Optimized Magnetic Stimulation Induced Hypoconnectivity Within the Executive Control Network Yields Cognition Improvements in Alzheimer's Patients.
Alzheimer's disease (AD) is a severe neurodegenerative disease, which mainly manifests as memory and progressive cognitive impairment. At present, there is no method to prevent the progression of AD or cure it, and effective intervention methods are urgently needed. Network-targeted intermittent theta burst stimulation (iTBS) may be effective in alleviating the cognitive symptoms of patients with mild AD. The abnormal function of the dorsolateral prefrontal cortex (DLPFC) within executive control network (ECN) may be the pathogenesis of AD. Here, we verify the abnormality of the ECN in the native AD data set, and build the relevant brain network. In addition, we also recruited AD patients to verify the clinical effects of DLPFC-targeted intervention, and explor the neuro-mechanism. Sixty clinically diagnosed AD patients and 62 normal controls were recruited to explore the ECN abnormalities. In addition, the researchers recruited 20 AD patients to explore the efficacy of 14-session iTBS treatments for targeted DLPFC interventions. Functional magnetic resonance imaging and neuropsychological assessment of resting state were performed before and after the intervention. Calculate the changes in the functional connectivity of related brain regions in the ECN, as well as the correlation between the baseline functional connectivity and the clinical scoring scale, to clarify the mechanism of the response of iTBS treatment to treatment. Our results showed that compared with normal control samples, the brain function connection between the left DLPFC and the left IPL within the ECN of AD patients was significantly enhanced (t = 2.687, p = 0.008, FDR-corrected p = 0.045). And we found that iTBS stimulation significantly reduced the functional magnetic resonance imaging signal between the left DLPFC and the left IPL in the ECN (t = 4.271, p < 0.001, FDR-corrected p = 0.006), and it was related to the improvement of the patient's clinical symptoms (r = -0.470, p = 0.042). This work provides new insights for targeted brain area interventions. By targeted adjusting the functional connection of ECN to improve the clinical symptoms and cognitive function of AD patients.


Histamine and tryptase levels in allergic conjunctivitis and vernal keratoconjunctivitis.
Tryptase is useful as a specific and accurate indicator of mast cell activation, whereas histamine, a mast cell's major mediator, also exists in basophils. The aim of this study is to investigate histamine and tryptase levels in allergic conjunctiva. We measured histamine and tryptase levels in conjunctival epithelial cell suspension of children with allergic conjunctivitis (AC) and vernal kerato-conjunctivitis (VKC), and controls, and we evaluated correlations with clinical observations. Both the histamine and tryptase levels in VKC were significantly higher than controls (p < 0.05, p < 0.01), and histamine levels in VKC was also greater than AC (p < 0.05). The histamine/tryptase (H/T) ratios were 0.03 +/- 0.04 in AC, 0.08 +/- 0.09 in VKC and 0.006 +/- 0.006 in controls. The H/T ratios in VKC were significantly higher than controls (p < 0.05) and AC (p < 0.05), and were also found to correlate with the superficial punctate keratopathy (SPK) score (r2 = 0.89). Analyzing the histamine and tryptase levels in conjunctival epithelium may be useful in evaluating the allergic ocular surface, especially in the cases with SPK, where the increase in the histamine levels is not accompanied by an increase in tryptase levels. This suggests an important role for inflammatory cells such as basophils infiltrating into the conjunctival epithelium in allergic reactions.


A simple method of separating metallic and semiconducting single-walled carbon nanotubes based on molecular charge transfer.
Interaction of as-prepared single-walled carbon nanotubes (SWNTs), containing a mixture of metallic and semiconducting species with the potassium salt of coronene tetracarboxylic acid, I, in an aqueous medium provides a simple method of separating semiconducting and metallic species. The metallic nanotubes precipitate out on interaction with I while the semiconducting nanotubes remain in solution. The method avoids centrifugation and is amenable for large-scale separation and can be used as a routine laboratory procedure. Interestingly, interaction with strong electron acceptor molecules brings about metal-semiconductor transitions in SWNTs.


Differences in diagnostic test results and hematologic data between aged and young horses.
Hematologic data and results of diagnostic tests were compared between aged (greater than or equal to 20 years old) and young (less than or equal to 5 years old) horses to identify hematologic and metabolic changes associated with aging. Initial data were obtained from 8 aged and 6 young mares (group 1). Similar data were collected from a second group of aged (3 mares and 3 geldings) and young (1 mare and 5 geldings) horses (group 2). Dexamethasone suppression tests (DST) and necropsies were performed on 6 additional mares and mare 8 from group 1 (group 3). Complete blood counts and serum biochemical profiles were compared between young and aged horses of groups 1 and 2. Mean corpuscular volume was higher (P less than 0.05) in aged horses. Oral glucose tolerance and insulin response to orally administered glucose were measured in 13 aged horses (groups 1 and 2) and 6 young mares of group 1. In group 1, plasma ascorbic acid values were lower (P less than 0.05) in aged horses than in young horses maintained under the same conditions and feeding regimens. An apparent age-related hyperinsulinemic response to orally administered glucose identified in group-1 mares was probably a result of a high occurrence of subclinical hypophyseal and/or thyroid adenomas. Of 13 aged horses necropsied (groups 2 and 3), 10 had hypophyseal and/or thyroid adenomas that, in group 2, were consistently associated (P less than 0.05) with hyperinsulinemic responses to orally administered glucose. All horses in groups 2 and 3 were given a 24-hour DST.(ABSTRACT TRUNCATED AT 250 WORDS)


Management of substernal and intrathoracic goiters.
Goiters that descend into the mediastinum can cause respiratory embarrassment, dysphagia, vascular compression, vocal cord paralysis, and sudden death. Although many such goiters remain clinically silent, their ability to produce sudden and unpredictable respiratory distress is well known. The condition was not considered uncommon in the first half of the twentieth century; some authors reported series of hundreds of thyroidectomies for intrathoracic goiter. Though seen less frequently today, the only effective treatment for mediastinal goiter is surgical removal. We report our experience with the management of 70 consecutive patients with substernal or intrathoracic goiters. The clinical presentation, preoperative evaluation, operative technique, and results and complications of therapy are discussed. Consideration is also given to the pathogenesis of intrathoracic extension. The transcervical approach for resection is emphasized--even goiters extending to the aortic arch were safely removed without requiring sternotomy. A multidisciplinary team approach, including the surgeon, anesthesiologist, and endocrinologist, is essential. Because of more conservative trends in the selection of patients for thyroidectomy, the incidence of mediastinal goiter may be increasing.


Acidic cellular environments: activation of latent TGF-beta and sensitization of cellular responses to TGF-beta and EGF.
Transient (about 2 hr) acidification to approx. pH 5.0 of agar-gelled overlayers containing untransformed NRK-49F or KiMSV-transformed NRK-49F cells in the presence of fetal calf serum or crude 49F-cell conditioned medium, as sources of latent TGF-beta, elicited EGF-dependent colony formation of 49F cells and inhibited spontaneous growth of transformed cells. Pure, active TGF-beta (porcine, type I) had the same effects on these respective cell types, suggesting that the above results were due to activation of latent TGF-beta in the transiently acidic cellular environment. Similar acidifications in the absence of a source of latent TGF-beta enhanced the positive growth response of 49F and AKR-2B cells to EGF and active TGF-beta and also the negative growth response of KiMSV-transformed 49F cells to active TGF-beta. These results are compatible with the idea that acidic cellular environments, particularly in tumor tissues, are conducive to activation of latent TGF-beta, perhaps in conjunction with other activating mechanisms, and to an enhanced response to some growth factors. However, the heterogeneity of cell populations within tumoral masses presents an obstacle to a clear understanding of the consequences of such activation.


Painless redissection of the ascending aorta after complete resolution of the thrombosed false lumen: a case report.
An 86-year-old woman presented with sudden back pain. Computed tomography (CT) revealed thrombosed type A acute aortic dissection (AD) with a large ascending aorta. Due to the patient's advanced age, medical therapy was performed. While an ulcer-like projection was recognized at the ascending aorta on follow-up CT, the patient was eventually discharged without surgery. Four-months follow-up CT showed complete resorption of the thrombus in the false lumen. While the patient was asymptomatic after discharge, 1 year later, CT revealed overt AD involving the ascending aorta. In order to prevent aortic events, we performed graft replacement of the ascending aorta.


A RNAi-based therapeutic proof of concept targets salmonid whirling disease in vivo.
Myxobolus cerebralis is a cnidarian-myxozoan parasite that causes salmonid whirling disease. M. cerebralis alternates between two hosts: (1) a vertebrate salmonid and (2) an invertebrate oligochaete, Tubifex tubifex. There is no successful treatment for salmonid whirling disease. MyxSP-1 is a M. cerebralis serine protease implicated in whirling disease pathogenesis. We hypothesized that short-interfering RNA (siRNA)-induced RNA interference (RNAi) can silence MyxSP-1 in the invertebrate host and abrogate the M. cerebralis life cycle. This would preclude whirling disease infection in the salmonid host. To test this hypothesis, we first developed a siRNA delivery protocol in T. tubifex. Second, we determined the effective dose for siRNA treatment of M. cerebralis-infected T. tubifex. M. cerebralis-infected T. tubifex were treated with different concentrations of MyxSP-1 or negative control siRNAs (1μM, 2μM, 5μM or 7μM) at 15°C for 24h, 48h, 72h and 96h, respectively. We monitored MyxSP-1 knockdown using real-time quantitative PCR (qPCR). siRNA treatment with MyxSP-1 siRNA at 2μM concentration for 24h at 15°C showed maximum significant MyxSP-1 knockdown in T. tubifex. Third, we determined the time points in the M. cerebralis life cycle in T. tubifex at which siRNA treatment was most effective. M. cerebralis-infected T. tubifex were treated with MyxSP-1 or negative control siRNAs (2μM concentration for 24h at 15°C) at 24 hours post-infection (24hpi), 48hpi, 72hpi, 96hpi, 1 month post-infection (1mpi), 2mpi and 3mpi, respectively. We observed that siRNA treatment of T. tubifex was most effective at 1mpi, 2mpi and 3mpi. Fourth, we immersed specific-pathogen-free rainbow trout fry in water inhabited by MyxSP-1 siRNA-treated T. tubifex (at 1mpi, 2mpi and 3mpi). The salmonids did not develop whirling disease and showed significant MyxSP-1 knockdown. We also observed long-term RNAi in T. tubifex. Together these results demonstrate a novel RNAi-based therapeutic proof of concept in vivo against salmonid whirling disease.


Tumor growth suppression by a mouse/human chimeric anti-CEA antibody and lymphokine-activated killer cells in vitro and in SCID mouse xenograft model.
The mouse/human chimeric antibody Ch F11-39, recently generated by ourselves, shows the same high specificity and affinity for carcinoembryonic antigen (CEA) as those of its parental mouse monoclonal antibody. Ch F11-39 is capable of mediating antibody-dependent cell-mediated cytotoxicity (ADCC) with human peripheral blood lymphocytes (PBL). Interleukin-2 (IL-2) modulates the function of immunocytes, in particular inducing lymphokine-activated killer (LAK) cells and enhancing ADCC. In the present study, we therefore tested the combination immunotherapy of Ch F11-39 with LAK cells in vitro and in severe combined immunodeficiency (SCID) mice bearing human CEA-producing tumors. In vitro experiments using human gastric tumor cell lines, Ch F11-39 effectively mediated ADCC against CEA-positive MKN-45 cells, but not against CEA-negative cells. The specificity of ADCC for Ch F11-39 was demonstrated by experiments with irrelevant target cells or irrelevant antibody. ADCC activity of PBL with Ch F11-39 was enhanced by double after preincubation with IL-2 at 10 U/ml. The concentration of Ch F11-39 required for 50% maximal cell killing was about 0.25 microgram/ml at 10 U/ml of IL-2. Increasing ADCC was triggered by IL-2 earlier (1 day) than the generation of LAK cells (3 days). Control human IgG blocked the ADCC, suggesting that the enhancement of ADCC by IL-2 may be caused by activation of effector cells expressing Fc receptors. In vivo anti-tumor activity of combined immunotherapy was estimated using SCID mice inoculated s.c. with 1 x 10(7) MKN-45 cells. The i.v. administration of LAK cells and i.p. administration of Ch F11-39 and IL-2 produced a marked growth inhibition of MKN-45 tumors in SCID mice (about 50% reduction in tumor size as compared to the control untreated group, measured 15 days after treatment). In summary, the enhanced antitumor activity of Ch F11-39 with LAK cells suggests that it might be a useful immunotherapeutic reagent for CEA-expressing tumors.


[Experimental study of the effect of formaldehyde during embryogenesis on the activity of rat liver enzyme systems in ontogenesis].
The pregnant rats were treated with formaldehyde (0.5 mg/kg daily per os) during whole period of pregnancy. The activity of cytochrome-c-oxidase, malate dehydrogenase, nucleotidase, glucose-6-phosphatase, beta-glucuronidase, N-acetyl-beta-glucosaminidase, beta-galactosidase, H(+)-ATPase, glutamate dehydrogenase, NAD- and NADP-isocitrate dehydrogenase, fructose-bisphosphate aldolase, glucose-6-phosphate dehydrogenase and content of protein in liver celts of offsprings (newborns, 2 weeks age and 2 months age) were studied. It was shown differences in development enzyme systems of control and experimental animals during ontogenesis.


[Cytokines induced by experimental anti-tetanus immunization. Vaccine formulation effect].
Several factors are involved in the selective activation of T helper 1 or T helper 2 cells, such as the type of antigen-presenting cells involved in the immune response and the different physical characteristics of antigens. The aim of this work was to evaluate if adding other antigens to tetanus toxoid modifies the original immune response. BALB/c mice were immunized with tetanus and diphtheria toxoids associated with whole-cell Bordetella pertussis (DTPw vaccine), B. pertussis soluble antigens (DTPa vaccine) or Salmonella typhi plus DTPa (DTPaSt vaccine). DTPw and DTPaSt immunization induced a T helper 1/T helper 2 (Th1/Th2) anti-tetanus response with gamma interferon and interleukin 5 production. DTPa immunization induced a Th2 response with production of interleukin 5 and interleukin 6. Only DTPw vaccine induced higher levels of IL-12 in non-immunized mice. Our findings indicate that the co-injection of whole-cell antigens such as B. pertussis or S. typhi, modifies the anti-tetanus response shifting it from Th2 to Th1 type. However, the original Th2 immune response is not modified when the vaccine consists only of soluble antigens.


Oral carvedilol in escalating doses in the acute treatment of atrial fibrillation.
To study the efficacy of oral carvedilol in acute treatment of atrial fibrillation (AF) with fast ventricular rate. In an open-label, single-arm trial, oral carvedilol was administered to 35 patients of AF in escalating doses from 3.125 mg o.d. to 12.5 mg b.i.d. A successful result was seen in 25 patients (71.4%) with 4 converting to sinus rhythm, rate control to less than 90 bpm in 16 and a 20% rate reduction in 5 patients. Two patients developed hypotension needing withdrawal of the drug. Escalating doses of oral carvedilol can be effectively and safely used in the acute treatment of AF with fast ventricular rate.


P3 amylase isoenzyme in patients with cholelithiasis.
The plasma P3 amylase isoenzyme was determined in 25 patients with proven cholelithiasis. In six patients who had a single gallstone and normal pancreas at operation, the total plasma amylase was within normal limits and the P3 amylase isoenzyme was absent. In the remaining 19 patients who had multiple gallstones, pancreatitis was found at surgery in 10. In this group of 10 patients, the total plasma amylase was above the reference range for healthy individuals in only five (50%), while the P3 amylase isoenzyme band was detected in all 10 (100%). It is concluded that P3 amylase isoenzyme is superior to the total plasma amylase in the diagnosis of pancreatitis in patients with gallstone.


Prediction of cervical cancer recurrence using textural features extracted from 18F-FDG PET images acquired with different scanners.
To identify an imaging signature predicting local recurrence for locally advanced cervical cancer (LACC) treated by chemoradiation and brachytherapy from baseline 18F-FDG PET images, and to evaluate the possibility of gathering images from two different PET scanners in a radiomic study. 118 patients were included retrospectively. Two groups (G1, G2) were defined according to the PET scanner used for image acquisition. Eleven radiomic features were extracted from delineated cervical tumors to evaluate: (i) the predictive value of features for local recurrence of LACC, (ii) their reproducibility as a function of the scanner within a hepatic reference volume, (iii) the impact of voxel size on feature values. Eight features were statistically significant predictors of local recurrence in G1 (p < 0.05). The multivariate signature trained in G2 was validated in G1 (AUC=0.76, p<0.001) and identified local recurrence more accurately than SUVmax (p=0.022). Four features were significantly different between G1 and G2 in the liver. Spatial resampling was not sufficient to explain the stratification effect. This study showed that radiomic features could predict local recurrence of LACC better than SUVmax. Further investigation is needed before applying a model designed using data from one PET scanner to another.


'Nothing to do with the science': How an elite sociotechnical imaginary cements policy resistance to public perspectives on science and technology through the machinery of government.
That policymakers adopt technoscientific viewpoints and lack reflexivity is a common criticism of scientific decision-making, particularly in response to moves to democratize science. Drawing on interviews with UK-based national policymakers, I argue that an elite sociotechnical imaginary of 'science to the rescue' shapes how public perspectives are heard and distinguishes what is considered to be legitimate expertise. The machinery of policy-making has become shaped around this imaginary - particularly its focus on science as a problem-solver and on social and ethical issues as 'nothing to do with the science' - and this gives this viewpoint its power, persistence and endurance. With this imaginary at the heart of policy-making machinery, regardless of the perspectives of the policymakers, alternative views of science are either forced to take the form of the elite imaginary in order to be processed, or they simply cannot be accounted for within the policy-making processes. In this way, the elite sociotechnical imaginary (and technoscientific viewpoint) is enacted, but also elicited and perpetuated, without the need for policymakers to engage with or even be aware of the imaginary underpinning their actions.


Office evaluation of dementia. How to arrive at a clear diagnosis and choose appropriate therapy.
About half of patients presenting with dementia have Alzheimer's disease, which cannot be prevented or reversed. Treatment of these patients is aimed at improving their quality of life and helping their families provide supportive care. About 15% of patients with dementia can be successfully treated. A detailed patient history, thorough physical examination, and appropriate laboratory testing are important to identify the treatable causes of dementia, such as normal-pressure hydrocephalus, Korsakoff's psychosis, and drug toxicity.


Bispecific antibodies: a novel approach for targeting prominent biomarkers.
Many types of cancers are prevalent in India and worldwide. Monoclonal antibodies (MAbs) are one of the major types of cancer therapeutics, which have included MAbs of hybridoma, chimeric, humanized, or human origin. MAbs are mostly generated currently by direct cloning from B cells. Bispecific antibodies (BAbs), as the name suggests, have two different antigen-binding domains in a single molecule and thus have dual functionality/specificity combined in a single antibody. In addition to the detection of two different antigenic molecules, the dual functionality of BAbs can be utilized to mount T-cell-mediated killing of tumor cells wherein one Fv binds to the tumor-specific antigen and the another recruits T cells to the site of action. Breast cancer and prostate cancer are among the most prevalent cancers in women and men, respectively. Biomarkers such as HER2 and ER/PR are expressed in breast cancer, while overexpression of hepsin and prostate-specific membrane antigen is observed in prostate cancer. Developing BAbs against these biomarkers may be a potent therapeutic option to target breast and prostate cancer, respectively. Therefore, an efficient method using recombinant DNA technology and mammalian cell culture platform is required to generate BAbs against specific diseases as biomarkers as well as for the generation of antibody-based therapeutics.


Fistula of the Stump: A Novel Approach With a "Stapled" Stent.
Postoperative bronchopleural fistulas are serious and uncommon complications after pneumonectomy. Available therapeutic approaches are medical, endoscopic, and/or surgical. A 42-year-old man underwent left pneumonectomy. Three years later he was admitted to an intensive care unit with pneumonia of the remaining lung, severe respiratory insufficiency, and a bronchopleural fistula with an air fluid level filling in the pneumonectomy cavity. A left chest drain was placed, and broad-spectrum antibiotics and mechanical ventilation were administered. Because of the unstable clinical condition, a blind end endobronchial stent closed by a stapler was placed in the left bronchial stump. He improved in a couple of months and underwent definitive surgical sealing of the fistula.Endoscopic interventions are usually safe and free from associated complications. They are an excellent option, when patient's clinical condition is contraindication to immediate surgery.


Unilateral high myopia leading to asymmetric disc edema in idiopathic intracranial hypertension.
Asymmetrical disc edema in idiopathic intracranial hypertension (IIH) is an uncommon finding, with an unclear understanding. This report reinforces the importance of recognizing this entity in IIH diagnosis, and not misdiagnose the condition as unilateral disc edema. In this unique report, the causative association of asymmetric optic disc edema, with optic nerve kink, due to unilateral high myopia, is documented.


Impact of axisymmetric deformation on MR elastography of a nonlinear tissue-mimicking material and implications in peri-tumour stiffness quantification.
Solid tumour growth is often associated with the accumulation of mechanical stresses acting on the surrounding host tissue. Due to tissue nonlinearity, the shear modulus of the peri-tumoural region inherits a signature from the tumour expansion which depends on multiple factors, including the soft tissue constitutive behaviour and its stress/strain state. Shear waves used in MR-elastography (MRE) sense the apparent change in shear modulus along their propagation direction, thereby probing the anisotropic stiffness field around the tumour. We developed an analytical framework for a heterogeneous shear modulus distribution using a thick-shelled sphere approximation of the tumour and soft tissue ensemble. A hyperelastic material (plastisol) was identified to validate the proposed theory in a phantom setting. A balloon-catheter connected to a pressure sensor was used to replicate the stress generated from tumour pressure and growth while MRE data were acquired. The shear modulus anisotropy retrieved from the reconstructed elastography data confirmed the analytically predicted patterns at various levels of inflation. An alternative measure, combining the generated deformation and the local wave direction and independent of the reconstruction strategy, was also proposed to correlate the analytical findings with the stretch probed by the waves. Overall, this work demonstrates that MRE in combination with non-linear mechanics, is able to identify the apparent shear modulus variation arising from the strain generated by a growth within tissue, such as an idealised model of tumour. Investigation in real tissue represents the next step to further investigate the implications of endogenous forces in tissue characterisation through MRE.


A one-step matrix application method for MALDI mass spectrometry imaging of bacterial colony biofilms.
Matrix-assisted laser desorption/ionization imaging of biofilms cultured on agar plates is challenging because of problems related to matrix deposition onto agar. We describe a one-step, spray-based application of a 2,5-dihydroxybenzoic acid solution for direct matrix-assisted laser desorption/ionization imaging of hydrated Bacillus subtilis biofilms on agar. Using both an optimized airbrush and a home-built automatic sprayer, region-specific distributions of signaling metabolites and cannibalistic factors were visualized from B. subtilis cells cultivated on biofilm-promoting medium. The approach provides a homogeneous, relatively dry coating on hydrated samples, improving spot to spot signal repeatability compared with sieved matrix application, and is easily adapted for imaging a range of agar-based biofilms. Copyright © 2016 John Wiley & Sons, Ltd.


Whole-sequence analysis indicates that the Y chromosome C2*-Star Cluster traces back to ordinary Mongols, rather than Genghis Khan.
The Y-chromosome haplogroup C3*-Star Cluster (revised to C2*-ST in this study) was proposed to be the Y-profile of Genghis Khan. Here, we re-examined the origin of C2*-ST and its associations with Genghis Khan and Mongol populations. We analyzed 34 Y-chromosome sequences of haplogroup C2*-ST and its most closely related lineage. We redefined this paternal lineage as C2b1a3a1-F3796 and generated a highly revised phylogenetic tree of the haplogroup, including 36 sub-lineages and 265 non-private Y-chromosome variants. We performed a comprehensive analysis and age estimation of this lineage in eastern Eurasia, including 18,210 individuals from 292 populations. We discovered that the origin of populations with high frequencies of C2*-ST can be traced to either an ancient Niru'un Mongol clan or ordinary Mongol tribes. Importantly, the age of the most recent common ancestor of C2*-ST (2576 years, 95% CI = 1975-3178) and its sub-lineages, and their expansion patterns, are consistent with the diffusion of all Mongolic-speaking populations, rather than Genghis Khan himself or his close male relatives. We concluded that haplogroup C2*-ST is one of the founder paternal lineages of all Mongolic-speaking populations, and direct evidence of an association between C2*-ST and Genghis Khan has yet to be discovered.


Locally Recurrent Lentigo Maligna and Lentigo Maligna Melanoma: Characteristics and Time to Recurrence After Surgery.
Various studies have reported local recurrence (LR) rates after surgical treatment of lentigo maligna (LM) and lentigo maligna melanoma (LMM). However, the time to LR of LM/LMM is not currently known, as few studies report time to LR and have long-term follow-up. To define time to LR in LM/LMM after surgical treatment, and to describe features of observed LR. Retrospective single-center study of consecutive patients presenting with locally recurrent LM/LMM. Six hundred forty-nine cases of LM/LMM were reviewed; 29 (21 LM, and 8 LMM) of 41 locally recurrent cases had original histology reports and were included. The mean time to LR was 57.5 months (range 7-194). For cases presenting as primary LM, LR was also in situ in 14/21 (67%) of cases. Seven of 21 LM recurred as LMM. Of the 8 primary LMM, 3/8 (37.5%) presented with subsequent LMM and all were slightly deeper on re-excision. The mean time to LR of LM/LMM is at least 57.5 months, underscoring the importance of long-term follow-up. Seven of 21 LM recurred as invasive disease, but the lack of development of LMM from LM in most recurrent cases confirms LM is slowly progressive.


Borylenes: An Emerging Class of Compounds.
Free borylenes (R-B:) have only been spectroscopically characterized in the gas phase or in matrices at very low temperatures. However, in recent years, a few mono- and bis(Lewis base)-stabilized borylenes have been isolated. In both of these compounds the boron atom is in the formal oxidation state +I which contrasts with classical organoboron derivatives wherein the element is in the +III oxidation state. Mono(Lewis base)-stabilized borylenes are isoelectronic with singlet carbenes, and their reactivity mimics to some extent that of transition metals. They can activate small molecules, such as H2 , and coordinate an additional ligand; in other words, they are boron metallomimics. Bis(Lewis base)borylene adducts are isoelectronic with amines and phosphines. In contrast to boranes, which act as electron acceptors and thus Lewis acids, they are electron-rich and act as ligands for transition metals.


Pharmacodynamic evaluation of intermittent versus extended and continuous infusions of piperacillin/tazobactam in a hollow-fibre infection model against Klebsiella pneumoniae.
To compare bacterial killing and the emergence of resistance to piperacillin/tazobactam, administered by intermittent versus prolonged infusion (i.e. extended or continuous), for ceftriaxone-resistant Klebsiella pneumoniae clinical isolates in an in vitro dynamic hollow-fibre infection model (HFIM). K. pneumoniae 68 (Kp68; MIC = 8 mg/L, producing SHV-106 and DHA-1) and K. pneumoniae 69 (Kp69; MIC = 1 mg/L, producing CTX-M-14) were studied in the HFIM over 7 days (initial inoculum ~107 cfu/mL). Six piperacillin/tazobactam dosing regimens for Kp68 (4/0.5 g 8 hourly as 0.5 and 4 h infusions, 12/1.5 g/24 h continuous infusion, 4/0.5 g 6 hourly as 0.5 and 3 h infusions and 16/2 g/24 h continuous infusion) and three piperacillin/tazobactam dosing regimens for Kp69 (4/0.5 g 8 hourly as 0.5 and 4 h infusions and 12/1.5 g/24 h continuous infusion) were simulated (piperacillin clearance = 14 L/h, creatinine clearance = 100 mL/min). Total and resistant populations and MICs were quantified/determined. For Kp68, all simulated dosing regimens exhibited approximately 4 log10 of bacterial killing at 8 h followed by regrowth to approximately 1011 cfu/mL within 24 h. The MICs for resistant subpopulations exceeded 256 mg/L at 72 h. Similarly, for Kp69, all simulated dosing regimens exhibited approximately 4 log10 of bacterial killing over 8 h; however, only the continuous infusion prevented bacterial regrowth. Compared with intermittent infusion, prolonged infusion did not increase initial bacterial killing and suppression of regrowth of plasmid-mediated AmpC- and ESBL-producing K. pneumoniae. However, continuous infusion may suppress regrowth of some ESBL-producing susceptible K. pneumoniae, although more data are warranted to confirm this observation.


Evidence for aerobic glycolysis in lambda-carrageenan-wounded skeletal muscle.
Classically, increased lactate production in wounded tissue is ascribed to anaerobic glycolysis although its oxygen consumption has been found to be similar to normal tissue. This apparent inconsistency was studied in a standardized isolated perfused wound model. Male Sprague-Dawley rats were wounded (group W) with intramuscular injections of lambda-carrageenan and fed ad lib.; not wounded and pair fed to the decreased food intake of the wounded animals (group PFC); or not wounded and fed ad lib. (group ALC). After 5 days, the hindlimbs of animals from each group were either perfused using a standard perfusate with added [U-14C]glucose or [1-14C]pyruvate or assayed for the tissue content of lactate and pyruvate. In addition, the effect of a 30% hemorrhage on the tissue lactate and pyruvate concentration was examined. Wounding increased glucose uptake and lactate production by 100 and 96%, respectively, above that seen in ALC animals. Oxygen consumption was unchanged by wounding (5.74, 5.14, and 5.83 mumole/min/100 g in W, PFC, and ALC, respectively). Glucose and pyruvate oxidation were also unaltered among the groups. Hemorrhage resulted in a comparable increase in lactate and pyruvate in tissue from wounded and pair-fed control animals (above those concentrations found in tissue harvested without preexisting hemorrhage). As a consequence, the same relationship in L/P ratio was maintained after hemorrhage. Taken together, these results confirm the presence of aerobic glycolysis in wounded tissue (unchanged oxygen consumption, glucose, and pyruvate oxidation). In addition, pyruvate dehydrogenase activity in the wound was apparently the same as that found in muscle from pair-fed control animals.


Optimal dosage regimen of meropenem for pediatric patients based on pharmacokinetic/pharmacodynamic considerations.
A population pharmacokinetic (PK) model for meropenem in Japanese pediatric patients with various infectious diseases was developed based on 116 plasma concentrations from 50 pediatric patients. The population PK parameters developed in this analysis are useful for calculation of the percent time above minimum inhibitory concentration (%T>MIC) and for optimal dosing of meropenem in pediatric patients. After dosing at 20 mg/kg t.i.d. by 0.5-h infusion (approved standard dose for pediatric patients in Japan), the target value of 50%T>MIC was achieved, indicating that 20 mg/kg t.i.d. by 0.5-h infusion is effective for susceptible bacteria. In contrast, for bacteria with higher MICs such as Pseudomonas aeruginosa (MIC ≥ 2 µg/mL), the probability of target attainment of 50%T>MIC was 60.7% at a dose of 40 mg/kg t.i.d. by 0.5-h infusion (highest dose approved for pediatric patients in Japan). The simulations described in this article indicated that 40 mg/kg t.i.d. with a longer infusion duration (e.g., 4 h) is more effective against bacteria with a MIC higher than 2 µg/mL. The predicted probability of target attainment for 50%T>MIC (97.0%) was well correlated not only to the microbiological efficacy rate (97.0%) but also to the clinical efficacy rate (95.9%) in the present phase 3 study.


Identification of inorganic ions in post-blast explosive residues using portable CE instrumentation and capacitively coupled contactless conductivity detection.
Novel CE methods have been developed on portable instrumentation adapted to accommodate a capacitively coupled contactless conductivity detector for the separation and sensitive detection of inorganic anions and cations in post-blast explosive residues from homemade inorganic explosive devices. The methods presented combine sensitivity and speed of analysis for the wide range of inorganic ions used in this study. Separate methods were employed for the separation of anions and cations. The anion separation method utilised a low conductivity 70 mM Tris/70 mM CHES aqueous electrolyte (pH 8.6) with a 90 cm capillary coated with hexadimethrine bromide to reverse the EOF. Fifteen anions could be baseline separated in 7 min with detection limits in the range 27-240 microg/L. A selection of ten anions deemed most important in this application could be separated in 45 s on a shorter capillary (30.6 cm) using the same electrolyte. The cation separation method was performed on a 73 cm length of fused-silica capillary using an electrolyte system composed of 10 mM histidine and 50 mM acetic acid, at pH 4.2. The addition of the complexants, 1 mM hydroxyisobutyric acid and 0.7 mM 18-crown-6 ether, enhanced selectivity and allowed the separation of eleven inorganic cations in under 7 min with detection limits in the range 31-240 microg/L. The developed methods were successfully field tested on post-blast residues obtained from the controlled detonation of homemade explosive devices. Results were verified using ion chromatographic analyses of the same samples.


Picture resembling hemicentral retinal vein occlusion in the acquired immunodeficiency syndrome: is it related to cytomegalovirus?
Three HIV-seropositive subjects presented with diffuse inferior retinal hemorrhages. The first patient had an inferior hemicentral vein occlusion with subsequent development of an inferior cytomegalovirus retinitis. Two other patients had an inferior 'hemorrhagic' cytomegalovirus retinitis mimicking a venous occlusion, with the retinitis being subtle in 1 patient. We speculate that: (1) venous occlusion may predispose to cytomegalovirus infection of the retina by stasis and ischemic loss of endothelium; (2) early cytomegalovirus infection of the large retinal veins may give the picture of a hemorrhagic retinopathy in a subset of patients with cytomegalovirus retinitis. The differential diagnoses of hemorrhagic retinopathy in HIV-seropositive subjects include: cytomegalovirus retinitis, retinal vein occlusion, syphilitic retinitis and retinopathy of severe anemia.


[Delivery of epididymis-specific mRNAs from mouse epididymosomes into N2a and TM4 cells].
To investigate whether mouse epididymis-specific mRNAs Adam7 and Crisp1 can be delivered into N2a and TM4 cells, and to provide an experimental basis for exploring the function of epididymal mRNAs. Using RT-PCR, we detected the presence of epididymis-specific genes (Adam7, Crisp1, Defb22, Wfdc2, and Wfdc9) in the testis, epididymis, epididymosome and sperm of adult male BALB/c mice as well as in the human testis, seminal vesicles and sperm. We isolated epididymosomes of BALB/c mice by low-speed centrifugation, filtration and ultracentrifugation, fluorescently labeled them by PKH26, co-incubated them for 1 hour with the N2a and TM4 cells after 24 hours of starvation culture, and observed whether they were fused with the N2a and TM4 cells and ingested using the epididymosomes without PKH26 labeling, PKH26 dye without epididymosomes, and non- epididymosome or -PKH26 dye as controls. Then we detected the epididymis-specific genes in the N2a and TM4 cells after 1-hour co-incubation by RT-PCR. Adam7 and Crisp1 were present in the mouse epididymis, epididymosomes and sperm, and in the human seminal vesicles and sperm as well, but not in the testes of either the mice or men. PKH26 and Hoechst33258 fluorescence double-labeling showed that the mouse epididymosomes were fused with the N2a and TM4 cells and ingested; RT-PCR revealed the mRNAs of Adam7 and Crisp1 in the N2a and TM4 cells after 1-hour co-incubation; and Western blot exhibited the CRISP1 protein in the N2a and TM4 cells incubated with epididymosomes. Epididymosomes can deliver epididymis-specific mRNAs Adam7 and Crisp1 into N2a and TM4 cells, where Crisp1 may be translated into proteins, though their function and significance need to be further studied.


Prevalence of opioid-induced adverse events across opioids commonly used for analgesic treatment in Japan: a multicenter prospective longitudinal study.
Although opioids have been shown to be effective for cancer pain, opioid-induced adverse events (AEs) are common. To date, little is known about the differences in risks of AEs by opioid type. This study was performed to compare the prevalence of AEs across opioids commonly used for analgesic treatment in Japan. This study was conducted as a preplanned secondary analysis of a multicenter prospective longitudinal study of inpatients with cancer pain who received specialized palliative care for cancer pain relief. We assessed daily AEs until termination of follow-up. We rated the severity of AEs based on the Common Terminology Criteria for Adverse Events version 5.0. We computed adjusted odds ratios for each AE (constipation, nausea and vomiting, delirium, and drowsiness) with the following variables: opioid, age, sex, renal dysfunction, and primary cancer site. In total, 465 patients were analyzed. Based on the descriptive analysis, the top four most commonly used opioids were included in the analysis: oxycodone, hydromorphone, fentanyl, and tramadol. With respect to the prevalence of AEs among all analyzed patients, delirium (n = 25, 6.3%) was the most frequent, followed by drowsiness (n = 21, 5.3%), nausea and vomiting (n = 19, 4.8%), and constipation (n = 28, 4.6%). The multivariate logistic analysis showed that no single opioid was identified as a statistically significant independent predictor of any AE. There was no significant difference in the prevalence of AEs among oxycodone, fentanyl, hydromorphone, and tramadol, which are commonly used for analgesic treatment in Japan.


Low-dose chemotherapy as a prelude to intensive treatment of spontaneous leukemia-lymphoma in AKR mice.
Groups of AKR mice bearing spontaneous leukemia-lymphoma were treated with five different combinations of chemotherapy or chemoradiotherapy. Each treatment combination was given in two sequences--high dose first and low dose last, or low dose first and high dose last--administered over 6-7 days. When the initial treatment was a high dose of chemotherapy, radiotherapy, or chemoradiotherapy, mortality in the first 24 hours exceeded 40%, and at least 70% of the mice in each group were dead within 2 weeks. When low-dose chemotherapy was given first, mortality in the first 24 hours was minimal but, most significantly, no deaths occurred in the 24 hours after subsequent high-dose treatment. In the most successful group (100 mg cyclophosphamide/kg on day 0, and 250 mg cyclophosphamide/kg and 400 R total-body X-irradiation on day 7), the median survival time increased significantly as compared with the median survival time among mice given the same regimen in reverse sequence (p less than 0.001) or among untreated control mice (p less than 0.01). With this regimen, survival 60 days after the last treatment was 47%. No mouse survived 30 days when the sequence of treatments was reversed. From these results, we conclude that chemotherapeutic and chemoradiotherapeutic regimens for AKR spontaneous leukemia-lymphoma should be designed so that low, minimally lethal doses precede higher doses.


A dodecapeptide comprising the extended chain-alpha 4 region of the restriction endonuclease EcoRI specifically binds to the EcoRI recognition site.
The restriction endonuclease EcoRI binds and cleaves DNA containing GAATTC sequences with high specificity. According to the crystal structure, most of the specific contacts of the enzyme to the DNA are formed by the extended chain region and the first turn of alpha-helix alpha 4 (amino acids 137-145). Here, we demonstrate that a dodecapeptide (WDGMAAGNAIER), which is identical in the underlined parts of its sequence to EcoRI amino acids 137-145, specifically binds to GAATTC sequences. The peptide inhibits DNA cleavage by EcoRI but not by BamHI, BclI, EcoRV, HindIII, PacI, and XbaI. DNA cleavage by XbaI is slowed down at sites that partially overlap with EcoRI sites. The peptide inhibits cleavage of GAATTC sites by ApoI, which recognizes the sequence RAATTY. It interferes with DNA methylation by the EcoRI methyltransferase but not by the BamHI methyltransferase. It competes with EcoRI for DNA binding. Based on these results, the DNA binding constant of the peptide to GAATTC sequences was calculated to be 3 x 10(4) M-1. DNA binding is not temperature-dependent, suggesting that binding of the peptide is entropy-driven. As the peptide does not show any nonspecific binding to DNA, its DNA binding specificity is similar to that of EcoRI, in spite of the fact that the affinity is much smaller. These results suggest that contacts to the phosphate groups in EcoRI mainly provide binding affinity, whereas the specificity of EcoRI is based to a large extent on sequence-specific base contacts.


Characterizing chronic and acute health risks of residues of veterinary drugs in food: latest methodological developments by the joint FAO/WHO expert committee on food additives.
The risk assessment of residues of veterinary drugs in food is a field that continues to evolve. The toxicological end-points to be considered are becoming more nuanced and in light of growing concern about the development of antimicrobial resistance, detailed analysis of the antimicrobial activity of the residues of veterinary drugs in food is increasingly incorporated in the assessment. In recent years, the Joint FAO/WHO Expert Committee on Food Additives (JECFA) has refined its approaches to provide a more comprehensive and fit-for-purpose risk assessment. This publication describes in detail the consideration of acute and chronic effects, the estimation of acute and chronic dietary exposure, current approaches for including microbiological endpoints in the risk assessment, and JECFA's considerations for the potential effects of food processing on residues from veterinary drugs. JECFA now applies these approaches in the development of health-based guidance values (i.e. safe exposure levels) for residues of veterinary drugs. JECFA, thus, comprehensively addresses acute and chronic risks by using corresponding estimates for acute and chronic exposure and suitable correction for the limited bioavailability of bound residues by the Gallo-Torres model. On a case-by-case basis, JECFA also considers degradation products that occur from normal food processing of food containing veterinary drug residues. These approaches will continue to be refined to ensure the most scientifically sound basis for the establishment of health-based guidance values for veterinary drug residues.


Diacylglycerol activates the influx of extracellular cations in T-lymphocytes independently of intracellular calcium-store depletion and possibly involving endogenous TRP6 gene products.
In Jurkat and human peripheral blood T-lymphocytes, 1-oleoyl-2-acetyl-sn-glycerol (OAG), a membrane-permeant analogue of diacylglycerol, activated the influx of Ca(2+), Ba(2+) and Sr(2+). OAG also caused plasma-membrane depolarization in Ca(2+)-free media that was recovered by the addition of bivalent cation, indicating the activation of Na(+) influx. OAG-induced cation influx was (i) mimicked by the natural dacylglycerol 1-stearoyl-2-arachidonyl-sn-glycerol, (ii) not blocked by inhibiting protein kinase C or in the absence of phospholipase C activity and (iii) blocked by La(3+) and Gd(3+). Differently from OAG, both thapsigargin and phytohaemagglutinin activated a potent influx of Ca(2+), but little influx of Ba(2+) and Sr(2+). Moreover, the influx of Ca(2+) activated by thapsigargin and that activated by OAG were additive. Furthermore, several drugs (i.e. econazole, SKF96365, carbonyl cyanide p-trifluoromethoxyphenylhydrazone, 2-aminoethoxy diphenylborate and calyculin-A), while inhibiting the influx of Ca(2+) induced by both thapsigargin and phytohaemagglutinin, did not affect OAG-stimulated cation influx. Transient receptor potential (TRP) 3 and TRP6 proteins have been shown previously to be activated by diacylglycerol when expressed heterologously in animal cells [Hofmann, Obukhov, Schaefer, Harteneck, Gudermann and Schultz (1999) Nature (London) 397, 259-263]. In both Jurkat and peripheral blood T-lymphocytes, mRNA encoding TRP proteins 1, 3, 4 and 6 was detected by reverse transcriptase PCR, and the TRP6 protein was detected by Western blotting in a purified plasma-membrane fraction. We conclude that T-cells express a diacylglycerol-activated cation channel, unrelated to the channel involved in capacitative Ca(2+) entry, and associated with the expression of TRP6 protein.


D1 dopamine receptor regulation of the levels of the cell-cycle-controlling proteins, cyclin D, P27 and Raf-1, in cerebral cortical precursor cells is mediated through cAMP-independent pathways.
Previously, we demonstrated that dopamine D1 receptor (D1R) agonists inhibit epidermal growth factor (EGF)-induced passage of mouse fetal cerebral cortical precursor cells from the G1 phase to the S phase of the cell cycle. Here, we report that this action of D1R agonists may involve regulation of cyclin D, and P27, which respectively promote and suppress the G1 to S transition. Furthermore, regulation of Raf-1, a component of the receptor tyrosine kinase mitogen-activated protein kinase pathway engaged in the mitogenic activity of EGF, may also be involved. Specifically, levels of cyclin D and Raf-1 decrease, whereas those of P27 first increase and then decrease in a dose-dependent fashion in response to the D1R agonist, SKF38393. This agonist also promotes Raf-1 phosphorylation on serine 338 residue, suggesting increased activation of this protein. Only the latter effect can be blocked by adenylyl cyclase (AC) and cAMP-dependent protein kinase A (PKA) inhibitors, and mimicked by agonists of the cAMP signaling pathway. Another D1R agonist, SKF83959, which stimulates phospholipase Cbeta (PLCbeta) but not AC, reduces levels of Raf-1 and cyclin D similar to SKF38393. However, we detected only down-regulation of P27 by this agonist. Additionally, the concentration-dependent patterns of both SKF38393- and SKF83959-induced alterations in the levels of P27 closely resemble the effects of these ligands on the levels of the D1R-PLCbeta-associated second-messenger cascades linker, calcyon. These findings suggest that D1R-induced suppression of the cell cycle progression in EGF-supported fetal cortical precursor cells represents a net effect of competing cell cycle promoting and inhibiting molecular changes, which involve cyclin D, P27 and Raf-1. The data also show that cAMP second messenger cascade is not engaged in the D1R-induced regulation of the levels of these three proteins. Such regulation probably involves PLCbeta-associated pathways.


A Three-Component Arene Difunctionalization: Merger of C(sp3 )/(sp2 )-H Bond Addition.
A tandem three-component C-H bond addition involving the activation of an inert C(sp3 )-H bond is reported. The process enables the direct regioselective synthesis of 1,2-difunctionalized arenes with the formation of C(sp3 )- and C(sp2 )-C(arene) bonds. 2-Iodobenzoic acid derivatives behave as masked bifunctional reagent (BFR) and react with 2-pyridyl-methyl sulfoximine (MPyS) protected aliphatic acids bearing α,α-disubstituted groups, and alkenes to produce β-aryl-δ-alkenyl amide derivatives in a single operation. The transformation involves Pd(II)/Pd(IV) and Pd(II)/Pd(0) catalytic systems. Detailed mechanistic studies, including density functional theory (DFT) calculations, reveal the formation of large T-shaped palladacycles and the onset of a 1,2-palladium migration via decarboxylation.


Di-, tri-, tetra-, and hexanuclear copper(II) mono-organophosphates: structure and nuclearity dependence on the choice of phosphorus substituents and auxiliary N-donor ligands.
Reactions of 2,6-dimethylphenyl phosphate (dmppH(2)) and 2,6-diisopropylphenyl phosphate (dippH(2)) with copper(II) precursors have been investigated in the presence of auxiliary N-donor ligands, and new structural types of copper phosphates have been isolated. Copper acetate reacts with dmppH(2) in the presence of either 3,5-di-tert-butyl pyrazole (dbpz) or 3,5-dimethyl pyrazole (dmpz), leading to the isolation of tetrameric complex [Cu(dmpp)(dbpz)](4) 1 and hexanuclear cage complex [Cu(6)(PO(4))(dmpp)(3)(OAc)(3)(dmpz)(9)] 2, respectively. Whereas compound 1 is a cubane-shaped cluster whose Cu(4)O(12)P(4) core resembles the double-4-ring (D4R) zeolite SBU, compound 2 is a novel hexanuclear copper complex with an unprecedented structure in metal phosphate chemistry. Use of bulkier dippH(2) in the above reactions, however, yielded metal-free acid-base complexes [(dippH)(dbpz)(dbpzH)] 3 and [(dippH)(dmpz)(dmpzH)] 4, respectively. The reactions carried out between copper acetate and dmppH(2) or dippH(2) in the presence of chelating ligand 1,10-phenanthroline produced structurally similar dimeric copper phosphates [Cu(phen)(dmpp)(CH(3)OH)](2).2CH(3)OH 5 and [Cu(phen)(dipp)(CH(3)OH)](2).2CH(3)OH 6 with a S4R SBU core. Changing the copper source to [Cu(2)(bpy)(2)(OAc)(OH)(H(2)O)].2ClO(4) and carrying out reactions both with dippH(2) and with dmppH(2) result in the formation of trinuclear copper phosphates [Cu(3)(bpy)(3)(dmpp)(2)(CH(3)OH)(3)].2ClO(4).2CH(3)OH 7 and [Cu(3)(bpy)(3)(dipp)(2)(CH(3)OH)(3)].2ClO(4).2CH(3)OH 8. The three copper ions in 7 and 8 are held together by two bridging phosphate ligands to produce a tricyclic derivative whose core resembles the 4=1 SBU of zeolites. Compounds 1-8 have been characterized by elemental analysis and IR, absorption, emission, and EPR spectroscopic techniques. The crystal structures of compounds 1, 2, 4, 5, 6, and 8 have also been established by single-crystal X-ray diffraction studies.


[The investigation into dynamics of depression level and the quality of life in the patients after myocardial infarction under the influence of the program of physical rehabilitation].
The evaluation of the psychological condition of the patients who survived myocardial infarction and its correction taking into consideration the peculiar features of the individual reaction to the disease are the indispensable components of physical rehabilitation. The present article was designed to report the results of the study on the influence of the authors' physical rehabilitation program on the prevalence of depression and the life quality characteristics of the patients treated after myocardial infarction during the follow-up period. The patients of the main group (n=30) were enrolled in the original physical rehabilitation program. Those comprising the group of comparison (n=30) were given a course of rehabilitation in accordance with the scheme that had been recommended by the leading scientists and generally accepted in the Ukraine for the patients recovering after myocardial infarction under conditions of the out-patient clinics, spa and health resort facilities or convalescent centers. The study has demonstrated that the patients of both groups exhibited positive dynamics of their clinical condition (e.g. the decrease in the number of depressed subjects); however, this tendency was more pronounced in the main group where the number of the patients experiencing depression decreased by 61% at the end of the observation period (р<0,05). The analysis of the causes of anxiety associated with this pathology in the individual patients has demonstrated that the main factors responsible for the deterioration of the quality of life were the necessity of treatment, the limitations on the everyday physical activity, and the feeling of emotional tension. Moreover, the positive dynamics of the characteristics being evaluated was documented in the patients of the main group which gives reason to conclude that the program of physical rehabilitation proposed by the authors for the treatment of the patients after myocardial infarction is highly efficient during the follow-up period. Suffice it to say that 23 (76,7%) patients of the main group did not consider their lives as of poor quality by the end of the study period (р<0,01). There were only 18 such patients in the control group (р<0,05). The results of the present study provide a basis for recommending the proposed authors' program of physical rehabilitation for the patients treated after myocardial infarction with the emphasis on the necessity to do special dynamic exercises for the cervical and thoraco-cervical spine segments to be supplemented by the relevant educational program.


MAGED1 is a novel regulator of a select subset of bHLH PAS transcription factors.
Transcription factors of the basic helix-loop-helix (bHLH) PER-ARNT-SIM (PAS) family generally have critical and nonredundant biological roles, but some bHLH PAS proteins compete for common cofactors or recognise similar DNA elements. Identifying factors that regulate function of bHLH PAS proteins, particularly in cells where multiple family members are coexpressed, is important for understanding bHLH PAS factor biology. This study identifies and characterises a novel interaction between melanoma-associated antigen D1 (MAGED1) and select members of the bHLH PAS transcription factor family. MAGED1 binds and positively regulates the transcriptional activity of family members SIM1, SIM2, NPAS4 and ARNT2, but does not interact with AhR, HIF1α and ARNT. This interaction is mediated by PAS repeat regions which also form the interface for bHLH PAS dimerisation, and accordingly MAGED1 is not found in complex with bHLH PAS dimers. We show that MAGED1 does not affect bHLH PAS protein levels and cannot be acting as a coactivator of transcriptionally active heterodimers, but rather appears to interact with nascent bHLH PAS proteins in the cytoplasm to enhance their function prior to nuclear import. As a selective regulator, MAGED1 may play an important role in the biology of these specific factors and in general bHLH PAS protein dynamics.


Limits of size scalability of diffusion and growth: Atoms versus molecules versus colloids.
Understanding fundamental growth processes is key to the control of nonequilibrium structure formation for a wide range of materials on all length scales, from atomic to molecular and even colloidal systems. While atomic systems are relatively well studied, molecular and colloidal growth are currently moving more into the focus. This poses the question to what extent growth laws are size scalable between different material systems. We study this question by analyzing the potential energy landscape and performing kinetic Monte Carlo simulations for three representative systems. While submonolayer (island) growth is found to be essentially scalable, we find marked differences when moving into the third (vertical) dimension.


Parent involvement approach and changes in eating pathology within an adolescent obesity intervention.
Although adolescents with obesity have heightened risk for eating pathology, the impact of differential parent involvement on eating pathology after obesity treatment is unknown. We examined differences in eating pathology in adolescents whose parents were randomized to distinct interventions within adolescent obesity treatment. Participants were 82 adolescent/parent dyads (adolescents: 63 % female; 55 % racial/ethnically marginalized) enrolled in TEENS+, a 4-month behavioral weight loss intervention. Parents were randomized to either a parent weight loss treatment (TEENS+PWL) or parent skills training (TEENS+PAC). Adolescents completed the Eating Disorder Examination-Questionnaire with Instructions (EDE-Q-I) and Child Depression Inventory (CDI) at baseline, 4 m, and 7 m. Group differences in eating pathology (global score; eating concern, weight concern, shape concern, restraint) and depression across time points were evaluated with linear mixed models. No significant differences were observed between TEENS+PAC and TEENS+PWL in eating pathology or depression, nor were there group by time interactions. Time point differences were observed for all EDE-Q-I and CDI outcomes, except eating concerns; pairwise contrasts revealed a variety of change patterns. Weight and shape concerns decreased from 0 to 4 m; observed reductions were maintained at 7 m. Restraint was highest at 4 m and decreased at 7 m but did not return to baseline. EDE-Q-I global scores significantly declined over time. Depression decreased over time, but a significant difference was only observed between 0 and 7 m. Neither parent intervention yields harm related to eating pathology in adolescents engaged in obesity treatment. Obesity treatment does not appear to have iatrogenic effects on eating pathology in adolescents.


Vorapaxar and Amyotrophic Lateral Sclerosis: Coincidence or Adverse Association?
Vorapaxar, a novel antiplatelet thrombin PAR-1 inhibitor, is currently approved for post myocardial infarction and peripheral artery disease indications with concomitant use of clopidogrel and/or aspirin. The vorapaxar safety profile was acceptable. However, aside from heightened bleeding risks, excesses of solid cancers and diplopia, there were more amyotrophic lateral sclerosis (ALS) diagnoses after vorapaxar. To assess the Food and Drug Administration (FDA) reviews on the potential association of vorapaxar with ALS. The review the public FDA records on reported adverse events after vorapaxar. Incidence of ALS after vorapaxar and placebo. The ALS risk appears very small, about 1 case per 10,000 treated subjects, but quite probable. Indeed, there were overall 2 placebo and 4 vorapaxar ALS incidences in the Phase III clinical trials. Potential adverse association of vorapaxar with ALS risks may be related to off-target neuronal PAR receptor(s) blockade beyond platelet inhibition.


Survey of the vectorial competence of ticks in an endemic area of spotted fever group rickettsioses in Fukui Prefecture, Japan.
The prevalence of SFGR in ixodid ticks in the Mt. Arashima-dake area in the northern part of Fukui Prefecture was surveyed, because of strong suspicions that the first case identified in this Prefecture had become infected with R. helvetica in this region. The ticks identified consisted of three genera and six species; I.ovatus, I. persulcatus, I. monospinosus, H. flava, H. japonica and D. taiwanensis. Of all 222 ticks collected, only I. monospinosus ticks (8 of 32 examined) were positive for SFGR isolates, which were genetically identified as R. helvetica. Ticks (157 of all 222) positive for SFGR-DNA fragments consisted of I. monospinosus (14 of 32), I. persulcatus (11 of 55), I. ovatus (3 of 38), H. flava (5 of 21) and H. japonica (2 of 9). Of these, thirteen I. monospinosus, eight I. persulcatus, three I. ovatus, two H. flava and one H. japonica were identified by nucleotide sequences as positive for R. helvetica. DNA fragments from three H. flava and one H. japonica showed greater homology to R. japonica than to R. helvetica or R. asiatica. The present results indicate that it is most likely that the vector tick of R. helvetica infection in Fukui Prefecture is I. monospinosus.


[Postsurgical computed tomography of uncemented hip arthroplasty].
Presentation of the value of postsurgical computed tomography (CT) to diagnose loosening of uncemented femoral stems. Incremental CT and spiral CT were performed on six femora with implanted uncemented stems after the entire femora were embedded in polymethylmethacrylate. The femora were subsequently sectioned (thickness 1 mm, separation 8 mm) and the medial and lateral contact areas of the prosthetic stem compared with the CT data. The CT showed a contact of femoral stem and cortical bone between 0.4 mm (3.4 %) and 4.8 mm (47.1 %) and the section specimens between 0.9 mm (8.7 %) and 3.4 mm (36.7 %). No correlation was found between the results (r = 0.61), since the individual differences were up to 24 % in almost all sections. Neither single-slice nor two-slice CT is capable of demonstrating the direct bone-endoprosthesis contact. Multidetector row CT (MDCT) is conceivably more accurate to measure the cortical contact of the femoral stem.


Protective Effect of L-Theanine on Haloperidol-Induced Orofacial.
Tardive dyskinesia (TD) is a severe side effect of chronic neuroleptic treatment consisting of abnormal involuntary movements, characterized by orofacial dyskinesia (OD). Haloperidol (HAL)- induced OD has been widely used as an animal model to study the neuropathophysiology of human TD with its pathophysiology strongly associated with striatal oxidative stress. L-Theanine (LT), one of the major amino acid components in green tea, has potent antioxidative effects and is able to protect against various oxidative injuries. In this study, we examined the potential protective effects of LT on HAL-induced behavioral and neurochemical dysfunction in rats. HAL treatment (1 mg/kg i.p. for 21 days) induced significant increases (P < 0.001) in the frequency of vacuous chewing movement (VCM) and tongue protrusion (TP) as well as the duration of facial twitching (FT). LT treatment (100, 300 mg/kg orally for 35 days, starting 14 days before HAL injection) was able to prevent most of the HAL-induced OD. LT treatment was also able to reduce the lipid peroxidation (LPO) production, and enhance the antioxidation power in striatum from rats with HAL treatment. The above results indicate that LT has a protective role against HAL-induced OD, probably via its powerful antioxidative properties. Thus, LT may have a clinically relevant therapeutic effect in delaying or treating TD.


GRAM domain-containing protein 1B (GRAMD1B), a novel component of the JAK/STAT signaling pathway, functions in gastric carcinogenesis.
Dysregulated JAK/STAT signaling has been implicated in the molecular pathogenesis of gastric cancer. However, downstream effectors of STAT signaling that facilitate gastric carcinogenesis remain to be explored. We previously identified the Drosophila ortholog of human GRAMD1B in our genome-wide RNAi screen to identify novel components of the JAK/STAT signaling pathway in Drosophila. Here, we examined the involvement of GRAMD1B in JAK/STAT-associated gastric carcinogenesis. We found that GRAMD1B expression is positively regulated by JAK/STAT signaling and GRAMD1B inhibition decreases STAT3 levels, suggesting the existence of a positive feedback loop. Consistently, GRAMD1B and JAK/STAT signaling acted synergistically to promote gastric cancer cell survival by upregulating the expression of the anti-apoptotic molecule Bcl-xL. Interestingly, our immunohistochemical analysis for GRAMD1B revealed a gradual loss of cytoplasmic staining but an increase in the nuclear accumulation of GRAMD1B, as gastric tissue becomes malignant. GRAMD1B expression levels were also found to be significantly associated with clinicopathological features of the gastric cancer patients, particularly the tumor grades and lymph node status. Moreover, GRAMD1B and pSTAT3 (Tyr705) showed a positive correlation in gastric tissues, thereby confirming the existence of a close link between these two signaling molecules in vivo. This new knowledge about JAK/STAT-GRAMD1B regulation deepens our understanding of JAK/STAT signaling in gastric carcinogenesis and provides a foundation for the development of novel biomarkers in gastric cancer.


Management of severe acute respiratory distress syndrome: a primer.
This narrative review explores the physiology and evidence-based management of patients with severe acute respiratory distress syndrome (ARDS) and refractory hypoxemia, with a focus on mechanical ventilation, adjunctive therapies, and veno-venous extracorporeal membrane oxygenation (V-V ECMO). Severe ARDS cases increased dramatically worldwide during the Covid-19 pandemic and carry a high mortality. The mainstay of treatment to improve survival and ventilator-free days is proning, conservative fluid management, and lung protective ventilation. Ventilator settings should be individualized when possible to improve patient-ventilator synchrony and reduce ventilator-induced lung injury (VILI). Positive end-expiratory pressure can be individualized by titrating to best respiratory system compliance, or by using advanced methods, such as electrical impedance tomography or esophageal manometry. Adjustments to mitigate high driving pressure and mechanical power, two possible drivers of VILI, may be further beneficial. In patients with refractory hypoxemia, salvage modes of ventilation such as high frequency oscillatory ventilation and airway pressure release ventilation are additional options that may be appropriate in select patients. Adjunctive therapies also may be applied judiciously, such as recruitment maneuvers, inhaled pulmonary vasodilators, neuromuscular blockers, or glucocorticoids, and may improve oxygenation, but do not clearly reduce mortality. In select, refractory cases, the addition of V-V ECMO improves gas exchange and modestly improves survival by allowing for lung rest. In addition to VILI, patients with severe ARDS are at risk for complications including acute cor pulmonale, physical debility, and neurocognitive deficits. Even among the most severe cases, ARDS is a heterogeneous disease, and future studies are needed to identify ARDS subgroups to individualize therapies and advance care.


Harnessing Electron Spin Hyperpolarization in Chromophore-Radical Spin Probes for Subcellular Resolution in Electron Paramagnetic Resonance Imaging: Concept and Feasibility.
Obtaining a subcellular resolution for biological samples doped with stable radicals at room temperature (RT) is a long-sought goal in electron paramagnetic resonance imaging (EPRI). The spatial resolution in current EPRI methods is constrained either because of low electron spin polarization at RT or the experimental limitations associated with the field gradients and the radical linewidth. Inspired by the recent demonstration of a large electron spin hyperpolarization in chromophore-nitroxyl spin probe molecules, the present work proposes a novel optically hyperpolarized EPR imaging (OH-EPRI) method, which combines the optical method of two-photon confocal microscopy for hyperpolarization generation and the rapid scan (RS) EPR method for signal detection. An important aspect of OH-EPRI is that it is not limited by the abovementioned restrictions of conventional EPRI since the large hyperpolarization in the spin probes overcomes the poor thermal spin polarization at RT, and the use of two-photon optical excitation of the chromophore naturally generates the required spatial resolution, without the need for any magnetic field gradient. Simulations based on time-dependent Bloch equations, which took into account both the RS field modulation and the hyperpolarization generation by optical means, were performed to examine the feasibility of OH-EPRI. The simulation results revealed that a spatial resolution of up to 2 fL can be achieved in OH-EPRI at RT under in vitro conditions. Notably, the majority of the requirements for an OH-EPRI experiment can be fulfilled by the currently available technologies, thereby paving the way for its easy implementation. Thus, the proposed method could potentially bridge the sensitivity gap between the optical and magnetic imaging techniques.


Anti-tumor activity of cetuximab plus avelumab in non-small cell lung cancer patients involves innate immunity activation: findings from the CAVE-Lung trial.
We recently conducted Cetuximab-AVElumab-Lung (CAVE-Lung), a proof-of-concept, translational and clinical trial, to evaluate the combination of two IgG1 monoclonal antibodies (mAb): avelumab, an anti-PD-L1 drug, and cetuximab, an anti-epidermal growth factor receptor (EGFR) drug, as second- or third-line treatment in non-small cell lung cancer (NSCLC) patients. We have reported clinically relevant anti-tumor activity in 6/16 patients. Clinical benefit was accompanied by Natural Killer (NK) cell-mediated antibody-dependent cell cytotoxicity (ADCC). Among the 6 responding patients, 3 had progressed after initial response to a previous treatment with single agent anti-PD-1, nivolumab or pembrolizumab. We report long-term clinical follow-up and additional findings on the anti-tumor activity and on the immune effects of cetuximab plus avelumab treatment for these 3 patients. As of November 30, 2021, 2/3 patients were alive. One patient was still on treatment from 34 months, while the other two patients had progression free survival (PFS) of 15 and 19 months, respectively. Analysis of serially collected peripheral blood mononuclear cells (PBMC) revealed long-term activation of NK cell-mediated ADCC. Comprehensive genomic profile analysis found somatic mutations and germline rare variants in DNA damage response (DDR) genes. Furthermore, by transcriptomic analysis of The Cancer Genome Atlas (TCGA) dataset we found that DDR mutant NSCLC displayed high STING pathway gene expression. In NSCLC patient-derived three-dimensional in vitro spheroid cultures, cetuximab plus avelumab treatment induced additive cancer cell growth inhibition as compared to single agent treatment. This effect was partially blocked by treatment with an anti-CD16 mAb, suggesting a direct involvement of NK cell activation. Furthermore, cetuximab plus avelumab treatment induced 10-, 20-, and 20-fold increase, respectively, in the gene expression of CCL5 and CXCL10, two STING downstream effector cytokines, and of interferon β, as compared to untreated control samples. DDR mutations may contribute to DDR-induced STING pathway with sustained innate immunity activation following cetuximab plus avelumab combination in previously treated, PD-1 inhibitor responsive NSCLC patients.


Impact of dietary protein level and source of polyunsaturated fatty acids on lipid metabolism-related protein expression and fatty acid concentrations in porcine tissues.
The study assessed the effects of reduced protein (RPD) vs high protein diet (HPD) in combination with n-3/n-6 PUFA-containing plant oils [linseed oil (LO)/sunflower seed oil (SO)] supplementation on lipid metabolism-related protein expression and fatty acid concentrations in porcine tissues. Forty male Landrace pigs (castrates) were allocated into four groups fed diets different in dietary protein and PUFA level and one control group. SCD-1 protein expression in pig muscle, back fat, and liver was not affected by diet. The protein expression of precursor (pSREBP-1c) and active nuclear form of SREBP-1c (mSREBP-1c) in muscle and back fat was affected by diet, however not in liver of pigs. In contrast, the expression of ACC and FAS expression was significantly affected by diet only in the liver. The fatty acid concentrations in muscle, liver, and back fat resulted in higher n-3 PUFA concentrations of LO groups compared to the SO groups.


Twin T-graphene: a new semiconducting 2D carbon allotrope.
Two dimensional carbon allotropes with multiple atomic layers have attracted significant interest recently. In this work a new three atomic layer thick 2D carbon allotrope, twin T-graphene, is proposed. The sp2 hybridized dynamically stable phase is a nonmagnetic semiconducting material with an indirect band gap of 1.79 eV. Thermal stability investigations indicate that the material undergoes no change in the bonding pattern at 2000 K. The study of its mechanical properties indicates that it is an elastically isotropic soft material with low values of elastic constants. The electron mobility of the semiconductor is found to be nearly 375 cm2 V-1 s-1. The material when doped with single nitrogen in the tetragonal site undergoes a drastic change in its electronic properties and manifests itself in the form of a bipolar magnetic semiconductor which is a potential spintronic material. The study of the optical properties clearly indicates an optical gap of 1.89 eV. The material shows optical response in the visible range. Two sharp characteristic EELS peaks indicate the presence of this material. All these characteristics indicate that this material can have potential photocatalytic activity and be an attractive material for the applications in field effect transistors.


A genetic risk score comprising known venous thromboembolism loci is associated with chronic venous disease in a multi-ethnic cohort.
Chronic venous disease is common and shares some risk factors with venous thromboembolism (VTE). Several genetic loci have been discovered and well-replicated for VTE in European descent populations. We examined associations of a genetic risk score (GRS), comprising known VTE loci, with chronic venous disease. The San Diego Population Study (SDPS) is a multi-ethnic cohort that evaluated 2404 men and women aged 29-91 from 1994 to 1998 for chronic venous disease. The current study includes 1447 participants genotyped for 33 variants in 22 established VTE risk loci. Using these variants, unweighted and weighted GRS were constructed. Logistic regression was used to examine associations with venous disease. In non-Hispanic whites, African-Americans, Hispanics, and Asians, each standard deviation increment higher of the unweighted 33-SNP GRS was associated with a 1.45-fold (95% CI (1.26, 1.67)), 1.74-fold (1.18, 2.55), a 1.80-fold (1.30, 2.51), and 1.88-fold (1.30, 2.73) greater odds, respectively, for moderate plus severe disease. The difference in c-statistics was significant between a known venous risk factor model and a model adding the 33-SNP GRS for whites (p=0.008), African-Americans (0.03), and Hispanics (p=0.04), with marginal significance in Asians (p=0.06). GRS comprising variants primarily from VTE findings in European descent populations were associated with chronic venous disease across all race/ethnic groups, and contributed significantly to prediction, indicating some level of generalizability to other race/ethnic groups. Future work should focus on more in depth examination of racial/ethnic group genetic architecture in relation to chronic venous disease.


Polyesterurethane foam scaffold for smooth muscle cell tissue engineering.
Reconstruction of the genitourinary tract, using engineered urological tissues, requires a mechanically stable biodegradable and biocompatible scaffold and cultured cells. Such engineered autologous tissue would have many clinical implications. In this study a highly porous biodegradable polyesterurethane-foam, DegraPol was evaluated with tissue engineered human primary bladder smooth muscle cells. The cell-polymer constructs were characterized by histology, scanning electron microscopy, immunohistochemistry and proliferation assays. Smooth muscle cells grown on DegraPol showed the same morphology as when grown on control polystyrene surface. Positive immunostaining with alpha smooth muscle actin indicated the preservation of the specific cell phenotype. Micrographs from scanning electron microscopy showed that the cells grew on the foam surface as well as inside the pores. In addition they grew as cell aggregates within the foam. The smooth muscle cells proliferated on the Degrapol; however, proliferation rate decreased due to apoptosis with time in culture. This study showed that Degrapol has the potential to be used as a scaffold.


Acculturation and manifestation of depressive symptoms among Korean-American older adults.
The present study examined the role of acculturation in manifestation of depressive symptoms among 230 Korean-American older adults (M age = 69.8, SD = 7.05) in Florida. Given the cultural emphasis on modesty and self-effacement in the traditional Korean society, we hypothesized that older Korean-Americans who were less acculturated to American culture, when compared to the more acculturated ones, would be more likely to inhibit positive affects in depressive symptom reports. Using two validated measures of depressive symptoms, the short forms of the Geriatric Depression Scale (GDS-SF) and the Center for Epidemiologic Studies-Depression Scale (CES-D), different response patterns for low and high acculturation groups were identified. First, there was low comparability in the factor structures for both the GDS-SF and the CES-D across low and high acculturation groups. A differential item function (DIF) analysis based on partial correlations indicated that older adults in the low acculturation group inhibited endorsing positive affect items; one item in the GDS-SF (#7 'feel happy') and two items in the CES-D (# 5 'felt hopeful' and # 8 'was happy'). The finding suggests the substantial cultural influences in expressing emotions, especially those related to positive affects. Implications are discussed from a cultural perspective.


Conquering combined thoracic organ and liver transplantation: indications and outcomes for heart-liver and lung-liver transplantation.
Combined thoracic organ and liver transplantation has been shown to be a viable treatment option for patients with end-stage disease lung or heart and disease. There are increasing number of cases reported in the literature, as the number of institutions utilizing this strategy is growing. Herein, we review the current literature of combined thoracic and liver transplantation. A larger number of combined heart or lung and liver transplants (CHLT and CLLT) are being performed. A recent literature search showed approximately 231 CHLT and 89 CLLT and being described. One-year patient survival ranged from 71 to 80% for CLLT and 80-93% for CHLT, respectively. Indications for combined transplant and disease-specific outcomes are still being evaluated. Additionally, salvage modalities such as extracorporeal membrane oxygenation and ex-vivo lung perfusion are also being described. Combined thoracic and liver transplant continues to be a viable treatment option for patients with end-stage disease that would likely not survive single transplant alone. Salvage modalities, such as extracorporeal membrane oxygenation and ex-vivo lung perfusion, may help in extending candidacy for this combined transplant. Outcomes, to date, are similar to results observed for solitary thoracic organ recipients, justifying CHLT and CLLT as a viable option for these patients. Continued identification of outcomes is needed to justify allocation of dual organs to a single recipient.


The effect of long-term feeding of soya-bean flour diets on pancreatic growth in the rat.
1. Pancreatic growth was measured in rats by changes in pancreatic weight, nucleic acid content and protein content after feeding diets of heated soya-bean flour (HSF), raw soya-bean flour (RSF), 200 g raw soya-bean flour + 800 g heated soya-bean flour/kg (80 HSF) and 400 g raw soya-bean flour + 600 g heated soya-bean flour/kg (60 HSF) for periods up to 36 weeks. Control rats of comparable age to soya-bean flour-fed rats were continued on rat cubes during the 36-week study. 2. Cube-fed rats remained significantly heavier than rats fed on soya-bean flour diets. Analysis of variance showed rats fed on HSF were significantly heavier than RSF-fed rats and rats fed on 80 HSF significantly heavier than those fed on 60 RSF. 3. Pancreatic indices in HSF-fed rats were similar to comparable control rats. 4. Hypertrophy was found in rats fed on the RSF-containing diets with the extent of enlargement corresponding to the RSH content. Hyperplasia was also found in rats fed on RSF and 60 HSF. 5. The greatest pancreatic growth was seen in RSF-fed rats with all the indices peaking at 8 weeks followed by a decline and then a rise again at 36 weeks. 6. The fall in pancreatic indices in rats fed on RSF for 12 and 24 weeks is most likely an effect of general malnutrition due to the multiple deficiences in amino acids which occur in animals fed on RSF. The rise at 36 weeks may reflect increased body growth or the beginning of adenomatous changes.


Who killed whom?: victimization and culpability in the social construction of murder.
Based on in-depth interviews with relatives of people convicted of murder, this article examines the ways in which everyday understandings of 'murder' are socially constructed, as revealed by the narratives of murderers' relatives. To this end, interviewees' explanations of the killings are analysed and a distinction is drawn between interviewees who understood the killings committed by their relatives as manslaughter and those who accepted the murder verdict. In defining the offences in this way, interviewee s identified the significance of victimization and culpability to understandings of interpersonal violence. Through the analysis of interview data, it is possible to examine the ways in which 'murder' is seen to have occurred only when particular criteria of victimization and culpability are met.


POD-1/TCF21 Reduces SHP Expression, Affecting LRH-1 Regulation and Cell Cycle Balance in Adrenocortical and Hepatocarcinoma Tumor Cells.
POD-1/TCF21 may play a crucial role in adrenal and gonadal homeostasis and represses Sf-1/SF-1 expression in adrenocortical tumor cells. SF-1 and LRH-1 are members of the Fzt-F1 subfamily of nuclear receptors. LRH-1 is involved in several biological processes, and both LRH-1 and its repressor SHP are involved in many types of cancer. In order to assess whether POD-1 can regulate LRH-1 via the same mechanism that regulates SF-1, we analyzed the endogenous mRNA levels of POD-1, SHP, and LRH-1 in hepatocarcinoma and adrenocortical tumor cells using qRT-PCR. Hereafter, these tumor cells were transiently transfected with pCMVMycPod-1, and the effect of POD-1 overexpression on E-box elements in the LRH-1 and SHP promoter region were analyzed by ChIP assay. Also, Cyclin E1 protein expression was analyzed to detect cell cycle progression. We found that POD-1 overexpression significantly decreased SHP/SHP mRNA and protein levels through POD-1 binding to the E-box sequence in the SHP promoter. Decreased SHP expression affected LRH-1 regulation and increased Cyclin E1. These findings show that POD-1/TCF21 regulates SF-1 and LRH-1 by distinct mechanisms, contributing to the understanding of POD-1 involvement and its mechanisms of action in adrenal and liver tumorigenesis, which could lead to the discovery of relevant biomarkers.


Comparison between two molar incisor hypomineralization detection criteria in epidemiological surveys.
There is no consensus on which molar incisor hypomineralization (MIH) indices are more suitable for epidemiological surveys. To compare the operational aspects and diagnostic ability of the MIH index (simplified/MIH_s and extended/MIH_e) with the MIH-Severity Scoring System (MIH-SSS) in classifying and diagnosing MIH. This cross-sectional study assessed the indices in a homogeneous group of 680 6- to 10-year-old schoolchildren in Bauru, Brazil, who had at least one first permanent molar, ensuring consistent conditions. Followed by toothbrushing, the children seated on school chairs were examined by the two calibrated researchers under artificial lighting, using mouth mirror and WHO probe, and chronometer recording the duration of examinations. The prevalence of MIH was 24.7%. The most common characteristic of MIH was demarcated opacity, with a prevalence of 81.7% and 85.45% according to the MIH_s and the MIH-SSS, respectively. A positive association was observed among the MIH_s, the MIH_e, and the MIH-SSS (chi-squared test; p < .01). The MIH-SSS demonstrated a shorter average application time than both versions of the MIH index (ANOVA/Tukey; p < .05). Additionally, fluorosis was found to be the most prevalent among other developmental defects of enamel, with a prevalence of 38.38%. All systems effectively diagnosed MIH and its characteristics.


Evaluation of Phenol-Substituted Diphyllin Derivatives as Selective Antagonists for Ebola Virus Entry.
Ebola virus (EBOV) is an aggressive filoviral pathogen that can induce severe hemorrhagic fever in humans with up to 90% fatality rate. To date, there are no clinically effective small-molecule drugs for postexposure therapies to treat filoviral infections. EBOV cellular entry and infection involve uptake via macropinocytosis, navigation through the endocytic pathway, and pH-dependent escape into the cytoplasm. We report the inhibition of EBOV cell entry via selective inhibition of vacuolar (V)-ATPase by a new series of phenol-substituted derivatives of the natural product scaffold diphyllin. In cells challenged with Ebola virus, the diphyllin derivatives inhibit viral entry dependent upon structural variations to low nanomolar potencies. Mechanistically, the diphyllin derivatives had no effect on uptake and colocalization of viral particles with endocytic marker LAMP1 but directly modulated endosomal pH. The most potent effects were reversible exhibiting higher selectivity than bafilomycin or the parent diphyllin. Unlike general lysosomotrophic agents, the diphyllin derivatives showed no major disruptions of endocytic populations or morphology when examined with Rab5 and LAMP1 markers. The dilated vacuole phenotype induced by apilimod treatment or in constitutively active Rab5 mutant Q79L-expressing cells was both blocked and reversed by the diphyllin derivatives. The results are consistent with the action of the diphyllin scaffold as a selective pH-dependent viral entry block in late endosomes. Overall, the compounds show improved selectivity and minimal cytotoxicity relative to classical endosomal acidification blocking agents.


The three-dimensional configuration of the elastic fiber network in canine saphenous vein. A stereo scanning electron microscopic study.
Stereo scanning electron microscopy was used to study the normal arrangement of elastic fibers in canine saphenous veins. Selective alkali digestion and autoclaving exposed a network of interconnecting elastic fibers throughout the venous wall. 14 normal saphenous veins were surgically removed from 7 healthy dogs. Unfixed 1-cm segments of the isolated specimens were digested by sonication for 30 min in 0.5 N NaOH solution and then autoclaved for 30 min. The digested specimens were then fixed and routinely prepared for scanning electron microscopy. Large longitudinally oriented fibers in each tunica branched and anastomosed with adjacent fibers. Small fibers branched off at almost right angles and interconnected the longitudinal fibers. The configuration of the elastic network varied between the tunicae of the venous wall. The different networks were interconnected by anastomosing fibers of adjacent tunica to form a single elastic cylinder throughout the venous wall. The internal elastic lamina consisted of a single layer of fibers with a fishnet-like arrangement around the periphery of the luminal surface. Large, longitudinally oriented elastic fibers of the tunica media branched and anastomosed as in the internal elastic lamina. However, they also had tangential orientation and traversed different levels within the media. As a result, stratified layers were not formed. The external lamina consisted of several parallel layers of longitudinally oriented ribbons of elastic. Thick fibers interconnected these broad ribbons on the same and adjacent levels to form discontinuous layers. The configuration of the elastic network of the canine saphenous vein is compared to that previously reported for human saphenous vein. It is suggested that the architecture of this elastic network would contribute to vascular integrity and flexibility as well as aid in the distribution of stress throughout the venous wall. Basic knowledge of the elastic fiber network in this vein may be applied to future studies of diseased and grafted vessels.


Colorimetric sensor assay for discrimination of proteins based on exonuclease I-triggered aggregation of DNA-functionalized gold nanoparticles.
Proteins play a key role in disease diagnosis, and protein discrimination is an important but difficult issue. Here, we report a novel strategy for improving protein discrimination through a facile colorimetric sensor array, which is based on DNA-gold nanoparticle (AuNP) conjugates manipulated by exonuclease I (Exo I). Different proteins exhibit diverse affinities toward the three DNAs, and the DNA-protein binding is resistant to the digestion of Exo I and protects the AuNPs from aggregation in high concentrations of NaCl media, forming distinct response patterns of the array. These response patterns as "fingerprints" can be acquired on the sensor array and then identified by linear discriminant analysis (LDA). The sensor array achieved the correct discrimination of 15 proteins at a 10 nM level in buffer solution and real serum samples. Also, the sensor array had the capability to discriminate individual proteins and the mixtures of them. Remarkably, the practicability of the sensor array was further confirmed by the identification of 35 unknown protein samples with 100% accuracy.


Problems and prospects of acquistion of human cadaver for medical education in Nigeria.
To determine the factors affecting cadaver acquisition in Nigeria, and to find a solution to the problem. The research was conducted from May 2009 to November 2010 in the Anatomy and Histopathology Departments of selected medical schools and government hospitals in Nigeria. It was a retrospective study done on the basis of simple random sampling technique. A total of 38 questionnaires were distributed of which 34 were received and analysed statistically by percentage method. Problems identified in cadaver acquisition included: religion, culture, ignorance and love even after death. Steps which may change the scenario were identified as education, provision of ambulance and donation centres, improved acquisitions procedures and formalities, and government legislation. Alternatives to cadaver dissection include the use of audio-visual aids, models of body parts and anirnal bodies, but the scarcity of cadavers in most colleges will affect the quality of anatomical knowledge and subsequent clinical practice. The supply of cadavers will remain scarce and affected by religious and moral factors. There is a need to promote the concept of voluntary donation of one's body for the good of the others which is essentially a humanitarian approach and rewarding in terms of promoting the cause of medical education in Nigeria.


A highly efficient microfluidic nano biochip based on nanostructured nickel oxide.
We present results of the studies relating to fabrication of a microfluidic biosensor chip based on nickel oxide nanorods (NRs-NiO) that is capable of directly measuring the concentration of total cholesterol in human blood through electrochemical detection. Using this chip we demonstrate, with high reliability and in a time efficient manner, the detection of cholesterol present in buffer solutions at clinically relevant concentrations. The microfluidic channel has been fabricated onto a nickel oxide nanorod-based electrode co-immobilized with cholesterol esterase (ChEt) and cholesterol oxidase (ChOx) that serves as the working electrode. Bare indium tin oxide served as the counter electrode. A Ag/AgCl wire introduced to the outlet of the microchannel acts as a reference electrode. The fabricated NiO nanorod-based electrode has been characterized using X-ray diffraction, Raman spectroscopy, HR-TEM, FT-IR, UV-visible spectroscopy and electrochemical techniques. The presented NRs-NiO based microfluidic sensor exhibits linearity in the range of 1.5-10.3 mM, a high sensitivity of 0.12 mA mM(-1) cm(-2) and a low value of 0.16 mM of the Michaelis-Menten constant (Km).


Diagnosis of familial amyloidotic polyneuropathy: isolation of variant prealbumin.
A novel, small-scale method was developed for detecting carriers of a prealbumin variant associated with type 1 familial amyloidotic polyneuropathy (FAP). Prealbumin isolated from plasma by a two-step preliminary chromatographic procedure was further separated into two peaks by reverse-phase high-performance liquid chromatography. The normal and variant prealbumins were identified by secondary ion mass spectrometry. The procedure is relatively simple, reliable, and applicable to the definitive diagnosis of FAP in affected patients and also as a preclinical test for the offspring of patients with FAP.


Continuous versus pulsed tones in audiometry.
The purpose of this study was to compare auditory thresholds obtained for continuous and pulsed tones in listeners with normal hearing. Auditory thresholds, test-retest reliability, false-positive responses, and listener preference were compared for both signals. Hearing thresholds and test-retest reliability were comparable for the 2 signals, and there were no significant differences in the number of false positives or the number of presentations required to reach threshold. Listener preference, however, indicated that pulsed tones were preferred over continuous tones by 67% of the listeners when listening to low-level or high-frequency tones. These findings, coupled with previous reports demonstrating the benefits of using automatically pulsed tones in threshold assessment for listeners with tinnitus, support the general use of pulsed tones in clinical audiometry.


Body mass, fat percentage, and fat free mass as reference variables for lung function: effects on terms for age and sex.
Sex specific cross sectional reference values for lung function indices usually employ a linear model with terms for age and stature. The effects of also matching for body mass index (BMI = mass/stature(2)) or its components, fat percentage of body mass (fat%) and fat free mass index (FFMI = fat free mass/stature(2)) were studied. The subjects were 458 asymptomatic male and female non-smokers (383 men) and 22 female ex-smokers. Measurements were made of ventilatory capacity, lung volumes, transfer factor (diffusing capacity, single breath CO method), and body composition (skinfold method). Linear and proportional regression models were used. Terms for fat% and FFMI significantly improved the accuracy of reference values for all the primary lung function indices. The improvements in subjects with atypical physiques (fat% and FFMI at the ends of the distributions for the subjects) were in the range 0.3-2.3 SD compared with conventional regression equations. The new partial regression coefficients on age were independent of age related changes in body fat. The coefficient for total lung capacity (TLC) on age in men was now positive. Most differences between the sexes were eliminated. A term for BMI improved the descriptions of subdivisions of TLC but lacked the other advantages. Allowance for fat% and FFMI increases the accuracy of reference equations for lung function, particularly for subjects with a lot of fat and little muscle or vice versa. Allowance for BMI is less informative.