Cryotherapy of Renal Lesions: Enhancement on Contrast-Enhanced Sonography on Postoperative Day 1 Does Not Imply Viable Tissue Persistence.
To investigate whether persistent enhancement detected on contrast-enhanced sonography at postoperative day 1 (early contrast-enhanced sonography) after cryoablation of renal tumors implies the presence of residual viable tumor tissue, defined as residual enhancing tissue on reference imaging (computed tomography or magnetic resonance imaging) performed 6 months after the procedure. Seventy-four patients with percutaneous cryoablation of renal tumors had early contrast-enhanced sonography from November 2011 to August 2015. Two independent readers evaluated early contrast-enhanced sonographic findings and contrast-enhanced sonographic investigations performed 1 month after cryoablation of lesions that displayed enhancement on early contrast-enhanced sonography. They scored intralesional enhancement in 4 groups: no enhancement, few intralesional vessels, focal enhancing areas, and diffuse enhancement. Inter-reader agreement in evaluating lesion vascularity on early contrast-enhanced sonography was assessed with weighted κ statistics. Computed tomography or magnetic resonance imaging performed 6 months after the treatment was the reference procedure for assessing the absence or presence of residual disease. Inter-reader agreement in assessing intratumoral vascularization on early contrast-enhanced sonography was very good (κ = 0.90). Enhancement was absent for both readers in 33 of 74 cases; only a few intralesional vessels were visible in 21; whereas diffuse or focal enhancement was present in 13. In the remaining 7 patients, there were differences. Four lesions with focal enhancement on early contrast-enhanced sonography and 1 that was considered avascular had residual tumors on reference imaging. Ablation was successful in the remaining 69 of 74 patients (93%). After cryoablation, intratumoral enhancement on early contrast-enhanced sonography does not imply tumor cell viability.


[Traumatic arteriovenous pial fistula masquerading as a carotid-cavernous fistula: an uncommon disorder with an unusual presentation].
Traumatic intracranial pial arteriovenous fistulae are infrequent lesions. Their cardinal signs have been related to mass effect and hemorrhage, but their clinical manifestations due to venous retrograde flow into ophthalmic veins has never been described. This phenomenon is usually seen in dural arteriovenous fistula draining to the cavernous sinus or carotid-cavernous sinus fistula.A traumatic intracranial pial arteriovenous fistula arising from the supraclinoid internal carotid artery in a young patient was revealed by aggressive behavior and ophthalmologic manifestations. The endovascular management included the use of coils, stent, and ethylene-vinyl alcohol with transient balloon occlusion of the parent vessel.


Non-antibiotic effect of antibiotics.
In the present study, we demonstrated the efficacy of low-dose, long-term therapy with erythromycin and an erythromycin-related compound, roxithromycin, in patients with chronic lower respiratory tract disease including diffuse panbronchiolitis (DPB), and investigated the anti-inflammatory action of such drugs. Treatment significantly improved the mean value of respiratory function tests and arterial blood gas analysis, except for PaCO2 in the erythromycin-treated group and residual volume/total lung capacity (RV/TLC) and PaCO2 in the roxithromycin-treated group. Bronchoalveolar lavage (BAL) analysis revealed that neutrophils had accumulated in the pre-treatment lavage fluid, compared with that of healthy volunteers, and the levels of neutrophil chemotactic activity (NCA), interleukin-1beta (IL-1beta), interleukin-8 (IL-8) and leukotriene B4 (LTB4) in BAL fluid of the patients were significantly higher than those in healthy volunteers. Macrolide therapy caused a significant reduction in the percentage of neutrophils, NCA and mean IL-1beta, IL-8 and LTB4 concentration in BAL fluid of the patients. The quantitative expression of Mac---1 on peripheral neutrophils significantly increased, compared with that in healthy volunteers, before therapy and significantly decreased after therapy. We also evaluated the in vitro inhibitory effects of macrolides on IL---8 production by vitamin D3-induced human monocytic cell line THP-1 cells when stimulated with lipopolysaccharide and serum. The present study has also provided evidence for T-cell activation in BAL fluid of the patients, and a significantly reduced number of activated T-cells was observed after macrolide therapy. These results indicate that macrolides may act by reducing pulmonary inflammation through reduction of neutrophil accumulation, as a consequence of reduced chemotactic gradient and cytokine production at the inflammatory sites in the lung or of reduced neutrophil adhesion molecules in the circulation. Ultimately the mechanism may involve suppression of neutrophil oxidative and proteolytic products. Lymphocytes are important cellular components of bronchial inflammation, in addition to neutrophils, in this disease, and macrolide antibiotics may also act as an immunosuppressant to inhibit T-cell activation. This is believed to be one reason why macrolides are effective in chronic lower respiratory tract disease.


Analysis of oral papillomas, leukoplakias, and invasive carcinomas for human papillomavirus type related DNA.
Five papillomas, five leukoplakias, and six carcinomas were investigated for the presence of papillomavirus group-specific antigens and viral DNA. Viral proteins were identified with genus-specific papillomavirus antibodies. Cloned human papillomavirus (HPV) 11 and 16 DNA were used as probes in Southern blot hybridization at conditions of different stringency in order to determine viral DNA. Four of five papillomas, four of five leukoplakias, and three of six carcinomas reacted with HPV DNA probes and revealed some stained cells after exposure to HPV antibodies. HPV type 16 was found in one carcinoma and HPV type 11 was demonstrated in another case of carcinoma.


The cytological diagnosis of extra-oral plasmablastic lymphoma: a rare entity.
Non-Hodgkin's Lymphomas (NHLs) which are associated with the Acquired Immunodeficiency Syndrome (AIDS) are heterogeneous. Plasmablastic Lymphoma (PBL) was first recognized as an aggressive, invariably fatal subtype of Non-Hodgkin's Lymphoma which occurred mostly in patients with AIDS, with distinct histomorphologic and immunophenotypic findings, which affected the jaw and the oral mucosa exclusively. Subsequently, there have been case reports which have described extra-oral plasmablastic lymphomas in the lung, jejunum, caecum, nasal mucosa, etc. We are reporting a case of this rare subtype of diffuse large B-cell lymphoma which presented as a soft tissue mass, which we believe is the first case to be diagnosed by FNAC.


Endoscopic Management of Recalcitrant Marginal Ulcers by Covering the Ulcer Bed.
Management options for marginal ulcers (MU) vary from medical therapy to revision surgery. Medical therapy is often ineffective and revision surgery is associated with a high morbidity and possible recurrence. To evaluate technical feasibility, efficacy, and safety of endoscopic management of MU by covering the ulcer bed using oversewing and/or deploying a fully covered self-expandable metallic stent (FCSEMS). Medical records of consecutive patients who underwent endoscopic suturing and/or FCSEMS deployment for recalcitrant MU between August 2016 and June 2017 at a single academic center were reviewed. Recalcitrant MU was defined as an ulcer that persists after 6 to 8 weeks despite maximal medical therapy (open capsule PPI, 40 mg bid as well as sucralfate qid), cessation of smoking and nonsteroidal anti-inflammatory drugs (NSAIDs), and Helicobacter pylori eradication. Eleven patients (age range 31-60; all females) with mean BMI of 27.72 ± 5.93 kg/m2 underwent endoscopic suturing and/or stent deployment for recalcitrant MU with abdominal pain at a median of 50 months (range 3-120) post-Roux-en-Y gastric bypass (RYGB). Seven patients were managed by oversewing, two were managed by FCSEMS, and two patients required both. Technical success was 100%. All patients reported resolution of abdominal pain at 1 week. Surveillance endoscopy performed in 10/11 (90.9%) patients at 8 weeks revealed complete ulcer healing in 9/10 (90%). No adverse events were reported. Endoscopic management is an effective and safe method to treat MU and should be considered an alternative to surgical revision. It appears effective for perforated and recalcitrant MU.


Acidogenic phosphorus recovery from the wastewater sludge of the membrane bioreactor systems with different iron-dosing modes.
A novel acidogenic phosphorus recovery (APR) process was developed in combination with Fe(III)-based chemical phosphorus removal and a membrane bioreactor (MBR) for enhanced wastewater treatment and effective P recovery. Two different system configurations were evaluated: Fe-dosing MBR (Fe-MBR), with the Fe-dosing into the MBR, and Fe-enhanced primary sedimentation followed by the MBR (FeP-MBR). The results show that both systems performed well for enhanced nutrient (N and P) removals and P recovery, with approximately 50% of the total P recovered from the municipal wastewater in the form of vivianite. Compared to the Fe-MBR system, FeP-MBR achieved more efficient P recovery under low food-waste loading conditions, maintained a higher ratio of biomass in activated sludge and experienced a slower rate of membrane fouling. Important functional bacteria were identified, including Prevotella and Selenomonas, which are active in hydrolysis and acidogenesis of sludge, and Aeromonas and Sulfurospirillum, which are involved in dissimilatory iron reduction.


Body fat regulation after partial lipectomy in Siberian hamsters is photoperiod dependent and fat pad specific.
Siberian hamsters exhibit seasonal fluctuations in body weight (fat). Initial exposure to a short photoperiod results in body fat loss that reverses after approximately 22 wk of short-day exposure. The purpose of this study was to determine whether Siberian hamsters are able to recover body fat after surgical reduction of total lipid stores and if so, whether this ability is photoperiod dependent and fat pad specific. Either the largest pair of internal fat pads, the epididymal white adipose tissue (EWAT) or one pair of two large external depots, the inguinal (IWAT) fat pads, were removed from male hamsters housed for 22 wk in a long (LD) or short (SD) photoperiod. Retroperitoneal fat pad (RWAT) mass was increased in LD EWAT- and IWAT-lipectomized hamsters. IWAT mass also was increased in the LD EWAT-lipectomized hamsters. Neither SD-lipectomized group compensated for body fat loss in any of the measured fat pads. Increased food intake was not necessary for total body fat recovery, but undereating partially may be responsible for the lack of recovery in SDs. The results of these experiments demonstrate a photoperiod-dependent ability of male Siberian hamsters to regulate total body fat after partial lipectomy. In addition, recovery involves a fat pad-specific compensatory response to partial lipectomy, rather than a general increase in lipid deposition in all fat depots.


N-terminal pro B-type natriuretic peptide and left ventricular diameter independently predict mortality in dogs with mitral valve disease.
To determine whether natriuretic peptide concentrations would predict all cause mortality in dogs with degenerative mitral valve disease. One hundred dogs with naturally occurring degenerative mitral valve disease were prospectively recruited for this longitudinal study. Analysis of outcome was undertaken for 73 dogs for which the outcome was known. Dogs underwent physical examination, electrocardiography and echocardiography. Natriuretic peptide concentrations were measured by Enzyme-linked immunosorbent assay. The ability of natriuretic peptide concentrations, clinical, electrocardiographic and echocardiographic data, to predict all cause mortality was determined using univariable and multivariable Cox proportional hazards analyses. Thirty dogs died during the period of follow-up. Two variables were independently predictive of all cause mortality; these were the normalised left ventricular end-diastolic diameter and the N-terminal pro B-type natriuretic peptide concentration. An increase of the left ventricular end-diastolic diameter by 0.1 increased the hazard of all cause mortality by 20% (95% confidence interval: 4 to 37%, P=0.01) and a 100 pmol/l increase in N-terminal pro B-type natriuretic peptide increased the hazard by 7% (95 confidence interval: 2 to 11%, P=0.003). N-terminal pro B-type natriuretic peptide concentration and left ventricular end-diastolic diameter are significantly and independently predictive of all cause mortality in dogs with degenerative mitral valve disease.


Ultra-thin NaCl films as protective layers for graphene.
The ageing of graphene is an important issue that limits its technological applications. Capping layers are a good option for circumventing this problem. In this work, we propose the use of ultra-thin NaCl films as easily-removable protective layers. We have carried out a detailed characterization of the NaCl/graphene interface on metal substrates, namely Cu(111) and Ir(111), by means of complementary microscopy, electron diffraction and spectroscopic techniques. Interestingly, we show that NaCl neither interacts in a chemical way with graphene nor intercalates through it. We demonstrate that the NaCl film is stable under ambient conditions, protecting the graphene surface from oxidation. In addition, after removing the protective layer, graphene remains intact.


Mapping of TH1 helper T-cell epitopes on major secreted mycobacterial antigen 85A in mice infected with live Mycobacterium bovis BCG.
TH1 cytokine secretion was examined in response to synthetic peptides of the 85A component of the major secreted, fibronectin-binding antigen 85 complex from Mycobacterium tuberculosis in seven different mouse strains infected with live M. bovis BCG. Twenty-eight overlapping 20-mer peptides covering the complete mature 295-amino-acid (AA) protein were synthesized. Significant interleukin-2 (IL-2) and gamma interferon (IFN-gamma) secretion could be measured following in vitro stimulation of spleen cells with these peptides. H-2d haplotype mice reacted preferentially against the amino-terminal half of the protein, i.e., against peptide 5 (AA 41 to 60) and especially against peptide 11 (AA 101 to 120), which contained an I-Ed binding motif. H-2b haplotype mice, on the other hand, reacted against peptides from both amino- and carboxy-terminal halves of the protein, peptide 25 (AA 241 to 260) being the most potent stimulator of IL-2 and IFN-gamma production. (BALB/c x C57BL/6)F1 animals with the H-2d/b haplotype weakly recognized peptides specific for both parental lines. Finally, CBA/J (H-2k) and major histocompatibility complex class II mutant B6.C.bm12 mice, carrying a mutant I-A beta bm12 allele on an H-2b background, reacted only very weakly to the 85A peptides. Reactive T cells isolated from lungs of BCG-infected H-2b haplotype mice recognized the same epitopes as spleen cells, especially peptide 25. These data confirm previous findings regarding the powerful IL-2 and IFN-gamma-inducing properties of antigen 85 during infection with live M. bovis BCG.


Evidence for liver injury in the setting of obstructive sleep apnea.
Obstructive sleep apnea (OSA) and non-alcoholic fatty liver disease (NAFLD) are both strongly associated with obesity. Whether OSA is an independent risk factor for liver injury is uncertain. To assess the hypothesis that OSA is associated with liver injury independent of obesity. We reviewed the histories of 73 consecutive patients referred to a hospital-based sleep lab because of suspected OSA. OSA was determined to be present if the apnea-hypopnea index was > 10. Obesity was defined as a BMI ≥ 30 kg/m 2 . Patients were included for analysis if they had aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels obtained within 60 days of sleep study. Patients with evidence of viral hepatitis, autoimmune-, metabolic- or established alcoholic-liver disease were excluded. Patients who reported alcohol intake equivalent to a dose ≥ 20 g/day were also excluded. 53 of 73 patients met study criteria. Patients were subdivided for analysis into groups meeting or not meeting OSA and obesity criteria, and having or not having elevated aminotransferase levels. 35/53 patients (66%) had OSA. 31/53 (58%) patients were obese. 15 (28%) and 12 (23%) patients had elevated AST and ALT, respectively. Mean age, gender distribution, mean BMI and percentage with either diabetes or hyperlipidemia were not significantly different in those with or without OSA. Elevated ALT was found in 11/35 (31%) patients with OSA, compared to 1/18 patients without OSA (p = 0.041). Frequency of elevated AST [obese 11/31 (35%); non-obese 4/22 (18%)] or ALT [obese 10/31 (32%); non-obese 2/22 (9%)] was not significantly different in the obese and non-obese cohorts. OSA may be a risk factor for liver injury independent of obesity. The prevalence and nature of liver disease in the setting of OSA should be determined with larger, prospective studies. The impact of OSA treatment, if any, on liver injury should be similarly evaluated.


Single molecule protein stabilisation translates to macromolecular mechanics of a protein network.
Folded globular proteins are attractive building blocks for biopolymer-based materials, as their mechanically resistant structures carry out diverse biological functionality. While much is now understood about the mechanical response of single folded proteins, a major challenge is to understand and predictably control how single protein mechanics translates to the collective response of a network of connected folded proteins. Here, by utilising the binding of maltose to hydrogels constructed from photo-chemically cross-linked maltose binding protein (MBP), we investigate the effects of protein stabilisation at the molecular level on the macroscopic mechanical and structural properties of a protein-based hydrogel. Rheological measurements show an enhancement in the mechanical strength and energy dissipation of MBP hydrogels in the presence of maltose. Circular dichroism spectroscopy and differential scanning calorimetry measurements show that MBP remains both folded and functional in situ. By coupling these mechanical measurements with mesoscopic structural information obtained by small angle scattering, we propose an occupation model in which higher proportions of stabilised, ligand occupied, protein building blocks translate their increased stability to the macroscopic properties of the hydrogel network. This provides powerful opportunities to exploit environmentally responsive folded protein-based biomaterials for many broad applications.


Collaboration Scripts or Checklists to Engage Novice Observers in Immersive Simulation?
In simulation, students often observe their peers perform a task. It is still unclear how different types of instructional guidance can turn the observational phase into an active learning experience for novices. This mixed-method study aims to understand similarities and differences between use of collaboration scripts and checklists by observers in terms of cognitive load and perception of learning. Second-year pharmacy students ( N = 162) were randomly assigned to 1 of 4 conditions when observing a simulation: collaboration scripts (heuristic to analyze in dyads while observing), checklists, both, or no guidance. We measured observers' intrinsic and extraneous cognitive load and self-perceived learning and conducted focus group interviews. Intrinsic cognitive load was significantly lower for checklists (M = 3.6/10) than for scripts (M = 4.7/10) or scripts and checklists combined (M = 4.7/10). Extraneous cognitive load was significantly lower for checklists (M = 1.5/10) than for scripts combined with checklists (M = 2.6/10) or no guidance (M = 1.8/10). There was no statistical difference between conditions for self-perceived learning. Coding of focus group interviews revealed 6 themes on observers' perception of learning under different conditions of instructional guidance. Students explained that collaboration scripts felt more complex, whereas checklists were perceived as a simple fact-checking exercise. Observing the simulation, regardless of guidance, was a meaningful learning experience. With or without guidance, observers are actively engaged with the simulation, but their effort differed depending on instructions. When choosing between checklists or collaboration scripts, educators should be guided by the type of simulation task.


Melatonin suppresses migration and invasion via inhibition of oxidative stress pathway in glioma cells.
Melatonin, an indolamine produced and secreted predominately by the pineal gland, exhibits a variety of physiological functions, possesses antioxidant and antitumor properties. In this study, we have shown that pharmacologic concentration (1mm) of melatonin significantly reduced cell migration and invasion of T98G and U251 glioma cells after 24-hr treatment and inhibited expression of matrix metalloproteinase 2 (MMP 2) and MMP 9. The melatonin inhibition of cell migration and invasion was associated with its reduction of intracellular basal free radical generation. Melatonin at pharmacologic concentration also inhibited the constitutive activation of the reactive oxygen species downstream transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Furthermore, pyrrolidine dithiocarbamate, a NF-κB-specific inhibitor, at 10μm displayed anti-migration and invasion effects and inhibition of MMP 2 and MMP 9 expression resembling that of melatonin. Taken together, it is concluded that inhibition of migration and invasion of glioma cells by melatonin is associated with the latter in its inhibition of oxidative stress pathway. This suggests a potential therapeutic application of melatonin in the treatment of glioma.


AutoCyte Interactive Screening System. Experience at a university hospital cytology laboratory.
To evaluate the AutoCyte Interactive Screening System (AutoCyte-Screen) as a prescreener for the cytologic detection of cervicovaginal abnormalities. Eight hundred fifty-six AutoCyte Preparation System from cervicovaginal samples were evaluated by AutoCyte-Screen. AutoCyte-Screen displayed 120 cell images and 6 low-power images for review by the cytotechnologist. The cytotechnologist classified the case as WNL, abnormal or unsatisfactory. AutoCyte-Screen then revealed its classification as either unsatisfactory, WNL, abnormal or undecided. These classifications were combined to form an interactive result that was compared to the diagnosis from previous manual review. Interactive results were as follows: 251 (29.3%) abnormal, 581 (67.9%) WNL and 24 (2.8%) unsatisfactory. The abnormal interactive result contained 15 ASCUS/AGUS and 25 SILs; the WNL interactive result contained 5 ASCUS/AGUS and 2 SILs. No ASCUS/AGUS or SILs were in the unsatisfactory interactive category. The false negative proportion was 10.5% for the interactive diagnostic method vs. 15.7% for manual review for LSIL. The interactive use of AutoCyte-Screen can effectively select those cases which are most likely to contain an epithelial abnormality and could therefore be used as a triage system to select cases for manual review. A case with an interactive result of unsatisfactory and abnormal should receive full manual review, while those classified as WNL may require a less extensive review for quality assurance purposes. This resultant decrease in the manual screening load could increase laboratory efficiency.


Simulation of the gastric digestion of proteins of meat bolus using a reaction-diffusion model.
A reaction-diffusion mathematical model has been developed to predict the gastric digestion of meat proteins. The model takes into account pepsin diffusion and proton diffusion in bolus particles and the pH buffering capacity of meat. The computations show that the size of bolus particles and the change in gastric pH have a substantial effect on the percentage of protein digested in the stomach and that the pH buffering capacity of meat has to be accounted for to properly calculate the gastric digestibility of meat. The intensity of surface transfers between stomach fluid and bolus particles has a significant impact on protein digestibility, whereas the variation in pepsin content in the stomach between individuals appears to have little effect on protein digestibility. From a nutritional standpoint, the simulations show that meat protein digestibility is high under normal physiological stomach conditions. However, in a situation where masticatory capacity, hydrochloric acid secretion and gastric motor function performances are reduced, such as with advancing age, protein digestibility rapidly decreases, ultimately leading to near-zero digestibility value in the stomach in extreme cases.


Endometrial preparation for third-party parenting and cryopreserved embryo transfer.
The advent of third party parenting ushered in the era of artificial stimulation of the endometrium. Initially intended only for patients with ovarian failure, exogenous induction of endometrial receptivity was quickly shown to be as good as natural endometrial preparation, with the advantage that the timing of embryo transfer could be controlled. It is perhaps surprising that even though the ovary produces a variety of steroids, that estradiol (E2) and progesterone (P) alone would be needed to achieve optimal receptivity; no other substance has ever been shown to improve on the basic regimen of E2 and P. A variety of routes of administration are available for both E2 and P and physiologic (or supraphysiologic) serum or endometrial tissue levels of both can be achieved. The optimal duration of E2 stimulation and the timing of the onset of P administration continue to be debated, but it appears that imitating the sequence that normally occurs in nature leads to optimal results. The poorly responsive endometrium and cases of recurrent implantation failure remain a challenge, but the clear majority of patients can successfully achieve pregnancy as long as embryos of adequate quality are transferred.


Cross-resistance to photofrin-mediated photodynamic therapy and UV light and recovery from photodynamic therapy damage in Rif-8A mouse fibrosarcoma cells measured using viral capacity.
Photodynamic therapy (PDT) utilizes the localized delivery of light to activate a photosensitizing drug (such as Photofrin) which is selectively retained by the tumour tissues. The intrinsic in vitro sensitivity of tumour cells to PDT is thought to be an important determinant of clinical tumour response to PDT. In this work we show the feasibility of using a viral capacity assay for adenovirus (Ad) DNA synthesis as an indicator of cellular sensitivity to and recovery from Photofrin-mediated PDT. Rif-1 mouse fibrosarcoma cells and a PDT resistant derivative, Rif-8A, as well as Chinese hamster ovary (CHO) cells and CHO-MDR multi-drug resistant mutant cells were studied. Consistent with the clonogenic survival of these cells, the capacity of PDT-treated cells for Ad DNA synthesis was greater for Rif-8A compared to Rif-1 cells and for CHO-MDR compared to CHO-N cells. Delaying infection of the Rif cells from immediately after, to 6 hours after PDT, resulted in an increased capacity for Ad DNA synthesis, which was greater for Rif-8A compared to Rif-1 cells, suggesting that the increased resistance of Rif-8A cells to PDT results from an elevated recovery and/or repair of PDT damage. The capacity of UV-irradiated cells for Ad DNA synthesis was also greater for Rif-8A compared to Rif-1 cells indicating a cross-resistance of Rif-8A cells to UV. These results suggest some overlap in the types of cellular damage induced by UV and PDT and/or overlap in the pathways for the repair of UV and PDT damage in Rif cells.


Berberrubine attenuates mucosal lesions and inflammation in dextran sodium sulfate-induced colitis in mice.
Ulcerative colitis (UC) is a chronic relapsing disease without satisfactory treatments, in which intestinal inflammation and disrupted intestinal epithelial barrier are two main pathogeneses triggering UC. Berberrubine (BB) is deemed as one of the major active metabolite of berberine (BBR), a naturally-occurring isoquinoline alkaloid with appreciable anti-UC effect. This study aimed to comparatively investigate the therapeutic effects of BB and BBR on dextran sodium sulfate (DSS)-induced mouse colitis model, and explore the potential underlying mechanism. Results revealed that BB (20 mg/kg) produced a comparable therapeutic effect as BBR (50 mg/kg) and positive control sulfasalazine (200 mg/kg) by significantly reducing the disease activity index (DAI) with prolonged colon length and increased bodyweight as compared with the DSS group. BB treatment was shown to significantly ameliorate the DSS-induced colonic pathological alternations and decreased histological scores. In addition, BB markedly attenuated colonic inflammation by alleviating inflammatory cell infiltration and inhibiting myeloperoxidase (MPO) and cytokines (TNF-α, IFN-γ, IL-1β, IL-6, IL-4 and IL-10) productions in DSS mice. Furthermore, BB treatment substantially upregulated the expression of tight junction (TJ) proteins (zonula occludens-1, zonula occludens-2, claudin-1, occludin) and mRNA expression of mucins (mucin-1 and mucin-2), and decreased the Bax/Bcl-2 ratio. In summary, BB exerted similar effect to its analogue BBR and positive control in attenuating DSS-induced UC with much lower dosage and similar mechanism. The protective effect observed may be intimately associated with maintaining the integrity of the intestinal mucosal barrier and mitigating intestinal inflammation, which were mediated at least partially, via favorable modulation of TJ proteins and mucins and inhibition of inflammatory mediators productions in the colonic tissue. This is the first report to demonstrate that BB possesses pronounced anti-UC effect similar to BBR and sulfasalazine with much smaller dosage. BB might have the potential to be further developed into a promising therapeutic option in the treatment of UC.


Vasodilation by in vivo activation of astrocyte endfeet via two-photon calcium uncaging as a strategy to prevent brain ischemia.
Decreased cerebral blood flow causes brain ischemia and plays an important role in the pathophysiology of many neurodegenerative diseases, including Alzheimer's disease and vascular dementia. In this study, we photomodulated astrocytes in the live animal by a combination of two-photon calcium uncaging in the astrocyte endfoot and in vivo imaging of neurovasculature and astrocytes by intravital two-photon microscopy after labeling with cell type specific fluorescent dyes. Our study demonstrates that photomodulation at the endfoot of a single astrocyte led to a 25% increase in the diameter of a neighboring arteriole, which is a crucial factor regulating cerebral microcirculation in downstream capillaries. Two-photon uncaging in the astrocyte soma or endfoot near veins does not show the same effect on microcirculation. These experimental results suggest that infrared photomodulation on astrocyte endfeet may be a strategy to increase cerebral local microcirculation and thus prevent brain ischemia.


Immunomodulatory effects of interferon-gamma on autoreactive nephritogenic T-cell clones.
We examined the immunomodulatory effects of interferon-gamma (IFN-gamma) on renal-derived CD4+ alpha/beta + T cells, called mouse renal (MR) cells, isolated from animals with murine chronic graft-versus-host disease, a model of autoimmune glomerulonephritis. MR T cells express a Th2 cytokine profile, although IFN-gamma expression is also detected in a subset of clones that adoptively transfers renal disease to naive recipients. In view of disparate patterns of IFN-gamma expression, we evaluated the effects of exogenous IFN-gamma on nephritogenic (MR1.3) and nonnephritogenic (MR1.6) clonal activity. These studies examined IFN-gamma-mediated effects on clonal proliferation, cytokine production, nephritogenic potential, and IFN-gamma receptor expression. IFN-gamma mediated dose-dependent inhibition of MR1.3 and MR1.6 proliferation. This cytostatic effect was not mediated by inhibiting cytokine genes, as expression of interleukin (IL)-4, IL-10, IL-13, and IFN-gamma after IFN-gamma treatment was not markedly altered in either clone, although baseline IL-13 expression was enhanced in MR1.6. IFN-gamma markedly altered the functional phenotype of MR1.6, as pretreated recipients developed severe mononuclear cell infiltrates and tubular damage following adoptive transfer of MR1.6. Neutralizing anti-IFN-gamma antibodies did not inhibit MR1.3 nephritogenicity, but did block MR1.6-induced disease in IFN-gamma-treated mice. Although both clones constitutively expressed the IFN-gamma receptor beta chain, IFN-gamma exposure decreased its expression in MR1.3 cells, but did not markedly change its expression in MR1.6 cells. These studies describe an unusual permissive role for IFN-gamma in modulating nephritogenic Th2 activity in vivo, which facilitates the initiation of cell-mediated autoimmune renal injury. Apparent differential effects of IFN-gamma on distinct T-cell clones may be mediated in part by alterations in cytokine receptor expression.


Characterization of symbiont populations in life-history stages of mussels from chemosynthetic environments.
The densities of chemoautotrophic and methanotrophic symbiont morphotypes were determined in life- history stages (post-larvae, juveniles, adults) of two species of mussels (Bathymodiolus azoricus and B. heckerae) from deep-sea chemosynthetic environments (the Lucky Strike hydrothermal vent and the Blake Ridge cold seep) in the Atlantic Ocean. Both symbiont morphotypes were observed in all specimens and in the same relative proportions, regardless of life-history stage. The relative abundance of symbiont morphotypes, determined by transmission electron microscopy, was different in the two species: chemoautotrophs were dominant (13:1-18:1) in B. azoricus from the vent site; methanotrophs were dominant (2:1-3:1) in B. heckerae from the seep site. The ratio of CH4:H2S is proposed as a determinant of the relative abundance of symbiont types: where CH4:H2S is less than 1, as at the Lucky Strike site, chemoautotrophic symbionts dominate; where CH4:H2S is greater than 2, as at the seep site, methanotrophs dominate. Organic carbon and nitrogen isotopic compositions of B. azoricus (delta 13C = -30 per thousand; delta 15N = -9 per thousand) and B. heckerae (delta 13C = -56 per thousand; delta 15N = -2 per thousand) varied little among life-history stages and provided no record of a larval diet of photosynthetically derived organic material in the post-larval and juvenile stages.


Previous oral contraceptive use and breast cancer risk according to hormone replacement therapy use among postmenopausal women.
To assess postmenopausal breast cancer risk in relation to particular patterns of oral contraceptive (OC) use according to hormone replacement therapy (HRT) exposure. Time-dependent Cox regression models were used to analyse information on postmenopausal women from a large-scale French cohort. Among a total of 68,670 women born between 1925 and 1950, 1405 primary invasive postmenopausal breast cancer cases were identified from 1992 to 2000. A non-significant decrease in risk of around 10% was associated with ever OC use as compared to never OC use in postmenopausal women. No significant interaction was found between OC and HRT use on postmenopausal breast cancer risk. Breast cancer risk decreased significantly with increasing time since first OC use (test for trend: p=0.01); this was consistent after adjustment for duration of use or for time since last use. No increase in breast cancer risk was associated with previous OC exposure among postmenopausal women, probably because the induction window had closed. Some women may develop breast cancer soon after exposure to OCs, leading to a deficit of cases of older women. Further investigation is therefore required to identify young women at high risk.


Bioglycans and natural glycosides as a promising research topic in bioorganic chemistriy.
This review defines bioorganic chemistry as one of the most important constituents of physico-chemical biology, which is a fundamental life science. The problems and goals of bioorganic chemistry are examined through a comparatively small number of examples. Bioorganic chemistry is supposed to be a logical continuation of the chemistry of the natural substances that arose many years ago. Bioorganic chemistry has contributed some achievements in solving the problems of the chemical structure, biological function, and physiological activity of biopolymers and low-molecular-weight bioregulators, as well as in the elucidation of the molecular mechanisms of different life processes. The most striking achievements in bioorganic chemistry are discussed in this paper. However, this review discusses not only the general achievements in this field of science, but also research data obtained by scientists from the Pacific Institute of Bioorganic Chemistry, Far East Branch, Russian Academy of Sciences (Vladivostok, Russia), and the Institute of Physiology, Komi Science Centre, The Urals Branch, Russian Academy of Sciences (Syktyvkar, Russia). Particular attention is focused on comprehensive research into polysaccharides and biopolymers (bioglycans) and some natural glycosides that the author of this review has studied for a long time. The author has worked in these institutes for a long time and was honored by being chosen to head one of the scientific schools in the field of bioorganic chemistry and molecular immunology.


Augmentation of natural killer cell activity by ImuVert: a biological response modifier derived from Serratia marcescens.
The natural killer (NK) cell activity of peripheral blood mononuclear cells (PBMC) from healthy human volunteers was studied following in vitro incubation with ImuVert, a biological response modifier derived from the bacterium Serratia marcescens. Exposure of these cells to ImuVert for as little as 10 minutes followed by an additional incubation in vitro of at least 12 hours and optimally 18 hours resulted in a substantial, consistent, and dose-dependent augmentation of NK cell activity against K562 tumor cells. Additional studies indicate that the augmented cell expressed the leu 11 cell surface marker and that peripheral blood monocytes were essential in the induction of augmented NK cell activity but were not the effector cell of NK activity.


Sturge-Weber syndrome: an update on the relevant issues for neurosurgeons.
Sturge-Weber syndrome (SWS) is a neurocutaneous facomatosis characterized by facial and leptomeningeal angioma, glaucoma, seizures, and neurological disability. Therefore, a challenging multidisciplinary interaction is required for its management. The goal of this paper is to review the main aspects of SWS and to present an illustrative pediatric series. The pertinent literature has been analyzed, focused mainly on etiopathogenesis, pathology, clinical features, diagnostic tools, management, and outcome of the disease. Moreover, a series of 11 children operated on for refractory epilepsy between 2005 and 2015 (minimum follow-up 5 years, mean follow-up 9.6 years) is reported. The series consists of six boys and five girls with 6.5-month and 16.2-month mean age at seizure onset and at surgery, respectively. Seizures affected all children, followed by hemiparesis and psychomotor delay (81%), glaucoma (54%), and other neurological deficits (45%). All children underwent hemispherectomy (anatomical in three cases, functional in two cases, hemispherotomy in six cases); one patient needed a redo hemispherotomy. Mortality was nil; disseminated intravascular coagulation and interstitial pneumonia occurred in one patient each; three children had subdural fluid collection. Eight patients (72%) are in the ILAE Class 1 (completely seizure and aura free), two in Class 2 (only auras, no seizure), and one in Class 3 (1-3 seizure days per year). AEDs discontinuation was possible in 73% of cases. The most important news from the literature concerned the pathogenesis (role of the mutation of the GNAQ gene in the abnormal SWS vasculogenesis), the clinical findings (the features and pathogenesis of the stroke-like episodes are being understood), the diagnostic tools (quantitative MRI and EEG), and both the medical (migraine, seizures) and surgical management (epilepsy). The epileptic outcome of SWS patients is very good (80% are seizure-free), if compared with other hemispheric syndromes. The quality of life is affected by the neurological and cognitive deficits. SWS still is an etiological and clinical challenge. However, the improvements over the time are consistent. In particular, the neurosurgical treatment of refractory epilepsy provides very good results as long as the indication to treatment is correct.


Adhesion and fusion efficiencies of human immunodeficiency virus type 1 (HIV-1) surface proteins.
In about half of patients infected with HIV-1 subtype B, viral populations shift from utilizing the transmembrane protein CCR5 to CXCR4, as well as or instead of CCR5, during late stage progression of the disease. How the relative adhesion efficiency and fusion competency of the viral Env proteins relate to infection during this transition is not well understood. Using a virus-cell fusion assay and live-cell single-molecule force spectroscopy, we compare the entry competency of viral clones to tensile strengths of the individual Env-receptor bonds of Env proteins obtained from a HIV-1 infected patient prior to and during coreceptor switching. The results suggest that the genetic determinants of viral entry were predominantly enriched in the C3, HR1 and CD regions rather than V3. Env proteins can better mediate entry into cells after coreceptor switch; this effective entry capacity does not correlate with the bond strengths between viral Env and cellular receptors.


[Diagnosis of respiratory sleep disorders in newborns with suspected apneas: comparison between nocturnal saturometry and polygraphy].
Night Continuous Saturometry (CSO2) is used in Neonatal Units to detect events of hypoxemia in Newborns (NB) with apnea episodes. Polygraphy (PG) has a larger number of measuring channels. Our goal was to evaluate the diagnostic performance of CSO2 compared to Polygra phy in NB with suspected sleep apneas. Results of CSO2 and PG performed simultaneously in RN with suspected apneas were retrospectively analyzed over a three-year period. A 2-channel Masimo Radical-7® pulse oximeter and an Apnea Link Plus® polygraph with 5 simulta neous recording channels were used. Altered PG was defined as: desaturation index under 80% per hour > 1 and/or number of desaturations under 80% > 20 seconds greater than one in the whole va lidated registry and/or hypoapnea apnea index > 1 event per hour. In parallel, altered SpO2C was de fined when one or both of the 80% saturation criteria were altered. Sensitivity, specificity, predictive values and Likelihood Ratio (LLR) for CSO2 were calculated. Results were expressed in absolute value, with 95% confidence interval. Simultaneous 40 CSO2 and PG were performed; 80% (32/40) of them were preterm infants, 60% (24/40) males. 38% (15/40) of the CSO2 and 15% (6/40) of the PGs were altered (p < 0.05). CSO2 has a 100% Sensitivity, 74% Specificity, 40% VPP, 100% VPN, LLR + 3.78 and LLR-0. In the studied NB, CSO2 has a high diagnostic value, however, it may present false positives; It is suggested to use as a screening method and to perform diagnostic confirmation with another sleep test, such as PG.


Real-time fMRI for brain-computer interfacing.
Brain-computer interfaces (BCIs) based on functional magnetic resonance imaging (fMRI) provide an important complement to other noninvasive BCIs. While fMRI has several disadvantages (being nonportable, methodologically challenging, costly, and noisy), it is the only method providing high spatial resolution whole-brain coverage of brain activation. These properties allow relating mental activities to specific brain regions and networks providing a transparent scheme for BCI users to encode information and for real-time fMRI BCI systems to decode the intents of the user. Various mental activities have been used successfully in fMRI BCIs so far that can be classified into the four categories: (a) higher-order cognitive tasks (e.g., mental calculation), (b) covert language-related tasks (e.g., mental speech and mental singing), (c) imagery tasks (motor, visual, auditory, tactile, and emotion imagery), and (d) selective attention tasks (visual, auditory, and tactile attention). While the ultimate spatial and temporal resolution of fMRI BCIs is limited by the physiologic properties of the hemodynamic response, technical and analytical advances will likely lead to substantially improved fMRI BCIs in the future using, for example, decoding of imagined letter shapes at 7T as the basis for more "natural" communication BCIs.


Hyporesponsiveness to erythropoiesis-stimulating agent in non-dialysis-dependent CKD patients: The BRIGHTEN study.
Among non-dialysis-dependent chronic kidney disease (ND-CKD) patients, a low hematopoietic response to erythropoiesis-stimulating agents (ESAs) is a predictor for poor renal and cardiovascular outcome. To assess the method for evaluating hyporesponsiveness to ESA in patients with ND-CKD, a multicenter, prospective, observational study of 1,980 adult patients with ND-CKD with renal anemia was conducted. Darbepoetin alfa (DA) and iron supplement administrations were provided according to the recommendation of the attached document and the guidelines of JSDT (Japanese Society of Dialysis and Transplantation). The primary outcomes were progression of renal dysfunction and major adverse cardiovascular events. ESA responsiveness was assessed using pre-defined candidate formulae. During the mean follow-up period of 96 weeks, renal and cardiovascular disease (CVD) events occurred in 683 (39.6%) and 174 (10.1%) of 1,724 patients, respectively. Among pre-set candidate formulae, the one expressed by dividing the dose of DA by Hb level at the 12-week DA treatment was statistically significant in predicting renal (hazard ratio [HR], 1.449; 95% confidence interval [CI], 1.231-1.705; P<0.0001) and CVD events (HR, 1.719; 95% CI, 1.239-2.386; P = 0.0010). The optimum cut-off values for both events were close to 5.2. In conclusion, hyporesponsiveness to ESA in ND-CKD cases, which is associated with a risk for renal and CVD events, may be evaluated practicably as the dose of DA divided by the Hb level at the 12-week DA treatment, and the cut-off value of this index is 5.2. A search for the causes of poor response and measures for them should be recommended in such patients. Trial registration: ClinicalTrials. gov Identifier: NCT02136563; UMIN Clinical Trial Registry Identifier: UMIN000013464.


Pulmonary function in chronic renal failure: effects of dialysis and transplantation.
Many possible pulmonary complications of renal disease have been described, but little is known of their physiological importance or the effects on them of different forms of renal replacement therapy. Four groups were recruited, each containing 20 patients. The groups consisted of patients with chronic renal failure before dialysis (group 1); patients receiving continuous ambulatory peritoneal dialysis, never having received a transplant (group 2); patients receiving haemodialysis, never having received a transplant (group 3); and patients after their first successful cadaveric renal transplant (group 4). All were attending the same regional dialysis and transplant unit. None was known to have clinically important lung or chest wall disease. Flow-volume loops were recorded before and after 400 micrograms of salbutamol, and plethysmographic lung volumes and airway conductance and single breath carbon monoxide transfer factor were measured. Only nine of 80 patients had normal lung function. The reductions in spirometric values were minor. Whole lung carbon monoxide transfer factor was reduced in all groups (mean % predicted with 95% confidence intervals: group 1 81.7% (74-89%); group 2 69.7% (62-77%); group 3 87.5% (80-96%); group 4 82.5% (78-87%]. The values were significantly lower in those having continuous ambulatory peritoneal dialysis (group 2). Residual volume was reduced significantly in the group who had undergone renal transplantation (85.7%, 77-94%). There was no correlation between these changes and smoking habit, age, duration or severity of renal failure, duration of treatment, or biochemical derangement. It is concluded that abnormal lung function is common in renal disease. The main change is a reduction in carbon monoxide transfer that persists after transplantation. The likeliest explanation is that subclinical pulmonary oedema progresses to fibrosis before transplantation. The fibrosis may worsen further to cause the reduced residual volume in the recipients of grafts.


Is newborn imitation developmentally homologous to later social-cognitive skills?
To assess claims about developmental homologies, or devologies, longitudinal data are needed. Here, we illustrate this with the debate about the purported foundational role of neonatal imitation in children's social and cognitive development. Cross-sectional studies over the past 35 years have clarified neither the prevalence of imitation in newborns nor its relationships to later developing skills. Thus, scholars have been able to maintain diametrically opposing explanations of neonatal imitation in the literature. Here, we discuss this issue and outline how large-scale longitudinal approaches promise to resolve such debates and have the potential to use individual difference measures to uncover links to later development.


Immunogenicity and protective efficacy of mucosal delivery of recombinant hcp of Campylobacter jejuni Type VI secretion system (T6SS) in chickens.
The type VI secretion system (T6SS) has recently emerged as a new pattern of protein secretions in Campylobacter jejuni (C. jejuni). Within the T6SS cluster, hemolysin co-regulated protein (hcp) is considered as a hallmark of functional T6SS and holds key role in bacterial virulence. As poultry is the primary reservoir of C. jejuni and the major sources for human infection, we evaluated the capacity of recombinant hcp (rhcp) immunization in blocking C. jejuni colonization in chickens with an aim to control bacterial transmission to humans via poultry food chain. Considering the mucosal route is the primary portal for C. jejuni entry and gut mucosa offers the apposite site for C. jejuni adherence, we investigated the immune-protective potential of intra-gastric administration of rhcp using chitosan-based nanoparticles. To achieve this goal, full length coding sequence of hcp gene from C. jejuni was cloned and expressed in E. coli. Purified rhcp was entrapped in chitosan-Sodium tripolyphosphate nanoparticles (CS-TPP NPs) and orally gavaged in chickens. Our results suggest that intra-gastric immunization of CS-TPP-rhcp induces consistent and steady increase in intestinal (sIgA) and systemic antibody (IgY) response against rhcp with significant reduction in cecal load of C. jejuni. The protection afforded by rhcp associated cellular responses with Th1 and Th17 profile in terms of increased expression of NFkB, IL-1β, IL-8, IL-6, IFN-γ and IL-17 A genes. Though systemic immunization of rhcp with IFA resulting in a robust systemic (IgY) and local (sIgA) antibody response, mucosal administration of rhcp loaded CS-TPP NPs was found to be superior in terms of bacterial clearance. Altogether, present study suggests that chitosan based intra-gastric delivery of rhcp have several advantages over the injectable composition and could be a promising vaccine approach to effectively control C. jejuni colonization in chickens.


The challenges experienced by Iranian war veterans living with chemical warfare poisoning: a descriptive, exploratory study.
This exploratory, descriptive study investigates the experiences of Iranian war veterans living with chronic disease acquired as a result of chemical warfare. Sulphur mustard (SM) is considered one of the most important agents of chemical warfare and was widely used during the Iran-Iraq conflict in 1980-1988. There are approximately 100 000 Iranian SM casualties who suffer from serious long-term progressive health problems involving their respiratory organs, eyes and skin. Seventeen male Iranian war veterans aged between 30 and 59 years and four victims' family members participated in the study. Data was generated during individual in-depth interviews that used open-ended questions. Grounded theory techniques, including the constant comparative method of concurrent data generation and analysis, were employed in the analysis of data. Preliminary results indicate two main thematic categories: social isolation and physical disability. It is argued that a lack of knowledge about the outcomes of SM poisoning, physical restrictions and difficulty in adjusting socially decreases war veterans' functional capacity and levels of independence.


What passive euthanasia is.
Euthanasia can be thought of as being either active or passive; but the precise definition of "passive euthanasia" is not always clear. Though all passive euthanasia involves the withholding of life-sustaining treatment, there would appear to be some disagreement about whether all such withholding should be seen as passive euthanasia. At the core of the disagreement is the question of the importance of an intention to bring about death: must one intend to bring about the death of the patient in order for withholding treatment to count as passive euthanasia, as some sources would indicate, or does withholding in which death is merely foreseen belong to that category? We may expect that this unclarity would be important in medical practice, in law, and in policy. The idea that withholding life-sustaining treatment is passive euthanasia is traced to James Rachels's arguments, which lend themselves to the claim that passive euthanasia does not require intention to end life. Yet the argument here is that Rachels's arguments are flawed, and we have good reasons to think that intention is important in understanding the moral nature of actions. As such, we should reject any understanding of passive euthanasia that does not pay attention to intent. James Rachels's work on active and passive euthanasia has been immensely influential; but this is an influence that we ought to resist.


Enhancement of immunologic tumor regression by intratumoral administration of dendritic cells in combination with cryoablative tumor pretreatment and Bacillus Calmette-Guerin cell wall skeleton stimulation.
We developed an effective immunotherapy, which could induce antitumor immune responses against shared and unique tumor antigens expressed in autologous tumors. Intratumoral administration of dendritic cells is one of the individualized immunotherapies; however, the antitumor activity is relatively weak. In this study, we attempted to enhance the antitumor efficacy of the i.t. dendritic cell administration by combining dendritic cells stimulated with Bacillus Calmette-Guerin cell wall skeleton (BCG-CWS) additionally with cryoablative pretreatment of tumors and analyzed the therapeutic mechanisms. These two modifications (cryoablation of tumors and BCG-CWS stimulation of dendritic cells) significantly increases the antitumor effect on both the treated tumor and the untreated tumor, which was distant at the opposite side, in a bilateral s.c. murine CT26 colon cancer model. Further analysis of the augmented antitumor effects revealed that the cryoablative pretreatment enhances the uptake of tumor antigens by the introduced dendritic cells, resulting in the induction of tumor-specific CD8(+) T cells responsible for the in vivo tumor regression of both treated and remote untreated tumors. This novel combination i.t. dendritic cell immunotherapy was effective against well-established large tumors. The antitumor efficacy was further enhanced by depletion of CD4(+)CD25(+)FoxP3(+) regulatory T cells. This novel dendritic cell immunotherapy with i.t. administration of BCG-CWS-treated dendritic cells following tumor cryoablation could be used for the therapy of cancer patients with multiple metastases.


Effects of Combined Epidermal Growth Factor and Gastrin on PDX1 Expression in Experimental Type 1 Diabetic Rats.
INTRODUCTION:: The aim of this study was to investigate whether combined epidermal growth factor (EGF) and gastrin can correct the hyperglycemia induced by streptozotocin (STZ) in rats and to determine the involvement of the transcription factor pancreatic and duodenal homeobox 1 (PDX1) in this process. METHODS:: Rat diabetes was induced by intraperitoneal injection of STZ. The mRNA and protein levels of insulin and PDX1 were determined by real-time reverse transcriptase polymerase chain reaction and immunohistochemistry. Serum levels of C-peptide and insulin were analyzed using radioimmunoassay kits. RESULTS:: The combined administration of EGF and gastrin efficiently reversed the hyperglycemia induced by STZ. Elevated insulin concentration was detected in diabetic rats treated with EGF plus gastrin. The authors also found that both insulin and PDX1 expression were reduced in STZ-treated rats. Interestingly, the combination treatment also significantly enhanced the mRNA levels of insulin and PDX1, and that of their protein products. CONCLUSIONS:: Therapy with EGF plus gastrin corrected hyperglycemia and maintained insulin content in STZ-induced diabetic rats via up-regulation of PDX1 expression, suggesting that this combination treatment may provide a valuable approach for pancreatic islet neogenesis in vivo.


Polio eradication efforts in regions of geopolitical strife: the Boko Haram threat to efforts in sub-Saharan Africa.
The World Health Organization aims to eradicate wild poliovirus worldwide by the end of 2018. Cameroon and Nigeria, neighboring countries, have been affected by the terrorist and militant activities of the Islamist sect Boko Haram. Impacted regions are mainly the far North of Cameroon and Northern Nigeria. Targets of Boko Haram aggression in these zones include violence against polio workers, disruption of polio immunization campaigns, with consequent reduced access to health care and immunization. In addition to this significant problem, Northern Nigeria has historically seen rejection of polio virus vaccine initiatives. It remains to know how health systems can continue operations against polio in areas where Boko Haram operates. If appropriate measures are not urgently taken, it will be not possible to meet the 2018 goal of polio virus eradication. The response should include specialized immunization activities in conflict zones, will engagement of leaders. Countries should also explore immunization activities by soldiers and military personnel.


Blood group antigens in transitional cell tumours of the urinary bladder. An immunohistochemical study.
Patients presenting histologically identical non-invasive tumours of the urinary bladder suffer a variable unpredictable clinical course, making the identification of prognostic markers relevant in the clinical setting. Recent histochemical studies have demonstrated that changes in cell surface carbohydrates during malignant transformation involve the blood group antigens. These oligosaccharides, initially defined on erythrocytes, are widely distributed in human tissue including human urothelium. This study was conducted in order to evaluate the prognostic value of blood group antigen determination in superficial bladder cancer. The aims of the present study were: 1. To standardize the immunohistochemical staining technique for blood group antigens, 2. To investigate the pattern of blood group antigen expression in non-neoplastic urothelium, the genetic heterogeneity, 3. To examine changes in the blood group antigen expression in bladder cancer, and 4. to assess the prognostic value of blood group antigen expression in superficial bladder cancers of morphological similar appearance. The ABH, Lewis, and Thomsen-Friedenreich (T) blood group antigens were studied by means of the Tween 20-modified indirect immunoperoxidase staining technique. Serial dilutions of antibodies and lectins were applied on dewaxed routinely processed tissue sections of normal ureters and transitional cell tumours. The reciprocal value of the highest dilution of antibody and lectin still giving staining defined the endpoint titer and allowed semiquantitative estimation of antigen content. In non-neoplastic urothelium the ABH, Lewis and T blood group antigens were heterogeneously expressed, and the expression correlated to the Lewis blood type. This indicates 1) a genetic regulated synthesis of ABH and Lewis blood group antigens similar to that operating in saliva, other secretions, epithelia, and erythrocytes, 2) a possible linkage between ABH-, Lewis-, and T antigen systems, if steric hindrance can be excluded. Based on the above findings in non-neoplastic urothelium the deviation in tumours from normal blood group antigen expression was quantified on a scale from 0 (normal) to 3 (total loss) for each antigen system separately. All scores were related to histological stage and grade suggesting a parallelism between morphological dedifferentiation and the degree of abnormal blood group expression. In superficial low grade tumours only A and Lewis a scores were related to prognosis. This held only true for patients with tumours of normal or nearly normal A and Lewis a antigen expression (scores 0 and 1), who had a favorable course as regards invasive recurrence and/or papillomatosis within 5 years. Prediction of an unfavorable outcome was not possible. Only a small number of superficial tumours exhibited normal blood group antigen expression.(ABSTRACT TRUNCATED AT 400 WORDS)


Definition of the initial immunologic modifications upon in vitro gliadin challenge in the small intestine of celiac patients.
Mucosal cell-mediated immune response is considered the central event in the pathogenesis of celiac disease. In cultured intestinal explants from celiacs in remission, we have characterized the early stages of gliadin-induced immune activation. Intestinal biopsy specimens (15 treated celiacs and 13 controls) were cultured with gliadin or maize prolamine digests for 24 hours as well as for 1, 2, 4, 6, 8, and 12 hours in some subjects. The expression of immunologic markers was detected by immunocytochemistry. Gliadin challenge may initiate two parallel pathways, one of which leads to T-cell activation and another that precedes it. Epithelial cells overexpress DR molecules after 1 hour, and in a second stage T lymphocytes become fully activated. Moreover, T lymphocytes migrate in the upper mucosal layers. T lymphocytes that migrate in the higher lamina propria compartments are mainly CD4+ and show markers of activation; migrating intraepithelial lymphocytes are CD8+ and do not express these markers. In vitro gliadin challenge is a suitable model to reproduce various immunologic features of celiac lesions; these may be caused by different pathways. The comprehension of these phenomena is essential to clarify the distinctive pathogenic mechanisms leading to disease and may help in defining novel therapeutic approaches.


Tissue recovery practices and bioburden: a systematic review.
For successful transplantation, allografts should be free of microorganisms that may cause harm to the allograft recipient. Before or during recovery and subsequent processing, tissues can become contaminated. Effective tissue recovery methods, such as minimizing recovery times (<24 h after death) and the number of experienced personnel performing recovery, are examples of factors that can affect the rate of tissue contamination at recovery. Additional factors, such as minimizing the time after asystole to recovery and the total time it takes to perform recovery, the type of recovery site, the efficacy of the skin prep performed immediately prior to recovery of tissue, and certain technical recovery procedures may also result in control of the rate of contamination. Due to the heterogeneity of reported recovery practices and experiences, it cannot be concluded if the use of other barriers and/or hygienic precautions to avoid contamination have had an effect on bioburden detected after tissue recovery. Qualified studies are lacking which indicates a need exists for evidence-based data to support methods that reduce or control bioburden.


The Integrated and Disability Health Program of AUSL Bologna. The Alstom experience for employment access in high functioning autism spectrum disorders.
The Integrated and Disability Health Program (IDHP) of Bologna deals with the assessment and treatment of both young and adults with high and low functioning autism spectrum disorder (ASD). The IDHP and Alstom Ferroviaria SPA started a highly innovative project for the employment of young adults diagnosed with high functioning ASD. The project consisted of a six months' internship, for a total amount of 560 hours, and a renewal for another 6 months and involved a group of 5 young adults with high-functioning ASD, aged between 18 and 42 years, coming from Bologna or the suburbs. During the internship, a job coach trained in autism spectrum disorders was provided by IDHP. The intervention was based on Behavioral Skills Training (BST). As a result, the following advantages of BST model were found: very effective in small group; learning occurred by observation and modelling, feedback was received by the trainer and other group members.


[Effects of mental adaptation on vegetative, hormonal and sensory reactions in preoperative period].
Fifty-seven urological patients whose emotional behavioral reactions were characterized by somatic anxiety caused by mental adaptation were examined under conditions of preoperative emotional stress. On day 5 after admission to hospital the hormonal, autonomic, and sensory responses decreased in patients with previously manifest anxiety, which was due to decrease of anxiety because of appearance of some psychopathological features. Satisfactory hormonal, autonomic, and mental adaptation was observed on day 5 after admission to hospital in patients with moderately expressed anxiety. In patients with previously predominating parasympatotonia and a low level of anxiety, the hormonal and autonomic areactivity and mental adaptation observed in the same terms were due to augmenting psychopathological features.


Ankyrins: Roles in synaptic biology and pathology.
Ankyrins are broadly expressed adaptors that organize diverse membrane proteins into specialized domains and link them to the sub-membranous cytoskeleton. In neurons, ankyrins are known to have essential roles in organizing the axon initial segment and nodes of Ranvier. However, recent studies have revealed novel functions for ankyrins at synapses, where they organize and stabilize neurotransmitter receptors, modulate dendritic spine morphology and control adhesion to the presynaptic site. Ankyrin genes have also been highly associated with a range of neurodevelopmental and psychiatric diseases, including bipolar disorder, schizophrenia and autism, which all demonstrate overlap in their genetics, mechanisms and phenotypes. This review discusses the novel synaptic functions of ankyrin proteins in neurons, and places these exciting findings in the context of ANK genes as key neuropsychiatric disorder risk-factors.


Splenomegaly in dogs. Predictors of neoplasia and survival after splenectomy.
Splenomegaly confirmed by surgery or necropsy in 100 dogs was diagnosed histologically as benign neoplasia (n = 1), primary splenic malignancy (n = 59), neoplastic metastases (n = 6), and nonneoplastic disease (n = 34). Dogs with known systemic disease, such as lymphoma and mast cell tumor, that caused splenomegaly were not included in the study. Hemangiosarcoma was the most common splenic disease (43 cases). Overall mean age of the dogs was 10.7 years, the most common breed was German Shepherd dog, and 72 of the dogs weighed more than 21 kg. Dogs with anemia, nucleated red blood cells, abnormal red blood cell morphology, or splenic rupture had a significantly greater chance of having splenic neoplasia (P less than 0.002). A multivariable logistic regression analysis found that the presence of anemia and splenic rupture in dogs with splenomegaly was up to 69% accurate in predicting presence of splenic neoplasia. After splenectomy, the median survival time of dogs with splenic neoplasia was 13 weeks. For dogs with nonneoplastic splenomegaly it was at least 36 weeks.


TTD: Therapeutic Target Database describing target druggability information.
Target discovery is one of the essential steps in modern drug development, and the identification of promising targets is fundamental for developing first-in-class drug. A variety of methods have emerged for target assessment based on druggability analysis, which refers to the likelihood of a target being effectively modulated by drug-like agents. In the therapeutic target database (TTD), nine categories of established druggability characteristics were thus collected for 426 successful, 1014 clinical trial, 212 preclinical/patented, and 1479 literature-reported targets via systematic review. These characteristic categories were classified into three distinct perspectives: molecular interaction/regulation, human system profile and cell-based expression variation. With the rapid progression of technology and concerted effort in drug discovery, TTD and other databases were highly expected to facilitate the explorations of druggability characteristics for the discovery and validation of innovative drug target. TTD is now freely accessible at: https://idrblab.org/ttd/.


[Prevalence of vitamin D deficiency and its correlation with PTH, biochemical bone turnover markers and bone mineral density, among patients from ambulatories].
Consequences of VD deficiency include rickets and osteomalacia. However, marginal concentrations of 25-hydroxyvitamin D (25(OH)VD) are associated with secondary hyperparathyroidism and osteoporosis. In this context, levels of 25(OH)VD capable to elevate parathyroid hormone (PTH) could be considered as insufficient. The VD insufficiency, although widely prevalent, is still under-recognized and under-treated. The authors have studied 180 patients followed in a endocrinology clinic in Belo Horizonte, who had 25(OH)VD measured, correlating it with PTH, biochemical bone turnover markers and bone mineral density. To determine the sufficiency of VD, 25(OH)VD was correlated with PTH and the cutoff found was of 32ng/ml. CTX-1 and PTH were significantly negative correlated to 25(OH)VD and the prevalence of VD insufficiency was 42%. One concludes that the VD insufficiency is widely prevalent among patients who frequently come to our offices, alerting us for the importance to assess VD status more often and to practice politics for prevention of VD insufficiency.


[Biochemical studies in the postmortem diagnosis of the disseminated intravascular coagulation syndrome].
Sulfite-alkaline method after Rampling and Gaffney is proposed for measuring fibrinogen and fibrin degradation products in cadaveric blood. Normal values for cadaveric blood are determined and qualitative paracoagulation tests proposed. Such biochemical studies can be used, along with histological, for more accurate postmortem diagnosis of the DIC syndrome.


MLST reveals potentially high-risk international clones of Enterobacter cloacae.
To perform the first multinational Enterobacter cloacae clonality study, using the MLST scheme newly developed in Japan. The analysis included 195 rectal carriage E. cloacae isolates resistant to expanded-spectrum cephalosporins (ESCs), collected from patients in 12 hospital units across Europe and Israel. All of the isolates were typed by PFGE and 173 isolates were subjected to MLST. ESC resistance was analysed phenotypically; genes encoding ESBLs and carbapenemases were identified by PCR and sequencing. MLST distinguished 88 STs, which correlated with the PFGE data. PFGE was more discriminatory, producing 129 pulsotypes (169 patterns). Numerous STs were observed in several countries each. The most widespread were ST66, ST78, ST108 and ST114, each having at least 10 isolates from three to five countries, diversified into multiple pulsotypes, with clusters of related isolates in one or more centres. Analysis of the STs against the MLST database revealed several epidemic clonal complexes, such as those with central genotypes ST74 (including ST78) or ST114 (including ST66). ESC resistance was equally related to overexpression of the AmpC cephalosporinase and to ESBL production. Among ESBL producers some spreading subclones were identified, including specific ST66, ST78 and ST114 pulsotypes, associated with CTX-M-15 production. Several isolates produced carbapenemase VIM-1 or KPC-2. Together with the information available in the MLST database, our results suggest that, like Escherichia coli and Klebsiella pneumoniae, E. cloacae harbours clonal lineages of increased epidemic potential that may be associated with resistance spread.


Corneal grafting for the treatment of feline corneal sequestrum: a retrospective study of 18 eyes (13 cats).
To determine the clinical outcome of corneal grafting for the treatment of feline corneal sequestrum (FCS). Domestic cats. A review of the medical records of cats that underwent keratoplasty as a treatment of FCS at the VTH-UAB, from 2002 to 2012, was carried out. Thirteen cats (18 eyes) of different breed, age, and gender were included. Persian cats were overrepresented (12/13;92%). There were nine males and four females, of a mean age of 3.4 years (0.7-7.1). Ipsilateral chronic corneal ulceration was reported as the most common concurrent ocular disease (6/18;33%). Keratoplasty was performed bilaterally in 5 cats (5/13;38%) and unilaterally in 8 (8/13;62%). Lamellar keratoplasty was performed in 17 eyes (17/18;95%) and full-thickness keratoplasty in 1 (1/18;5%). Mean graft size was 8.3 mm (4-11.5). Fresh homologous graft was performed in 2 eyes (2/18;11%) and frozen graft in 16 (16/18;89%). Of the latter group, homologous graft was performed in 6 eyes (6/16;37.5%) and heterologous in 10 (10/16;62.5%). In all the cats, postoperative treatment included topical antibiotics, corticosteroids, cycloplegics, and 0.2% cyclosporine A. Median follow-up time was 18.2 months, and main postoperative complications were diffuse mild epithelial pigment formation (2/18;11%), graft malacia (1/18;5%), and sequestrum recurrence (1/18;5%). Mean epithelial healing time was 19.2 days. Good visual outcome was achieved in all the eyes (100%), the majority of them having faint or mild corneal opacity (15/18;83%). Keratoplasty is an effective surgical treatment for FCS. The donor tissue provides excellent tectonic support to the affected corneas, with good visual and cosmetic outcome.


Loss of Intercalated Cells (ITCs) in the Mouse Amygdala of Tshz1 Mutants Correlates with Fear, Depression, and Social Interaction Phenotypes.
The intercalated cells (ITCs) of the amygdala have been shown to be critical regulatory components of amygdalar circuits, which control appropriate fear responses. Despite this, the molecular processes guiding ITC development remain poorly understood. Here we establish the zinc finger transcription factor Tshz1 as a marker of ITCs during their migration from the dorsal lateral ganglionic eminence through maturity. Using germline and conditional knock-out (cKO) mouse models, we show that Tshz1 is required for the proper migration and differentiation of ITCs. In the absence of Tshz1, migrating ITC precursors fail to settle in their stereotypical locations encapsulating the lateral amygdala and BLA. Furthermore, they display reductions in the ITC marker Foxp2 and ectopic persistence of the dorsal lateral ganglionic eminence marker Sp8. Tshz1 mutant ITCs show increased cell death at postnatal time points, leading to a dramatic reduction by 3 weeks of age. In line with this, Foxp2-null mutants also show a loss of ITCs at postnatal time points, suggesting that Foxp2 may function downstream of Tshz1 in the maintenance of ITCs. Behavioral analysis of male Tshz1 cKOs revealed defects in fear extinction as well as an increase in floating during the forced swim test, indicative of a depression-like phenotype. Moreover, Tshz1 cKOs display significantly impaired social interaction (i.e., increased passivity) regardless of partner genetics. Together, these results suggest that Tshz1 plays a critical role in the development of ITCs and that fear, depression-like and social behavioral deficits arise in their absence.SIGNIFICANCE STATEMENT We show here that the zinc finger transcription factor Tshz1 is expressed during development of the intercalated cells (ITCs) within the mouse amygdala. These neurons have previously been shown to play a crucial role in fear extinction. Tshz1 mouse mutants exhibit severely reduced numbers of ITCs as a result of abnormal migration, differentiation, and survival of these neurons. Furthermore, the loss of ITCs in mouse Tshz1 mutants correlates well with defects in fear extinction as well as the appearance of depression-like and abnormal social interaction behaviors reminiscent of depressive disorders observed in human patients with distal 18q deletions, including the Tshz1 locus.


Localization of glyoxylate-cycle marker enzymes in peroxisomes of senescent leaves and green cotyledons.
Crude particulate homogenates from leaves of barley (Hordeum vulgare L.), rice (Oryza sativa L.), leaf-beet (Beta vulgaris var. cicla L.) and pumpkin (Cucurbita pepo L.) cotyledons were separated on sucrose density gradients. The peroxisomal fractions appeared at a buoyant density of 1.25 g·cm(-3) and contained most of the activities of catalase (EC 220.127.116.11), and hydroxypyruvate reductase (EC 188.8.131.52) on the gradients. In peroxisomal fractions from detached leaves and green cotyledons incubated in permanent darkness we detected the presence of isocitrate lyase (EC 126.96.36.199) and malate synthase (EC 184.108.40.206), key enzymes of the glyoxylate cycle, and β-oxidation activity (except in pumpkin). As proposed by H. Gut and P. Matile (1988, Planta 176, 548-550) the glyoxylate cycle may be functional during leaf senescence, and the presence of two key enzymes indicates a transition from leaf peroxisome to glyoxysome; for pumpkin cotyledons in particular a double transition occurs (glyoxysome to leaf peroxisome during greening, and leaf peroxisome to glyoxysome during senescence).


Equivalence of Chinese version of the Cohen-Mansfield Agitation Inventory.
This paper is a report of a study undertaken to translate the Cohen-Mansfield Agitation Inventory from the original English into a Chinese language version and to establish the content, semantic and technical equivalence of the Chinese version. Ensuring the equivalence of a translated Chinese version of the Cohen-Mansfield Agitation Inventory for patients with dementia is an essential requirement for identifying culturally specific expressions of agitated behaviours. In Phase I, five experts scrutinized the Inventory items to determine whether the behaviour described was relevant to the agitated behaviours present in the Taiwanese culture. In Phase II, experts did the initial translation into Chinese and then back-translated it into English. Four bilingual observers rated 31 residents with dementia to determine semantic equivalence across versions. In Phase III, the agitated behaviours of 32 residents were assessed by four observers using staff ratings and direct observation to determine the technical equivalence of the Chinese version. The study was carried out in Taiwan from August 2004 to April 2005. In Phase I, the rating of behaviours described on the Cohen-Mansfield Agitation Inventory was relevant to the agitated behaviours based on Taiwanese culture with a content validity index (CVI) value of 0.993. In Phase II, intra-class coefficients for all items on the Chinese version and split-halves of Chinese and English versions ranged from 0.69 to 0.74. In Phase III, six possible results for estimation of reliability across methods and raters for the Chinese version ranged from 0.63 to 0.86. The Chinese Cohen-Mansfield Agitation Inventory had modest psychometric properties. Further studies are needed to assess criterion and conceptual equivalence.


Characteristics of and risk factors for intervertebral disk extrusions in Pekingese.
OBJECTIVE To characterize and identify risk factors for intervertebral disk extrusion (IVDE) in Pekingese. DESIGN Retrospective case-control study. ANIMALS 426 Pekingese (81 with confirmed IVDE and 345 without IVDE) admitted to a veterinary teaching hospital from 2005 through 2015. PROCEDURES Medical records were reviewed and data were extracted regarding age, sex, body weight, body condition score, coat color, chief reason for initial evaluation, body system involved, and diagnosis. Survey radiographs of the vertebral column were examined. Data were compared between the confirmed IVDE and non-IVDE groups. RESULTS Confirmed IVDE was uncommon in dogs < 2 years of age (2/81 [2%]). The extrusion was primarily located in the thoracolumbar (n = 57 [70%]) and cervical (22 [27%]) regions; the most common sites were T12-13 and C6-7. The number of radiographically visible calcified disks was significantly greater in the confirmed IVDE versus non-IVDE group, and the presence of calcified disks in the T10-L4 region was associated with increased odds of IVDE (OR, 21.2). Black coat color was significantly more prevalent in the confirmed IVDE versus non-IVDE group and was associated with increased odds of developing IVDE (OR, 1.6). Mean body weight and the proportion of spayed female dogs were significantly greater in the confirmed IVDE versus non-IVDE group. CONCLUSIONS AND CLINICAL RELEVANCE Several risk factors for confirmed IVDE in Pekingese were identified that could be useful for counseling clients about the disease or, with additional research, designing selective breeding programs to reduce the prevalence of IVDE in the breed.


Estradiol and COVID-19: Does 17-Estradiol Have an Immune-Protective Function in Women Against Coronavirus?
Objective: Female sex hormones have a pro-inflammatory effect, which may help to minimize inflammation. Estrogen's immunoregulatory properties play a significant role in the bi-directional neuroendocrine-immune activity in females. As a result, sex hormones can play a role in men's high mortality rate from coronavirus-2019 (COVID-19). It is aimed to clarify the role of 17-estradiol (E2) in the battle against COVID-19. Materials and methods: Until April 2021, a study on PubMed was performed. COVID-19, 17-estradiol (E2), immunoregulatory properties, pregnancy, menopausal symptoms, hormonal therapy, ER/ expression on immune cells, and mortality were some of the concepts used in the search. Results: Regulation of pro-inflammatory immune processes against COVID-19 appears to be associated with increased immune function (pro-inflammatory), anti-inflammatory regulation, and antiviral defense. Women with a severe coronavirus infection had higher serum IgG antibody levels than men, and their IgG production was faster in the early stages of infection. 17-estradiol (E2) levels of blood will increase by 100-fold during pregnancy. COVID-19 in pregnant women had a 15-fold lower mortality rate than other women. While menopause replacement therapy (MRT) for pre/post-menopausal women and its effectiveness in reducing COVID-19 infection is debatable. Conclusion: MRT may be considered as a viable treatment option for pre/post-menopause women with coronavirus, referring to the fact that sex hormones reduce inflammatory responses and modulate ACE2 expression. The task's difficulty and achieving the desired outcome seem to be challenging.


Estimation of life's essential 8 score with incomplete data of individual metrics.
The American Heart Association's Life's Essential 8 (LE8) is an updated construct of cardiovascular health (CVH), including blood pressure, lipids, glucose, body mass index, nicotine exposure, diet, physical activity, and sleep health. It is challenging to simultaneously measure all eight metrics at multiple time points in most research and clinical settings, hindering the use of LE8 to assess individuals' overall CVH trajectories over time. We obtained data from 5,588 participants in the Nurses' Health Studies (NHS, NHSII) and Health Professionaĺs Follow-up Study (HPFS), and 27,194 participants in the 2005-2016 National Health and Nutrition Examination Survey (NHANES) with all eight metrics available. Individuals' overall cardiovascular health (CVH) was determined by LE8 score (0-100). CVH-related factors that are routinely collected in many settings (i.e., demographics, BMI, smoking, hypertension, hypercholesterolemia, and diabetes) were included as predictors in the base models of LE8 score, and subsequent models further included less frequently measured factors (i.e., physical activity, diet, blood pressure, and sleep health). Gradient boosting decision trees were trained with hyper-parameters tuned by cross-validations. The base models trained using NHS, NHSII, and HPFS had validated root mean squared errors (RMSEs) of 8.06 (internal) and 16.72 (external). Models with additional predictors further improved performance. Consistent results were observed in models trained using NHANES. The predicted CVH scores can generate consistent effect estimates in associational studies as the observed CVH scores. CVH-related factors routinely measured in many settings can be used to accurately estimate individuals' overall CVH when LE8 metrics are incomplete.


Coactivating signals for the hepatic lymphocyte gamma interferon response to Francisella tularensis.
The facultative intracellular bacterium Francisella tularensis is capable of causing systemic infections in various hosts, including mice and humans. The liver is a major secondary site of F. tularensis infection, but hepatic immune responses to the pathogen remain poorly defined. Immune protection against the pathogen is thought to depend on the cytokine gamma interferon (IFN-gamma), but the cellular basis for this response has not been characterized. Here we report that natural killer cells from the livers of naïve uninfected mice produced IFN-gamma when challenged with live bacteria in vitro and that the responses were greatly increased by coactivation of the cells with either recombinant interleukin-12 (IL-12) or IL-18. Moreover, the two cytokines had strong synergistic effects on IFN-gamma induction. Neutralizing antibodies to either IL-12 or IL-18 inhibited IFN-gamma production in vitro, and mice deficient in the p35 subunit of IL-12 failed to show IFN-gamma responses to bacterial challenge either in vitro or in vivo. Clinical isolates of highly virulent type A Francisella tularensis subsp. tularensis organisms were comparable to the live attenuated vaccine strain of Francisella tularensis subsp. holarctica in their ability to induce IL-12 and IFN-gamma expression. These findings demonstrate that cells capable of mounting IFN-gamma responses to F. tularensis are resident within the livers of uninfected mice and depend on coactivation by IL-12 and IL-18 for optimum responses.


Better prognostic determination and feature characterization of cutaneous melanoma through integrative genomic analysis.
Melanoma is the most dangerous type of skin cancer and has highly heterogeneous features. Despite progress in melanoma classification, interpatient heterogeneity remains difficult to predict, especially in terms of long-term survival. Here, based on mRNA-seq, miRNA-seq and DNA methylation data from 447 cutaneous melanoma patients in the Cancer Genome Atlas, we performed integrative and single-dataset clustering analyses. A novel group of patients was identified, including 301 with better, 55 with poorer and 91 with intermediate prognoses. Immune genes were upregulated in the better prognostic group, and higher immune scores (representing a greater extent of immune cell infiltration into tumor tissues) were associated with better prognoses. Higher expression of 115 genes was determined to predict better outcomes. The better prognostic group also exhibited DNA hypomethylation, and immune pathways were enriched among the hypomethylated genes. Using exome-seq data from the same patients, we observed that the better prognostic group harbored the highest number of mutations. The mutational signature in the better prognostic group was associated with ultraviolet light exposure. These integrated investigations have potential therapeutic significance, as they clarify the molecular heterogeneity of cutaneous melanoma and enhance its classification.


Genetic markers of cholesterol transport and gray matter diffusion: a preliminary study of the CETP I405V polymorphism.
Variations of the cholesteryl ester transfer protein polymorphism (CETP I405V/rs5882) have been associated with an increased risk for neurodegeneration, particularly when examined in conjunction with the epsilon 4 isoform of apolipoprotein E (ApoE4). Despite these identified relationships, the impact of I405V on gray matter microstructure remains unknown. The present study examined the impact of the CETP I405V polymorphism on gray matter integrity among 52 healthy adults between ages 51 and 85. Gray matter was measured bilaterally using diffusion tensor imaging (DTI) metrics of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). Participants were grouped according to a dominant statistical model (II genotype vs. IV/VV genotypes) and secondary analyses were completed to examine the interactive effects of CETP and ApoE4 on DTI metrics. Compared to individuals with the IV/VV genotypes, II homozygotes demonstrated significantly higher MD in bilateral temporal, parietal, and occipital gray matter. Secondary analyses revealed higher FA and AD in the left temporal lobe of IV/VV genotypes with an ApoE4 allele. Our results provide preliminary evidence that CETP II homozygosity is a predisposing risk factor for gray matter abnormalities in posterior brain regions in healthy older adults, independent of an ApoE4 allele.


Epithelial properties of human colonic carcinoma cell line Caco-2: effect of secretagogues.
Human colonic carcinoma Caco-2 cells grown in vitro form epithelial layers of highly polarized cells. Unlike colonic adsorptive cells they possess a mucosal membrane with very limited ionic conductance, even after exposure to aldosterone. When grown on filters, Caco-2 cells were sensitive to various secretagogues; these included 10(-5) M dibutyryl adenosine 3',5'-cyclic monophosphate (DBcAMP) and 10(-10) M vasoactive intestinal peptide, both of which, added serosally, enhanced the short-circuit current. The same applied to mucosal forskolin. Caco-2 cell sensitivity to serosal epinephrine was lower. Ion substitutions and 22Na-36Cl flux measurements indicated the possibility of secretagogue-dependent chloride secretion. Measurements on cells grown on Petri dishes and exposed to 1 mM DBcAMP for 1 h enabled detection of more profound modifications. Sustained 20-mV cell depolarization and a large reduction in the relative electrical resistance of the mucosal membrane were concomitant with a sizable decrease in 36Cl accumulation. These results suggest that Caco-2 cells, which to some extent resemble colonic crypt cells, possess the cAMP-dependent mucosal chloride conductance characteristic of secretory cells.


Making Coaxial Wires Out of Janus Dendrimers for Efficient Charge Transport.
Highly conductive coaxial supramolecular wires are prepared by using a new family of Janus dendrimers that combines two rigid aromatic parts and two flexible aliphatic parts. The two external regions consist of a promesogenic block based on a third generation Percec-type dendron with four terminal dodecyloxy alkyl chains, whereas the two internal regions are formed by one, two, or three carbazole units bearing flexible spacers. These functional Janus dendrimers self-organize in columnar liquid crystal phases with a strong coaxial segregation within each column. Interestingly, the charge mobility studies revealed that these Janus dendrimers display semiconductor properties with hole mobility values up to 0.5 cm2 V-1 s-1, depending on the packing within the columns which can be tuned by the number of carbazole functional units. The high hole mobility values measured in these materials are among the highest values reported for columnar liquid crystals.


AAHA/AAFP pain management guidelines for dogs & cats.
Pain management in dogs and cats has undergone a dramatic evolution in the past decade. Current approaches focus on anticipation and prevention of pain, as well as both pharmacologic and nonpharmacologic management techniques. The veterinary team plays an essential role in educating pet owners about recognizing and managing pain in their pets.


Fibrinogen-clotting enzyme, pictobin, from Bothrops pictus snake venom. Structural and functional characterization.
A thrombin-like enzyme, pictobin, was purified from Bothrops pictus snake venom. It is a 41-kDa monomeric glycoprotein as showed by mass spectrometry and contains approx. 45% carbohydrate by mass which could be removed with N-glycosidase. Pictobin coagulates plasma and fibrinogen, releasing fibrinopeptide A and induces the formation of a friable/porous fibrin network as visualized by SEM. The enzyme promoted platelet aggregation in human PRP and defibrination in mouse model and showed catalytic activity on chromogenic substrates S-2266, S-2366, S-2160 and S-2238. Pictobin interacts with the plasma inhibitor α2-macroglobulin, which blocks its interaction with fibrinogen but not with the small substrate BApNA. Heparin does not affect its enzymatic activity. Pictobin cross reacted with polyvalent bothropic antivenom, and its deglycosylated form reduced its catalytic action and antivenom reaction. In breast and lung cancer cells, pictobin inhibits the fibronectin-stimulated migration. Moreover, it produces strong NADH oxidation, mitochondrial depolarization, ATP decrease and fragmentation of mitochondrial network. These results suggest by first time that a snake venom serinprotease produces mitochondrial dysfunction by affecting mitochondrial dynamics and bioenergetics. Structural model of pictobin reveals a conserved chymotrypsin fold β/β hydrolase. These data indicate that pictobin has therapeutic potential in the treatment of cardiovascular disorders and metastatic disease.


Performance evaluation of Unified Medical Language System®'s synonyms expansion to query PubMed.
PubMed is the main access to medical literature on the Internet. In order to enhance the performance of its information retrieval tools, primarily non-indexed citations, the authors propose a method: expanding users' queries using Unified Medical Language System' (UMLS) synonyms i.e. all the terms gathered under one unique Concept Unique Identifier. This method was evaluated using queries constructed to emphasize the differences between this new method and the current PubMed automatic term mapping. Four experts assessed citation relevance. Using UMLS, we were able to retrieve new citations in 45.5% of queries, which implies a small increase in recall. The new strategy led to a heterogeneous 23.7% mean increase in non-indexed citation retrieved. Of these, 82% have been published less than 4 months earlier. The overall mean precision was 48.4% but differed according to the evaluators, ranging from 36.7% to 88.1% (Inter rater agreement was poor: kappa = 0.34). This study highlights the need for specific search tools for each type of user and use-cases. The proposed strategy may be useful to retrieve recent scientific advancement.


Fitness-valley crossing with generalized parent-offspring transmission.
Simple and ubiquitous gene interactions create rugged fitness landscapes composed of coadapted gene complexes separated by "valleys" of low fitness. Crossing such fitness valleys allows a population to escape suboptimal local fitness peaks to become better adapted. This is the premise of Sewall Wright's shifting balance process. Here we generalize the theory of fitness-valley crossing in the two-locus, bi-allelic case by allowing bias in parent-offspring transmission. This generalization extends the existing mathematical framework to genetic systems with segregation distortion and uniparental inheritance. Our results are also flexible enough to provide insight into shifts between alternate stable states in cultural systems with "transmission valleys". Using a semi-deterministic analysis and a stochastic diffusion approximation, we focus on the limiting step in valley crossing: the first appearance of the genotype on the new fitness peak whose lineage will eventually fix. We then apply our results to specific cases of segregation distortion, uniparental inheritance, and cultural transmission. Segregation distortion favouring mutant alleles facilitates crossing most when recombination and mutation are rare, i.e., scenarios where crossing is otherwise unlikely. Interactions with more mutable genes (e.g., uniparental inherited cytoplasmic elements) substantially reduce crossing times. Despite component traits being passed on poorly in the previous cultural background, small advantages in the transmission of a new combination of cultural traits can greatly facilitate a cultural transition. While peak shifts are unlikely under many of the common assumptions of population genetic theory, relaxing some of these assumptions can promote fitness-valley crossing.