Neural Responses to Sexual Stimuli in Heterosexual and Homosexual Men and Women: Men's Responses Are More Specific.
Patterns of genital arousal in response to gendered sexual stimuli (i.e., sexual stimuli presenting members of only one sex at a time) are more predictive of men's than of women's sexual orientations. Additional lines of evidence may shed light on the nature of these differences. We measured neural activation in homosexual and heterosexual men and women using fMRI while they viewed three kinds of gendered sexual stimuli: pictures of nude individuals, pictures of same-sex couples interacting, and videos of individuals self-stimulating. The primary neural region of interest was the ventral striatum (VS), an area of central importance for reward processing. For all three kinds of stimuli and for both VS activation and self-report, men's responses were more closely related to their sexual orientations compared with women's. Furthermore, men showed a much greater tendency to respond more positively to stimuli featuring one sex than to stimuli featuring the other sex, leading to higher correlations among men's responses as well as higher correlations between men's responses and their sexual orientations. Whole-brain analyses identified several other regions showing a similar pattern to the VS, and none showed an opposite pattern. Because fMRI is measured identically in men and women, our results provide the most direct evidence to date that men's sexual arousal patterns are more gender specific than women's.


Dynamic imaging of the hepatitis C virus NS5A protein during a productive infection.
Hepatitis C virus (HCV) NS5A is essential for viral genome replication within cytoplasmic replication complexes and virus assembly at the lipid droplet (LD) surface, although its definitive functions are poorly understood. We developed approaches to investigate NS5A dynamics during a productive infection. We report here that NS5A motility and efficient HCV RNA replication require the microtubule network and the cytoplasmic motor dynein and demonstrate that both motile and relatively static NS5A-positive foci are enriched with host factors VAP-A and Rab5A. Pulse-chase imaging revealed that newly synthesized NS5A foci are small and distinct from aged foci, while further studies using a unique dual fluorescently tagged infectious HCV chimera showed a relatively stable association of NS5A foci with core-capped LDs. These results reveal new details about the dynamics and maturation of NS5A and the nature of potential sites of convergence of HCV replication and assembly pathways. Hepatitis C virus (HCV) is a major cause of serious liver disease worldwide. An improved understanding of the HCV replication cycle will enable development of novel and improved antiviral strategies. Here we have developed complementary fluorescent labeling and imaging approaches to investigate the localization, traffic and interactions of the HCV NS5A protein in living, virus-producing cells. These studies reveal new details as to the traffic, composition and biogenesis of NS5A foci and the nature of their association with putative sites of virus assembly.


Improving Functional Language and Social Motivation with a Parent-Mediated Intervention for Toddlers with Autism Spectrum Disorder.
Recent research suggests that children with autism spectrum disorder (ASD) may now be reliably identified in later infancy, highlighting the need for empirically-validated interventions for infants and toddlers with early symptoms of ASD. Using a multiple baseline design across 15- to 21-month-old toddlers, this study implemented a brief, parent-mediated, Pivotal Response Treatment program, focusing on improving expressive communication. The results indicated that verbal communication improved as a consequence of the intervention, with concomitant improvements in untreated areas for all participants. Following the intervention, symptoms of autism decreased and parents reported satisfaction with the program's ease of implementation and observed child gains. The results are discussed in terms of developing very early interventions to improve developmental trajectories for infants and toddlers.


Initial Report of Second-Line FOLFIRI in Combination with Ramucirumab in Advanced Gastroesophageal Adenocarcinomas: A Multi-Institutional Retrospective Analysis.
The randomized phase III RAINBOW trial established paclitaxel (pac) plus ramucirumab (ram) as a global standard for second-line (2L) therapy in advanced gastric and gastroesophageal junction adenocarcinoma, together gastroesophageal adenocarcinoma (GEA). Patients (pts) receiving first-line (1L) FOLFOX often develop neuropathy that renders continued neurotoxic agents in the 2L setting unappealing and other regimens more desirable. As such, FOLFIRI-ram has become an option for patients with 2L GEA. FOLFIRI-ramucirumab (ram) has demonstrated safety and activity in 2L colorectal cancer, but efficacy/safety data in GEA are lacking. Patients with GEA treated with 2L FOLFIRI-ram between August 2014 and April 2018 were identified. Clinicopathologic data including oxaliplatin neurotoxicity rates/grades (G), 2L treatment response, progression-free survival (PFS), overall survival (OS), safety, and molecular features were abstracted from three U.S. academic institutions. Kaplan-Meier survival analysis was used to generate PFS/OS; the likelihood ratio test was used to determine statistical significance. We identified 29 pts who received 2L FOLFIRI-ram. All pts received 1L platinum + fluoropyrimidine, and 23 of 29 (79%) had post-1L neuropathy; 12 (41%) had G1, and 11 (38%) had G2. Patients were evenly split between esophagus/gastroesophageal junction (12; 41%) and gastric cancer (17; 59%). Among evaluable pts (26/29), the overall response rate was 23% (all partial response) with a disease control rate of 79%. Median PFS was 6.0 months and median OS was 13.4 months among all evaluable pts. Six- and 12-month OS were 90% (n = 18/20) and 41% (n = 7/17). There were no new safety signals. We provide the first data suggesting FOLFIRI-ram is a safe, non-neurotoxic regimen comparing favorably with the combination of pac + ram used in the seminal RAINBOW trial. Results of this study provide initial support for the safety and efficacy of second-line (2L) FOLFIRI-ramucirumab (ram) after progression on first-line platinum/fluoropyrimidine in patients with gastroesophageal adenocarcinoma (GEA). The overall response, progression-free survival, overall survival, and toxicity profile compare favorably with paclitaxel (pac) + ram and highlight the importance of the ongoing phase II RAMIRIS trial examining FOLFIRI-ram versus pac + ram in 2L GEA (NCT03081143). FOLFIRI-ram may warrant consideration for inclusion as an alternate regimen in consensus guidelines for GEA.


Multiple vortex vein ampulla varicosities.
Vortex vein ampulla varicosities are asymptomatic, harmless, findings in the retina. They are incidentally picked up on routine eye examination or when presenting for unrelated ocular symptoms. Clinicians and other eye care professionals unaware of this condition may be alarmed and may subject patients to unnecessary anxiety and expensive investigations. We present a rare case of varicosity of two vortex veins involving one quadrant of the retina. We have also shown simple clinical methods of establishing the diagnosis of vortex vein varicosity.


Point-of-Care Testing in Burn Patients.
Severe burn injury has an impact on the coagulation system, but a unique definition regarding these changes is still missing. The results of conventional coagulation assays (CCAs) measured in daily clinical practice are often interpreted as coagulopathic, which implies a bleeding tendency. However, viscoelastic coagulation assays (VCA) like Rotational Thromboelastometry (ROTEM) and Thromboelastography (TEG) depict a hypercoagulable state. Therefore, hemostatic interventions should not be indicated according to deranged CCA results, but only in case of clinically relevant bleeding plus indicative VCA results. Massive blood loss mainly results from surgical excision of burn wounds. VCAs seem to be capable of guiding target-oriented coagulation management in this context. Owing to the increased thromboembolic risk, it appears rational to individualize pharmacologic venous thromboembolism prophylaxis by using sensitive laboratory tests and drug monitoring. Studies evaluating the use of new VCA test modifications are highly warranted and may substantially improve outcome in this difficult-to-treat patient population.


The optimal particle-mesh interpolation basis.
The fast Ewald methods are widely used to compute the point-charge electrostatic interactions in molecular simulations. The key step that introduces errors in the computation is the particle-mesh interpolation. In this work, the optimal interpolation basis is derived by minimizing the estimated error of the fast Ewald method. The basis can be either general or model specific, depending on whether or not the charge correlation has been taken into account. By using the TIP3P water as an example system, we demonstrate that the general optimal basis is always more accurate than the B-spline basis in the investigated parameter range, while the computational cost is at most 5% more expensive. In some cases, the optimal basis is found to be two orders of magnitude more accurate. The model specific optimal basis further improves the accuracy of the general optimal basis, but requires more computational effort in the optimization, and may not be transferable to systems with different charge correlations. Therefore, the choice between the general and model specific optimal bases is a trade-off between the generality and the accuracy.


Peptide ligands of pp60(c-src) SH2 domains: a thermodynamic and structural study.
Thermodynamic measurements, structural determinations, and molecular computations were applied to a series of peptide ligands of the pp60(c-src) SH2 domain in an attempt to understand the critical binding determinants for this class of molecules. Isothermal titration calorimetry (ITC) measurements were combined with structural data derived from X-ray crystallographic studies on 12 peptide-SH2 domain complexes. The peptide ligands studied fall into two general classes: (1) dipeptides of the general framework N-acetylphosphotyrosine (or phosphotyrosine replacement)-Glu or methionine (or S-methylcysteine)-X, where X represents a hydrophobic amine, and (2) tetra- or pentapeptides of the general framework N-acetylphosphotyrosine-Glu-Glu-Ile-X, where X represents either Glu, Gln, or NH2. Dipeptide analogs which featured X as either hexanolamine or heptanolamine were able to pick up new hydrogen bonds involving their hydroxyl groups within a predominantly lipophilic surface cavity. However, due to internal strain as well as the solvent accessibility of the new hydrogen bonds formed, no net increase in binding affinity was observed. Phosphatase-resistant benzylmalonate and alpha,alpha-difluorobenzyl phosphonate analogs of phosphotyrosine retained some binding affinity for the pp60(c-src) SH2 domain but caused local structural perturbations in the phosphotyrosine-binding site. In the case where a reversible covalent thiohemiacetal was formed between a formylated phosphotyrosine analog and the thiol side chain of Cys-188, deltaS was 25.6 cal/(mol K) lower than for the nonformylated phosphotyrosine parent. Normal mode calculations show that the dramatic decrease in entropy observed for the covalent thiohemiacetal complex is due to the inability of the phosphotyrosine moiety to transform lost rotational and translational degrees of freedom into new vibrational modes.


Conservative surgical treatment for primary breast cancer.
The definition of conservative surgery should be limited to procedures preserving at least part of the breast. A randomized trial on conservative treatment of breast cancer, using in the control arm the Halsted mastectomy and in the second arm the QU.A.RT. method (quadrantectomy, axillary dissection, radiotherapy) was started in June 1973 at the National Cancer Institute of Milan. Patients with clinical or mammographic evidence of a breast cancer less than 2 cm in diameter without palpable lymph nodes (T1N0) were selected for the trial. The results lead to the conclusion that radical mastectomy appears to involve unnecessary mutilation in this kind of patients. Many problems are now connected with the future of conservative surgery of the breast. The first is the choice of cases, the second is multicentricity of breast cancer, the third is the risk of delayed carcinogenesis connected with the irradiation of the breast. Anyway, it is likely that a great proportion of breast cancers will benefit from a treatment which, without decreasing the survival rates, will be less multilating and therefore the quality of life will improve.


Antigen localization within the splenic marginal zone restores humoral immune response and IgG class switch in complement C4-deficient mice.
Defects of early complement components (C1, C4 and C2) are associated with the development of systemic lupus erythematosus (SLE). The availability of complement knockout mice has increased our knowledge on the role of complement in the regulation of adaptive immunity. An impaired removal of apoptotic bodies, a disturbed clearance of IgG immune complexes (ICs) and an insufficient B-cell regulation via complement receptors CD21/CD35 have been discussed as explanations for the induction of autoimmunity; however, a unifying hypothesis for the loss of B-cell tolerance in the absence of C1 or C4 is still lacking. Using IgM-containing ICs, we observed a significant accumulation of antigen within the splenic marginal zone (MZ) of C4-deficient mice but not in C3-deficient or complement receptors CD21/CD35-deficient mice. The targeting of antigen toward the MZ restored adaptive immunity (antibody response and class switch) in C4-deficient animals. A new explanation for the association of SLE and complement C4 deficiency would be that in the absence of C4, natural antibodies (IgM type) localize more self-antigen toward the MZ so that the auto-antibody response is increased and autoimmune disease ensues. As such, an inadequate localization of self-antigens might be responsible for the annulment of peripheral B-cell tolerance in the absence of C4.


Human endogenous retroviral protein triggers deficit in glutamate synapse maturation and behaviors associated with psychosis.
Mobile genetic elements, such as human endogenous retroviruses (HERVs), produce proteins that regulate brain cell functions and synaptic transmission and have been implicated in the etiology of neurological and neurodevelopmental psychiatric disorders. However, the mechanisms by which these proteins of retroviral origin alter brain cell communication remain poorly understood. Here, we combined single-molecule tracking, calcium imaging, and behavioral approaches to demonstrate that the envelope protein (Env) of HERV type W, which is normally silenced but expressed in patients with neuropsychiatric conditions, alters the N-methyl-d-aspartate receptor (NMDAR)-mediated synaptic organization and plasticity through glia- and cytokine-dependent changes. Env expression in the developing hippocampus was sufficient to induce behavioral impairments at the adult stage that were prevented by Env neutralization or tuning of NMDAR trafficking. Thus, we show that a HERV gene product alters glutamate synapse maturation and generates behavioral deficits, further supporting the possible etiological interplay between genetic, immune, and synaptic factors in psychosis.


Mortality decline after implementation of standard protocols for treating patients with acute myocardial infarction.
To compare 30-day mortality in patients receiving different types of medication from 1992 to 1997, when no consensual treatment for acute myocardial infarction was available, versus 30-day mortality in patients being treated between 2000 and 2002 after standardization of that treatment was obtained in our service. In the first and second study periods, 172 and 143 patients, respectively, admitted with the diagnosis of acute myocardial infarction were retrospectively assessed. Their diagnoses were confirmed, and the following statistical tests were performed: the chi-square test for comparing proportions and the Student t test and the Mann-Whitney test for comparing the means or medians. The analysis showed no difference in regard to white men with a mean age of 61 years in the 2 study periods. In regard to the traditional risk factors, a difference was observed only in the incidence of dyslipidemia (17 and 29%). In regard to the therapeutic strategy adopted, the following was observed: 1) a significant increase in the use of thrombolytic agents (39 and 61.5%), acetylsalicylic acid (70.9 and 96.5%), beta-blockers (34.8 and 67.8%), angiotensin-converting enzyme inhibitors (45.9 and 74.8%), and nitrates (61 and 85.3%); and 2) a significant reduction in the use of calcium channel blockers (16.8 and 5.3%), antiarrhythmics (29.1 and 9.7%), and diuretics (50.6 and 26.6%). The use of inotropic agents did not differ between the study periods (29.6 and 32.1%). The 30-day mortality showed a statistically significant reduction from 22.7 to 10.5%. The implementation of standard protocols for the treatment of acute myocardial infarction was accompanied by a significant reduction in the 30-day mortality rate.


Protein acetylation in the critical biological processes in protozoan parasites.
Protein lysine acetylation has emerged as a major regulatory post-translational modification in different organisms, present not only on histone proteins affecting chromatin structure and gene expression but also on nonhistone proteins involved in several cellular processes. The same scenario was observed in protozoan parasites after the description of their acetylomes, indicating that acetylation might regulate crucial biological processes in these parasites. The demonstration that glycolytic enzymes are regulated by acetylation in protozoans shows that this modification might regulate several other processes implicated in parasite survival and adaptation during the life cycle, opening the chance to explore the regulatory acetylation machinery of these parasites as drug targets for new treatment development.


Interleukin-6 production by human neutrophils after Fc-receptor cross-linking or exposure to granulocyte colony-stimulating factor.
Polymorphonuclear neutrophils (PMNs) are essential effector cells in host defense and tissue inflammatory responses. These responses may be initiated after cross-linking of cell surface Fc receptors that bind the constant portion of IgG (FcgammaR). We evaluated the effect of cross-linking FcgammaRI or FcgammaRII on interleukin-6 (IL-6) production by purified PMNs from normal donors or from patients being treated with recombinant human granulocyte colony-stimulating factor (rhG-CSF). In PMNs from normal donors, IL-6 mRNA was detected by reverse transcriptase-polymerase chain reaction only after FcgammaRI or FcgammaRII cross-linking. We also found that IL-6 mRNA could be detected in PMNs after either in vitro or in vivo rhG-CSF treatment in the absence of FcgammaR cross-linking. IL-6 protein was found to be produced intracellularly and secreted by PMNs after cross-linking FcgammaRI or FcgammaRII or after rhG-CSF stimulation. Cross-linking FcgammaRI or FcgammaRII on PMNs from patients treated with rhG-CSF resulted in a synergistic increase in IL-6 secretion. Upregulation of IL-6 production by PMNs after rhG-CSF treatment may contribute to a clinical engraftment syndrome that occurs during periods of rapid increase in PMN numbers in patients receiving rhG-CSF.


Clinical characteristics and surgical resection of multifocal papillary thyroid carcinoma: 168 cases.
To investigate clinical characteristics and surgical treatment of multifocal papillary thyroid carcinoma. A total of 648 patients diagnosed with papillary thyroid carcinoma were enrolled, 168 with multifocal papillary thyroid carcinoma. Clinicopathological factors including gender, age at diagnosis, family history of thyroid tumor, multiplicity and bilaterality of tumor, extra-thyroidal extension, lymph node involvement and other factors were statistically compared. The incidence of multifocal papillary thyroid carcinoma was 25.9% and 117 presented with bilateral thyroid gland lesions. In multifocal group, patients had a higher ratio of male subjects, family history of thyroidal tumor, neck lymph node metastasis and extra-thyroidal extension by B-ultrasound. Solitary papillary thyroid carcinoma tended to be with a higher rate of benign goiters. In multifocal group, males with neck lymphadenectasis, ≥ 3 tumor masses or bilaterality of tumors tended to present with larger tumors, a higher incidence of neck lymph node metastasis and extra-thyroidal extension. 164 cases completed the follow-up, 5 died, 1 suspected with lung metastasis and still survived, 6 underwent repeated surgery due to lymph node recurrence at 3-41 months postoperatively and 2 surgically treated with recurrent gland tumor. Overall 1-, 2-, 5-, and 10-year survival rate was 98.2%, 97.4%, 96.5% and 96.5%, respectively. Multifocal papillary thyroid carcinoma is more malignant and highly differentiated than solitary lesions. Total thyroidectomy combined with neck dissection of central compartment could be utilized as standard treatment. Lateral nodular dissection should be considered for the patients with lymph node metastasis.


[Pervasive developmental disorders: neurological perspectives].
The pervasive disorders of development (TPD) or disorders within the spectrum of autism (TEA) are two terms which are often used to describe a well-defined group of behaviour disorders characterized by changes in social interaction and language communication together with repetitive behaviour patterns. This group of disorders has multiple etiologies and the clinical manifestations vary in severity. In this study the incidence of a selected group of neurological changes and neurodiagnostic tests in 421 children with TDP is analyzed. 11% of the children had genetic disorders such as chromosomial disorders, genetic syndromes and family incidence. 18% of the children had motor disorders with hypotonicity being the commonest (85%). 71% of the children were stereotyped. 59% of the children had cogniscitive functions which were appropriate, or nearly so, for their chronological age, 28% of the children had language regression. 13% had epileptic crises. The electroencephalogram and cerebral magnetic resonance were abnormal in 29% and 19% respectively of the children on whom these tests were done.


Spectrophotometric and spectrofluorimetric studies on azilsartan medoxomil and chlorthalidone to be utilized in their determination in pharmaceuticals.
The recently approved angiotensin II receptor blocker, azilsartan medoxomil (AZL), was determined spectrophotometrically and spectrofluorimetrically in its combination with chlorthalidone (CLT) in their combined dosage form. The UV-spectrophotometric technique depends on simultaneous measurement of the first derivative spectra for AZL and CLT at 286 and 257 nm, respectively, in methanol. The spectrofluorimetric technique depends on measurement of the fourth derivative of the synchronous spectra intensities of AZL in presence of CLT at 298 nm in methanol. The effects of different solvents on spectrophotometric and spectrofluorimetric responses were studied. For, the spectrofluorimetric study, the effect of pH and micelle-assisted fluorescence enhancement were also studied. Linearity, accuracy, and precision were found to be satisfactory over the concentration ranges of 8-50 μg mL(-1) and 2-20 μg mL(-1) for AZL and CLT, respectively, in the spectrophotometric method as well as 0.01-0.08 μg mL(-1) for AZL in the spectrofluorimetric method. The methods were successfully applied for the determination of the studied drugs in their co-formulated tablets. The developed methods are inexpensive and simple for the quality control and routine analysis of the cited drugs in bulk and in pharmaceuticals.


Adjuvant chemotherapy in resected stage-II nonseminomatous germ cell tumors of testis. In which cases is it necessary?
In an attempt to reduce the recurrence rate and to improve survival in resected stage-II nonseminomatous testicular cancer, two consecutive series of patients were treated with adjuvant vinblastine-bleomycin (VB) continuous infusion, or cisplatin, vinblastine, bleomycin (PVB). 11 former patients who received no adjuvant chemotherapy and 5 who refused the adjuvant treatment were considered historical controls. After a median follow-up of 5 years, relapses were 4 in 15 patients treated with VB (27%), 1 in 29 treated with PVB (3%) and 8 in the untreated (50%). Adjuvant PVB significantly reduced the recurrence rate (p less than 0.001), while VB did not (p = 0.4). However, the advantage of adjuvant PVB was evident only in patients with retroperitoneal metastases larger than 5 cm, macroscopic extranodal spread, and tumor invasion into retroperitoneal veins, who were classified as pathologic stage II-C: no relapse and 100% survival following adjuvant PVB in 11 cases, versus 86% relapses and 28.5% survival in 7 untreated patients (p less than 0.01); 2 relapses and 2 survivors in 3 treated with VB. On the other hand, only 1 of the 39 patients with less extensive retroperitoneal disease died of testicular cancer, and he was in the VB adjuvant treatment group. We conclude that only aggressive adjuvant chemotherapy significantly reduces the recurrence rate and improves survival in resected stage-II nonseminomatous testis cancer. However, it is mandatory only in the very high risk subset II-C of patients, while the others could be carefully followed at monthly intervals and safely treated with aggressive chemotherapy only in the event of relapse.


Age and gender differences in the relation of chronic diseases to activity of daily living (ADL) disability for elderly South Koreans: based on representative data.
This study investigated the gender and age differential effect of major chronic diseases on activity of daily living (ADL) disability. Surveyfreq and Surveylogistic regression analyses were employed on the 2005 Korean National Health and Nutrition Examination Survey (KNHANES) with a sample of 3609 persons aged 65-89. After adjusting for potential covariates, stroke, among elderly men more so than women, had a 2-3 times greater odds of engendering ADL disability in the 65-69 (p < 0.05) and 70-79 age groups (p < 0.01). In comparison to elderly women, cancer, diabetes, and incontinence in elderly men was associated with a higher risk of ADL disability in the 70-79 age group (p < 0.05), and this association was also observed for pulmonary disease in the 80-89 age group. Among elderly women, however, a significant association between incontinence and ADL disability was identified in all three age groups. In addition, this association was found in pulmonary disease and diabetes in elderly women aged 70-79 years. Significant gender differences were observed in the association between stroke in the 60-79 age group and cancer in the 70-79 age group. Age and gender differences were observed in the effect of chronic diseases on ADL disability.


Modeling old-age wealth with endogenous early-life outcomes: The case of Mexico.
This paper contributes to the literature on the life course and aging by examining the association between early-life outcomes and late-life well being, using data from the Mexican Health and Aging Study. Empirical research in this area has been challenged by the potential endogeneity of the early-life outcomes of interest, an issue which most studies ignore or downplay. Our contribution takes two forms: (1) we examine in detail the potential importance of two key life-cycle outcomes, age at marriage (a measure of family formation) and years of educational attainment (a measure of human capital investment) for old-age wealth, and (2) we illustrate the empirical value of past context variables that could help model the association between early-life outcomes and late-life well being. Our illustrative approach, matching macro-level historical policy and census variables to individual records to use as instruments in modeling the endogeneity of early-life behaviors, yields a statistically identified two-stage model of old-age wealth with minimum bias. We use simulations to show that the results for the model of wealth in old age are meaningfully different when comparing the approach that accounts for endogeneity with an approach that assumes exogeneity of early-life outcomes. Furthermore, our results suggest that in the Mexican case, models which ignore the potential endogeneity of early-life outcomes are likely to under-estimate the effects of such variables on old-age wealth.


Metastasis to the thyroid gland: report of a large series from the Mayo Clinic.
Metastases to the thyroid gland are not as unusual as previously believed. This study reports the largest number of patients with metastatic disease of the thyroid to date, confirms the accuracy of fine-needle aspiration (FNA) in diagnosing metastasis, and reviews the incidence and management through our institutional experience. This study entailed review of all thyroid FNAs performed at Mayo Clinic, Rochester during the period 1980 to 2010 and identified 97 patients with a metastatic solid neoplasm of the thyroid gland. Frequent primary tumor sites included kidney (22%), lung (22%), and head and neck (12%). The median age at discovery of thyroid metastasis was 63 years. The time from diagnosis of primary tumor to metastasis to the thyroid gland was most considerable for renal cell carcinoma (mean 113 mo). Forty-one patients underwent thyroid resection with an average tumor size of 3 cm. Median survival in all patients with metastases was 20 months (range, 1 to 228 mo). Patients who underwent thyroid resection had a median survival of 30 months (range, 3 to 171 mo), whereas survival in patients without thyroid surgery was 12 months (range, 1 to 228 mo, log-rank test P=0.09). Our experience over the last 30 years confirms that FNA remains a sensitive and specific method to detect metastases to the thyroid. In any patient with a history of a malignancy, a new thyroid mass should be promptly evaluated for recurrent malignancy as early diagnosis and surgical resection resulted in a nonstatistically significant increased median survival.


Safety and pitfalls in frozen elephant trunk implantation.
The frozen elephant trunk (FET) procedure, or open stent grafting, is a tool for the combined open and endovascular treatment via a median sternotomy of extensive aortic disease involving both aortic arch and descending thoracic aorta. The technique aims to stabilize the maximum extent of the thoracic aorta in one step, with the goal of either rendering a secondary intervention to the downstream aorta unnecessary or producing an easy landing zone for secondary thoracic endovascular aortic repair (TEVAR) or open surgery. Even though large case series have reported good results, we still have no conclusive evidence as to which patients and what kind of pathologies benefit from this technique. The surgical sequences described for total arch replacement with the FET procedure are just as varied as the associated devices and indications. This article focuses on important perioperative and surgical aspects, as well as potential complications during FET procedures.


Vasopressin receptors from cultured mesangial cells resemble V1a type.
Mesangial cells respond to vasopressin by contraction and increased prostaglandin production. The purpose of the present study is to characterize vasopressin receptors from these cells. Glomeruli were isolated from rat kidneys and plated for explant growth of mesangial cells. Membranes were prepared from cells grown for 6 wk and tested for their ability to bind [3H]vasopressin (lysine vasopressin). These membranes contained a single class of specific vasopressin binding sites [equilibrium dissociation constant (Kd) = 10 +/- 1 nM, maximal binding capacity (Bmax) = 270 +/- 7 fmol/mg protein for 5 determinations]. Vasopressin induced a dose-dependent (apparent Kact value = 2 nM) accumulation of labeled inositol phosphates in myo[3H]inositol-prelabeled mesangial cells incubated in the presence of 10 mM of Li. Conversely, vasopressin failed to alter the adenylate cyclase activity of mesangial cell membranes. Competition experiments with a series of vasopressin structural analogues that have different degrees of affinity for V2-(renal), V1a- (vascular and hepatic), and V1b- (adenohypophyseal) receptors, indicated that vasopressin receptors from rat glomerular mesangial cells resemble the V1a- receptor subtype.


An evaluation of childhood rhinorrhea.
The differences in children with allergic and nonallergic rhinitis were reviewed. Thirty-two patients were studied prospectively. Ten patients were diagnosed as having allergic rhinitis (AR) on the basis of history correlating with RAST's and elevated IgE for age. Twenty-two patients had no evidence of atopy as a cause for their rhinorrhea and were classified as having vasomotor rhinitis (VMR). In this group 10 patients demonstrated eosinophilic nonallergic rhinitis (ENR). Responsiveness of the various group to medical therapy was noted. It was found that patients with AR and ENR are significantly more responsive to medical therapy than patients with VMR. The authors feel that there is a definite advantage in performing nasal cytology for determining eosinophilia in chronic childhood rhinorrhea.


Upper and lower airway pathology in young children with allergic- and non-allergic rhinitis.
Allergic- and non-allergic rhinitis are very common diseases in childhood in industrialized countries. Although these conditions are widely trivialized by both parents and physicians they induce a major impact on quality of life for the affected children and a substantial drainage of health care resources. Unfortunately, diagnostic specificity is hampered by nonspecific symptom history and lack of reliable diagnostic tests which may explain why the pathology behind such diagnoses is poorly understood. Improved understanding of the pathophysiology of allergic- and non-allergic rhinitis in young children may contribute to the discovery of new mechanisms involved in pathogenesis and help direct future research to develop correctly timed preventive measures as well as adequate monitoring and treatment of children with rhinitis. Asthma is a common comorbidity in subjects with allergic rhinitis and epidemiological surveys have suggested a close connection between upper and lower airway diseases expressed as the "united airways concept". Furthermore, an association between upper and lower airway diseases also seems to exist in non-atopic individuals. Nevertheless, the nature of this association is poorly understood and there is a paucity of data objectivizing this association in young children. The aim of this thesis was to describe pathology in the upper and lower airways in young children from the COPSAC birth cohort with investigator-diagnosed allergic- and non-allergic rhinitis. Nasal congestion is a key symptom in both allergic- and non-allergic rhinitis, and eosinophilic inflammation is a hallmark of the allergic diseases. In paper I, we studied nasal eosinophilia and nasal airway patency assessed by acoustic rhinometry in children with allergic rhinitis, non-allergic rhinitis and healthy controls. Allergic rhinitis was significantly associated with nasal eosinophilia and irreversible nasal airway obstruction suggesting chronic inflammation and structural remodeling of the nasal mucosa in children already at age 6 years. Non-allergic rhinitis exhibited no change in the nasal airway patency, but some nasal eosinophilia albeit less than children with allergic rhinitis. These findings suggest different pathology in allergic- and non-allergic rhinitis which may have important clinical implications for early pharmacological treatment of rhinitis in young children. In paper II, we utilized the nasal airway patency end-points derived from paper I to examine whether upper and lower airway patency are associated. Upper airway patency was assessed by acoustic rhinometry before and after intranasal α-agonist and lower airway patency by spirometry before and after inhaled β2-agonist. Upper and lower airway patencies were strongly associated and independent of body size, rhinitis and asthma. The association was consistent for both baseline values and for decongested nasal airway patency and post-β2 FEV1. Blood and nasal eosinophilia were also associated with nasal airway obstruction. This suggests generalized diminished airway dimensions as a novel susceptibility factor for concurrent symptoms of asthma and rhinitis in early childhood and supports the notion of a common pathophysiology in asthma and rhinitis. The clinical interpretation of these findings is that all children presenting either rhinitis or asthma should be considered inflamed in the entire respiratory tract. In paper III, we aimed to describe asthma and intermediary asthma end-points associated with allergic- and non-allergic rhinitis in preschool-aged children. At age 7 years, we evaluated prevalence of asthma, eczema, food sensitization, and filaggrin mutations; levels of total IgE, FeNO, and blood-eosinophils; lung function and bronchial responsiveness to cold dry air. We found that asthma was similarly associated with allergic- and non-allergic rhinitis suggesting a link between upper and lower airway diseases beyond an allergy associated inflammation. Only children with allergic rhinitis had increased bronchial responsiveness and elevated FeNO suggesting different endotypes of asthma symptoms in young children with allergic- and non-allergic rhinitis. We also found bronchial hyperresponsiveness and raised values of FeNO in children with allergic rhinitis without asthma suggesting sub-clinical bronchial inflammation and supporting the allergic disease process to involve both upper and lower airways. In conclusion, these observations objectively show marked differences in nasal pathology in young children with allergic- and non-allergic rhinitis and lend support to a close connection between upper and lower airway diseases partly from an allergy driven process, but equally from non-allergic mechanisms.


Lower serum sodium is associated with increased short-term mortality in hospitalized patients with worsening heart failure: results from the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) study.
The prognostic value of serum sodium in patients hospitalized for worsening heart failure has not been well defined. The Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) study randomized 949 patients with systolic dysfunction hospitalized for worsening heart failure to receive 48 to 72 hours of intravenous milrinone or placebo in addition to standard therapy. In a retrospective analysis, we investigated the relationship between admission serum sodium and the primary end point of days hospitalized for cardiovascular causes within 60 days of randomization, as well as the secondary end points of in-hospital mortality, 60-day mortality, and 60-day mortality/rehospitalization. The number of days hospitalized for cardiovascular causes was higher in the lowest sodium quartile: 8.0 (4.5, 18.5) versus 6 (4, 13) versus 6 (4, 11.5) versus 6 (4, 12) days (P<0.015 for comparison with the lowest quartile). Lower serum sodium was associated with higher in-hospital and 60-day mortality: 5.9% versus 1% versus 2.3% versus 2.3% (P<0.015) and 15.9% versus 6.4% versus 7.8% versus 7% (P=0.002), respectively. There was a trend toward higher mortality/rehospitalization for patients who were in the lowest sodium quartile. Multivariable-adjusted Cox proportional hazards analysis showed that serum sodium on admission, when modeled linearly, predicted increased 60-day mortality: sodium (per 3-mEq/L decrease) had a hazard ratio of 1.18 with a 95% CI of 1.03 to 1.36 (P=0.018). In patients hospitalized for worsening heart failure, admission serum sodium is an independent predictor of increased number of days hospitalized for cardiovascular causes and increased mortality within 60 days of discharge.


Time-reversed ultrasonically encoded optical focusing into scattering media.
Light focusing plays a central role in biomedical imaging, manipulation, and therapy. In scattering media, direct light focusing becomes infeasible beyond one transport mean free path. All previous methods1-3 to overcome this diffusion limit lack a practical internal "guide star."4 Here we proposed and experimentally validated a novel concept, called Time-Reversed Ultrasonically Encoded (TRUE) optical focusing, to deliver light into any dynamically defined location inside a scattering medium. First, diffused coherent light is encoded by a focused ultrasonic wave to provide a virtual internal "guide star"; then, only the encoded light is time-reversed and transmitted back to the ultrasonic focus. The TRUE optical focus-defined by the ultrasonic wave-is unaffected by multiple scattering of light. Such focusing is especially desirable in biological tissue where ultrasonic scattering is ~1000 times weaker than optical scattering. Various fields including biomedical and colloidal optics can benefit from TRUE optical focusing.


Comparison of responses to strenuous eccentric exercise of the elbow flexors between resistance-trained and untrained men.
This study compared resistance-trained and untrained men for changes in commonly used indirect markers of muscle damage after maximal voluntary eccentric exercise of the elbow flexors. Fifteen trained men (28.2 +/- 1.9 years, 175.0 +/- 1.6 cm, and 77.6 +/- 1.9 kg) who had resistance trained for at least 3 sessions per week incorporating exercises involving the elbow flexor musculature for an average of 7.7 +/- 1.4 years, and 15 untrained men (30.0 +/- 1.5 years, 169.8 +/- 7.4 cm, and 79.9 +/- 4.4 kg) who had not performed any resistance training for at least 1 year, were recruited for this study. All subjects performed 10 sets of 6 maximal voluntary eccentric actions of the elbow flexors of one arm against the lever arm of an isokinetic dynamometer moving at a constant velocity of 90 degrees .s. Changes in maximal voluntary isometric and isokinetic torque, range of motion, upper arm circumference, plasma creatine kinase activity, and muscle soreness before, immediately after, and for 5 days after exercise were compared between groups. The trained group showed significantly (P < 0.05) smaller changes in all of the measures except for muscle soreness and faster recovery of muscle function compared with the untrained group. For example, muscle strength of the trained group recovered to the baseline by 3 days after exercise, where the untrained group showed approximately 40% lower strength than baseline. These results suggest that resistance-trained men are less susceptible to muscle damage induced by maximal eccentric exercise than untrained subjects.


Expression of constitutively activated Akt in the mammary gland leads to excess lipid synthesis during pregnancy and lactation.
Expression of constitutively activated Akt in the mammary glands of transgenic mice results in a delay in post-lactational involution. We now report precocious lipid accumulation in the alveolar epithelium of mouse mammary tumor virus-myr-Akt transgenic mice accompanied by a lactation defect that results in a 50% decrease in litter weight over the first 9 days of lactation. Although ductal structures and alveolar units develop normally during pregnancy, cytoplasmic lipid droplets appeared precociously in mammary epithelial cells in early pregnancy and were accompanied by increased expression of adipophilin, which is associated with lipid droplets. By late pregnancy the lipid droplets had become significantly larger than in nontransgenic mice, and they persisted into lactation. The fat content of milk from lactating myr-Akt transgenic mice was 65-70% by volume compared to 25-30% in wild-type mice. The diminished growth of pups nursed by transgenic mothers could result from the high viscosity of the milk and the inability of the pups to remove sufficient quantities of milk by suckling. Transduction of the CIT3 mammary epithelial cell line with a recombinant human adenovirus encoding myr-Akt resulted in an increase in glucose transport and lipid biosynthesis, suggesting that Akt plays an important role in regulation of lipid metabolism.


Most primary adrenal lymphomas are diffuse large B-cell lymphomas with non-germinal center B-cell phenotype, BCL6 gene rearrangement and poor prognosis.
Primary adrenal lymphoma is extremely rare, accounting for <1% of non-Hodgkin lymphomas, and lymphoma-associated chromosomal translocations have yet to be reported in this entity. We performed a retrospective study of 10 cases in immunocompetent patients including 4 males and 6 females with a median age of 68 years. The most common presenting symptoms were abdominal pain and fever; unexpectedly, clinically evident adrenal insufficiency was detected only in one patient. The mean tumor size at diagnosis was 8.5 cm. Half of the patients had bilateral involvement. All cases presented with stage IE disease without regional nodal involvement. Histologically, eight cases were diffuse large B-cell lymphoma, all of which carried a non-germinal center B-cell phenotype. Fluorescence in situ hybridization revealed BCL6 gene rearrangement in 5 (83%) of 6 diffuse large B-cell lymphomas investigated. The remaining cases were one case each of plasmablastic lymphoma and extranodal NK/T-cell lymphoma, nasal type, the first and third case of primary adrenal lymphoma of these particular lymphoma subtypes in the English literature, respectively. At a median follow-up of 4.5 months, 7 patients died of lymphoma, 1 died of an unrelated disease, 1 was alive with disease, and 1 was alive without disease. The prognosis of these patients was poor as compared with those with nodal diffuse large B-cell lymphoma. We speculate that the poor outcome of primary adrenal lymphoma might be related to the bulky tumor size at presentation, non-germinal center B-cell phenotype, and frequent BCL-6 gene rearrangement.


Doppler ultrasound of the testis in azoospermic subjects as a parameter of testicular function.
Azoospermia frequently represents the end-point of different pathological conditions that cause important quantitative and qualitative alterations of both spermatogenesis and testicular structure, including intratesticular blood vessels. In this study we performed colour Doppler ultrasound of the testis in 12 azoospermic subjects affected by primary testicular pathology (four bilateral post-orchitis, four postradiotheraphy for cancer, four post-traumatic) aged 28.2+/-3.3 (mean+/-SD) years, in six subjects affected by obstructive azoospermia aged 29.7+/-2.4 years and in 20 age-matched fertile subjects (aged 28.6+/-2.5 years). The analysis of intratesticular vessels per organ was quantified using a semiquantitative score: category 0, no vessels visible; category 1, between one and three intratesticular vessels visible; and category 2, more than three vessels visible. In obstructive azoospermic patients and in fertile subjects there were always more than three intratesticular vessels. No intratesticular vessels were detected in eight testes (33.3%) and fewer than three vessels in 16 testes (66.6%) in subjects affected by primary testicular pathology. In azoospermic subjects the testicular structure of the testis was evaluated by diagnostic fine needle aspiration cytology (FNAC) performed in the middle portion of the testis. In non-obstructive azoospermic patients this procedure showed the presence of only Sertoli cells in all cases. When detectable vessels were present, a new aspiration was performed in these areas. In 12 out of 16 cases, spermatogenetic cells including mature spermatozoa, were found when the FNAC was performed in testicular regions showing the presence of blood vessels. These results indicate that colour Doppler sonography of the testis may be useful in the differential diagnosis of azoospermia and suggest the evaluation of the intratesticular blood vessel distribution before performing any method to retrieve intratesticular spermatozoa for intracytoplasmic sperm injection.


[A political matter: science and ideology in the 21st century].
In the last two decades, history of science and science studies have been quite reluctant to adopt the notion of ideology when analyzing the dynamics of science. This may be an effect of the decreasing popularity of neo-marxist approaches within this disciplinary field; but it is also due to the fact that alternative approaches have been developed, for example Michel Foucault's notion of problematization, Roland Barthes' semiotic mythology, Bruno Latour's re-interpretation of the ontological difference between fact and fetish in science, or Donna Haraway's semi-fictional re-narrations of the techno-scientific world. This contribution undertakes to sketch the impact of two strands of 19th century immanentism on the authors named above, and on their use of concepts related to the notion of ideology, namely fetish, fetishism, myth and mythology respectively. It is argued that in some respect, Marx' concept of commodity fetishism is worth being re-examined, since it articulates a dialectical relation of 'reality' and 'seeming', and its impact on Barthes' mythology is deeper than it might appear at first glance.


One-stage Full Mouth Disinfection Using 20% Propolis Hydroalcoholic Solution: A Clinico-microbiologic Study.
Propolis is a resinous substance produced by honeybees which has many therapeutic properties because of its unique composition. It has been widely used since many years for different medicinal purposes. The aim of this study was to investigate the effects of one-stage full mouth disinfection (OSFMD) using 20% propolis hydroalcoholic solution in chronic periodontitis patients. Thirty patients diagnosed with chronic periodontitis and presenting three or more nonadjacent teeth with deep pockets were selected for the study. Clinical parameters including gingival index, plaque index, bleeding on probing, probing pocket depth, and clinical attachment level were recorded at baseline in all the patients followed by subgingival plaque sampling. All the thirty patients were randomly allocated into two groups; 15 patients (control group) were subjected to scaling and root planning (SRP) alone, and in remaining 15 patients (test group), SRP was done followed by OSFMD using 20% propolis hydroalcoholic solution after 24 h. All the patients were kept at periodic recall, and clinical and microbiological parameters were again taken at 4 weeks and 12 weeks. There was a significant improvement for all the clinical parameters, with higher probing depth reduction and attachment gain in the test group when compared to the control group. Furthermore, the microbiological counts of the periodontopathogens were found to decrease considerably more in the test group. SRP followed by OSFMD with propolis extract after 24 h was more effective than SRP alone in chronic periodontitis patients.


Microarray analysis reveals induction of lipoprotein genes in mucoid Pseudomonas aeruginosa: implications for inflammation in cystic fibrosis.
The main cause of the high morbidity and mortality of cystic fibrosis (CF) is the progressive lung inflammation associated with Pseudomonas aeruginosa colonization. During the course of chronic CF infections, P. aeruginosa undergoes a conversion to a mucoid phenotype. The emergence of mucoid P. aeruginosa in CF is associated with increased inflammation, respiratory decline, and a poor prognosis. Here we show, by the use of microarray analysis, that upon P. aeruginosa conversion to mucoidy, there is a massive and preferential induction of genes encoding bacterial lipoproteins. Bacterial lipoproteins are potent agonists of Toll-like receptor 2 (TLR2) signaling. The expression of TLR2 in human respiratory epithelial cells was ascertained by Western blot analysis. Human respiratory epithelial cells responded in a TLR2-dependent manner to bacterial lipopeptides derived from Pseudomonas lipoproteins induced in mucoid strains. The TLR2 proinflammatory response was further augmented in CF cells. Thus, the excessive inflammation in CF is the result of a global induction in mucoid P. aeruginosa of lipoproteins that act as proinflammatory toxins (here termed lipotoxins) superimposed on the hyperexcitability of CF cells. Blocking the signaling cascade responding to bacterial lipotoxins may provide therapeutic benefits for CF patients.


Glomerular permselectivity in the isolated perfused rat kidney.
Glomerular permselectivity characteristics were studied in the Sprague-Dawley rat in vivo and in the isolated rat kidney perfused with an erythrocyte-free Krebs-Henseleit buffered 5% albumin solution (IPK). IPK permselectivity in vitro, assessed by fractional clearances of neutral dextran (FCND) and dextran sulfate (FCDS) with molecular radii 18-43 A, was essentially similar to that of the Sprague-Dawley rat in vivo. The negative charge barrier of the IPK glomerular filter was intact [e.g., FCND of 36 A = 0.10 +/- 0.01 (SE) vs. FCDS of 36 A = 0.01 +/- 0.00 (P less than 0.01)]. Dextrans of an intermediate size (26-34 A) had lower fractional clearances in the IPK than in vivo [e.g., FCND of 30 A in IPK = 0.23 +/- .04 vs. FCND of 30 A in vivo 0.40 +/- 0.01 (P less than 0.01)]. This decreased clearance of dextrans of an intermediate molecular size is predicted by pore theory, since the IPK has an increased afferent glomerular plasma flow rate. As glomerular permselectivity characteristics in the IPK simulate in vivo characteristics, such preparations are suitable in vitro models in which to study factors that modulate permselectivity. The demonstration that the glomerular filter in the IPK has a normal negative charge barrier indicates that the increased protein excretion in IPK systems cannot be attributed to abnormalities of this component of the filtration barrier.


Overestimation of ulcerative colitis due to melanosis coli.
Melanosis coli is a benign pigment deposition in the colonic mucosa that can be seen at the time of colonoscopy especially in patients with history of laxative use. In conditions in which the endoscopic findings influence therapeutic decisions, melanosis coli can lead to overestimation of disease aggressiveness and unnecessary therapy. We describe a case in which the finding of melanosis coli affected the treatment of a patient with mild ulcerative colitis exacerbation.


A syndemic of psychosocial health disparities and associations with risk for attempting suicide among young sexual minority men.
We examined a syndemic of psychosocial health issues among young men who have sex with men (MSM), with men and women (MSMW), and with women (MSW). We examined hypothesized drivers of syndemic production and effects on suicide attempts. Using a pooled data set of 2005 and 2007 Youth Risk Behavior Surveys from 11 jurisdictions, we used structural equation modeling to model a latent syndemic factor of depression symptoms, substance use, risky sex, and intimate partner violence. Multigroup models examined relations between victimization and bullying experiences, syndemic health issues, and serious suicide attempts. We found experiences of victimization to increase syndemic burden among all male youths, especially MSMW and MSM compared with MSW (variance explained = 44%, 38%, and 10%, respectively). The syndemic factor was shown to increase the odds of reporting a serious suicide attempt, particularly for MSM (odds ratio [OR] = 5.75; 95% confidence interval [CI] = 1.36, 24.39; P < .001) and MSMW (OR = 5.08; 95% CI = 2.14, 12.28; P < .001) compared with MSW (OR = 3.47; 95% CI = 2.50, 4.83; P < .001). Interventions addressing multiple psychosocial health outcomes should be developed and tested to better meet the needs of young MSM and MSMW.


Selective Targeting of SH2 Domain-Phosphotyrosine Interactions of Src Family Tyrosine Kinases with Monobodies.
The binding of Src-homology 2 (SH2) domains to phosphotyrosine (pY) sites is critical for the autoinhibition and substrate recognition of the eight Src family kinases (SFKs). The high sequence conservation of the 120 human SH2 domains poses a significant challenge to selectively perturb the interactions of even the SFK SH2 family against the rest of the SH2 domains. We have developed synthetic binding proteins, termed monobodies, for six of the SFK SH2 domains with nanomolar affinity. Most of these monobodies competed with pY ligand binding and showed strong selectivity for either the SrcA (Yes, Src, Fyn, Fgr) or SrcB subgroup (Lck, Lyn, Blk, Hck). Interactome analysis of intracellularly expressed monobodies revealed that they bind SFKs but no other SH2-containing proteins. Three crystal structures of monobody-SH2 complexes unveiled different and only partly overlapping binding modes, which rationalized the observed selectivity and enabled structure-based mutagenesis to modulate inhibition mode and selectivity. In line with the critical roles of SFK SH2 domains in kinase autoinhibition and T-cell receptor signaling, monobodies binding the Src and Hck SH2 domains selectively activated respective recombinant kinases, whereas an Lck SH2-binding monobody inhibited proximal signaling events downstream of the T-cell receptor complex. Our results show that SFK SH2 domains can be targeted with unprecedented potency and selectivity using monobodies. They are excellent tools for dissecting SFK functions in normal development and signaling and to interfere with aberrant SFK signaling networks in cancer cells.


A Tropical Composting Operation Unit at São Paulo Zoo as a Source of Bacterial Proteolytic Enzymes.
Composting operation systems are valuable sources of microorganisms and enzymes. This work reports the assessment of proteolytic enzymes from cultivable bacteria isolated from a composting facility of the São Paulo Zoo Park (SPZPF), São Paulo, Brazil. Three hundred bacterial isolates were obtained and identified based on 16S rRNA gene as belonging to 13 different genera. The most common genus among the isolates was Bacillus (67%); some of which show high proteolytic activity in their culture media. Biochemical assays of hydrolytic activities using FRET peptides as substrates allowed the characterization of a repertoire of serine proteases and metalloproteases with different molecular weights secreted by Bacillus strains isolated from composting. Furthermore, thermostable serine and metalloproteases were detected in the composting leachate, which might be of interest for industrial applications.


Clinical staging and serum cytokines in bipolar patients during euthymia.
Changes in serum cytokines and altered neutrophin concentration have been associated with bipolar disorder (BD). Our aim here was to analyze peripheral blood biomarkers according to the clinical stages of BD. Euthymic BD-I patients were grouped according to their level of functioning in early-stage (n=25) and late-stage (n=23), and compared to healthy siblings (n=23) and genetically unrelated healthy controls (n=21). Neurotrophin (neurotrophin-3 and BDNF) concentration and biomarkers of inflammation, including cytokines (IL-6, IL-10 and TNF-α), leukocytes count and acute phase proteins, were measured. IL-10 concentration was significantly increased in early-stage patients compared to late-stage patients, healthy siblings and controls whereas TNF-α concentration was significantly increased in late-stage patients compared to controls. Total leukocytes, neutrophil and monocyte count were significantly increased in late-stage patients compared to healthy siblings and controls. The concentration of IL-6, neurotrophin-3 and BDNF was unchanged in euthymia. Healthy siblings did not show significant changes in any biomarker. The concentration of IL-10, TNF-α, neutrophil and monocytes subtype count in blood is altered in patients with BD during euthymic state. The link between peripheral inflammation and different stages in BD deserves further studies.


Taking Telemedicine to the Next Level in Diabetes Population Management: a Review of the Endo ECHO Model.
Worldwide increases in diabetes prevalence in the face of limited medical resources have prompted international interest in innovative healthcare delivery models. Project ECHO (Extension for Community Healthcare Outcomes) is a "telementoring" program which has been shown to increase capacity for complex disease management in medically underserved regions. In contrast to a traditional telemedicine model which might connect a specialist with one patient, the ECHO model allows for multiple patients to benefit simultaneously by building new expertise. We recently applied the ECHO model to improve health outcomes of patients with complex diabetes (Endo ECHO) living in rural New Mexico. We describe the design of the Endo ECHO intervention and a 4-year, prospective program evaluation assessing health outcomes, utilization patterns, and cost-effectiveness. The Endo ECHO evaluation will demonstrate whether and to what extent this intervention improves outcomes for patients with complex diabetes living in rural New Mexico, and will serve as proof-of-concept for academic medical centers wishing to replicate the model in underserved regions around the world.


The role of advanced lipid testing in the prediction of cardiovascular disease.
Advanced lipid testing has been suggested by some experts to identify patients with substantial residual risk for more aggressive targeting of lifestyle and pharmacologic therapies. It measures the subpopulation of lipoproteins and apolipoproteins, which include lipoprotein (a), apolipoprotein A-I, and apolipoprotein B, and measures of lipoprotein particle composition such as LDL particle (LPL-P) and HDL particle (HDL-P) number and size. Obesity is associated with smaller LDL-P and HDL-P sizes. Moderate weight loss via fasting/calorie restriction is associated with LDL-P size increase, whereas moderate weight loss via endurance exercise is associated with HDL-P size increase. Diets high in carbohydrates are associated with a more atherogenic advanced lipoprotein profile characterized by smaller LDL-P and HDL-P sizes. In summary, lifestyle changes such as weight loss, exercise, and dietary modification correlate with improvement in the profile of advanced lipoproteins. Regrettably, therapies targeting HDL and HDL composition have been disappointing to date.


Evaluation of serum biomarkers in nutritional disorders: glycated apolipoprotein B, fasting serum glucose, fructosamine, stable and labile glycated hemoglobin in diabetic and non-diabetic subjects.
Glycated apolipoprotein B (ApoB-G), a non enzymatically glycated protein, has recently been associated with myocardial infarction. Our aim is to evaluate, in diabetic and non diabetic subjects, the relationship of ApoB-G with serum fasting glucose, fructosamine, stable and labile fractions of glycated hemoglobin ((S)HbA(1c), (L)HbA(1c), respectively) and insulin. The subjects were recruited from a previous study on ApoB-G and myocardial infarction: 141 of them were studied, 43 with and 98 without diabetes. ApoB-G was measured using a monoclonal antibody, and linear regression and correlation were used for statistical analysis of the data. ApoB-G was higher in diabetic than in non diabetic subjects. There was a statistically significant correlation of ApoB-G with triglycerides (r = 0.38, p = 0.01) in diabetic subjects, and with total proteins (r = 0.37, p = 0.0002), triglycerides (r = 0.34, p = 0.0007), and cholesterol (r = 0.23, p = 0.02) in non diabetic subjects. In the most parsimonious multiple linear regression model of ApoB-G on all the other serum variables, there was a statistically significant association of ApoB-G with triglycerides, in both diabetic and non diabetic subjects. The main results of this study suggest that serum ApoB-G is associated with serum triglycerides in both diabetic and non diabetic subjects.


Diversity and Distribution of a Novel Genus of Hyperthermophilic Aquificae Viruses Encoding a Proof-Reading Family-A DNA Polymerase.
Despite the high abundance of Aquificae in many geothermal systems, these bacteria are difficult to culture and no viruses infecting members of this phylum have been isolated. Here, we describe the complete, circular dsDNA Uncultivated Virus Genome (UViG) of Thermocrinis Octopus Spring virus (TOSV), derived from metagenomic data, along with eight related UViGs representing three additional viral species. Despite low overall similarity among viruses from different hot springs, the genomes shared a high degree of synteny, and encoded numerous genes for nucleotide metabolism, including a PolA-type DNA polymerase polyprotein with likely accessory functions, a DNA Pol III sliding clamp, a thymidylate kinase, a DNA gyrase, a helicase, and a DNA methylase. Also present were conserved genes predicted to code for phage capsid, large and small subunits of terminase, portal protein, holin, and lytic transglycosylase, all consistent with a distant relatedness to cultivated Caudovirales. These viruses are predicted to infect Aquificae, as multiple CRISPR spacers matching the viral genomes were identified within the genomes and metagenomic contigs from these bacteria. Based on the predicted atypical bi-directional replication strategy, low sequence similarity to known viral genomes, and unique position in gene-sharing networks, we propose a new putative genus, "Pyrovirus," in the order Caudovirales.


A literature review: robots in medicine.
Robotic systems employed in the laboratory, in rehabilitation, and in surgery are reviewed. The advantages of using a robot system over manual procedures in the laboratory to prepare samples is discussed, and some of the obstacles are noted. A typical laboratory robot is described. Rehabilitative applications in the major research areas of tactile sensors, assistive devices for the blind, prosthetics, and orthotics are examined. Manipulators that can help a disabled individual with important everyday tasks and other assistive robotic systems in rehabilitation are described. A variety of robots that assist or perform surgery is surveyed. These applications include positioning in stereotactic neurosurgery, patient manipulation, an in vivo spinal kinematic instrument, and robotic radial keratotomy, among others.


Factors associated with the amount of public home care received by elderly and intellectually disabled individuals in a large Norwegian municipality.
This study reports an analysis of factors associated with home care use in a setting in which long-term care services are provided within a publicly financed welfare system. We considered two groups of home care recipients: elderly individuals and intellectually disabled individuals. Routinely collected data on users of public home care in the municipality of Trondheim in October 2012, including 2493 people aged 67 years or older and 270 intellectually disabled people, were used. Multivariate regression analysis was used to analyse the relationship between the time spent in direct contact with recipients by public healthcare personnel and perceived individual determinants of home care use (i.e. physical disability, cognitive impairment, diagnoses, age and gender, as well as socioeconomic characteristics). Physical disability and cognitive impairment are routinely registered for long-term care users through a standardised instrument that is used in all Norwegian municipalities. Factor analysis was used to aggregate the individual items into composite variables that were included as need variables. Both physical disability and cognitive impairment were strong predictors of the amount of received care for both elderly and intellectually disabled individuals. Furthermore, we found a negative interaction effect between physical disability and cognitive impairment for elderly home care users. For elderly individuals, we also found significant positive associations between weekly hours of home care and having comorbidity, living alone, living in a service flat and having a safety alarm. The reduction in the amount of care for elderly individuals living with a cohabitant was substantially greater for males than for females. For intellectually disabled individuals, receiving services involuntarily due to severe behavioural problems was a strong predictor of the amount of care received. Our analysis showed that routinely collected data capture important predictors of home care use and thus facilitate both short-term budgeting and long-term planning of home care services.


Biomarker signatures correlate with clinical outcome in refractory metastatic colorectal cancer patients receiving bevacizumab and everolimus.
A novel combination of bevacizumab and everolimus was evaluated in refractory colorectal cancer patients in a phase II trial. In this retrospective analysis, plasma samples from 49 patients were tested for over 40 biomarkers at baseline and after one or two cycles of drug administration. Analyte levels at baseline and change on-treatment were correlated with progression-free survival (PFS) and overall survival (OS) using univariate Cox proportional hazard modeling. Multivariable analyses were conducted using Cox modeling. Significant changes in multiple markers were observed following bevacizumab and everolimus treatment. Baseline levels of six markers significantly correlated with PFS and OS, including CRP, Gro-α, IGFBP-1, TF, ICAM-1, and TSP-2 (P < 0.05). At C2D1, changes of IGFBP-3, TGFβ-R3, and IGFBP-2 correlated with PFS and OS. Prognostic models were developed for OS and PFS (P = 0.0002 and 0.004, respectively). The baseline model for OS consisted of CRP, Gro-α, and TF, while the on-treatment model at C2D1 included IGFBP-2, IGFBP-3, and TGFβ-R3. These data demonstrated that multiple biomarkers were significantly modulated in response to bevacizumab and everolimus. Several markers correlated with both PFS and OS. Interestingly, these markers are known to be associated with inflammation and IGF signaling, key modulators of mTOR biology.


Outcome of surgically treated birth-related brachial plexus injuries in twenty cases.
Birth-related brachial plexus injury occurs in 0.19-2.5 per 1,000 live births, of which 70-92% improve with conservative management. With the advent of microsurgical techniques, patients who fail expectant treatment may benefit from brachial plexus exploration and reconstruction. From 1991 to 1996, 87 patients were referred to the multidisciplinary brachial plexus clinic at St. Louis Children's Hospital. Twenty patients were selected for surgical management. The average age at surgery was 10.5 months (range 3-35, median = 8), with an average follow-up of 23.9 months (range 7-45, median = 24). Two patients were lost to follow-up. Surgical procedures included neurolysis (n = 8), neurotization (n = 2), nerve grafting (n = 5), and a combination (n = 3) of the above. Two patients underwent exploration without repair. Intercostal nerves, pectoral nerves, and C4 roots were used for neurotizations, and the sural nerve was used for nerve grafting. Results from 18 patients were available for follow-up review. Fifteen patients (83% demonstrated clinical improvement postoperatively. Of the 3 patients without improvement, 2 underwent exploration without repair, and one underwent neurolysis of the axillary nerve. Of patients undergoing reconstruction, 93% had improved strength postoperatively. No subjects had worsening neurologic status, and there were no complications. These results suggest that surgery for birth-related brachial plexus injury may show favorable outcomes if patients are selected appropriately. Patients undergoing neurolysis and nerve grafting had more favorable outcomes than those undergoing neurotization.


IGF-1 Receptor Insufficiency Leads to Age-Dependent Attenuation of Osteoblast Differentiation.
In the current study, we determined the effects of IGF-1 receptor haploinsufficiency on osteoblast differentiation and bone formation throughout the lifespan. Bone mineral density was significantly decreased in femurs of male and female Igf1r(+/-) mice compared with wild-type mice. mRNA expression of osteoblast differentiation markers was significantly decreased in femurs and calvariae from Igf1r(+/-) mice compared with cells from wild-type mice. Bone morphogenetic protein-7-induced ectopic bone in Igf1r(+/-) mice was significantly smaller with fewer osteoblasts but more lipid droplets and had reduced expression of osteoblast differentiation markers compared with wild-type mice. In bone marrow cells from middle-aged and old wild-type and Igf1r(+/-) male mice, palmitate inhibited osteoblast markers expression. In cells from young wild-type male mice, palmitate did not inhibit marker expression, but in cells from young male Igf1r(+/-) mice, palmitate inhibited bone sialoprotein and osterix but not osteocalcin or type I collagen (TIC). In female wild-type mice, palmitate inhibited osteoblast markers expression in cells from young, middle-aged, and old mice except TIC in cells from middle-aged mice. Palmitate inhibited bone sialoprotein expression in cells from middle-aged and old female Igf1r(+/-) mice and osteocalcin, osterix, and TIC expression in young and middle-aged female Igf1r(+/-) mice but stimulated expression in cells from old female Igf1r(+/-) mice. We conclude that IGF-1 receptor haploinsufficiency results in a prolipid accrual phenotype in bone in association with inhibition of growth factor-induced osteoblast differentiation, a situation which may phenocopy age-related decreases in bone formation.


C12 derivatives of the hydroperoxide lyase pathway are produced by product recycling through lipoxygenase-2 in Nicotiana attenuata leaves.
In response to diverse stresses, the hydroperoxide lyase (HPL) pathway produces C(6) aldehydes and 12-oxo-(9Z )-dodecenoic acid ((9Z )-traumatin). Since the original characterization of (10E )-traumatin and traumatic acid, little has been added to our knowledge of the metabolism and fluxes associated with the conversion of (9Z )-traumatin into diverse products in response to wounding and herbivory. A liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) method was developed to quantify C(12) derivatives of the HPL pathway and to determine their metabolism after wounding and simulated herbivory in Nicotiana attenuata leaves. Ninety-eight per cent of the (9Z )-traumatin produced was converted to 9-hydroxy-(10E )-traumatin (9-OH-traumatin); two-thirds by product recycling through lipoxygenase-2 (NaLOX2) activity and one-third by nonenzymatic oxidation. Thirty-eight per cent of the de novo produced 9-OH-traumatin was conjugated to glutathione, consistent with this oxylipin being a reactive electrophile species. 12-OH-(9Z )-dodecenoic and dodecenedioic acids also showed rapid increases after wounding and simulated herbivory and a role for C(12) derivatives as signals in these processes was consistent with their ability to elicit substantial changes in gene expression. These results underscore the importance of metabolite reflux through LOX2, an insight which creates new opportunities for a functional understanding of C(12) derivatives of the HPL pathway in the regulation of stress responses.


Assays for Studying the Role of Vitronectin in Bacterial Adhesion and Serum Resistance.
Bacteria utilize complement regulators as a means of evading the host immune response. Here, we describe protocols for evaluating the role vitronectin acquisition at the bacterial cell surface plays in resistance to the host immune system. Flow cytometry experiments identified human plasma vitronectin as a ligand for the bacterial receptor outer membrane protein H of Haemophilus influenzae type f. An enzyme-linked immunosorbent assay was employed to characterize the protein-protein interactions between purified recombinant protein H and vitronectin, and binding affinity was assessed using bio-layer interferometry. The biological importance of the binding of vitronectin to protein H at the bacterial cell surface in evasion of the host immune response was confirmed using a serum resistance assay with normal and vitronectin-depleted human serum. The importance of vitronectin in bacterial adherence was analyzed using glass slides with and without vitronectin coating, followed by Gram staining. Finally, bacterial adhesion to human alveolar epithelial cell monolayers was investigated. The protocols described here can be easily adapted to the study of any bacterial species of interest.


An evaluation of two different exercise regimes during the first year following stroke: a randomised controlled trial.
The purpose of this randomised controlled trial was to evaluate the effects of two different exercise approaches during the first 12 months post stroke on Instrumental Activities of Daily Living (IADL), motor function, gait performance, balance, grip strength, and muscle tone. This study is a double-blind longitudinal randomised trial of first-time-ever stroke patients. Seventy-five patients were included: 35 in an intervention group and 40 in a self-initiated exercise group. After discharge from acute rehabilitation, patients assigned in the intervention group had physiotherapy for a minimum amount of 80 hours during the first year. Patients in the self-initiated exercise group were not recommended any specific therapy besides treatment when needed. Main outcome measures were Instrumental Activities of Daily Living according to Fillenbaum, Motor Assessment Scale, 6-Minute Walk Test, Berg Balance Scale, Timed Up-and-Go Test, grip strength, Modified Ashworth Scale, and pulse monitoring. The patients were tested on admission, at discharge, and after 3, 6, and 12 months post stroke by an experienced investigator, blinded to group assignment. Twelve months post stroke showed higher levels of independence in all items of the Instrumental Activities of Daily Living Test and improvements in the results of Motor Assessment Scale, 6-Minute Walk Test, Berg Balance Scale, Timed Up-and-Go, and grip strength in both groups. Only a few significant differences were seen between groups, and they were in favour of the self-initiated exercise group (e.g., ability to use the telephone independently). Attending examination sessions following each intervention phase appeared to be strong motivators for training, irrespective of group allocation.


Risk factors for ER visits due to asthma exacerbations in patients enrolled in a program for the control of asthma and allergie rhinitis in Feira de Santana, Brazil..
To determine the risk factors for ER visits due to asthma exacerbations in patients monitored at a referral center. Prospective cohort study of 253 outpatients (children and adults) with asthma who were monitored for 12 months at the Referral Center of the Program for the Control of Asthma and Allergic Rhinitis in the city of Feira de Santana, Brazil. Exacerbations were common, and 36.5% of the patients sought ER treatment within the twelve-month period. The risk factors for asthma exacerbations were being over 20 years of age (OR = 1.34: (95% CI: 1.06-1.70), residing in an urban area (OR = 1.19; 95% CI: 1.06-1.33); having a low level of education (OR = 1.53: 95% CI: 1.00-2.39); having severe asthma (OR = 1.65; 95% CI: 1.24-2.18); and having chronic rhinitis (OR = 2.20; 95% CI: 1.00-4.80). In this cohort, having chronic rhinitis, having asthma that is more severe and having a low level of education were the main risk factors for ER visits due to asthma exacerbations. These results are similar to those reported for asthma patients who are receiving no regular treatment.


Plasmid transfer in Pediococcus spp.: intergeneric and intrageneric transfer of pIP501.
Transfer of the broad-host-range resistance plasmid pIP501 from Streptococcus faecalis to Pediococcus pentosaceus and Pediococcus acidilactici occurred between cells immobilized on nitrocellulose filters in the presence of DNase. Expression of the pIP501-linked erythromycin and chloramphenicol resistance determinants was observed in transconjugants. Intrageneric transfer of pIP501 from a P. pentosaceus donor to various pediococcal recipients occurred at frequencies of 10(-4) to 10(-7) transconjugants per input donor cell. Intergeneric transfer of plasmid pIP501 from P. pentosaceus to S. faecalis, Streptococcus sanguis (Challis), and Streptococcus lactis was observed. Similar mating experiments showed no evidence for the transfer of the broad-host-range R-plasmid pAM beta 1 to Pediococcus spp. recipients.


Microorganisms in Fermented Apple Beverages: Current Knowledge and Future Directions.
Production of fermented apple beverages is spread all around the world with specificities in each country. 'French ciders' refer to fermented apple juice mainly produced in the northwest of France and often associated with short periods of consumption. Research articles on this kind of product are scarce compared to wine, especially on phenomena associated with microbial activities. The wine fermentation microbiome and its dynamics, organoleptic improvement for healthy and pleasant products and development of starters are now widely studied. Even if both beverages seem close in terms of microbiome and process (with both alcoholic and malolactic fermentations), the inherent properties of the raw materials and different production and environmental parameters make research on the specificities of apple fermentation beverages worthwhile. This review summarizes current knowledge on the cider microbial ecosystem, associated activities and the influence of process parameters. In addition, available data on cider quality and safety is reviewed. Finally, we focus on the future role of lactic acid bacteria and yeasts in the development of even better or new beverages made from apples.


Automated determination of angiotensin-converting enzyme in serum.
This is an adaptation of the Fujirebio "ACEcolor" kit for automated measurement of angiotensin-converting enzyme (EC 184.108.40.206) in serum with the Cobas Fara centrifugal analyzer. The linear range extends to an activity of 110 U/L. Results obtained by the present method and by the manual method were identical, and correlated closely (r = 0.983) with those by Cushman's modified method. The reference interval for 77 adult blood-bank donors was 9-25 U/L (mean 17, SD 4 U/L). Within-run and between-run CVs are 1.7 and 4.0%, respectively. The present method permits rapid, precise, and economical measurement of the enzyme and allows users of a Cobas Fara centrifugal analyzer to introduce a fully automated assay for angiotensin-converting enzyme into their clinical laboratory.


Deep brain stimulation in a Chinese Tourette's syndrome patient.
A 31-year-old Chinese man with intractable severe, lifelong Tourette's syndrome characterised by forceful self-injurious motor tics and socially embarrassing vocal tics was treated with bilateral deep brain stimulation. Electrodes were implanted into the thalamic targets at the centromedian-parafascicular complex according to Hassler's nomenclature. A dramatic reduction of tics resulted. At 18 months postoperatively, there was an 81% improvement in his total tics count and a 58% improvement in his Yale Global Tic Severity Scale. His modified Rush video scale decreased from 13 to 8 and visual analogue scale from 10 to 3. These data show that bilateral deep brain stimulation of the thalamus can have a favourable immediate effect on severe tics in a selected group of adult patients suffering from intractable Tourette's syndrome and postoperatively the beneficial effects persisted for at least 18 months.


American Telemedicine Association: Telestroke Guidelines.
The following telestroke guidelines were developed to assist practitioners in providing assessment, diagnosis, management, and/or remote consultative support to patients exhibiting symptoms and signs consistent with an acute stroke syndrome, using telemedicine communication technologies. Although telestroke practices may include the more broad utilization of telemedicine across the entire continuum of stroke care, with some even consulting on all neurologic emergencies, this document focuses on the acute phase of stroke, including both pre- and in-hospital encounters for cerebrovascular neurological emergencies. These guidelines describe a network of audiovisual communication and computer systems for delivery of telestroke clinical services and include operations, management, administration, and economic recommendations. These interactive encounters link patients with acute ischemic and hemorrhagic stroke syndromes with acute care facilities with remote and on-site healthcare practitioners providing access to expertise, enhancing clinical practice, and improving quality outcomes and metrics. These guidelines apply specifically to telestroke services and they do not prescribe or recommend overall clinical protocols for stroke patient care. Rather, the focus is on the unique aspects of delivering collaborative bedside and remote care through the telestroke model.


Programmed cell death in castor bean endosperm is associated with the accumulation and release of a cysteine endopeptidase from ricinosomes.
The cells of the endosperm of castor bean seeds (Ricinus communis) undergo programmed cell death during germination, after their oil and protein reserves have been mobilized. Nuclear DNA fragmentation first was observed at day 3 in the endosperm cells immediately adjacent to the cotyledons and progressed across to the outermost cell layers by day 5. We also detected the accumulation of small organelles known as ricinosomes, by using an antibody against a cysteine endoprotease. By the time the nuclear DNA was susceptible to heavy label by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling, the ricinosomes had released into the cytoplasm their content of cysteine endoprotease, which became activated because of the cleavage of its propeptide. The cysteine endoprotease is distinguished by a C-terminal KDEL sequence, although it is not retained in the lumen of the endoplasmic reticulum and is a marker for ricinosomes. Homologous proteases are found in the senescing tissues of other plants, including the petals of the daylily. Ricinosomes were identified in this tissue by electron microscopy and immunocytochemistry. It seems that ricinosomes are not unique to Ricinus and play an important role in the degradation of plant cell contents during programmed cell death.


[Acute pancreatitis. Evidence-based practice guidelines, prepared by the Hungarian Pancreatic Study Group].
Acute pancreatitis is one of the most common diseases of the gastrointestinal tract associated with significant morbidity and mortality that requires up-to-date and evidence based treatment guidelines. The Hungarian Pancreatic Study Group proposed to prepare evidence based guideline for the medical and surgical management of acute pancreatitis based on the available international guidelines and evidence. The preparatory and consultation task force appointed by the Hungarian Pancreatic Study Group translated and, if it was necessary, complemented and/or modified the international guidelines. All together 42 relevant clinical questions were defined in 11 topics (Diagnosis and etiology, Prognosis, Imaging, Fluid therapy, Intensive care management, Prevention of infectious complications, Nutrition, Biliary interventions, Post-endoscopic retrograde cholangio-pancreatography pancreatitis, Indication, timing and strategy for intervention in necrotizing pancreatitis, Timing of cholecystectomy [or endoscopic sphincterotomy]). Evidence was classified according to the UpToDate® grading system. The draft of the guideline was presented and discussed at the consensus meeting on September 12, 2014. 25 clinical questions with almost total (more than 95%) and 17 clinical questions with strong (more than 70%) agreement were accepted. The present guideline is the first evidence based acute pancreatitis guideline in Hungary. The guideline may provide important help for tuition, everyday practice and for establishment of proper finance of acute pancreatitis. Therefore, the authors believe that these guidelines will widely become as basic reference in Hungary.


Fetomaternal placental transfer mechanisms of aromatic amino acids in Macaca mulatta.
We investigated aromatic amino acid transfer mechanisms from fetus to mother in third-trimester pregnancies in rhesus monkeys after the administration of radioactive phenylalanine to the fetal circulation. The results indicated that fetomaternal transfer takes place mainly by facilitated diffusion via specific membrane carriers. This mechanism might participate in regulating amino acid concentrations in the fetus.


An unusual presentation of enzootic bovine leukosis.
A 6-year-old, Holstein x Simmental cow diagnosed with pyelonephritis had increasing difficulty rising and became recumbent, despite treatment with antibiotics. A serological test for the bovine leukemia virus was positive; at necropsy, the left kidney and ureter and the myocardium showed lesions of lymphosarcoma, confirmed by histology.


Cardiac response to water activities in children with Long QT syndrome type 1.
Swimming is a genotype-specific trigger in long QT syndrome type 1 (LQT1). To examine the autonomic response to water activities in children and adolescents with LQT1. In this cross-sectional study, LQT1 patients were age and sex matched to one healthy control subject. Electrocardiograms (ECGs) were recorded during face immersion (FI), swimming, diving, and whole-body submersion (WBS). Heart rate (HR) and heart rate variability (HRV) was measured. The high frequency (HF) component of HRV was interpreted to reflect parasympathetic activity, while the low frequency (LF) component was interpreted as reflecting the combined influence of sympathetic and parasympathetic activity on autonomic nervous modulation of the heart. Fifteen LQT1 patients (aged 7-19 years, all on beta-blocker therapy) and fifteen age and sex matched non-medicated controls were included. No significant ventricular arrhythmias were observed in the LQT1 population during the water activities. Out of these 15 matched pairs, 12 pairs managed to complete FI and WBS for more than 10 seconds and were subsequently included in HR and HRV analyses. In response to FI, the LQT1 group experienced a drop in HR of 48 bpm, compared to 67 bpm in the control group (p = 0.006). In response to WBS, HR decreased by 48 bpm in the LQT1 group and 70 bpm in the control group (p = 0.007). A significantly lower PTOT (p < 0.001) and HF (p = 0.011) component was observed before, during and after FI in LQT1 patients compared with the controls. Before, during and after WBS, a significantly lower total power (p < 0.001), LF (p = 0.002) and HF (p = 0.006) component was observed in the LQT1 patients. A significantly lower HR decrease in response to water activities was observed in LQT1 subjects on beta-blocker therapy, compared to matched non-medicated controls. The data suggests an impaired parasympathetic response in LQT1 children and adolescents. An aberrant autonomic nervous system (ANS) response may cause an autonomic imbalance in this patient group.


Combining the Hospital Frailty Risk Score With the Charlson and Elixhauser Multimorbidity Indices to Identify Older Patients at Risk of Poor Outcomes in Acute Care.
The Hospital Frailty Risk Score (HFRS) can be applied to medico-administrative datasets to determine the risks of 30-day mortality and long length of stay (LOS) in hospitalized older patients. The objective of this study was to compare the HFRS with Charlson and Elixhauser comorbidity indices, used separately or combined. A retrospective analysis of the French medical information database. The HFRS, Charlson index, and Elixhauser index were calculated for each patient based on the index stay and hospitalizations over the preceding 2 years. Different constructions of the HFRS were considered based on overlapping diagnostic codes with either Charlson or Elixhauser indices. We used mixed logistic regression models to investigate the association between outcomes, different constructions of HFRS, and associations with comorbidity indices. 743 hospitals in France. All patients aged 75 years or older hospitalized as an emergency in 2017 (n=1,042,234).Main outcome measures: 30-day inpatient mortality and LOS >10 days. The HFRS, Charlson, and Elixhauser indices were comparably associated with an increased risk of 30-day inpatient mortality and long LOS. The combined model with the highest c-statistic was obtained when associating the HFRS with standard adjustment and Charlson for 30-day inpatient mortality (adjusted c-statistics: HFRS=0.654; HFRS + Charlson = 0.676) and with Elixhauser for long LOS (adjusted c-statistics: HFRS= 0.672; HFRS + Elixhauser =0.698). Combining comorbidity indices and HFRS may improve discrimination for predicting long LOS in hospitalized older people, but adds little to Charlson's 30-day inpatient mortality risk.


Proteomic, genomic and translational approaches identify CRMP1 for a role in schizophrenia and its underlying traits.
Schizophrenia is a chronic illness of heterogenous biological origin. We hypothesized that, similar to chronic progressive brain conditions, persistent functional disturbances of neurons would result in disturbed proteostasis in the brains of schizophrenia patients, leading to increased abundance of specific misfolded, insoluble proteins. Identification of such proteins would facilitate the elucidation of molecular processes underlying these devastating conditions. We therefore generated antibodies against pooled insoluble proteome of post-mortem brains from schizophrenia patients in order to identify unique, disease-specific epitopes. We successfully identified such an epitope to be present on collapsin-response mediator protein 1 (CRMP1) in biochemically purified, insoluble brain fractions. A genetic association analysis for the CRMP1 gene in a large Finnish population cohort (n = 4651) corroborated the association of physical and social anhedonia with the CRMP1 locus in a DISC1 (Disrupted-in-schizophrenia 1)-dependent manner. Physical and social anhedonia are heritable traits, present as chronic, negative symptoms of schizophrenia and severe major depression, thus constituting serious vulnerability factors for mental disease. Strikingly, lymphoblastoid cell lines derived from schizophrenia patients mirrored aberrant CRMP1 immunoreactivity by showing an increase of CRMP1 expression, suggesting its potential role as a blood-based diagnostic marker. CRMP1 is a novel candidate protein for schizophrenia traits at the intersection of the reelin and DISC1 pathways that directly and functionally interacts with DISC1. We demonstrate the impact of an interdisciplinary approach where the identification of a disease-associated epitope in post-mortem brains, powered by a genetic association study, is rapidly translated into a potential blood-based diagnostic marker.


Fructose‑1,6‑bisphosphatase‑1 decrease may promote carcinogenesis and chemoresistance in cervical cancer.
Fructose-1,6-bisphosphatase-1 (FBP1), a gluconeogenesis rate-limiting enzyme expressed in various tissues, is important in the carcinogenesis of various cancers. To evaluate the association of FBP1 expression and carcinogenesis and chemoresistance in cervical cancer, the present study analyzed 140 patients of squamous cell carcinoma of cervical cancer (CSCC) who had adjuvant concurrent chemoradiation therapy following radical surgery. By detecting FBP1 protein expression in paraffin‑embedded tumor tissues through immunohistochemistry, it was observed that 50% of the cases had a low expression of FBP1, which was associated with a shorter overall survival time (P=0.011). In addition, FBP1 mRNA level was downregulated in tumor tissues, compared with cervical normal tissues. Among the tumor‑associated prognostic factors, loss of FBP1 expression (χ2‑test, P=0.025) was significantly associated with the tumor recurrence and greater tumor stage of cervical cancer patients (2‑test, P<0.0001). In 3‑(4,5)‑dimethylthiahiazo(‑z‑y1)-3,5-diphenytetrazoliumromide (MTT) assay of primary tumor cells, the median in vitro inhibition rate of cisplatin, carboplatin, nedaplatin, and oxaliplatin was 62, 47, 58 and 52%, respectively. Although there was no significant association between FBP1 expression and in vitro tumor inhibition rates of primary tumor cells, overexpression of FBP1 markedly suppressed carcinogenesis and restored the chemosensitivity to cisplatin in cervical cancer cell lines of HeLa and CaSki. Overall, decreased levels of FBP1 may be used as a predictor for poor prognosis of cervical cancer patients, however the mechanism requires further investigation.