Non-enzymatic glycation of IgG: an in vivo study.
The IgG glycation level of 30 healthy subjects and 60 type 2 diabetic patients with different degrees of metabolic control was evaluated by matrix-assisted laser desorption ionization mass spectrometry, a technique allowing the determination of mass increase of the IgG molecule. When applied to the digested mixture obtained by the action of papain on the plasma protein fraction, the same method established the mass increase of Fab and Fc fragments of IgG; for the former, a higher mass increase was found, possibly explained by its high reactivity to glucose. Experimental results were confirmed by molecular modeling calculations. Results suggest that the immunodeficiency observed in diabetic patients may be due to the inhibition of molecular recognition between antibody and antigen as a result of a change in functionality of the modified Fab fragment of IgG.


High-performance size-exclusion chromatography studies on the formation and distribution of polar compounds in camellia seed oil during heating.
Camellia seed oil (CSO) is rich in oleic acid and has a high number of active components, which give the oil high nutritional value and a variety of biological activity. The aim of the present study was to determine the changes in the content and distribution of total polar compounds (TPC) in CSO during heating. TPC were isolated by means of preparative flash chromatography and further analyzed by high-performance size-exclusion chromatography (HPSEC). The TPC content of CSO increased from 4.74% to 25.29%, showing a significantly lower formation rate as compared to that of extra virgin olive oil (EVOO) and soybean oil (SBO) during heating. Furthermore, heating also resulted in significant differences (P<0.05) in the distribution of TPC among these oils. Though the content of oxidized triacylglycerol dimers, oxidized triacylglycerol oligomers, and oxidized triacylglycerol monomers significantly increased in all these oils, their increased percentages were much less in CSO than those in EVOO, indicating that CSO has a greater ability to resist oxidation. This work may be useful for the food oil industry and consumers in helping to choose the correct oil and to decide on the useful lifetime of the oil.


TDP-43 and HERV-K Envelope-Specific Immunogenic Epitopes Are Recognized in ALS Patients.
The human endogenous retrovirus-K (HERV-K) and TAR DNA-binding protein 43 (TDP-43) have been associated with the pathophysiology of amyotrophic lateral sclerosis (ALS). Given these findings, we investigated the humoral response against HERV-K envelope surface (env-su) glycoprotein antigens and TDP-43 in the plasma of ALS patients and healthy controls (HCs). The measured levels of Abs against the different epitopes' fragments were significantly elevated in ALS patients, both in long-survivor (LS) and newly diagnosed (ND) patients, compared to HCs. We observed a positive correlation between HERV-K and TDP-43 antibodies (Abs) levels, which seemed to strengthen with disease progression, that was not found in HCs. The TDP-43 and HERV-K epitopes identified in this study are highly immunogenic and recognized by the humoral response of ALS patients. Increased circulating levels of Abs directed against specific HERV-K- and TDP-43-derived epitopes could serve as possible biomarkers.


The etiology and reversibility of muscle dysfunction in the aged.
Muscle weakness in the elderly is prevalent and morbid, closely linked to the frailty, functional decline, immobility, falls, and injuries in this population. The marked decrease in skeletal muscle strength and size with aging is a multifactorial syndrome which may be attributable in part to: (a) biological changes of aging itself; (b) the accumulation of acute and chronic diseases; (c) the assumption of a sedentary life style, and (d) selective or generalized nutritional inadequacies. Inactivity and undernutrition are potentially at least partially reversible with appropriate interventions, and therefore the delineation of the attributable risk of these two factors to the muscle weakness of aging is a critical research goal. Similarly, identification of appropriate modalities of physical activity and nutrition which have positive effects on muscle physiology in the aged is the focus of major investigations currently.


Association between magnitude of femoral head collapse and quality of life in patients with osteonecrosis of the femoral head.
The magnitude of femoral head collapse (MFHC) is one of the criteria for staging osteonecrosis of the femoral head (ONFH). The present study aimed to clarify the relationship between MFHC and hip pain or functional quality of life (QOL) scores in patients with ONFH. Seventy patients with ONFH who had femoral head collapse without osteoarthritic changes were divided into four groups based on MFHC by 1 mm. Pain was assessed using the visual analogue scale (VAS). QOL was evaluated using patient-reported outcome measures such as the Japanese Orthopaedic Association Hip-Disease Evaluation Questionnaire (JHEQ), Oxford Hip Score (OHS), and Short Form-12 Health Survey, version 2 (SF-12v2). We also explored the relationship between MFHC and QOL. Pain score and satisfaction score in the VAS, JHEQ pain subscale, JHEQ movement subscale, and JHEQ total score were significantly associated with MFHC, and no significant differences were found between groups in any subscale or total score for OHS and SF-12v2. In patients with ONFH, differences in MFHC by 1 mm were associated with deterioration of some pain VAS and QOL outcomes.


Understanding of Dynamic Contacting Behaviors of Underwater Gas Bubbles on Solid Surfaces.
Understanding of dynamic behaviors of gas bubbles on solid surfaces has significant impacts on gas-involving electrochemical reactions, mineral flotation, and so on in industry. Contact angle (θ) is widely employed to characterize the wetting behaviors of bubbles on solid surfaces; however, it usually fluctuates within the bubble's advancing (θa) and receding (θr) range. Although the term of most-stable contact angle (θms) was defined previously as the closest valuable approximation for thermodynamically meaningful contact angle for a droplet on a solid surface, it has not been widely studied; and the precise θms measurement methods are inadequate to describe bubbles' wetting behaviors on solid surfaces. Herein, we proposed to take θms as the mean value of θa and θr, as a more accurate descriptor of gas bubbles' dynamic behaviors on nonideal solid surfaces, similar to the definition of droplets' θms on solid surfaces. The feasibility and accuracy of the proposed θms have been evidenced by recording the bubbles' contacting behaviors on solid surfaces with varied wettabilities. In addition, it was found that the contact angle hysteresis (δ), as the difference between θa and θr, reached its maximum value when θms approached 90°, regardless of the roughness (r) of the substrates. Finally, built on the above concept, the lateral adhesion force (f) of the gas bubble on the solid interface, which worked on the three-phase contact line (TPCL) of an individual bubble on a solid surface against its lateral motion during the bubble advancing or receding process, was described quantitatively by combining θa, θr, and the liquid-gas interfacial tension (γlg). Experimental and theoretical data jointly confirmed that f reached its maximum value at θms ∼ 90°, namely, a "super-sticky" state, which described the dynamically most sluggish movement of the bubble along the solid surface.


Synthesis of the first diethylenetriaminepentahydroxamic acid (DTPH) bifunctional chelating agent.
Synthesis of a new pentahydroxamic acid bifunctional chelating agent (BCA), constructed on the aminoazaalkyl core of diethylenetriaminepentaacetic acid (DTPA), is reported. Rational modifications in the structure of DTPA, which could result in an enhancement of its chelation properties, add to the collection of diagnostic and therapeutic metals bound by this chelator, and might implement significant improvements in the in vivo behavior of this compound, are described. Further improvements in the stability of the ligand-metal complexes of DTPA may improve both diagnostic and therapeutic outcomes such as tumor-to-normal tissue ratios and target-delivered radioactivity. A combination of hydroxamate functions with the azaalkyl backbone of DTPA might be a suitable approach to generate such higher stabilities. This rationale may be justified by the well-known affinity of hydroxamates against different transition metals and favorable properties of DTPA as a versatile chelator. Thus, the N(4),N(alpha),N(alpha),N(epsilon),N(epsilon)-pentakis[[((N-hydroxy-N-methyl]carbonyl)methyl]-2, 6-diamino-4-azahexanoic hydrazide (5, DTPH) was designed and synthesized through a convergent synthesis and in 40.7% overall yield. Conjugation of this compound to the monoclonal antibody (MAb) Delta Ch2HuCC49, used as a model protein, was carried out to evaluate the efficiency of this molecule as a BCA. Radiolabeling of the DTPH-Delta CH2HuCC49 conjugate with lutetium-177 ((177)Lu) and biodistribution of the labeled conjugate in athymic nude mice, bearing LS174T human colon carcinoma xenografts, are reported.


Self-awareness of HbA1c and its association with glycemic control among patients with type 2 diabetes: A multicenter study.
To measure the self-awareness of hemoglobin A1c (HbA1c) prevalence among type 2 diabetic Saudi patients and its association with glycemic control, thereby identifying those factors that might affect their glycemic control. This multicenter study was carried out in outpatients' diabetes clinics in tertiary hospitals in Riyadh, Qassim, and Jeddah, Saudi Arabia. The data was collected using questionnaires. The subject's self-awareness on the HbA1c test was assessed based on the combined score of 4 questions. The latest HbA1c result before the time of data collection was obtained from medical records. Data was analyzed using bivariate and multivariate statistical methods. The prevalence of HbA1c self-awareness was approximately 44.5%. A total of 4 participants characteristics (glycemic control, education level, monthly income and number of follow-up visits) were associated with awareness of HbA1c. Whereas for better glycemic control; type of treatment, duration of diabetes, and self-awareness of HbA1c were independently statistically significantly associated. There is a positive association between HbA1c self-awareness and glycemic control. Glycemic control was good among those who were educated on the meaning of the test, their levels, and their target goal. Awareness among health care providers regarding the role of the patient's education regarding their condition might help in providing the patient with optimal care. Further studies with different experimental designs are needed to study this association, which will contribute to the development of a structured educational program.


Evolutionary dynamics of hepatitis C virus NS3 protease domain during and following treatment with narlaprevir, a potent NS3 protease inhibitor.
Narlaprevir, a hepatitis C virus (HCV) NS3/4A serine protease inhibitor, has demonstrated robust antiviral activity in a placebo-controlled phase 1 study. To study evolutionary dynamics of resistant variants, the NS3 protease sequence was clonally analysed in thirty-two HCV genotype 1-infected patients following treatment with narlaprevir. Narlaprevir monotherapy was administered for one week (period 1) followed by narlaprevir/pegylated interferon-alpha-2b combination therapy with or without ritonavir (period 2) during two weeks, interrupted by a washout period of one month. Thereafter, all patients initiated pegylated interferon-alpha-2b/ribavirin combination therapy. Longitudinal clonal analysis was performed in those patients with NS3 mutations. After narlaprevir re-exposure, resistance-associated mutations at position V36, T54, R155 and A156 were detected in five patients in >95% of the clones. Narlaprevir retreatment resulted in a 2.58 and 5.06 log10 IU/mL viral load decline in patients with and without mutations, respectively (P=<0.01). After treatment, resistant variants were replaced with wild-type virus within 2-24 weeks in three patients. However, the R155K mutation was still observed 3.1 years after narlaprevir dosing in two patients in 5% and 45% of the viral population. Resistant variants could be detected early during treatment with narlaprevir. A slower viral load decline was observed in those patients with resistance-associated mutations detectable by direct population sequencing. These mutations disappeared within six months following treatment with the exception of R155K mutation, which persisted in two patients.


Quantitative mass spectrometry analysis reveals a panel of nine proteins as diagnostic markers for colon adenocarcinomas.
Adenocarcinomas are cancers originating from the gland forming cells of the colon and rectal lining, and are known to be the most common type of colorectal cancers. The current diagnosis strategies for colorectal cancers include biopsy, laboratory tests, and colonoscopy which are time consuming. Identification of protein biomarkers could aid in the detection of colon adenocarcinomas (CACs). In this study, tissue proteome of colon adenocarcinomas (n = 11) was compared with the matched control specimens (n = 11) using isobaric tags for relative and absolute quantitation (iTRAQ) based liquid chromatography-mass spectrometry (LC-MS/MS) approach. A list of 285 significantly altered proteins was identified in colon adenocarcinomas as compared to its matched controls, which are associated with growth and malignancy of the tumors. Protein interaction analysis revealed the association of altered proteins in colon adenocarcinomas with various transcription factors and their targets. A panel of nine proteins was validated using multiple reaction monitoring (MRM). Additionally, S100A9 was also validated using immunoblotting. The identified panel of proteins may serve as potential biomarkers and thereby aid in the detection of colon adenocarcinomas.


Racial Disparities in Pediatric Mortality Following Transfusion Within 72 Hours of Operation.
Postoperative bleeding and transfusion are correlated with mortality risk. Furthermore, postoperative bleeding may often initiate the cascade of complications that leads to death. Given that minority children have increased risk of surgical complications, this study aimed to investigate the association of race with pediatric surgical mortality following postoperative transfusion. We used the NSQIP-P PUF to assemble a retrospective cohort of children <18 who underwent inpatient surgery during 2012-2021. We included White, Black, Hispanic, and 'Other' children who received a transfusion within 72 h of surgery. The primary outcome was defined as all-cause mortality within 30 days following the primary surgical procedure. Using logistic regression models, we estimated the risk-adjusted odds ratio (aOR) and 95% confidence intervals (CI) of mortality, comparing each racial/ethnic cohort to White children. A total of 466,230 children <18 years of age underwent inpatient surgical procedures from 2012 to 2021. Of these, 46,200 required transfusion and were included in our analysis. The majority of patients were non-Hispanic White (64.6%, n = 29,850), while 18.9% (n = 8752) were non-Hispanic Black, 11.7% (n = 5387) were Hispanic, and 4.8% (n = 2211) were 'Other' race. The overall rate of mortality following transfusion was 2.5%. White children had the lowest incidence of mortality (2.0%), compared to children of 'Other' race (2.5%), Hispanic children (3.1%), and Black children (3.6%). After adjusting for sex, age, comorbidities, case status, preoperative transfusion within 48 h, and year of operation, we found that Black children experienced 1.24 times the odds of mortality following a postoperative transfusion compared to a White child (aOR: 1.24; 95%CI, 1.03-1.51; P = 0.025). Hispanic children were also significantly more likely to die following a postoperative transfusion than White children (aOR: 1.19; 95%CI, 1.02-1.39; P = 0.027). We found that minority children who required a postoperative transfusion had a higher odds of death than White children. Future studies should explore adverse events following postoperative transfusion and the differences in their management by race that may contribute to the higher mortality rate for minority children. Level II. Not applicable.


Surgical attitude towards carcinoid tumour of the appendix. Review of the literature.
Carcinoid tumours of the gastrointestinal tract are most frequently located at the appendix. We report two cases: In the first case, we realized a simple appendicectomy. In the second case, two weeks after the appendicectomy was performed, according to the histological characteristics of the tumoral specimen, the patient underwent a laparoscopic right hemicolectomy with regional lymphadenectomy. In both cases, 5-HIAA (5 HydroxyIndolAceticAcid) is assayed regularly and remains normal.


Impact of methicillin-resistant Staphylococcus aureus on treatment of hand infections.
With the increasing incidence of methicillin-resistant Staphylococcus aureus (MRSA) in hand infections in urban centers, multiple studies have recommended using MRSA-effective antibiotics as first-line treatment of hand infections. This study assesses the effect of adopting this recommendation for the treatment of hand infections at the authors' hospital. Patients with hand infections drained in the authors' hospital were prospectively enrolled in an observational study over a 12-month period. Culture results and response to treatment were recorded. Twenty-two patients met inclusion criteria. Eleven of 14 patients with S aureus infections had MRSA. All of these patients responded to the initial antibiotic selected. Two patients had infections that did not respond to trimethoprim-sulfamethoxazole. One grew group A Streptococcus infection, and the other had lymphangitic streaking that suggested Streptococcus infection. Because of the high prevalence of MRSA among hand infections at the authors' institution, we continue to prescribe MRSA-effective antibiotics as first-line treatment of hand abscesses. Close follow-up is still necessary to confirm that each patient has responded appropriately to treatment or to allow modification of the treatment plan if the patient has not responded to treatment.


Mature lipid droplets are accessible to ER luminal proteins.
Lipid droplets are found in most organisms where they serve to store energy in the form of neutral lipids. They are formed at the endoplasmic reticulum (ER) membrane where the neutral-lipid-synthesizing enzymes are located. Recent results indicate that lipid droplets remain functionally connected to the ER membrane in yeast and mammalian cells to allow the exchange of both lipids and integral membrane proteins between the two compartments. The precise nature of the interface between the ER membrane and lipid droplets, however, is still ill-defined. Here, we probe the topology of lipid droplet biogenesis by artificially targeting proteins that have high affinity for lipid droplets to inside the luminal compartment of the ER. Unexpectedly, these proteins still localize to lipid droplets in both yeast and mammalian cells, indicating that lipid droplets are accessible from within the ER lumen. These data are consistent with a model in which lipid droplets form a specialized domain in the ER membrane that is accessible from both the cytosolic and the ER luminal side.


The prognostic role of neopterin in COVID-19 patients.
In Coronavirus disease-2019 (COVID-19) cases, hyper inflammation is associated with the severity of the disease. High levels of circulating cytokines were reported in severe COVID-19 patients. Neopterin produced by macrophages on stimulation with interferon-gamma, which is an important cytokine in the antiviral immune response, hence it can be used to predict the severity of disease in COVID-19 cases. In this study, it was aimed to determine the prognostic value of the neopterin for the prediction of severe disease in patients with COVID-19. This single-center, prospective study was conducted in hospitalized COVID-19 patients and healthy volunteers. Severe and mild COVID-19 cases were compared in terms of clinical and laboratory findings as well as serum neopterin levels on hospital admission. To assess the prognostic utility of neopterin between the severe and mild COVID-19 groups, a receiver-operating characteristic (ROC) curve was generated, and the area under the curve (AUC) was calculated. The median serum neopterin level was four times higher in COVID-19 patients than the healthy controls (46 vs. 12 nmol/L; p < .001). The AUC value of serum neopterin was 0.914 (95% confidence interval, 0.85-0.97). The sensitivity and specificity of serum neopterin for the cut-off value of 90 nmol/L to identify severe COVID-19 cases were 100% and 76%, respectively. Serum neopterin levels on hospitalization were significantly higher in severe COVID-19 disease than mild COVID-19 patients. Neopterin levels can be used as an early prognostic biomarker for COVID-19 on admission.


The cardiovascular manifestations of genetic disorders of collagen metabolism.
Current research in the biochemistry and molecular genetics of collagen metabolism has produced a sophisticated level of understanding of the mechanisms involved in the pathogenesis of a number of inherited diseases of connective tissue. Nowhere is this better exemplified than in the cardiovascular disorders associated with certain genetic disorders of collagen metabolism. For instance, the life-threatening vascular complications of Ehlers-Danlos syndrome IV, the Sack-Barabas type, appears to be related to a number of defects in the production of Type III procollagen. The large size of the collagen genes and the complexity of the biochemistry of collagen have not made research a simple task. Nevertheless, the location of certain genes is now known with a reasonable degree of accuracy and a few have been cloned in their entirety. The future investigation of these genetic mutations holds great excitement for those engaged in research in this fascinating field.


Patient safety culture at a surgical center: the nursing perception.
To analyze the safety culture of the patient from the perception of the nursing team of a surgical center. This is a cross-sectional and analytical study with 92 professionals from the nursing of a surgical center of a hospital in Teresina-PI, the data were collected from January to June of 2016, through the Hospital Survey on Patient Safety Culture questionnaire. In the analysis and interpretation of the data the guidelines of the AHRQ were followed. The evaluation of patient safety by the professionals was "Regular" (48.9%). The dimension of the safety culture with the most positive result was "Organizational learning-continuous improvement" (58.7%), and with least positive results were "Opening for communication" (32.3%) and "Feedback and communication about errors" (32.6%). There are problematic areas in the safety culture of the sector, which shows that this culture needs to be better developed, with special attention to the dimensions of the culture that presented a less positive evaluation.


The value of assessing myocardial deformation at recovery after dobutamine stress echocardiography.
The purpose of this study was to evaluate whether performing an assessment of myocardial deformation using speckle tracking imaging during the recovery period after dobutamine stress echocardiography (DSE) allows detection of significant coronary artery disease (CAD) in patients with chest discomfort. DSE and coronary angiography were performed in 44 patients with chest discomfort. The mean global longitudinal peak systolic strain (GLS) was measured at rest, at low stress (dobutamine infusion rate of 10 µg/kg/min) and at recovery (5 min after cessation of dobutamine infusion) of DSE using automated function imaging with apical views. Fractional flow reserve (FFR) was also performed in patients with intermediate coronary stenosis. CAD was defined as having a ≥ 70% diameter stenosis on coronary angiography or as having a FFR < 0.8. Patients were divided two groups based on the absence or presence of CAD [CAD (-) group vs. CAD (+) group]. There were no significant differences in the clinical characteristics and results of conventional echocardiography between the two groups. GLS at recovery was lower in the CAD (+) group than in the CAD (-) group (-18.0 ± 3.4% vs. -21.0 ± 1.9%, p = 0.003). The optimal cutoff of GLS at recovery for detection of CAD was -19% (sensitivity of 70.6%, specificity of 83.3%). Assessment of GLS at recovery of DSE is a reliable and objective method for detection of CAD. This finding may suggest that systolic myocardial stunning remains even after recovery of wall motion abnormalities in patients with CAD.


Pleomorphic adenoma (benign "mixed" tumor) of the human female breast. Case report.
A case of solitary pleomorphic adenoma, ("mixed" tumor of salivary gland type) of the left breast associated with the right breast fibroadenoma in 43-year-old woman is reported. The paper describes clinical, cytological, immunohistological and pathological findings in this case and indicates the importance of separating this benign entity from malignances with stromal metaplasia.


5-Fluorouracil in the Treatment of Keloids and Hypertrophic Scars: A Comprehensive Review of the Literature.
Hypertrophic (HTSs) and keloid scars are common dermatological complaints produced by disruption of the normal wound-healing process. Despite a wide array of therapeutic options available to treat these lesions, HTSs and keloids continue to pose a significant challenge to clinicians in everyday practice. The chemotherapeutic drug 5-fluorouracil (5-FU) is a well-known treatment option reserved for recalcitrant HTSs and keloid lesions. We present clinicians with a comprehensive review of the published data concerning the use of 5-FU in the treatment of HTSs and keloids. The current evidence suggests that 5-FU is a safe and practical alternative for the treatment of HTSs and keloids as it may substantially improve the appearance of proliferative scars and reduce the chance of recurrence. This therapeutic option is most effective in conjunction with adjuvant therapy such as corticosteroids. Additional randomized controlled clinical trials with large sample sizes should be conducted to corroborate the existing efficacy and safety data in patients with HTSs and keloids.


Development of a DNA vaccine targeting Merkel cell polyomavirus.
Merkel cell carcinoma (MCC) is a rare but devastating skin disease that is increasing in incidence within the United States. The poor prognosis of MCC patients and limited understanding of MCC pathogenesis warrants innovative treatments to control MCC. Several lines of evidence have pointed to Merkel cell polyomavirus (MCPyV) as the etiological agent of MCC. In particular, the amino terminus of MCPyV large T antigen (LT) (aa1-258) is expressed in all MCPyV-positive tumors and plays an important role in MCC oncogenesis, rendering it an ideal therapeutic target for vaccination. In the current study, we developed a DNA vaccine encoding MCPyV LT aa1-258 (pcDNA3-LT). Within our pcDNA3-LT DNA vaccine, we identified that MCPyV LT aa136-160 likely contains an LT-specific CD4+ T helper epitope. We have also created an LT-expressing B16/LT tumor model using B16, a murine melanoma cell line, to characterize the potency of our DNA vaccine. Using this tumorigenic B16/LT tumor model, we found that pcDNA3-LT DNA vaccine generates antitumor effects mainly mediated by CD4+ T cells against B16/LT tumors in vaccinated C57BL/6 mice. Thus, immunotherapy using pcDNA3-LT DNA vaccine may represent a promising approach for the control of MCPyV-associated lesions. The B16/LT tumor model further serves as a useful model for testing various vaccine strategies against MCC.


Cutaneous, Intranasal Blastomycosis Infection in Two Patients from Southern West Virginia: Diagnostic Dilemma.
Blastomycosis is a dimorphic fungus caused by the species of Blastomyces dermatitidisand Blastomyces gilchristii, which are endemic to the Ohio River and Mississippi River Valleys. It is commonly found in soil or decomposing wood. It is capable of infecting both immunocompromised and immunocompetent patients via the respiratory tract by inhaling conidia, where it may remain asymptomatic for a prolonged period of time. Extrapulmonary complications can occur in disseminated disease due to haematogenous spread from the lungs to other organ systems. Haematogenous dissemination from the lungs occurs most commonly to the skin. Although rare, primary cutaneous blastomycosis can also occur with direct inoculation through the trauma of the skin. Patients presenting with cutaneous blastomycosis are often misdiagnosed with malignant neoplasms and may not be appropriately managed until further testing and tissue biopsy. Currently, there are only four previous case reports of blastomycosis presenting in the intranasal region. We report two cases of cutaneous blastomycosis of the nasal passages and upper lip with pulmonary manifestations in Southern West Virginia. These patients first presented with cutaneous symptoms, which were originally treated for melanoma and squamous cell carcinoma and were later diagnosed with systemic blastomycosis.


[Prevalence of clinical manifestations of allergic reactions in HIV infection. Cross sectional study of 115 subjects].
A cross sectional survey was set up to study the relation between the prevalence of allergic-type reactions during HIV infection course. For each patient, a standardized interview about recent allergic-type manifestations (RATM), skin prick-tests to six common airborne allergens, IgE serum level were done. Among the 115 included patients, the mean CD4 lymphocyte count (CD4) was 214.7/mm3 (range: 0-1328/mm3). RATM were found in 8.8% of patients with CD4 < 50, in 30% of patients with CD4 between 51 and 200, in 36% of patients with CD4 between 201 and 350 and in 11.5% of patients with CD4 < 350 (p = 0.03). The risk of presenting RATM was 4.8 times (95% confidence interval = 1.7-13.5) higher in patients with CD4 between 51 and 350 than in other patients (p = 0.003). The proportion of positive prick-tests did not significantly vary according to the level of CD4. The increased frequency of RATM in patients with CD4 between 51 and 350/mm3 could be due to an allergic predisposition acquired during the course of HIV infection. The mechanisms explaining the reduced frequency of allergic manifestations when immunodeficiency is profound (CD4 < 50/mm3) remain to be explained.


Effect of intravenous substance P on laryngeal adductor activity in young dogs.
Reflex laryngeal adduction is a component of both the laryngeal chemoreflex and the esophagolaryngeal adductor reflex, two life-threatening reflexes that occur in immature animals. These two reflex responses are also thought to exist in infants and may play a role in causing life-threatening laryngospastic events and perhaps sudden infant death syndrome. Identifying neurotransmitters that mediate laryngeal adduction is important to understanding the mechanism of reflex laryngeal responses and to identifying potential means of pharmacologic prevention. Substance P (SP), a tachykinin, putatively functions as a sensory neurotransmitter and may play a role in mediating laryngeal reflexes. Substance P-immunoreactive-like fibers and receptors are present in the subepithelial tissues of the larynx, the vagus nerves, the nodose and jugular ganglia, and the vagal brain stem nuclei. In this investigation, the effect of SP infusion on laryngeal motor activity in an in vivo model is reported. Substance P was infused intravenously into 8 puppies (20 to 133 days of age, mean 81.2), on a mean of 3.0 occasions (range 1 to 6). Cardiovascular, respiratory, arterial blood gas, and cricothyroid (CT), thyroarytenoid (TA), and genioglossus electromyographic (EMG) responses to infusion of the tachykinin were recorded and subsequently analyzed. The SP infusion induced a marked increase in CT or TA EMG activity in 23 of 24 studies, and the increase was typically apparent within 60 seconds of the infusion. An increase in genioglossus EMG activity did not occur. An immediate, profound decrease in mean arterial pressure and an increase in respiratory rate and depth of chest wall excursion accompanied the laryngeal response. Arterial blood gas values remained unchanged (p > .05). The laryngeal adductor response to SP infusion was blocked when animals were pretreated with a systemic SP antagonist (Pfizer CP-96,345). This study demonstrates that peripheral infusion of the tachykinin SP induces a marked increase in laryngeal adductor activity. The response may be blocked by pretreatment of animals with a systemic SP antagonist. Because SP is thought to act primarily as a sensory neurotransmitter, these findings may be important in understanding the mechanism of reflex laryngeal adductor responses.


Cognitive-Behavioral Group Therapy for Latino youth with Type 1 Diabetes and depression: A case study.
This group case study describes the course of a 14-session Cognitive Behavioral Therapy (CBT) for Latino adolescents with Type 1 Diabetes Mellitus (T1DM) and depressive symptoms. The intervention, known as CBT-DM, is an adaptation of an efficacious group intervention for adolescent depression. The treatment rationale and cultural adaption model are described as well as procedures used to achieve sensitivity to the characteristics of the T1DM culture as experienced by Latino youth from Puerto Rico. Session-by-session protocol is reviewed and treatment gains on the group as a whole and on its individual members are presented, providing quantitative and qualitative data. Treatment feasibility, clients' acceptance and satisfaction with treatment, and follow-up data up to 6 months post-treatment are also examined, considering cognitive, behavioral, emotional, relational, medical, and functional outcomes. Complicating factors, barriers to care, and treatment implications are discussed in the context of treating clients with comorbid chronic physical illness and emotional problems also embedded in a Latino culture. Translation of evidence-based treatments for depression into primary care settings and adapting protocols to youth populations with other medical illnesses is proposed. Recommendations for clinicians are provided, emphasizing the establishment of collaborative relationships with clients, assessing their stage in the process of accepting their chronic illness, as well as understanding their overall context to avoid unnecessary attributions of pathology to their thoughts, behaviors, and feelings.


Novel methylotrophic bacteria isolated from the River Thames (London, UK).
Enrichment and elective culture for methylotrophs from sediment of the River Thames in central London yielded a diversity of pure cultures representing several genera of Gram-negative and Gram-positive bacteria, which were mainly of organisms not generally regarded as typically methylotrophic. Substrates leading to successful isolations included methanol, monomethylamine, dimethylamine, trimethylamine, methanesulfonate and dimethylsulfone. Several isolates were studied in detail and shown by their biochemical and morphological properties and 16S rRNA gene sequencing to be Sphingomonas melonis strain ET35, Mycobacterium fluoranthenivorans strain DSQ3, Rhodococcus erythropolis strain DSQ4, Brevibacterium casei strain MSQ5, Klebsiella oxytoca strains MMA/F and MMA/1, Pseudomonas mendocina strain TSQ4, and Flavobacterium sp. strains MSA/1 and MMA/2. The results show that facultative methylotrophy is present across a wide range of Bacteria, suggesting that turnover of diverse C(1)-compounds is of much greater microbiological and environmental significance than is generally thought. The origins of the genes encoding the enzymes of methylotrophy in diverse heterotrophs need further study, and could further our understanding of the phylogeny and antiquity of methylotrophic systems.


Thiazolidinediones--the new insulin enhancers.
Insulin resistance, characterized by reduced responsiveness to normal circulating levels of insulin, leads to hyperglycemia and hyperinsulinemia resulting in a deadly quartet of non-insulin dependent diabetes mellitus, obesity, hypertension and dyslipidemia These complications, also referred to as 'Syndrome X' have been associated with an increased risk of coronary heart disease. A number of non-pharmacological and pharmacological interventions are available for prevention and treatment of insulin resistance. However, introduction of thiazolidinediones, the new orally active class of drug, has proved to be a major breakthrough in this field. These agents have been shown to reduce insulin resistance by a novel mechanism of action. By interacting with a family of nuclear receptors known as peroxisome proliferator activated receptors thiazolidinediones are thought to enhance the actions of insulin, thereby increasing insulin dependent glucose disposal and reducing hepatic glucose output. A series of animal and clinical studies in patients with impaired Glucose Tolerance and NIDDM have demonstrated the safety and effect of various thiazolidinediones including ciglitazone, pioglitazone and troglitazone. Thus, thiazolidinediones by unlocking insulin resistance act as a key to glycemic control and hence are likely to prove a useful and rational therapy in NIDDM and possibly other disorders resulting from insulin resistance.


[Function and regulation of production of hepatocyte growth factor (HGF)].
Hepatocyte growth factor (HGF) was purified as a potent mitogen for rat hepatocytes in primary culture and is believed to be the most physiological hepatotrophic factor that triggers liver regeneration. HGF is one of the largest disulfide-linked cytokines, consisting of a 60-kDa heavy chain and a 35-kDa light chain. Human HGF is synthesized as a single polypeptide chain precursor of 728 amino acid residues that has an appreciable homology with plasminogen, and it is processed proteolytically to release an N-terminal signal peptide of 31 amino acids and to generate an active heterodimer after secretion. The novel serine protease HGF activator and urokinase-type plasminogen activator (u-PA) are responsible for the latter extracellular processing. HGF stimulates the proliferation of rat hepatocytes in primary culture at concentrations as low as 10 pM. It also stimulates the growth of various epithelial cells, endothelial cells, and some kinds of mesenchymal cells. HGF inhibits the proliferation of several tumor cell lines and induces apoptosis of some of them. It also has motogenic, morphogenic, anti-apoptotic, angiogenic, and immunoregulatory activities. The receptor of HGF is the product of c-met proto-oncogene with tyrosine kinase activity that mediates the transduction of multiple biological signals of HGF. During liver regeneration, HGF gene expression in the liver, spleen, and lung and HGF levels in the blood and liver increase prior to the induction of liver DNA synthesis. Liver regeneration is markedly inhibited by continuous administration of a neutralizing anti-HGF antibody. HGF production in cultured cells is induced by PKC-activating agents, cAMP-elevating agents, PKA-activating agents, growth factors, and inflammatory cytokines; and it is inhibited by TGF-beta, glucocorticoids, 1,25-dihydroxyvitamin D3, and retinoic acid. There are many reports on potential application of HGF as a therapeutic agent for organ diseases that are difficult to cure such as liver cirrhosis, chronic renal failure, pulmonary fibrosis, myocardial infarction, and arteriosclerosis obliterans utilizing its potent growth-stimulating activity for a wide variety of cells. ELISA kits for assays of serum and plasma HGF levels are clinically used to prognosticate the development of fulminant hepatic failure.


Genetic characterization of Nipah virus, Bangladesh, 2004.
Until 2004, identification of Nipah virus (NV)-like outbreaks in Bangladesh was based on serology. We describe the genetic characterization of a new strain of NV isolated during outbreaks in Bangladesh (NV-B) in 2004, which confirms that NV was the etiologic agent responsible for these outbreaks.


Enhanced fluid flow through nanoscale carbon pipes.
Recent experimental and theoretical studies demonstrate that pressure driven flow of fluids through nanoscale ( d < 10 nm) carbon pores occurs 4 to 5 orders of magnitude faster than predicted by extrapolation from conventional theory. Here, we report experimental results for flow of water, ethanol, and decane through carbon nanopipes with larger inner diameters (43 +/- 3 nm) than previously investigated. We find enhanced transport up to 45 times theoretical predictions. In contrast to previous work, in our systems, decane flows faster than water. These nanopipes were composed of amorphous carbon deposited from ethylene vapor in alumina templates using a single step fabrication process.


Surface alignment of 3D spherical harmonic models: application to cardiac MRI analysis.
The spherical harmonic (SPHARM) description is a powerful surface modeling technique that can model arbitrarily shaped but simply connected 3D objects and has been used in many applications in medical imaging. Previous SPHARM techniques use the first order ellipsoid for establishing surface correspondence and aligning objects. However, this first order information may not be sufficient in many cases; a more general method for establishing surface correspondence would be to minimize the mean squared distance between two corresponding surfaces. In this paper, a new surface matching algorithm is proposed for 3D SPHARM models to achieve this goal. This algorithm employs a useful rotational property of spherical harmonic basis functions for a fast implementation. Applications of medical image analysis (e.g., spatio-temporal modeling of heart shape changes) are used to demonstrate this approach. Theoretical proofs and experimental results show that our approach is an accurate and flexible surface correspondence alignment method.


Cyclic AMP signaling is required for function of the N-terminal and CR1 domains of adenovirus E1A in Saccharomyces cerevisiae.
We have constructed yeast vectors in which derivatives of the adenovirus E1A gene are expressed from the GAL1 promoter. Cells expressing E1A289 grow poorly and accumulate cells with a 1C DNA content. Using a series of E1A deletion mutants, we have identified three regions within the E1A protein that are necessary for the G1 growth phenotype; each deletion partially relieves the growth defect. These deletions span residues 4-25, 38-60 and 140-186, which fall within the N-terminal, CR1 and CR3 domains of E1A respectively. Expression of the first 82 residues of E1A, spanning just the N-terminal and CR1 domains, strongly inhibits yeast cell growth in G1 showing that these domains can function independently of other domains of E1A. Using this strong growth inhibition, we isolated a yeast mutant in the net1 gene that conferred resistance to the expression of E1A1-82. The mutant was insensitive to expression of both E1A1-82 and full length E1A, but remained sensitive to the toxicity caused by over-expression of a Gal4p-VP16 fusion. Finally, we found that the function of E1A in yeast depends on the cyclic AMP signaling pathway, providing a striking parallel with the action of E1A at the c-fos promoter in mammalian cells. These results suggest that a genetic analysis of the yeast model system will provide relevant new insights into mechanisms of gene regulation by E1A proteins.


Concomitant Aortic Root Replacement With Anterior Konno Annular Enlargement.
The need for concomitant aortic annular enlargement and aortic root replacement may be necessary in situations of multilevel left ventricular outflow tract obstruction and/or prior aortic or aortic valve surgery, particularly in the setting of congenital heart disease. It can be extremely tedious and fraught with numerous complications. Major challenges include bleeding in difficult-to-reach areas and the potential need for subsequent operations. This article describes a technique of concomitant aortic annular enlargement and aortic root replacement that minimizes the risk of significant blood loss and facilitates future surgery should it be necessary.


Role of the TGFβ/PDCD4/AP-1 Signaling Pathway in Nasopharyngeal Carcinoma and Its Relationship to Prognosis.
The objective of the present study was to evaluate the role of the TGFβ/PDCD4/AP-1 pathway in nasopharyngeal carcinoma (NPC) and its relationship to NPC prognosis. NPC tissues collected from 66 NPC patients were compared to 17 nasopharyngeal mucosa biopsy specimens collected as normal tissues. Immunohistochemical staining was performed to assess expression of transforming growth factor-β receptor I (TGFβRI), programmed cell death 4 (PDCD4) and activator protein-1 (AP-1). The Kaplan-Meier method was applied to evaluate NPC patient overall survival (OS) and progression-free-survival (PFS). Cox regression analysis was used to estimate independent prognostic factors for NPC. The human NPC cell line CNE2 was selected and treated with SB431542, an inhibitor of TGFβRI; expression of TGFβRI and PDCD4 in CNE2 cells was determined by western blotting. NPC tissues showed higher expression of TGFβRI and AP-1 but lower expression of PDCD4 than normal tissues (all P < 0.05). The results of Kaplan-Meier analysis showed that TGFβRI-positive patients and AP-1-positive patients had shorter OS and PFS than TGFβRI-negative patients and AP-1-negative patients; additionally, PDCD4-positive patients had higher OS and PFS than PDCD4-negative patients. Cox regression analysis revealed that advanced tumor stage, overexpression of TGFβRI and AP-1, and low expression of PDCD4 were unfavorable factors influencing OS and PFS in NPC patients. Compared with the control group, expression of TGFβRI decreased and that of PDCD4 increased significantly in CNE2 cells treated with the inhibitor (all P < 0.05). These findings indicate that the TGFβ/PDCD4/AP-1 pathway may be associated with NPC development and progression. High expression of TGFβRI and AP-1 and low expression of PDCD4 may be unfavorable prognostic factors for NPC.


First principle approach towards logic design using hydrogen-doped single-strand DNA.
Molecular logic gate has been proposed using single-strand DNA (ssDNA) consisting of basic four nucleobases. In this study, density functional theory and non-equilibrium Green's function based first principle approach is applied to investigate the electronic transmission characteristics of ssDNA chain. The heavily hydrogen-doped-ssDNA (H-ssDNA) chain is connected with gold electrode to achieve enhanced quantum-ballistic transmission along 〈1 1 1〉 direction. Logic gates OR, Ex-OR, NXOR have been implemented using this analytical model of H-ssDNA device. Enhanced logic properties have been observed for ssDNA after H adsorption due to improved electronic transmission. Dense electron cloud is considered as logic 'high' (1) output in presence of hydrogen molecule and on the contrary sparse cloud indicate logic 'low' (0) in the absence of hydrogen molecule. Device current is significantly increased from 0.2 nA to 2.4 µA (approx.) when ssDNA chain is heavily doped with hydrogen molecule. The current-voltage characteristics confirm the formation of various Boolean logic gate operations.


Risk of thromboembolism in women taking ethinylestradiol/drospirenone and other oral contraceptives.
The oral contraceptive ethinylestradiol 0.03 mg/drospirenone 3 mg contains a progestin component that differs from other oral contraceptives. Case reports and prescription event monitoring suggested that ethinylestradiol/drospirenone might be associated with an elevated risk of thromboembolism. We sought to estimate the association between ethinylestradiol/drospirenone and risk of thromboembolism relative to the association among other oral contraceptives. We identified ethinylestradiol/drospirenone initiators and a twofold larger group of other oral contraceptive initiators between June 2001 and June 2004 within a U.S. health insurer database. The comparison group was selected to have demographic and health care characteristics preceding oral contraceptive initiation that were similar to ethinylestradiol/drospirenone initiators. Thromboembolism during the follow-up of the cohorts was identified through claims for medical services, and only medical record-confirmed cases were included in analyses. The primary (as-matched) analysis used proportional hazards regression, whereas a secondary (as-treated) analysis accounted for changes in oral contraceptives during follow-up using Poisson regression. The 22,429 ethinylestradiol/drospirenone initiators and 44,858 other oral contraceptive initiators were followed for an average of 7.6 months, and there were 18 cases of thromboembolism in ethinylestradiol/drospirenone initiators and 39 in the comparators (rate ratio 0.9, 95% confidence interval 0.5-1.6). More than 9,000 women would need to be prescribed oral contraceptives to observe a difference of one case of thromboembolism. Results of the as-treated analysis were similar to those of the as-matched analysis. Ethinylestradiol/drospirenone initiators and initiators of other oral contraceptives are similarly likely to experience thromboembolism. II.


Radiotherapy for multiple myeloma with skin involvement.
Multiple myeloma metastatic to the skin is a rare occurrence that usually reflects a high tumour burden. Here, we report the case of a woman with known multiple myeloma who developed cutaneous lesions on the right leg. Limited-field radiation treatment was successfully used to decrease her tumour bulk. Unfortunately, the patient died of complications related to systemic treatment a few months after developing the cutaneous involvement.


The in situ saphenous vein bypass graft: radiologic aspects.
The use of the in situ saphenous vein for bypassing arterial occlusions in the lower extremities appears to have a higher patency rate than other bypass procedures but presents unique technical problems, such as lysing valves and occluding venous tributaries. Forty-four patients undergoing in situ bypasses had preoperative arteriograms. Special attention was paid to the small runoff vessels around the ankle, which are not suitable for reversed bypass procedures but may be adequate for in situ bypasses. Eight patients also had preoperative saphenous venograms, which revealed surgically important abnormalities in six cases. Postoperative arteriograms obtained within 2 weeks in 10 patients and within 2-12 months in 15 patients revealed persistent arteriovenous fistulas in four patients, stenoses in nine, occlusions in five, and progressive disease in the nonbypassed arteries in five patients. Early recognition of these problems led to 11 surgical repairs; nine repairs used the interventional radiologic procedures of balloon angioplasty, transcatheter embolization, and catheter thrombolysis. In this group of 44 patients, five patients died with patent bypasses and three patients required amputation despite functioning bypasses. Only four amputations were attributed to bypass failure. This low figure may be due to the close cooperation of the vascular surgeons and the vascular radiologists in dealing with these complicated cases.


[Psychological study of rape victims].
This paper covers a study of rape victims, according to the records of Clinic for Gynekology and Obstetrics in Novi Sad, in terms of the late psychological and psychiatric consequences. Several methods were used: special questionnaire, Minnesota Multiphasic Personality Inventory for estimating personality and selfdescriptive scale of depression, Beck Depression Inventory. Results emphasize that the group with the highest rape risk consists of female persons aged from 22 to 30 years, single, without children and with lower education level. Psychological and psychiatric and analysis shows pathological personality of victims in most cases. All victims tested, expressed intensive or mild degree of depression. Analysis of offense situation points to significant degree of victimization.


Validation of parental stress scale in a Greek sample of mothers with infants from 0 to 12 months.
Parenting an offspring is a rewarding, albeit challenging task, often accompanied by high levels of stress. It is important to accurately assess the stress associated with parenting, as severe forms of stress may affect the parent-child dyad and lead to poor child outcomes. The aim of this study was to translate and validate the Parental Stress Scale (PSS) in the Greek population. We implemented forward and back translation and conducted a pilot test. A total of 735 mothers (Mage = 34.6) with infants aged 0-12 months completed the PSS, the Edinburgh Postnatal Depression Scale, and the Hospital Anxiety and Depression Scale. The Greek PSS-18 showed good internal consistency (Cronbach's α = .83) and adequate convergent validity. Results of exploratory and confirmatory factor analysis revealed two underlying factors: positive aspects of parenting and negative aspects of parenting. Our data confirm the validity of the Greek version of the PSS-18 in mothers with infants aged 0-12 months. The Greek version of the PSS-18 could be a useful tool for professionals and researchers who are interested in perinatal period and the aspects of parenthood.


Targeting the tumor microenvironment: focus on angiogenesis.
Tumorigenesis is a complex multistep process involving not only genetic and epigenetic changes in the tumor cell but also selective supportive conditions of the deregulated tumor microenvironment. One key compartment of the microenvironment is the vascular niche. The role of angiogenesis in solid tumors but also in hematologic malignancies is now well established. Research on angiogenesis in general, and vascular endothelial growth factor in particular, is a major focus in biomedicine and has led to the clinical approval of several antiangiogenic agents including thalidomide, bevacizumab, sorafenib, sunitinib, pazopanib, temesirolimus, and everolimus. Indeed, antiangiogenic agents have significantly changed treatment strategies in solid tumors (colorectal cancer, renal cell carcinoma, and breast cancer) and multiple myeloma. Here we illustrate important aspects in the interrelationship between tumor cells and the microenvironment leading to tumor progression, with focus on angiogenesis, and summarize derived targeted therapies.


Resistance profile of the new nucleoside reverse transcriptase inhibitor apricitabine.
Apricitabine is a novel deoxycytidine nucleoside reverse transcriptase inhibitor (NRTI) currently in clinical development for the treatment of HIV infection. Apricitabine shows antiviral activity in vitro against HIV-1 strains and clinical isolates with mutations in the reverse transcriptase that confer resistance to other NRTIs, including M184V, thymidine analogue mutations (TAMs), nucleoside-associated mutations such as L74V and certain mutations at codon 69. Apricitabine has shown activity in treatment-experienced HIV-1-infected patients with NRTI resistance (with M184V and up to five TAMs) as well as in treatment-naive patients. Resistance to apricitabine is slow to develop in vitro and there has been little evidence of development of resistance to apricitabine in clinical use thus far, including patients receiving apricitabine for up to 48 weeks. The resistance profile of apricitabine suggests there is a low potential for cross-resistance with the currently available NRTIs and, thus, apricitabine may provide a treatment option for treatment-experienced HIV-1-infected patients with resistance to other NRTIs. In particular, the activity of apricitabine in the presence of the M184V mutation, which confers high-level resistance to lamivudine and emtricitabine, lends it to being used as a replacement for deoxycytidine analogues in patients who have failed treatment with lamivudine or emtricitabine.


[Medulla and upper cervical cord compression by bilateral vertebral artery presented with myelopathy and drop attack: case report].
A 51-year-old man had suffered from attacks of quadri-paresis and unconsciousness for previous three years prior to presentation. Prior to admission, he had been received anticonvulsants, but his symptoms showed no improvement. Neurological examination revealed hyper-reflexia of his left lower extremity and moderate decrease of sense of pain, temperature, and tactile sensation in his left extremities and trunk, while vibratory sensation was normal. Magnetic resonance(MR) imaging revealed a flow-void area in the craniocervical junction and marked narrowing of the medulla oblongata and upper cervical cord by compression of the vertebral arteries(VA). CT myelography also showed the compression and narrowing of the spinal cord. Vertebral angiography demonstrated symmetrical running course of the arteries, which curved medially at the level of craniocervical junction. Suboccipital craniectomy and C1 and upper half of C2 laminectomies were performed. After dural opening, the ventrolateral aspects of the lower medulla oblongata and the upper cervical cord were found to be compressed by the VA. The arteries were retracted dorsolaterally by GORE-TEX tapes so as to decompress the medulla oblongata and cervical cord, and the tapes were anchored to the residual part of C1 posterior arch. Postoperative MR imaging and CT myelography showed complete decompression, and the patient was relieved of his previous neurological symptoms.


Protease nexin-1 promotes secretory granule biogenesis by preventing granule protein degradation.
Dense-core secretory granule (DCG) biogenesis is a prerequisite step for the sorting, processing, and secretion of neuropeptides and hormones in (neuro)endocrine cells. Previously, chromogranin A (CgA) has been shown to play a key role in the regulation of DCG biogenesis in vitro and in vivo. However, the underlying mechanism of CgA-mediated DCG biogenesis has not been explored. In this study, we have uncovered a novel mechanism for the regulation of CgA-mediated DCG biogenesis. Transfection of CgA into endocrine 6T3 cells lacking CgA and DCGs not only recovered DCG formation and regulated secretion but also prevented granule protein degradation. Genetic profiling of CgA-expressing 6T3 versus CgA- and DCG-deficient 6T3 cells, followed by real-time reverse transcription-polymerase chain reaction and Western blotting analyses, revealed that a serine protease inhibitor, protease nexin-1 (PN-1), was significantly up-regulated in CgA-expressing 6T3 cells. Overexpression of PN-1 in CgA-deficient 6T3 cells prevented degradation of DCG proteins at the Golgi apparatus, enhanced DCG biogenesis, and recovered regulated secretion. Moreover, depletion of PN-1 by antisense RNAs in CgA-expressing 6T3 cells resulted in the specific degradation of DCG proteins. We conclude that CgA increases DCG biogenesis in endocrine cells by up-regulating PN-1 expression to stabilize granule proteins against degradation.


Health councils and conferences in Brazil: an integrative review.
This paper aimed to identify the thinking currents used for scientific production on health councils and conferences, from 1990 to 2017. This is an integrative review of literature carried out at the SciELO, LILACS and CAPES journals portals that resulted in the selection of 152 papers. They were analyzed by year of publication, author's institutional origin, dissemination media, object and type of study and theoretical approach. We identified that a gradual increase occurred in the number of publications over the study period and most empirical studies (92.8%) do not explicitly state the use of any theoretical approach in data analysis. The structuralist, post-structuralist and neo-institutionalist approaches used were mediated by a theoretical model, medium-range theories and concepts of authors of the European, North American and Latin American traditions. The knowledge produced about health council and conference in Brazil may benefit even more from the density of theoretical approaches to social and political sciences.


Regional hemodynamic effects of the AT1 receptor antagonist CV-11974 in conscious renal hypertensive rats.
Angiotensin II subtype 1 (AT1) receptor antagonists reduce mean arterial pressure in various experimental models of hypertension, including two-kidney, one clip (2K1C) renal hypertension. However, the regional hemodynamic mechanisms underlying the hypotensive effect of AT1 receptor antagonists in 2K1C rats under dynamic conditions have not been documented. Therefore, in the present study we determined the hemodynamic profile of the AT1 receptor antagonist CV-11974 in conscious 2K1C rats and sham-operated control rats. Approximately 4 weeks after clipping, rats underwent a further two-stage operation for implantation of Doppler flow probes on the contralateral (left) renal artery, superior mesenteric artery, and distal aorta as well as for the implantation of intravascular catheters. At least 24 hours after the last operation continuous recordings were made of mean arterial pressure; heart rate; and renal, mesenteric, and hindquarters flows and conductances (Doppler shift/mean arterial pressure) in response to three doses of CV-11974 (0.01, 0.1, and 1.0 mg/kg i.v.). CV-11974 caused a small hypotensive effect (decrease of approximately 15 mm Hg) in the sham group, but regional flows and vascular conductances did not change. By contrast, in 2K1C rats CV-11974 caused dose-dependent hypotension that was maximal (-19 +/- 6, -41 +/- 4, and -51 +/- 8 mm Hg, respectively) after 6 hours. These changes were associated with generalized vasodilatation (increased conductance) in all three vascular beds, although there were subtle differences with the different CV-11974 doses.(ABSTRACT TRUNCATED AT 250 WORDS)


Personalized treatment strategies for elderly patients with myelodysplastic syndromes.
Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic disorders characterized by ineffective hematopoiesis and peripheral cytopenia, and their possible transformation into acute myeloid leukemia (AML). They typically affect the elderly but, when making treatment decisions, considering chronological age may be insufficient because it poorly correlates with patient frailty: the challenge is to select the optimal treatment in these patients by balancing efficacy and toxicity. Areas covered: This review discusses the rationale for and methods of personalizing the treatment of elderly MDS patients. Expert commentary: Decisions concerning treatment strategies for elderly MDS patients should be made after assessing their frailty on the basis of a geriatric assessment and an estimate of age-adjusted life expectancy. We suggest that all elderly MDS patients should undergo a timed up and go test (TUGT) as a preliminary means of identifying frail patients, and that all non-frail patients should then undergo a comprehensive geriatric assessment (CGA) in order to distinguish fit and pre-frail patients. Fit patients should receive standard dose treatment; pre-frail patients should receive individualized therapy; and frail patients should receive symptom-related therapy. A repeated CGA may be useful to evaluate the hematological, cognitive and socio-relational effects of MDS treatment.


Implant stability in relation to osseointegration: an experimental study in the Labrador dog.
Resonance frequency analysis (RFA) is supposed to determine implant stability. The relation between RFA and the degree of bone-to-implant contact (BIC), however, is unclear. The objective of the present experiment was to evaluate RFA values in relation to osseointegration. In 20 Labrador dogs, all mandibular premolars were extracted bilaterally. After 3 months, four transmucosal screw-shaped experimental implants were placed in each mandibular premolar region. The implants (12 mm length, slashed circle 4.1mm, insertion depth 9 mm) were either SLA surface or turned surface implants. The animals were divided into four groups (five dogs in each group) to study healing following implant installation at 2 h, 4 days, 1, 2, 4, 6, 8 and 12 weeks. Two experimental implants of each type were installed in each edentulous premolar region. A plaque control program was initiated 2 weeks after each implant installation. RFA assessments were performed at the time of implant installation, at one to three occasions during the monitoring period and at the termination of the experiment. At the end of the experiment, the dogs were sacrificed and each implant site was dissected and processed for histological analysis. The results of the histological analysis, i.e. marginal bone level, degree of osseointegration (BIC%) and bone density, were compared with the corresponding Implant Stability Quotient (ISQ) values of the RFA assessment. No correlations between histological parameters of osseointegration and ISQ values could be identified. Marginal bone level changes, differences in BIC% and bone density were not reflected in the RFA at any time-point during the 12-week monitoring period. The value of RFA to predict implant stability over time and to determine at which time-point an implant may be exposed to functional load has to be questioned.


Comparison of two doses of tranexamic acid in adults undergoing cardiac surgery with cardiopulmonary bypass.
The optimal dose of tranexamic acid (TA) is still an issue. The authors compared two doses of TA during cardiac surgery in a multicenter, double-blinded, randomized study. Patients were stratified according to transfusion risk, then randomized to two TA doses: 10 mg/kg bolus followed by 1 mg·kg·h infusion (low dose) until the end of surgery or 30 mg/kg bolus followed by 16 mg·kg·h infusion (high dose). The primary endpoint was the incidence of blood product transfusion up to day 7. Secondary ones were incidences of transfusion for each type of blood product and amounts transfused, blood loss, repeat surgery, TA-related adverse events, and mortality. The low-dose group comprised 284 patients and the high-dose one 285. The primary endpoint was not significantly different between TA doses (63% for low dose vs. 60% for high dose; P = 0.3). With the high dose, a lower incidence of frozen plasma (18 vs. 26%; P = 0.03) and platelet concentrate (15 vs. 23%; P = 0.02) transfusions, lower amounts of blood products (2.5 ± 0.38 vs. 4.1 ± 0.39; P = 0.02), fresh frozen plasma (0.49 ± 0.14 vs.1.07 ± 0.14; P = 0.02), and platelet concentrates transfused (0.50 ± 0.15 vs. 1.13 ± 0.15; P = 0.02), lower blood loss (590 ± 50.4 vs. 820 ± 50.7; P = 0.01), and less repeat surgery (2.5 vs. 6%; P = 0.01) were observed. These results are more marked in patients with a high risk for transfusion. A high dose of TA does not reduce incidence of blood product transfusion up to day 7, but is more effective than a low dose to decrease transfusion needs, blood loss, and repeat surgery.


Behavioral Changes in Children After Emergency Department Procedural Sedation.
The purpose of this study was to determine the proportion of children undergoing procedural sedation for fracture reduction in the emergency department (ED) observed to experience negative postdischarge behaviors. Predictors of negative behaviors were evaluated, including anxiety. This was a prospective cohort study of children receiving intravenous ketamine sedation for ED fracture reduction. The child's anxiety prior to sedation was measured with the Modified Yale Preoperative Anxiety Scale. Negative behavioral changes were measured with the Post-Hospitalization Behavior Questionnaire 1 to 2 weeks after discharge. Descriptive statistics and odds ratios (ORs) were calculated. Chi-square test was used for comparisons between groups. Multivariable logistic regression models evaluated predictors of negative behavioral change after discharge. Ninety-seven patients were enrolled; 82 (85%) completed follow-up. Overall, 33 (40%) children were observed to be highly anxious presedation and 18 (22%) had significant negative behavior changes after ED discharge. Independent predictors for negative behaviors were high anxiety (OR = 9.0, 95% confidence interval [CI] = 2.3-35.7) and nonwhite race (OR = 6.5, 95% CI = 1.7-25.0). For children undergoing procedural sedation in the ED, two in five children have high preprocedure anxiety and almost one in four have significant negative behaviors 1 to 2 weeks after discharge. Highly anxious and nonwhite children have increased risk of negative behavioral changes that have not been previously recognized in the ED setting.


Ensemble transfer learning for Alzheimer's disease diagnosis.
There is considerable interest in developing inexpensive, nonintrusive diagnostic tests for Alzheimer's disease (AD), in the hope these tests will facilitate early diagnosis and support design of effective treatments. While tests based on blood-borne biomarkers such as microRNAs have shown promise, work to date indicates these tests often do not generalize well: diagnostic models derived for one patient group are not accurate when applied to a new cohort. This paper presents a novel ensemble-based transfer learning methodology which induces models that provide accurate diagnoses across distinct patient groups without retraining. The algorithm combines information from supervised ensemble learning and unsupervised ensemble clustering to enable robust transfer learning. The efficacy of the approach is illustrated through a case study involving microRNA-based AD diagnosis. In this test, we use our algorithm to learn a diagnostic model on data from one patient group and then apply the model to a different target group, obtaining diagnostic accuracy which actually exceeds that of a state-of-the-art model trained directly on the target group.


TASK-2: a K2P K(+) channel with complex regulation and diverse physiological functions.
TASK-2 (K2P5.1) is a two-pore domain K(+) channel belonging to the TALK subgroup of the K2P family of proteins. TASK-2 has been shown to be activated by extra- and intracellular alkalinization. Extra- and intracellular pH-sensors reside at arginine 224 and lysine 245 and might affect separate selectivity filter and inner gates respectively. TASK-2 is modulated by changes in cell volume and a regulation by direct G-protein interaction has also been proposed. Activation by extracellular alkalinization has been associated with a role of TASK-2 in kidney proximal tubule bicarbonate reabsorption, whilst intracellular pH-sensitivity might be the mechanism for its participation in central chemosensitive neurons. In addition to these functions TASK-2 has been proposed to play a part in apoptotic volume decrease in kidney cells and in volume regulation of glial cells and T-lymphocytes. TASK-2 is present in chondrocytes of hyaline cartilage, where it is proposed to play a central role in stabilizing the membrane potential. Additional sites of expression are dorsal root ganglion neurons, endocrine and exocrine pancreas and intestinal smooth muscle cells. TASK-2 has been associated with the regulation of proliferation of breast cancer cells and could become target for breast cancer therapeutics. Further work in native tissues and cells together with genetic modification will no doubt reveal the details of TASK-2 functions that we are only starting to suspect.


Association of Stages of Objective Memory Impairment With Incident Symptomatic Cognitive Impairment in Cognitively Normal Individuals.
Increasing evidence indicates that a subset of cognitively normal individuals has subtle cognitive impairment at baseline. We sought to identify them using the Stages of Objective Memory Impairment (SOMI) system. Symptomatic cognitive impairment was operationalized by a Clinical Dementia Rating (CDR) ≥0.5. We hypothesized that incident impairment would be higher for participants with subtle retrieval impairment (SOMI-1), higher still for those with moderate retrieval impairment (SOMI-2), and highest for those with storage impairment (SOMI-3/4) after adjusting for demographics and APOE ε4 status. A secondary objective was to determine whether including biomarkers of β-amyloid, tau pathology, and neurodegeneration in the models affect prediction. We hypothesized that even after adjusting for in vivo biomarkers, SOMI would remain a significant predictor of time to incident symptomatic cognitive impairment. Among 969 cognitively normal participants, defined by a CDR = 0, from the Knight Alzheimer Disease Research Center, SOMI stage was determined from their baseline Free and Cued Selective Reminding Test scores, 555 had CSF and structural MRI measures and comprised the biomarker subgroup, and 144 of them were amyloid positive. Cox proportional hazards models tested associations of SOMI stages at baseline and biomarkers with time to incident cognitive impairment defined as the transition to CDR ≥0.5. Among all participants, the mean age was 69.35 years, 59.6% were female, and mean follow-up was 6.36 years. Participants in SOMI-1-4 had elevated hazard ratios for the transition from normal to impaired cognition in comparison with those who were SOMI-0 (no memory impairment). Individuals in SOMI-1 (mildly impaired retrieval) and SOMI-2 (moderately impaired retrieval) were at nearly double the risk of clinical progression compared with persons with no memory problems. When memory storage impairment emerges (SOMI-3/4), the hazard ratio for clinical progression increased approximately 3 times. SOMI stage remained an independent predictor of incident cognitive impairment after adjusting for all biomarkers. SOMI predicts the transition from normal cognition to incident symptomatic cognitive impairment (CDR ≥0.5). The results support the use of SOMI to identify those cognitively normal participants most likely to develop incident cognitive impairment who can then be referred for biomarker screening.


Measurement of uridine diphosphate glucuronic acid concentrations and synthesis in animal tissues.
1. A method for the isolation from animal tissues of UDP-glucuronic acid by one-dimensional paper chromatography is described and its concentrations in some tissues of several species of vertebrates are reported; the incorporation of [(32)P]-phosphate into UDP-glucuronic acid in vivo was also investigated. 2. The concentration of UDP-glucuronic acid was higher in the liver of rats, rabbits and guinea pigs than in the same tissue of some species of birds, amphibia and fishes; also, the concentration of UDP-glucuronic acid in rat liver, kidney and small intestine was several times lower than that of the same tissues of guinea pigs. 3. The rate of [(32)P]-phosphate incorporation into UDP-glucuronic acid was very high in rat liver and kidney and almost reached equilibrium with the radioactivity of UDP-glucose 30min after the administration of the [(32)P]phosphate.


From Diagnosis to Treatment: Recent Advances in Patient-Friendly Biosensors and Implantable Devices.
Patient-friendly medical diagnostics and treatments have been receiving a great deal of interest due to their rapid and cost-effective health care applications with minimized risk of infection, which has the potential to replace conventional hospital-based medical procedures. In particular, the integration of recently developed materials into health care devices allows the rapid development of point-of-care (POC) sensing platforms and implantable devices with special functionalities. In this review, the recent advances in biosensors for patient-friendly diagnosis and implantable devices for patient-friendly treatment are discussed. Comprehensive analysis of portable and wearable biosensing platforms for patient-friendly health monitoring and disease diagnosis is provided, including topics such as materials selection, device structure and integration, and biomarker detection strategies. Moreover, specific challenges related to each biological fluid for wearable biosensor-based POC applications are presented. Also, advances in implantable devices, including recent materials development and wireless communication strategies, are discussed. Furthermore, various patient-friendly surgical and treatment approaches are reviewed, such as minimally invasive insertion and mounting, in vivo electrical and optical modulations, and post-operation health monitoring. Finally, the challenges and future perspectives toward the development of the patient-friendly diagnosis and treatment are provided.


Palliation of malignant tracheal strictures using silicone T tubes.
The use of silicone T tubes for intubation of malignant tracheobronchial strictures may provide some degree of palliation of this distressing condition. It was used in seven patients with malignant lesions and two with benign strictures (resulting from tracheal trauma and lung transplantation). Four patients (two with cancer) are still alive and well with the tube in position. All patients noted improvement in dyspnoea and stridor. The main problems were tube migration (one patient), tracheo-oesophageal fistula (one patient), and blockage of the tube by tumour (two patients) or encrusted secretions (three patients). Airway patency was restored when the tube was blocked by cleaning or by laser resection of the tumour. With careful supervision and education of the patient intubation can give useful palliation to patients with distressing upper airways obstruction.


Multivalent interactions of the SUMO-interaction motifs in RING finger protein 4 determine the specificity for chains of the SUMO.
RNF4 (RING finger protein 4) is a STUbL [SUMO (small ubiquitin-related modifier)-targeted ubiquitin ligase] controlling PML (promyelocytic leukaemia) nuclear bodies, DNA double strand break repair and other nuclear functions. In the present paper, we describe that the sequence and spacing of the SIMs (SUMO-interaction motifs) in RNF4 regulate the avidity-driven recognition of substrate proteins carrying SUMO chains of variable length.


[Livedoid vasculitis in a patient with antiphospholipid syndrome].
The authors present a clinical case of a 30 year old male patient admitted to the hospital for recurrent cyanosis and feet pain lasting for one year. In addition he presented bilateral purpuric lesions in the lateral maleolar region, one of which with ulceration. The finding of anticardiolipin antibodies associated with intraluminal thrombosis in the dermal vessels, allowed to conclude for Antiphospholipid syndrome. The cutaneous changes identified are named livedoid vasculitis.


Angry women mentally disordered offenders: a need to do more?
Anger is generally viewed as unfeminine and women who display anger are more likely to be unnecessarily labelled as 'psychotic' or 'dangerous'. There appears to be a link between those with a history of abuse and the psychiatric population, particularly among female mentally disordered offenders (MDOs) in high security care. A need exists for this problem to be rendered visible, which is ultimately the responsibility of those healthcare professionals charged with providing care and treatment for this population. This article proposes methodology which is aimed at stimulating and refocusing healthcare professionals' thinking in terms of female MDOs, and the need to provide tangible evidence of high quality forensic care.


Interleukin-8 (IL-8), melanoma growth-stimulatory activity, and neutrophil-activating peptide selectively mediate priming of the neutrophil NADPH oxidase through the type A or type B IL-8 receptor.
The capacity of neutrophils to generate superoxide (O-2) can be enhanced by prior exposure to "priming" agents such as interleukin-8 (IL-8), melanoma growth-stimulatory activity (MGSA), and neutrophil-activating peptide (ENA-78). The biological effects of these chemokines are mediated by at least two distinct receptors: type A (IL-8-RA) and type B (IL-8-RB). Using neutralizing monoclonal antibodies to IL-8-RA and IL-8-RB, we have investigated the contribution each receptor makes to the priming response. Preincubation with IL-8, MGSA, or ENA-78 enhanced the ability of neutrophils to generate O-2 following stimulation with the bacterial peptide formyl-Met-Leu-Phe. The priming effect of IL-8 was eliminated by an anti-IL-8 monoclonal antibody (mAb) that is known to bind IL-8 with high affinity and prevent receptor occupancy. Incubation of neutrophils with a neutralizing mAb specific for IL-8-RA blocked IL-8-induced priming but had no effect on priming by MGSA or ENA-78. In contrast, treatment with a neutralizing mAb specific for IL-8-RB failed to inhibit the priming effect of IL-8 but blocked both MGSA and ENA-78-induced priming. These observations indicate that the priming effect of IL-8 on the neutrophil respiratory burst is predominantly mediated via IL-8-RA, whereas priming by MGSA and ENA-78 is mediated by IL-8-RB.


[Systolic time intervals and echocardiography in monitoring adriamycin-treated tumor patients].
By means of systolic time intervals (PEP/LVET) and echocardiography (Vfr) 218 tumour patients were controlled concerning a cardiomyopathy induced by cytostatic agents. 13% of the patients (28/218) transgressed an absolute cumulative dose of 1,000 mg of doxorubicin or daunorubicin, of which, however, 12% (26/218) showed normal values for PEP/LVET. 11% of the patients (24/218) showed pathologic PEP/LVET values in 6% (49/787) of the investigations, in which case in 15 patients the clinical diagnosis of a cardiomyopathy could be assumed with simultaneously decreased shortening fraction. The sex and age distribution of this group corresponded to that one of the total cohort. The investigation presented confirm the value of systolic time intervals and of echocardiography as screening methods for a cardiomyopathy and speak against a general establishment of a borderline diagnosis.


Large-scale pesticide testing in olives by liquid chromatography-electrospray tandem mass spectrometry using two sample preparation methods based on matrix solid-phase dispersion and QuEChERS.
In this work we have evaluated the performance of two sample preparation methodologies for the large-scale multiresidue analysis of pesticides in olives using liquid chromatography-electrospray tandem mass spectrometry (LC-MS/MS). The tested sample treatment methodologies were: (1) liquid-liquid partitioning with acetonitrile followed by dispersive solid-phase extraction clean-up using GCB, PSA and C18 sorbents (QuEChERS method - modified for fatty vegetables) and (2) matrix solid-phase dispersion (MSPD) using aminopropyl as sorbent material and a final clean-up performed in the elution step using Florisil. An LC-MS/MS method covering 104 multiclass pesticides was developed to examine the performance of these two protocols. The separation of the compounds from the olive extracts was achieved using a short C18 column (50 mm x 4.6 mm i.d.) with 1.8 microm particle size. The identification and confirmation of the compounds was based on retention time matching along with the presence (and ratio) of two typical MRM transitions. Limits of detection obtained were lower than 10 microgkg(-1) for 89% analytes using both sample treatment protocols. Recoveries studies performed on olives samples spiked at two concentration levels (10 and 100 microgkg(-1)) yielded average recoveries in the range 70-120% for most analytes when QuEChERS procedure is employed. When MSPD was the choice for sample extraction, recoveries obtained were in the range 50-70% for most of target compounds. The proposed methods were successfully applied to the analysis of real olives samples, revealing the presence of some of the target species in the microgkg(-1) range. Besides the evaluation of the sample preparation approaches, we also discuss the use of advanced software features associated to MRM method development that overcome several limitations and drawbacks associated to MS/MS methods (time segments boundaries, tedious method development/manual scheduling and acquisition limitations). This software feature recently offered by different vendors is based on an algorithm that associates retention time data for each individual MS/MS transition, so that the number of simultaneously traced transitions throughout the entire chromatographic run (dwell times and sensitivity) is maximized.


Profiling overweight patients in the U.S. Navy: health conditions and costs.
The U.S.A. has the distinction of being the "fattest" nation in the world, with an estimated 34 million obese citizens. Of grave concern is the reported finding that obesity contributes to 20% of the annual mortality rate, primarily for such conditions as diabetes mellitus, digestive diseases, coronary heart disease, and cerebrovascular disease. In 1982, the Navy initiated the "Health and Physical Readiness Program" in order to establish body fat percentages and physical conditioning standards and to provide Navy personnel with weight reduction and other health promotion programs. Participation in such programs is expected to help overweight personnel solve their weight problems and reduce the risks of obesity-related conditions. The purpose of this study was (1) to identify the health conditions recorded in a sample of U.S. Navy enlisted men who had been diagnosed as obese during one or more of their admissions to a Naval hospital from 1974 through 1984, (2) to determine whether these disorders correspond with those reported in the scientific literature, and (3) to examine the obesity-related costs in terms of numbers of days hospitalized and career outcome. The patient population consisted of 518 U.S. Navy enlisted men who were given a primary diagnosis of obesity and 1,092 who received a secondary or additional diagnosis of obesity on at least one of their inpatient medical records between 1974 and 1984. A 10% sample of Navy male patients, all of whom had not been diagnosed as obese, was selected as a comparison group (n = 30,829). All diagnoses (ICD-9) for each hospitalization were included in the data compilations; however, each unique diagnosis was only counted once.(ABSTRACT TRUNCATED AT 250 WORDS)


Mechanosensing through immunoreceptors.
The immune response is orchestrated by a variety of immune cells. The function of each cell is determined by the collective signals from various immunoreceptors, whose expression and activity depend on the developmental stages of the cell and its environmental context. Recent studies have highlighted the presence of mechanical force on several immunoreceptor-ligand pairs and the important role of force in regulating their interaction and function. In this Perspective, we use the T cell antigen receptor as an example with which to review the current understanding of the mechanosensing properties of immunoreceptors. We discuss the types of forces that immunoreceptors may encounter and the effects of force on ligand bonding, conformational change and the triggering of immunoreceptors, as well as the effects of force on the downstream signal transduction, cell-fate decisions and effector function of immune cells.


Immunopathogenesis of Behcet's Disease.
Behcet's disease (BD) is a chronic systemic inflammatory vasculitis of unknown etiology characterized by recurrent episodes of oral aphthous ulcers, genital ulcers, skin lesions, ocular lesions, and other manifestations. Although the pathogenesis of BD is unclear, some studies have shown that immunological aberrations play an important role in the development and progression of BD. Infection-related trigger factors, including antigens and autoantigens, are believed to mediate the development of BD in patients with a genetic predisposition and subsequently activate the innate and adaptive immune systems, resulting in the production of numerous cytokines and chemokines to combat the infection-related factors. The study of the immunological mechanism of BD paves the way for the development of innovative therapies. Recently, novel biotherapy approaches, including interferon-α (IFN-α), tumor necrosis factor-α (TNF-α) antagonists, and other agents that target interleukins and their receptors, have shown promising results in the treatment of patients with refractory BD and have improved the prognosis of BD. In this review, we provide the current concepts of BD immunopathogenesis.


Impacts of orbital forcing and atmospheric carbon dioxide on Miocene ice-sheet expansion.
The processes causing the middle Miocene global cooling, which marked the Earth's final transition into an 'icehouse' climate about 13.9 million years ago (Myr ago), remain enigmatic. Tectonically driven circulation changes and variations in atmospheric carbon dioxide levels have been suggested as driving mechanisms, but the lack of adequately preserved sedimentary successions has made rigorous testing of these hypotheses difficult. Here we present high-resolution climate proxy records, covering the period from 14.7 to 12.7 million years ago, from two complete sediment cores from the northwest and southeast subtropical Pacific Ocean. Using new chronologies through the correlation to the latest orbital model, we find relatively constant, low summer insolation over Antarctica coincident with declining atmospheric carbon dioxide levels at the time of Antarctic ice-sheet expansion and global cooling, suggesting a causal link. We surmise that the thermal isolation of Antarctica played a role in providing sustained long-term climatic boundary conditions propitious for ice-sheet formation. Our data document that Antarctic glaciation was rapid, taking place within two obliquity cycles, and coincided with a striking transition from obliquity to eccentricity as the drivers of climatic change.


Variances in sagittal femoral shaft bowing in patients undergoing TKA.
We asked, "What are the quantitative variances in sagittal femoral bowing in patients who were indicated for total knee arthroplasty?" We retrospectively evaluated 145 consecutive patients who underwent 166 primary total knee arthroplasties with adequate preoperative nonrotated sagittal plane full-leg lateral radiographs. Digital radiographs were processed such that each femoral shaft was divided into three segments. A purpose-written program determined the flexion/extension of the femoral component using the Knee Society method of focusing on the distal femur and a second method using the whole femur. The median angle of curvature of the proximal, middle, and distal thirds of the femora were 5.4 degrees, 0.2 degree, and 3.1 degrees, respectively, with the largest bow occurring in the proximal segment followed by the distal segment and with the least bow in the middle segment. The median angles for femoral component flexion were considerably different with the whole femur angle showing more flexion (4 degrees) than that of the Knee Society angle (1.421 degrees). We found an inverse relationship between distal angle of curvature and height as well as weight. Men had greater proximal bowing and less distal bowing than women. The effects of these variances may have implications in development of osteoarthritis and total knee arthroplasty component survival.


Magnetic resonance imaging of articular cartilage of the knee: comparison between fat-suppressed three-dimensional SPGR imaging, fat-suppressed FSE imaging, and fat-suppressed three-dimensional DEFT imaging, and correlation with arthroscopy.
To compare signal-to-noise ratios (S/N) and contrast-to-noise ratios (C/N) in various MR sequences, including fat-suppressed three-dimensional spoiled gradient-echo (SPGR) imaging, fat-suppressed fast spin echo (FSE) imaging, and fat-suppressed three-dimensional driven equilibrium Fourier transform (DEFT) imaging, and to determine the diagnostic accuracy of these imaging sequences for detecting cartilage lesions in osteoarthritic knees, as compared with arthroscopy. Two sagittal fat-suppressed FSE images (repetition time [TR] / echo time [TE], 4000/13 [FSE short TE] and 4000/39 [FSE long TE]), sagittal fat-suppressed three-dimensional SPGR images (60/5, 40 degrees flip angle), and sagittal fat-suppressed echo-planar three-dimensional DEFT images (400/21.2) were acquired in 35 knees from 28 patients with osteoarthritis of the knee. The S/N efficiencies (S/Neffs) of cartilage, synovial fluid, muscle, meniscus, bone marrow, and fat tissue, and the C/N efficiencies (C/Neffs) of these structures were calculated. Kappa values, exact agreement, sensitivity, specificity, positive predictive value, and negative predictive value were determined by comparison of MR grading with arthroscopic results. The synovial fluid S/Neff on fat-suppressed FSE short TE images, fat-suppressed FSE long TE images, and fat-suppressed three-dimensional DEFT images showed similar values. Fat-suppressed three-dimensional DEFT images showed the highest fluid-cartilage C/Neff of all sequences. All images showed fair to good agreement with arthroscopy (kappa, 0.615 in FSE short TE, 0.601 in FSE long TE, 0.583 in three-dimensional SPGR, and 0.561 in three-dimensional DEFT). Although the sensitivity of all sequences was high (100% in FSE short TE, FSE long TE, and DEFT; 96.7% in SPGR), specificity was relatively low (67.6% in FSE short TE and FSE long TE; 85.3% in SPGR; 58.3% in DEFT). The peripheral area of bone marrow edema or whole area of bone marrow edema on fat-suppressed FSE images was demonstrated as low or iso-signal intensity on fat-suppressed three-dimensional DEFT images. Fat-suppressed three-dimensional SPGR imaging and fat-suppressed FSE imaging showed high sensitivity and high negative predictive values, but relatively low specificity. The Kappa value and exact agreement was the highest on fat-suppressed FSE short TE images. Fat-suppressed three-dimensional DEFT images showed results similar to the conventional sequences.


Puppy power.
Dogs have been used for many years to help people who are blind or have hearing loss. Now they are being trained to help people with medical conditions such as cancer, diabetes, seizures, Addison's disease and narcolepsy.


Improved Peptide and Protein Torsional Energetics with the OPLSAA Force Field.
The development and validation of new peptide dihedral parameters are reported for the OPLS-AA force field. High accuracy quantum chemical methods were used to scan φ, ψ, χ1, and χ2 potential energy surfaces for blocked dipeptides. New Fourier coefficients for the dihedral angle terms of the OPLS-AA force field were fit to these surfaces, utilizing a Boltzmann-weighted error function and systematically examining the effects of weighting temperature. To prevent overfitting to the available data, a minimal number of new residue-specific and peptide-specific torsion terms were developed. Extensive experimental solution-phase and quantum chemical gas-phase benchmarks were used to assess the quality of the new parameters, named OPLS-AA/M, demonstrating significant improvement over previous OPLS-AA force fields. A Boltzmann weighting temperature of 2000 K was determined to be optimal for fitting the new Fourier coefficients for dihedral angle parameters. Conclusions are drawn from the results for best practices for developing new torsion parameters for protein force fields.


Comparative analysis of postural control and vertical jump performance between three different measurement devices.
The aim of this study was to examine the concurrent validity of the HUMAC Balance System (HBS) and Balance Trainer BTG4 (BTG) in comparison to a laboratory-grade force platform (FP) for postural control (PC) and vertical jump performance (VJP) assessment. In addition, reliability of the three devices was measured for PC. Overall 22 participants (age = 37.8 ± 13.3 years; gender = 9 male, 13 female; height = 174.1 ± 10.5 cm; body mass = 75.3 ± 17.6 kg) were recruited to participate. Double and single leg standing balance tests with eyes open or closed and counter movement jumps (CMJ) were performed on two separate occasions. Reliability and concurrent validity for COP parameters and VJP were examined using intraclass correlation coefficients (ICC), Bland-Altman plots (BAP), standard error of measurement (SEM) and minimum detectable change (MDC). COP path length test-retest reliability was predominantly good to excellent for all three devices (ICC = 0.80-0.95). SEM and MDC values were high for all plates (SEM% = 8.0-15.2; MDC% = 22.8-44.5), with the HBS MDC values higher than the KIS and BTG in three of the four trials. ICC scores for concurrent validity were good to excellent for the BTG (ICC = 0.76-0.93) and moderate to good for the HBS (0.49-0.83). Band-Altman plots revealed a systematic bias for the HBS towards higher COP path length values under all conditions and for the BTG in two out of four trials towards lower values. Validity of VJP was excellent for the BTG (ICC = 1.0) and poor for the HBS (0.34), with a systematic bias towards lower values. The comparative analysis of PC and VJP revealed reliable and valid results for the BTG in comparison to a laboratory-grade force plate. The HBS showed reliable results for PC assessment with restrictions regarding its validity. Results of VJP showed that the HBS revealed deficits in the assessment of activities that require rapid, high force movements such as jumping and running. Due to the variable results of all three devices, it is recommended not to use them interchangeably.