different from that in controls in that the fluid-filled area of SD labyrinths is significantly larger than that of controls. Reduced cochlear modiolus area and inner area of the lateral semicircular canal (LSCC) may be associated with insufficient maturation of the inner ear. The aim of this study was to quantify the morphologies of the cochlea and LSCC using magnetic resonance imaging (MRI) and to evaluate their relationships with clinical symptoms in SD. Twenty-six unilateral SD patients with vertigo, 26 unilateral SD patients without vertigo and a matched control group without hearing loss were studied. The areas of cochlear modioli and LSCCs were traced on the MRI console and compared between SD patients with or without vertigo and control subjects. The ratio of the LSCC fluid-filled area to the total LSCC area was used to index the degree of dysplasia. The cochlear modiolus area was significantly less in SD ears (4.1+/-0.2 mm2) than in controls (4.3+/-0.4 mm2). The LSCC inner area was significantly less in SD ears (6.9+/-1.7 mm2) than in controls (9.1+/-1.8 mm2). These results suggest that the fluid-filled area of SD labyrinths is significantly larger than controls. Morphology did not differ between affected and contralateral sides or between ears with or without vertigo in SD patients.


Integrated currents between amalgams and a gold alloy in saline solutions and natural saliva with different chloride content.
The effect of different sodium chloride concentrations on the integrated currents (charge transfers) between dental amalgams and a gold alloy was studied in a bimetallic cell containing saliva or saline solutions. The integrated currents were only to a minor degree affected by increasing chloride concentrations for the high copper amalgams both in saliva and saline solutions. The integrated currents in the experiments involving conventional amalgam were several times higher than those for high copper amalgams. In saline solutions a charge transfer maximum was found at 0.2 M chloride. In saliva an increase of the charge transfer was found with increasing chloride content.


Subchronic administration of Catha edulis F. (khat) extract is marked by elevation of cardiac biomarkers and subendocardial necrosis besides blood pressure alteration in rats.
ETHNPHARMACOLOGICAL RELEVANCE: Khat is a widely chewed herb for its stimulant effect, however, its effects on the cardiovascular system are a source of growing concern, as prevalence of chewing is increasing and susceptible individuals may experience cardiovascular episodes. This study attempted to evaluate cardiovascular substrates that predispose individuals to these episodes by using both biochemical and morphologic-pathologic studies. Rats were treated with either Tween 80 (2% in distilled water) (CON), or khat extract (100mg/kg, K100; 200mg/kg, K200; or 400mg/kg, K400 doses) orally for 6 weeks. Blood pressure (BP) in each group was measured before dosing and 1, 2 and 3h after-dose as well as weekly for 6 weeks using Tail cuff method. On day 45, blood was drawn for assessment of cardiac biomarkers and animals were sacrificed, and histological examination was undertaken for any overt damage on the myocardium. K400 was the only dose that significantly increased BP at 2 (p<0.05) and 3h (p<0.001) postdose compared to predose level. Likewise, the 3h postdose BP of each week was significantly greater (p<0.001) than baseline BP only at 400mg/kg. However, when the weekly values were compared among themselves, the difference was not statistically significant and a progressive change in postdose BP had not been observed. On the other hand, predose systolic BP of K400 rats tended to decline at week 3 and significantly decreased (p<0.05) beyond week 4 compared to baseline values, but the decline was not significant for the rest of the doses. Biomarker assessments revealed that whereas levels of total creatine kinase were found to be elevated significantly for K100 (p<0.05), K200 and K400 (p<0.001 in both cases); aspartate aminotransferease was increased in K200 (p<0.01) and K400 (p<0.001) compared to CON rats. By contrast, levels of cardiac troponin T was significantly increased (p<0.001) only in K400 rats. Heart tissues of CON and K100 rats were normal, while those from K200 showed signs of focal lesions but normal architecture of the myocardium was maintained. K400 rats, however, displayed fragmentation and segmentation of fibers, edema and mottled staining. These findings collectively indicate that the high dose of crude khat extract modulated most of the hemodynamic, biochemical and histopathological parameters in rats and hence chronic use of khat at higher dose and for longer sessions bear a significant risk for cardiovascular morbidities.


Synthesis of type V collagen by fibroblasts derived from normal, inflamed and hyperplastic human connective tissues.
Increased type V collagen content is a feature of many inflammatory and fibroproliferative diseases. In order to understand the mechanism responsible for this increase we have studied type V collagen synthesis by fibroblasts obtained from normal, inflamed and phenytoin-hyperplastic human gingivae. Cultures were immunostained with antibodies to type V and I collagens to determine the proportion of cells producing type V collagen. In addition, cells were metabolically labeled with radioactive amino acids, and type V procollagen and collagen were fractionated and quantitated. Results showed that all the cells were stained by both anti-type V and type I antibodies. Anti-type V staining was observed outside the cells whereas anti-type I staining was localized intracellularly. The proportion of radioactive type V collagen in the individual cell strains ranged from 0-5.2% of the total collagens; however, differences among the three cell types were not statistically significant. No differences were observed in the procollagen [V] levels, which accounted for 6.5-15.1% of the total procollagens. We conclude that changes in fibroblast population may not be a significant factor contributing to increased type V collagen in inflammation and hyperplasia, and that the increase may be due to other factors such as modulation of synthesis activities by environmental ligands and resistance of type V collagen to degradation.


Establishing Relationship between Vitamins, Total Phenolic and Total Flavonoid Content and Antioxidant Activities in Various Honey Types.
Honey is a well-known natural sweetener and is rich in natural antioxidants that prevent the occurrence of oxidative stress, which is responsible for many human diseases. Some of the biochemical compounds in honey that contribute to this property are vitamins and phenolic compounds such as phenolic acids and flavonoids. However, the extent to which these molecules contribute towards the antioxidant capacity in vitro is inconsistently reported, especially with the different analytical methods used, as well as other extrinsic factors that influence these molecules' availability. Therefore, by reviewing recently published works correlating the vitamin, total phenolic, and flavonoid content in honey with its antioxidant activities in vitro, this paper will establish a relationship between these parameters. Based on the literature, vitamins do not contribute to honey's antioxidant capacity; however, the content of phenolic acids and flavonoids has an impact on honey's antioxidant activity.


The predictive accuracy of surgical planning using pre-op planning software and a robotic guidance system.
Navigation and robotic-guided systems are being used more often to facilitate efficient and accurate placement of hardware during spinal surgeries. Preoperative surgical planning is a key step in the safe use of these tools. No studies have yet investigated the predictive accuracy of surgical planning using a robotic guidance system. Data were prospectively collected from patients in whom Mazor X-Align ™ [Medtronic Inc., Minneapolis, MN., USA] robotic guidance system software was used to plan their spinal instrumentation in order to achieve the best possible correction and the plans executed intraoperatively under robotic guidance. A total of 33 patients (26 females, 7 males) were included. Their mean age was 51 years (12-79), and their mean BMI was 23.90 (15.55-35.91). Their primary diagnoses were scoliosis (20), kyphosis (5), spondylolisthesis (4), adjacent segment degeneration (3), and metastatic tumor (1). Preoperatively, the patients' mean coronal Cobb Angle (CA) was 36.5 ± 14.4°, and their mean sagittal CA was 27.7 ± 20.0°. The mean planned correction coronal CA was 0.2 ± 1.2°, and the mean planned correction sagittal CA was 28.4 ± 16.7°. Postoperatively, the patients' mean coronal CA that was achieved was 5.8 ± 7.4°, and their mean sagittal CA was 31.0 ± 18.3°. The mean difference between the planned and achieved angles was 5.5 ± 7.4° for the coronal, and 9.03 ± 9.01° for the sagittal CA. For the thoracic kyphosis and lumbar lordosis, the mean difference between the planned and postoperatively measured values was 15.3 ± 10.8 and 12.8 ± 9.6, respectively. This study indicates that the predictive accuracy of the use of preoperative planning software and robotic guidance to facilitate the surgical plan is within 6° and 9° in the coronal and sagittal planes, respectively.


Mechanical properties of the high cholesterol-containing membrane: An AFM study.
Cholesterol (Chol) content in most cellular membranes does not exceed 50 mol%, only in the eye lens's fiber cell plasma membrane, its content surpasses 50 mol%. At this high concentration, Chol induces the formation of pure cholesterol bilayer domains (CBDs), which coexist with the surrounding phospholipid-cholesterol domain (PCD). Here, we applied atomic force microscopy to study the mechanical properties of Chol/phosphatidylcholine membranes where the Chol content was increased from 0 to 75 mol%, relevant to eye lens membranes. The surface roughness of the membrane decreases with an increase of Chol content until it reaches 60 mol%, and roughness increases with a further increment in Chol content. We propose that the increased roughness at higher Chol content results from the formation of CBDs. Force spectroscopy on the membrane with Chol content of 50 mol% or lesser exhibited single breakthrough events, whereas two distinct puncture events were observed for membranes with the Chol content greater than 50 mol%. We propose that the first puncture force corresponds to the membranes containing coexisting PCD and CBDs. In contrast, the second puncture force corresponds to the "CBD water pocket" formed due to coexisting CBDs and PCD. Membrane area compressibility modulus (KA) increases with an increase in Chol content until it reaches 60 mol%, and with further increment in Chol content, CBDs are formed, and KA starts to decrease. Our results report the increase in membrane roughness and decrease KA at very high Chol content (>60 mol%) relevant to the eye lens membrane.


Degradation of Monosaccharides, Disaccharides, and Fructans in the Stomach of Horses Adapted to a Prebiotic Dose of Fructooligosaccharides and Inulin.
For a period of 20 days, 12 horses either received a prebiotic supplementation with fructooligosaccharides and inulin via Jerusalem artichoke meal (JAM) or corncob meal without grains (CMG) as placebo. The horses were euthanized 1 hour postprandial, gastric digesta was sampled from pars nonglandularis (PNG) and pars glandularis (PG), and concentrations of starch, mono- and disaccharides, fructans, d- and l-lactic acid, and short chain fatty acids were analyzed. Concentrations of starch and simple sugars were widely the same in JAM supplemented and not supplemented meals. However, fructans were less than half as much without supplementation as with supplementation of JAM. Glucose, fructose, sucrose, and fructans disappeared to a larger extent with prebiotic supplementation than without (106.6% vs. 86.7% glucose, 73.1% vs. 66.8% fructose, 91.5% vs. 14.7% sucrose, and 68.3% vs. 35.4% fructans remained in PNG; 81.9% vs. 38.3% glucose, 52.2% vs. 53.4% fructose, 47.1% vs. 0% sucrose, and 48.5% vs. 31.7% fructans remained in PG with CMG vs. JAM feeding). Disappearance of simple sugars and fructans was primarily associated with appearance of n-butyric acid (r = -0.21 - r = -0.33).


CD8+ tissue-resident memory T cells recruit neutrophils that are essential for flare-ups in contact dermatitis.
Allergic contact dermatitis (ACD) is classically described as a delayed-type hypersensitivity reaction. However, patients often experience flare-ups characterized by itching erythema, edema, and often vesicles occurring within hours after re-exposure of previously sensitized skin to the specific contact allergen. Recent studies have indicated that skin-resident memory T (TRM ) cells play a central role in ACD. However, the pathogenic role of TRM cells in allergen-induced flare-ups is not known. By the use of various mouse models and cell depletion protocols, we investigated the role of epidermal TRM cells in flare-up reactions to the experimental contact allergen 1-fluoro-2,4-dinitrobenzene. The inflammatory response was measured by changes in ear thickness, and the cellular composition in epidermis was determined by flow cytometry and confocal microscopy. Finally, adaptive transfer and inhibitors were used to determine the role of TRM cells, neutrophils, and CXCL1/CXCL2 in the response. We show that CD8+ TRM cells initiate massive infiltration of neutrophils in the epidermis within 12 h after re-exposure to the contact allergen. Depletion of neutrophils before re-exposure to the allergen abrogated the flare-up reactions. Furthermore, we demonstrate that CD8+ TRM cells mediate neutrophil recruitment by inducing CXCL1 and CXCL2 production in the skin, and that blockage of the C-X-C chemokine receptor type 1 and 2 inhibits flare-up reactions and neutrophil infiltration. As the first, we show that epidermal CD8+ TRM cells cause ACD flare-ups by rapid recruitment of neutrophils to the epidermis.


miR-873 suppresses H9C2 cardiomyocyte proliferation by targeting GLI1.
MicroRNAs (miRNAs) are a class of endogenous, non-coding small RNAs that regulate the expression of target genes. Previous studies have suggested that miRNAs are key regulators in cardiovascular systems. This study investigated the role of miR-873 in H9C2 cardiomyocytes by targeting glioma-associated oncogene 1 (GLI1). miR-873 was significantly up-regulated in serum samples from congenital heart disease (CHD) patients compared with those from normal individuals. Furthermore, miR-873 over-expression suppressed H9C2 proliferation and induced cell cycle arrest. Bioinformatic algorithms revealed a predicted target site for miR-873 in the 3'-untranslated region (3'UTR) of GLI1, which was verified using a dual-luciferase reporter assay. qPCR and western blot analysis also showed that miR-873 negatively regulated GLI1 mRNA and protein expression in H9C2 cells. Conversely, GLI1 over-expression partially reversed the growth-inhibitory effect of miR-873. To summarize, our data suggest that miR-873 is a novel miRNA that regulates H9C2 cell proliferation via targeting GLI1, and miR-873 may serve as a new potential biomarker diagnosis in CHD in the future.


Mitochondrial dysfunction induced by a SH2 domain-targeting STAT3 inhibitor leads to metabolic synthetic lethality in cancer cells.
In addition to its canonical role in nuclear transcription, signal transducer and activator of transcription 3 (STAT3) is emerging as an important regulator of mitochondrial function. Here, we demonstrate that a novel inhibitor that binds with high affinity to the STAT3 SH2 domain triggers a complex cascade of events initiated by interference with mitochondrial STAT3 (mSTAT3). The mSTAT3-drug interaction leads to mitochondrial dysfunction, accumulation of proteotoxic STAT3 aggregates, and cell death. The cytotoxic effects depend directly on the drug's ability to interfere with mSTAT3 and mitochondrial function, as demonstrated by site-directed mutagenesis and use of STAT3 knockout and mitochondria-depleted cells. Importantly, the lethal consequences of mSTAT3 inhibition are enhanced by glucose starvation and by increased reliance of cancer cells and tumor-initiating cells on mitochondria, resulting in potent activity in cell cultures and tumor xenografts in mice. These findings can be exploited for eliciting synthetic lethality in metabolically stressed cancer cells using high-affinity STAT3 inhibitors. Thus, this study provides insights on the role of mSTAT3 in cancer cells and a conceptual framework for developing more effective cancer therapies.


Health Care-Acquired Infections in Low- and Middle-Income Countries and the Role of Infection Prevention and Control.
Health care-associated infections (HAIs) account for many morbidity and mortality worldwide, with disproportionate adverse effects in low- and middle-income countries (LMIC). Many factors contribute to the impact in LMIC, including lack of infrastructure, inconsistent surveillance, deficiency in trained personnel and infection control programs, and poverty-related factors. Therefore, optimal approaches must be tailored for LMIC and balance effectiveness and cost in the control of HAIs.


Can the neuroeconomics revolution revolutionize psychiatry?
Neuroeconomics is a rapidly growing new research discipline aimed at describing the neural substrate of decision-making using incentivized decisions introduced in experimental economics. The novel combination of economic decision theory and neuroscience has the potential to better examine the interactions of social, psychological and neural factors with regard to motivational forces that may underlie psychiatric problems. Game theory will provide psychiatry with computationally principled measures of cognitive dysfunction. Given the relatively high heritability of these measures, they may contribute to improving phenotypic definitions of psychiatric conditions. The game-theoretical concepts of optimal behavior will allow description of psychopathology as deviation from optimal functioning. Neuroeconomists have successfully used normative or near-normative models to interpret the function of neurotransmitters; these models have the potential to significantly improve neurotransmitter theories of psychiatric disorders. This paper will review recent evidence from neuroeconomics and psychiatry in support of applying economic concepts such as risk/uncertainty preference, time preference and social preference to psychiatric research to improve diagnostic classification, prevention and therapy.


Argon vs diode laser trabeculoplasty.
To compare the efficacy of diode laser and argon laser trabeculoplasty in a randomized prospective study of 11 paired fellow eyes. Fellow eyes of 11 patients, having had no prior laser trabeculoplasty and requiring laser trabeculoplasty to lower intraocular pressure, were randomly assigned prospectively to diode laser trabeculoplasty in one eye and argon laser trabeculoplasty in the other eye. In the diode laser group, the average baseline intraocular pressure was 21.6 +/- 2.0 mm Hg before trabeculoplasty and 19.6 +/- 2.1 mm Hg (or a 7.7% +/- 11.5% mean pressure reduction) at 1 month, 19.3 +/- 2.6 mm Hg (or a 6.9% +/- 13.5% mean reduction) at 2 months, and 19.0 +/- 3.3 mm Hg (or a 2.4% +/- 16.9% mean reduction) at 3 months postoperatively. In the argon laser group, the average intraocular pressure was 24.4 +/- 3.5 mm Hg before treatment and 17.6 +/- 1.7 mm Hg (or a 24.7% +/- 11.4% mean pressure reduction) at 1 month, 16.8 +/- 2.5 mm Hg (or a 26.7% +/- 15.3% mean reduction) at 2 months, and 15.5 +/- 1.2 mm Hg (or a 30.0% +/- 16.5% mean reduction) at 3 months after laser trabeculoplasty. The difference between argon and diode laser intraocular pressure reduction was statistically significant at 1 month (P < .01), 2 months (P < .01), and 3 months (P < .05) after treatment. Argon laser trabeculoplasty appears to be more effective than diode laser therapy in lowering intraocular pressure during the first 3 months after treatment.


[Evidence-Based Practice competency and associated factors among Primary Care nurses in Spain].
To describe the Evidence-Based Practice (EBP) competency level in Primary Care (PC) nurses in Spain and to determine the associated factors. Cross-sectional, national survey design, carried out between January and March 2020. PC in Spain. Seven hundred eighty PC active nurses in the National Health Service with at least one year of professional experience. (1) Sociodemographic, professional and access to scientific information variables; (2) outcome variable: EBP competency (attitude, knowledge, skills and utilization) assessed through the EBP-COQ Prof© questionnaire. Bivariate and multiple lineal regression analyses were carried out. The mean score for the EBP competency of the PC nurses was 131.5 (standard deviation [SD] 17.0), according to dimensions: attitude 36.8 (SD 3.6); knowledge 38.2 (SD 8.9); skills 23.0 (SD 3.5); and utilization 33.3 (SD 6.1). The number of articles read in the last month has showed the most influence on all the EBP-COQ Prof© dimensions, followed by EBP training (more than 150h) and nursing students mentoring. The education level (master, specialist and doctorate) is associated with knowledge and skills dimensions, meanwhile belonging to a BPSO® center is associated with the EBP utilization. These findings can guide PC service managers to plan strategies that improve the EBP competency level of the nurses, aimed mainly at achieving real application in clinical practice. However, it is necessary to consider the possible impact of selection bias on the results.


Direct Optimization across Computer-Generated Reaction Networks Balances Materials Use and Feasibility of Synthesis Plans for Molecule Libraries.
The synthesis of thousands of candidate compounds in drug discovery and development offers opportunities for computer-aided synthesis planning to simplify the synthesis of molecule libraries by leveraging common starting materials and reaction conditions. We develop an optimization-based method to analyze large organic chemical reaction networks and design overlapping synthesis plans for entire molecule libraries so as to minimize the overall number of unique chemical compounds needed as either starting materials or reaction conditions. We consider multiple objectives, including the number of starting materials, the number of catalysts/solvents/reagents, and the likelihood of success of the overall syntheses plan, to select an optimal reaction network to access the target molecules. The library synthesis planning task was formulated as a network flow optimization problem, and we design an efficient decomposition scheme that reduces solution time by a factor of 5 and scales to instance with 48 target molecules and nearly 8000 intermediate reactions within hours. In four case studies of pharmaceutical compounds, the approach reduces the number of starting materials and catalysts/solvents/reagents needed by 32.2 and 66.0% on average and up to 63.2 and 80.0% in the best cases. The code implementation can be found at https://github.com/Coughy1991/Molecule_library_synthesis.


Depth-dependent intracortical myelin organization in the living human brain determined by in vivo ultra-high field magnetic resonance imaging.
Intracortical myelin is a key determinant of neuronal synchrony and plasticity that underpin optimal brain function. Magnetic resonance imaging (MRI) facilitates the examination of intracortical myelin but presents with methodological challenges. Here we describe a whole-brain approach for the in vivo investigation of intracortical myelin in the human brain using ultra-high field MRI. Twenty-five healthy adults were imaged in a 7 Tesla MRI scanner using diffusion-weighted imaging and a T1-weighted sequence optimized for intracortical myelin contrast. Using an automated pipeline, T1 values were extracted at 20 depth-levels from each of 148 cortical regions. In each cortical region, T1 values were used to infer myelin concentration and to construct a non-linearity index as a measure the spatial distribution of myelin across the cortical ribbon. The relationship of myelin concentration and the non-linearity index with other neuroanatomical properties were investigated. Five patients with multiple sclerosis were also assessed using the same protocol as positive controls. Intracortical T1 values decreased between the outer brain surface and the gray-white matter boundary following a slope that showed a slight leveling between 50% and 75% of cortical depth. Higher-order regions in the prefrontal, cingulate and insular cortices, displayed higher non-linearity indices than sensorimotor regions. Across all regions, there was a positive association between T1 values and non-linearity indices (P < 10-5). Both T1 values (P < 10-5) and non-linearity indices (P < 10-15) were associated with cortical thickness. Higher myelin concentration but only in the deepest cortical levels was associated with increased subcortical fractional anisotropy (P = 0.05). We demonstrate the usefulness of an automatic, whole-brain method to perform depth-dependent examination of intracortical myelin organization. The extracted metrics, T1 values and the non-linearity index, have characteristic patterns across cortical regions, and are associated with thickness and underlying white matter microstructure.


Gene expression during postembryonic segmentation in the centipede Lithobius peregrinus (Chilopoda, Lithobiomorpha).
Postembryonic segmentation (anamorphosis) is widespread among arthropods, but only partially known as for its developmental mechanics and control. Studies on developmental genetics of segmentation in anamorphic arthropods are mostly limited to the germ band stage, during early phases of embryonic development. This work presents the first data on the postembryonic expression of a segmentation gene in a myriapod. Using real-time PCR, we analyzed engrailed expression patterns during the anamorphic stages of the centipede Lithobius peregrinus. A variation pattern in en RNA level during anamorphosis suggests that gene expression is precisely modulated during this period of development and that engrailed is mainly expressed in the posterior part of the body, in the newly differentiating segments of each stage. As anamorphosis is possibly the primitive segmentation mode in arthropods, the postembryonic en expression pattern documented here provides evidence for a conservation of en role in ontogeny, across the embryonic/postembryonic boundary, as well as in phylogeny, across the same boundary, but in the opposite direction, from primitive postembryonic expression to the more derived expression in clades with exclusively embryonic segmentation.


Reproductive toxicity and toxicokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin. 3. Effects of single doses on the testis of male rats.
The effects of a single dose of TCDD on the testis were studied in rats. The animals were treated (subcutaneously) once with TCDD doses of 0, 0.5, 1.0, 3.0, 5.0 micrograms/kg body weight. Doses of 3.0 or 5.0 micrograms TCDD/kg reduced the number of spermatids/testis significantly (60% of the controls). Electron microscopic inspection revealed that both doses led to a dissolution on the germinal epithelium. Altered germ cells at all developmental stages occurred in all testes evaluated. Doses of 0.5 or 1.0 micrograms TCDD/kg did not induce any effects in the testis; therefore, under these experimental conditions of single exposure to rats the dose of 1.0 micrograms TCDD/kg can be considered as NOAEL.


Antibacterial and anti-inflammatory activities of some plants used for medicinal purposes in Kenya.
Aqueous, hexane and methanol extracts of 12 plant species, traditionally used in Kenya for treatment of ailments of infectious and/or inflammatory nature were screened for in vitro antibacterial and anti-inflammatory activities. Antibacterial activity was tested using the agar diffusion method while anti-inflammatory activity was tested using the cyclooxygenase (COX-1) assay. All the antibacterial activity was against Gram-positive bacteria with nine plant species showing some activity against Staphylococcus aureus. The highest activity was found in the methanol extracts of Maytenus senegalensis, Plectranthus barbatus, Zanthoxylum chalybeum, Zanthoxylum usambarense and hexane extracts of Spiranthes mauritianum. All the plant species showed some anti-inflammatory activities. In most cases, methanol extracts caused higher inhibition than aqueous and hexane extracts.


'Russian love,' or, what of lesbian studies in Russia?
This piece discusses the problems attending to the development of Lesbian Studies in Russia.


A role for macrophages under cytokine control in mediating resistance to ADI-PEG20 (pegargiminase) in ASS1-deficient mesothelioma.
Pegylated arginine deiminase (ADI-PEG20; pegargiminase) depletes arginine and improves survival outcomes for patients with argininosuccinate synthetase 1 (ASS1)-deficient malignant pleural mesothelioma (MPM). Optimisation of ADI-PEG20-based therapy will require a deeper understanding of resistance mechanisms, including those mediated by the tumor microenvironment. Here, we sought to reverse translate increased tumoral macrophage infiltration in patients with ASS1-deficient MPM relapsing on pegargiminase therapy. Macrophage-MPM tumor cell line (2591, MSTO, JU77) co-cultures treated with ADI-PEG20 were analyzed by flow cytometry. Microarray experiments of gene expression profiling were performed in ADI-PEG20-treated MPM tumor cells, and macrophage-relevant genetic "hits" were validated by qPCR, ELISA, and LC/MS. Cytokine and argininosuccinate analyses were performed using plasma from pegargiminase-treated patients with MPM. We identified that ASS1-expressing macrophages promoted viability of ADI-PEG20-treated ASS1-negative MPM cell lines. Microarray gene expression data revealed a dominant CXCR2-dependent chemotactic signature and co-expression of VEGF-A and IL-1α in ADI-PEG20-treated MPM cell lines. We confirmed that ASS1 in macrophages was IL-1α-inducible and that the argininosuccinate concentration doubled in the cell supernatant sufficient to restore MPM cell viability under co-culture conditions with ADI-PEG20. For further validation, we detected elevated plasma VEGF-A and CXCR2-dependent cytokines, and increased argininosuccinate in patients with MPM progressing on ADI-PEG20. Finally, liposomal clodronate depleted ADI-PEG20-driven macrophage infiltration and suppressed growth significantly in the MSTO xenograft murine model. Collectively, our data indicate that ADI-PEG20-inducible cytokines orchestrate argininosuccinate fuelling of ASS1-deficient mesothelioma by macrophages. This novel stromal-mediated resistance pathway may be leveraged to optimize arginine deprivation therapy for mesothelioma and related arginine-dependent cancers.


A cartilage conserving concept of a surgical tracheostomy-introduction and analysis of safety and complications of the Visor-tracheostomy-a retrospective monocentric comparative study over 8 years.
For decades, surgical tracheostomy using a Bjoerk-flap has been the standard procedure to create a reliable epithelialized tracheostomy in head and neck tumour surgery. This technique is being used as the gold standard approach in every surgical subspecialty. Preparation of the Bjoerk-flap requires splitting one or two tracheal rings, causing potential tracheal instability and tissue trauma. As a surgical alternative, the Visor-tracheostomy allows creating an epithelialized tracheostomy without splitting tracheal rings. This work aimed to prove the safety of the Visor-tracheostomy method, due to peri- and early postoperative complications. We present a step-by-step approach of this "new tracheostomy method". Monocentric, retrospective data within 8 years were evaluated. Complications such as wound infection, tracheostoma bleeding, tracheostoma dehiscence, and via falsa in a total of 453 tracheostomies (161 Bjoerk-flap and 292 Visor-tracheostomies) were compared and the results were analysed descriptively. Our data did not reveal a statistically significant difference in risk for a complication between the two methods (Visor-tracheostomy vs. Bjoerk-flap; p = 0.60; OR = 1.26, 95%-CI 0.60-2.82). This supports the hypothesis that applying the new cartilage conserving Visor-tracheostomy does not result in a reduction of safety for the patient. We contend, that the Visor-tracheostomy has the potential to supersede other surgical tracheostomy techniques in some indications. III (Comparative retrospective monocentric study).


New record of the genus Zombrus Marshall, 1897 (Hymenoptera: Braconidae: Doryctinae), with description of three new species from Vietnam.
The genus Zombrus Marshall, 1897, is newly recorded for Vietnam with four species. Three new species (Z. bicoloricorpus Long, sp. n., Z. flavicorpus Long van Achterberg, sp. n., and Z. tricoloricorpus Long, sp. n.) are described and illustrated, and one species (Z. pallidiventris Cameron, 1910) is reported for the first time from Vietnam and outside Indonesia. The key to Oriental and Palaearctic species of Zombrus and a checklist with distributions of the nine species from Oriental and Palaearctic regions are provided.


Stage A prostate cancer from pathologist's viewpoint.
Four hundred sixty-five departments of pathology in the United States were asked the following questions pertaining to Stage A prostatic cancer: (1) If a focus of adenocarcinoma is incidentally found in an enucleated specimen, what is the maximum diameter such a lesion may attain and still be considered an A-1 prostatic carcinoma? (2) If adenocarcinoma is incidentally found in a specimen resected transurethrally, how many chips may contain tumor and the lesion still be considered A-1 prostatic carcinoma? (3) What is your "routine pathologic examination" of a prostatic specimen? The majority of pathologists believe that the maximum diameter of a focal (A-1) lesion in an enucleated specimen is 5 mm., and the maximum number of transurethral chips containing tumor in a focal (A-1) lesion is three. The majority of pathologists section every chip when the specimen weighs less than 10 Gm. However, only 12 per cent of the pathologists section every chip when the specimen is greater than 10 Gm., while the others use a random section technique. There is a great diversity of techniques among pathologists in their methods of examining enucleated prostatic specimens.


A comparison of intraocular pressure measurements with the XPERT noncontact tonometer and Goldmann applanation tonometry.
The purpose of this study was to compare intraocular pressure measurements obtained with XPERT, an upgraded model of the noncontact tonometer, with those from Goldmann applanation tonometry. An average of three intraocular pressure measurements, generated by the XPERT, was compared with a single reading from a Goldmann applanation tonometer in 421 eyes of 220 patients. The standard deviation of the matched-pair differences (Sdiff) for the entire population was 2.3 mm Hg, whereas in a subset of 95 eyes with intraocular pressures of > or = 20 mm Hg by Goldmann applanation tonometry, the Sdiff was 3.3 mm Hg. The XPERT was found to provide reliable intraocular pressure measurements, especially within the normal range.


Metabolic consequences of hyperglycemia and insulin resistance.
Insulin is a pleiotropic hormone that exerts a multitude of effects on metabolism and various cellular processes in the body. The main metabolic actions of insulin are to stimulate glucose uptake in skeletal muscle and the heart and to suppress the production of glucose and very-low-density lipoprotein in the liver. Other metabolic effects of insulin include inhibition of glucose release from the liver, inhibition of the release of free fatty acids (FFAs) from adipose tissue, and stimulation of the process by which amino acids are incorporated into protein. Insulin resistance (IR) is a condition in which defects in the action of insulin are such that normal levels of insulin do not trigger the signal for glucose absorption. An excess of FFAs is implicated in the pathogenesis of IR. The effects of this condition can have profound pathophysiologic effects on various organs and tissues of the body. For example, IR is associated with impaired insulin signaling, impaired fibrinolysis, and inflammation. The clinical consequences include hyperglycemia-induced tissue damage, hypertension, dyslipidemia, metabolic syndrome, and cardiovascular disease. Pharmacotherapies that target IR include metformin and the thiazolidinediones. Endocannabinoid antagonists, agents that target obesity and associated cardiovascular and metabolic risk factors, are currently being developed.


In Situ Peroxidase Labeling Followed by Mass-Spectrometry Reveals TIA1 Interactome.
TIA1 is a broadly expressed DNA/RNA binding protein that regulates multiple aspects of RNA metabolism. It is best known for its role in stress granule assembly during the cellular stress response. Three RNA recognition motifs mediate TIA1 functions along with a prion-like domain that supports multivalent protein-protein interactions that are yet poorly characterized. Here, by fusing the enhanced ascorbate peroxidase 2 (APEX2) biotin-labeling enzyme to TIA1 combined with mass spectrometry, the proteins in the immediate vicinity of TIA1 were defined in situ. Eighty-six and 203 protein partners, mostly associated with ribonucleoprotein complexes, were identified in unstressed control and acute stress conditions, respectively. Remarkably, the repertoire of TIA1 protein partners was highly dissimilar between the two cellular states. Under unstressed control conditions, the biological processes associated with the TIA1 interactome were enriched for cytosolic ontologies related to mRNA metabolism, such as translation initiation, nucleocytoplasmic transport, and RNA catabolism, while the protein identities were primarily represented by RNA binding proteins, ribosomal subunits, and eicosanoid regulators. Under acute stress, TIA1-labeled partners displayed a broader subcellular distribution that included the chromosomes and mitochondria. The enriched biological processes included splicing, translation, and protein synthesis regulation, while the molecular function of the proteins was enriched for RNA binding activity, ribosomal subunits, DNA double-strand break repair, and amide metabolism. Altogether, these data highlight the TIA1 spatial environment with its different partners in diverse cellular states and pave the way to dissect TIA1 role in these processes.