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The SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) protein syntaxin-5 (Stx5) is essential for Golgi transport. In humans, the STX5 mRNA encodes two protein isoforms, Stx5 Long (Stx5L) from the first starting methionine and Stx5 Short (Stx5S) from an alternative starting methionine at position 55. In this study, we identify a human disorder caused by a single missense substitution in the second starting methionine (p.M55V), resulting in complete loss of the short isoform. Patients suffer from an early fatal multisystem disease, including severe liver disease, skeletal abnormalities and abnormal glycosylation. Primary human dermal fibroblasts isolated from these patients show defective glycosylation, altered Golgi morphology as measured by electron microscopy, mislocalization of glycosyltransferases, and compromised ER-Golgi trafficking. Measurements of cognate binding SNAREs, based on biotin-synchronizable forms of Stx5 (the RUSH system) and Förster resonance energy transfer (FRET), revealed that the short isoform of Stx5 is essential for intra-Golgi transport. Alternative starting codons of Stx5 are thus linked to human disease, demonstrating that the site of translation initiation is an important new layer of regulating protein trafficking. Mutations in genes critical for proper intra-Golgi transport can cause human syndromes due to defects in glycosylation of proteins. Here, the authors identify a human variant of Syntaxin-5 that causes fatal multisystem disease and mislocalization of glycosyltransferases due to altered Golgi transport. [ABSTRACT FROM AUTHOR]

Venous thromboembolism (VTE) is a serious and often fatal medical condition with an increasing incidence. The treatment of VTE is undergoing tremendous changes with the introduction of the new direct oral anticoagulants and clinicians need to understand new treatment paradigms. This manuscript, initiated by the Anticoagulation Forum, provides clinical guidance based on existing guidelines and consensus expert opinion where guidelines are lacking. In this chapter, we address the management of patients presenting with venous thrombosis in unusual sites, such as cerebral vein thrombosis, splanchnic vein thrombosis, and retinal vein occlusion. These events are less common than venous thrombosis of the lower limbs or pulmonary embolism, but are often more challenging, both for the severity of clinical presentations and outcomes and for the substantial lack of adequate evidence from clinical trials. Based on the available data, we suggest anticoagulant treatment for all patients with cerebral vein thrombosis and splanchnic vein thrombosis. However, in both groups a non-negligible proportion of patients may present with concomitant bleeding at the time of diagnosis. This should not contraindicate immediate anticoagulation in patients with cerebral vein thrombosis, whereas for patients with splanchnic vein thrombosis anticoagulant treatment should be considered only after the bleeding source has been successfully treated and after a careful assessment of the risk of recurrence. Finally, there is no sufficient evidence to support the routine use of antithrombotic drugs in patients with retinal vein occlusion. Future studies need to assess the safety and efficacy of the direct oral anticoagulants in these settings. [ABSTRACT FROM AUTHOR]

Background: There is a paucity of data available regarding the repeatability and reproducibility of superficial shear wave speed (SWS) measurements at imaging depths relevant to the pediatric population. Objective: To assess the repeatability and reproducibility of superficial shear wave speed measurements acquired from elasticity phantoms at varying imaging depths using three imaging methods, two US systems and multiple operators. Materials and methods: Soft and hard elasticity phantoms manufactured by Computerized Imaging Reference Systems Inc. (Norfolk, VA) were utilized for our investigation. Institution No. 1 used an Acuson S3000 US system (Siemens Medical Solutions USA, Malvern, PA) and three shear wave imaging method/transducer combinations, while institution No. 2 used an Aixplorer US system (SuperSonic Imagine, Bothell, WA) and two different transducers. Ten stiffness measurements were acquired from each phantom at three depths (1.0 cm, 2.5 cm and 4.0 cm) by four operators at each institution. Student's t-test was used to compare SWS measurements between imaging techniques, while SWS measurement agreement was assessed with two-way random effects single-measure intra-class correlation coefficients (ICCs) and coefficients of variation. Mixed model regression analysis determined the effect of predictor variables on SWS measurements. Results: For the soft phantom, the average of mean SWS measurements across the various imaging methods and depths was 0.84 ± 0.04 m/s (mean ± standard deviation) for the Acuson S3000 system and 0.90 ± 0.02 m/s for the Aixplorer system ( P = 0.003). For the hard phantom, the average of mean SWS measurements across the various imaging methods and depths was 2.14 ± 0.08 m/s for the Acuson S3000 system and 2.07 ± 0.03 m/s Aixplorer system ( P > 0.05). The coefficients of variation were low (0.5-6.8%), and interoperator agreement was near-perfect (ICCs ≥ 0.99). Shear wave imaging method and imaging depth significantly affected measured SWS ( P < 0.0001). Conclusion: Superficial shear wave speed measurements in elasticity phantoms demonstrate minimal variability across imaging method/transducer combinations, imaging depths and operators. The exact clinical significance of this variation is uncertain and may change according to organ and specific disease state. [ABSTRACT FROM AUTHOR]

Smoking continues to be the leading cause of preventable deaths in the USA, accounting for one in every five deaths every year, and cardiovascular (CV) disease remains the leading cause of those deaths. Hence, there is increasing awareness to quit smoking among the public and counseling plays an important role in smoking cessation. There are different pharmacological methods to help quit smoking that includes nicotine replacement products available over the counter, including patch, gum, and lozenges, to prescription medications, such as bupropion and varenicline. There have been reports of both nonserious and serious adverse CV events associated with the use of these different pharmacological methods, especially varenicline, which has been gaining media attention recently. Therefore, we systematically reviewed the various pharmacotherapies used in smoking cessation and analyzed the evidence behind these CV events reported with these therapeutic agents. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) is often used to treat heart failure accompanied with pulmonary edema. According to present knowledge, however, NO donors are contraindicated when systolic blood pressure is less than 90 mmHg. Based on recent findings and our own clinical experience, we formulated a hypothesis about the new breakthrough complex lifesaving effects of NO donors in patients with cardiac arrest and cardiopulmonary resuscitation therapy. It includes a direct hemodynamic effect of NO donors mediated through vasodilation of coronary arteries in cooperation with improvement of cardiac function and cardiac output through reversible inhibition of mitochondrial complex I and mitochondrial NO synthase, followed by reduction in reactive oxygen species and correction of myocardial stunning. Simultaneously, an increase in vascular sensitivity to sympathetic stimulation could lead to an increase in diastolic blood pressure. Confirmation of this hypothesis in clinical practice would mean a milestone in the treatment for cardiac arrest and cardiopulmonary resuscitation. [ABSTRACT FROM AUTHOR]

The article presents abstracts on topics for health factors related to liver which include demographics of alcoholic hepatitis, cholesterol ester storage disease and kidney transplant in hepatitis C.

Four unrelated patients having an unusual clinical phenotype, including multiple peripheral nerve sheath tumors, are reported. Their clinical features were not typical of any known familial tumor syndrome. The patients had multiple painful neurofibromas, including bilateral orbital plexiform neurofibromas, and spinal as well as mucosal neurofibromas. In addition, they exhibited a marfanoid habitus, shared similar facial features, and had enlarged corneal nerves as well as neuronal migration defects. Comprehensive NF1, NF2 and SMARCB1 mutation analyses revealed no mutation in blood lymphocytes and in schwann cells cultured from plexiform neurofibromas. Furthermore, no mutations in RET, PRKAR1A, PTEN and other RAS-pathway genes were found in blood leukocytes. Collectively, the clinical and pathological findings in these four cases fit no known syndrome and likely represent a new disorder. [ABSTRACT FROM AUTHOR]

Purpose: Sunitinib is an oral tyrosine kinase inhibitor of VEGF, PDGF, c-KIT, and flt-3 receptors. A pediatric phase I study of sunitinib capsules identified the maximum tolerated dose as 15 mg/m/day. This study was conducted to evaluate sunitinib given as a powder formulation. Methods: Sunitinib 15 mg/m was administered orally daily for 4 weeks on/2 weeks off to patients <21 years old with refractory solid tumors. Sunitinib capsules were opened, and the powder sprinkled onto applesauce or yogurt. Plasma levels of sunitinib and an active metabolite, SU12662, were measured, and pharmacokinetic parameters were estimated. Results: 12 patients, median age 13 (range 4-21) years, were treated. The most common first-cycle toxicities were leucopenia ( n = 6), fatigue ( n = 5), neutropenia ( n = 4), and hypertension ( n = 4). Three patients had dose-limiting toxicities (DLTs) in cycle 1 (dizziness/back pain, hand-foot syndrome, and intratumoral hemorrhage/hypoxia). A median peak plasma sunitinib concentration of 21 (range 6-36) ng/ml was reached at a median of 4 (range 4-8) h after the first dose. The median exposure (AUC) was 585 (range 196-1,059) h ng/l. The median half-life was 23 (range 13-36) h. The median trough concentration measured before day 14 dosing was 32 (range 12-58) ng/ml. Conclusions: The pharmacokinetic profile of sunitinib appears similar between a powder formulation and published data using capsules. The powder formulation allows patients unable to swallow capsules to receive sunitinib. [ABSTRACT FROM AUTHOR]

The article offers information on several studies on perioperative medicine and their clinical practice implications presented at the 33rd Annual Meeting of the Society of General Internal Medicine. It mentions that Revised Cardiac Risk Index (RCRI) is considered as a valid tool for predicting cardiac complications during a noncardiac surgery. It adds that prophylaxis has been recommended in the guidelines of American College of Chest Physicians (ACCP) for venous thromboembolism treatment.

Dysregulation of apoptosis or programmed cell death is a hallmark of human cancers that contributes to tumor development and progression, and may confer treatment resistance and therapeutic failure. Apoptosis is governed by both a mitochondria-mediated and a death receptor (DR)-mediated pathway. Within human cancer cells, both apoptotic pathways are regulated by proapoptotic and prosurvival Bcl-2 family proteins. Loss of proapoptotic genes or, alternatively, upregulation of prosurvival genes may lead to tumorigenesis in preclinical models. Expression of Bcl-2 family proteins has been shown to provide prognostic information in certain malignancies, including colon cancers, and therefore may be useful in determining which patients are more likely to suffer recurrence and metastasis. Such markers may assist in selecting patients to receive adjuvant chemotherapy and represent potential targets for therapeutic intervention. In the therapeutic arena, small molecule Bcl-2/Bcl-xL antagonists and DR agonists have been developed that enhance chemosensitivity in preclinical models and currently are undergoing evaluation in cancer patients. This review focuses on the current status of apoptotic regulatory proteins as biomarkers in colorectal cancers and their potential clinical utility. [ABSTRACT FROM AUTHOR]

The article presents abstracts of medical research. They include "Thyroid surgery and dealing with complications," "Electroporation therapy in head and neck cancer," "Digital volume tomography in oto-rhino-laryngology" and "Current diagnostics of swallowing disorders: the ENT specialists and phoniatricians role."

OBJECTIVE: Colon cancers with high frequency microsatellite instability (MSI-H) are preferentially located in the proximal colon. Given that 15–20% of sporadic colon cancers are MSI-H, we determined whether tumor site-specific differences in clinicopathological variables, biomarkers, and prognosis are due to inclusion of MSI-H cases. METHODS: TNM stage II and III primary colon carcinomas (N = 528) from patients enrolled in 5-fluorouracil-based adjuvant trials were analyzed for MSI using 11 microsatellite markers. Immunostaining for DNA mismatch repair (hMLH1, hMSH2, hMSH6) and p53 proteins was performed. DNA ploidy (diploid vs aneuploid/tetraploid) and proliferative indices (PI: S-phase + G2M) were analyzed by flow cytometry. RESULTS: MSI-H was found in 95 (18%) colon cancers. Proximal tumors (N = 286) were associated with MSI-H, older age (>65 yr), poor differentiation, and diploid DNA content compared with distal tumors (all P≤ 0.016). Nuclear p53 staining was more frequent in distal tumors ( P= 0.002); PI was unrelated to tumor site. When MSI-H tumors were excluded, no tumor site-related differences were found except for age, which remained associated with proximal cancers ( P= 0.030). Proximal site was associated with improved disease-free survival in all patients ( P= 0.042), but not when MSI-H cases were excluded ( P= 0.236). MSI-H status or loss of mismatch repair proteins, diploidy, and lower PI were associated with improved survival rates. CONCLUSIONS: Tumor site-related differences in clinicopathological variables, biomarkers, and prognosis of sporadic colon cancers can be explained by the inclusion of MSI-H cases. Older age, however, is associated with proximal tumor site independent of MSI status. [ABSTRACT FROM AUTHOR]

Autograft absolute lymphocyte count (A-ALC) is an independent prognostic factor for survival after autologous peripheral blood hematopoietic stem cell transplantation (APHSCT) for non-Hodgkin's lymphoma (NHL). Factors enhancing A-ALC collections are unknown. We hypothesize that apheresis instrument settings could affect A-ALC. Data from 127 NHL patients collected from 15 January 1999 to 30 July 2004 using a single apheresis instrument (COBE Spectra (SP), Baxter Amicus (AM), and CS3000 Plus (CS)) were analyzed. The primary end point of the study was to assess the correlation between apheresis instrument settings and A-ALC. The secondary end point was to determine the effect of apheresis instrument on survival post-APHSCT. Patients collected using SP achieved higher A-ALC compared to AM (with modified settings) or CS (P<0.05) and demonstrated superior overall (OS) and progression-free survival (PFS) (P<0.03). Multivariate analysis demonstrated A-ALC and not the apheresis instrument as an independent prognostic factor for OS and PFS, cancelling the prognostic effect of the apheresis instruments observed in the univariate analysis. The survival advantage observed by SP was from the higher A-ALC collected compared to AM and CS. These data suggest that apheresis instrument settings should be optimized to collect CD34+ cells as well as an A-ALC target, with direct impact on survival post-APHSCT.Bone Marrow Transplantation (2006) 37, 811–817. doi:10.1038/sj.bmt.1705338; published online 13 March 2006 [ABSTRACT FROM AUTHOR]

Absolute lymphocyte count (ALC) recovery postautologous stem cell transplantation is an independent predictor for survival in acute myelogenous leukemia (AML). The role of ALC recovery after induction chemotherapy (IC) in AML is unknown. We hypothesize that ALC recovery after IC has a direct impact on survival. We have now evaluated the impact of ALC recovery after IC on overall survival (OS) and leukemia-free survival (LFS) in 103 consecutive, newly diagnosed AML patients treated with standard IC and consolidation chemotherapy (CC) from 1998 to 2002. ALC recovery was studied at days 15 (ALC-15), 21 (ALC-21), 28 (ALC-28) after IC and before the first CC (ALC-CC). Superior OS and LFS at each time point were observed with an ALC-15, ALC-21, ALC-28, and ALC-CC 500 cells/μl. Patients with an ALC 500 cells/μl at all time points vs those who did not have superior OS and LFS (not reached vs 13 months, P<0.0001; and not reached vs 11 months, P<0.0001, respectively). Multivariate analysis demonstrated ALC 500 cells/μl at all time points to be an independent prognostic factor for survival. Our data suggest a critical role of lymphocyte (immune) recovery on survival after IC in AML.Leukemia (2006) 20, 29–34. doi:10.1038/sj.leu.2404032; published online 10 November 2005 [ABSTRACT FROM AUTHOR]

The article presents abstracts of medical research. The abstracts include "Direct Visualization of Ascaris lumbricoides in Small Intestine by Wireless Capsule Endoscopy," "Drug Interaction Presenting as an Acute Abdomen," "Closure of Entero-Vesical Fistula in Crohn's Disease with Infliximab: Two Years Follow up of Two Cases," "Dietary Fructose Intolerance Mimicking Irritable Bowel Syndrome," and "Cryptococcal Meningitis Presenting as a Fever of Unknown Origin Following Immunosuppressive Therapy for Autoimmune Hepatitis."

A letter to the editor is presented about a study that examined how oxytocin enhances anxiety in humans.

A letter to the editor is presented about a study which examined the association between secreted frizzled-related protein 3 (sFRP3) and early antidepressant responses in both mice and human models.

Placentas associated with preeclampsia are characterized by extensive apoptosis in trophoblast lineages. Syncytin-1 (HERVWE1) mediates the fusion of cytotrophoblasts to form syncytiotrophoblasts, which assume the placental barrier, fetal-maternal exchange and endocrine functions. While decreased syncytin-1 expression has been observed in preeclamptic placentas, it is not clear if this alteration is involved in trophoblast apoptosis. In the current study, we found that siRNA-mediated knockdown of syncytin-1 led to apoptosis in choriocarcinoma BeWo, a cell line of trophoblastic origin. Characterization of the apoptotic pathways indicated that this effect does not rely on the activation of caspases. Rather, decreased syncytin-1 levels activated the apoptosis inducing factor (AIF) apoptotic pathway by inducing the expression, cleavage, and nuclear translocation of AIF. Moreover, calpain1, the cysteine protease capable of cleaving AIF, was upregulated by syncytin-1 knockdown. Furthermore, treatment with calpain1 inhibitor MDL28170 effectively reversed AIF cleavage, AIF nuclear translocation, and cell apoptosis triggered by syncytin-1 downregulation, verifying the specific action of calpain1-AIF pathway in trophoblast apoptosis. We confirmed that preeclamptic placentas express lower levels of syncytin-1 than normal placentas, and observed an inverse correlation between syncytin-1 and AIF/calpain1 mRNA levels, a result consistent with the in vitro findings. Immunohistochemistry analyses indicated decreased syncytin-1 and increased AIF and calpain1 protein levels in apoptotic cells of preeclamptic placentas. These findings have for the first time revealed that decreased levels of syncytin-1 can trigger the AIF-mediated apoptosis pathway in BeWo cells. This novel mechanism may contribute to the structural and functional deficiencies of syncytium frequently observed in preeclamptic placentas. [ABSTRACT FROM AUTHOR]