Diagnostic clues for hyalinizing trabecular tumor on fine needle aspiration cytology.

Objectives: The hyalinizing trabecular tumor (HTT) is a rare benign neoplasm of the thyroid gland. This neoplasm has overlapping cytological features with Papillary Thyroid Carcinoma, Medullary Carcinoma and Follicular Neoplasm with Nuclear Features of Papillary Carcinoma. This can lead to misdiagnosis of malignancy in fine needle aspiration (FNA) cytology specimens with unnecessary total thyroidectomy. The aim of this study is to determine if there are some cytological features that could help us to suspect HTT on FNA specimens and avoid radical surgery. Material and Methods: With this purpose we have collected 6 cases diagnosed of HTT in Hospital Clínico San Carlos of Madrid (Spain) in the last 10 years and reviewed the cytological specimens. Result: We conclude that the presence of hyaline material in FNA specimens of HTT is a constant feature being a diagnostic clue. We must be cautious not to confuse it with dense colloid or amyloid material, the latter seen in Medullary Carcinoma. Papillary architecture and fibrovascular cores are not present in a HTT. Special stains as ki-67, calcitonin and Congo Red staining could help us in achieving the correct diagnosis. Conclusion: We feel the cytopathologists must be aware of the distinguishing features of this lesion, mainly the typical hyaline material to achieve a proper diagnosis and be able to reduce unnecessary aggressive management of these patients.

Changes over time in characteristics, resource use and outcomes among ICU patients with COVID-19-A nationwide, observational study in Denmark.

BACKGROUND: Characteristics and care of intensive care unit (ICU) patients with COVID-19 may have changed during the pandemic, but longitudinal data assessing this are limited. We compared patients with COVID-19 admitted to Danish ICUs in the first wave with those admitted later. METHODS: Among all Danish ICU patients with COVID-19, we compared demographics, chronic comorbidities, use of organ support, length of stay and vital status of those admitted 10 March to 19 May 2020 (first wave) versus 20 May 2020 to 30 June 2021. We analysed risk factors for death by adjusted logistic regression analysis. RESULTS: Among all hospitalised patients with COVID-19, a lower proportion was admitted to ICU after the first wave (13% vs. 8%). Among all 1374 ICU patients with COVID-19, 326 were admitted during the first wave. There were no major differences in patient's characteristics or mortality between the two periods, but use of invasive mechanical ventilation (81% vs. 58% of patients), renal replacement therapy (26% vs. 13%) and ECMO (8% vs. 3%) and median length of stay in ICU (13 vs. 10 days) and in hospital (20 vs. 17 days) were all significantly lower after the first wave. Risk factors for death were higher age, larger burden of comorbidities (heart failure, pulmonary disease and kidney disease) and active cancer, but not admission during or after the first wave. CONCLUSIONS: After the first wave of COVID-19 in Denmark, a lower proportion of hospitalised patients with COVID-19 were admitted to ICU. Among ICU patients, use of organ support was lower and length of stay was reduced, but mortality rates remained at a relatively high level.

Transfer of communication teaching skills from university to the clinical workplace - does it happen? A mixed methods study.

BACKGROUND: Communication skills learned in the classroom do not transfer easily into clinical practice because they are not reinforced by teachers in the workplace setting and because lack of faculty training restricts the transfer of communication skills in real patient encounters. Trained university-based communication skills teachers often work simultaneously as doctors in clinics. This study explored if and how the skills of these teachers play a role in communication skills training in the clinical workplace. METHODS: We used an exploratory sequential design: a mixed method approach that combined a survey with communication skills teachers, and qualitative individual interviews with these teachers and their educational leaders in clinical departments. The questionnaire was analysed using descriptive statistics. The interviews were analysed using content analysis. RESULTS: The response rate was 34 %. A majority (93 %) used their communication skills when communicating with patients and relatives. Less than half taught communication in clinical departments. Approximately half of the respondents stated that encouragement from their leaders or colleagues would inspire them to use their teaching skills in the workplace. However, only 20 % had told their leaders about their competencies in teaching communication. One third thought that they needed further teacher training to teach in the clinical workplace. Qualitative analysis showed that teaching opportunities existed but mainly consisted of random, one-off sessions that came about through the initiative of the communication skills teachers themselves. The teachers described several barriers, such as the challenge of teaching colleagues, as communication relates to identity and hierarchical structures, as well as a lack of requests from colleagues or management, and department culture prioritizing topics relating to medical expertise. None of the educational leaders made use of the teachers' specific communication skills in a structured way: some saw it as unimportant, while others saw it as a potential resource. CONCLUSION: Transfer of the teaching skills of communication skills teachers trained for university-based clinical communication training happened, but to a limited degree. Although both opportunities and barriers for transferring communication skills existed, barriers seemed to dominate, and opportunities for communication skills training in the workplace setting were not used to their full potential.

Genome Sequence of an Unknown Subtype of Hepatitis C Virus Genotype 6: Another Piece for the Taxonomic Puzzle.

The surveillance and correct subtyping of hepatitis C virus strains require available and up-to-date publicly available reference genomes. Here, we present the complete open reading frame sequence of a hepatitis C virus genotype 6 strain of an unknown subtype that was discovered during routine subtyping of patients in the clinic.

Salmon in Combination with High Glycemic Index Carbohydrates Increases Diet-Induced Thermogenesis Compared with Salmon with Low Glycemic Index Carbohydrates⁻An Acute Randomized Cross-Over Meal Test Study.

The study investigated the acute effects of meals containing either salmon or veal in combination with carbohydrates with high or low glycemic index (GI) on diet-induced thermogenesis (DIT) (primary endpoint), appetite sensations, and energy intake (EI). Twenty-five overweight men and women ingested four iso-caloric test meals: salmon with mashed potatoes (high GI) (SM), salmon with wholegrain pasta (low GI) (SP), veal with mashed potatoes (VM) and veal with wholegrain pasta (VP). Energy expenditure was measured in the fasting state and six times postprandially for 25 min with 5-min breaks between each measurement. Appetite sensations were measured every 30 min. Blood samples, from arterialized venous blood, were drawn every 20 min until an ad libitum buffet-style lunch was served 3.5 h later. DIT was 40% higher after the SM meal compared to the SP meal (p = 0.002). Prospective food consumption was lower after the SM meal compared with the VP meal (p = 0.01). There were no differences in satiety, hunger, fullness, or ad libitum EI between the test meals (all p > 0.05). In conclusion, salmon with high GI carbohydrates increased DIT compared to salmon with low GI carbohydrates. This indicates that DIT is sensitive to the GI of the carbohydrates after intake of salmon but not veal.

Meals based on cod or veal in combination with high or low glycemic index carbohydrates did not affect diet-induced thermogenesis, appetite sensations, or subsequent energy intake differently.

The objective of this study was to investigate the acute effects of meals containing protein from either cod or veal in combination with high or low glycemic index (GI) carbohydrates, on diet-induced thermogenesis (DIT) (primary endpoint), appetite, energy intake (EI), as well as postpranidal ghrelin, glucose, and insulin responses. Twenty-three overweight men and women (mean ±â€¯SD age: 30.0 ±â€¯7.6 y, BMI: 27.2 ±â€¯1.4 kg/m2) consumed 4 test meals: cod with mashed potatoes (high GI carbohydrate), cod with wholegrain pasta (low GI carbohydrate), veal with mashed potatoes, and veal with wholegrain pasta (∼2010 kJ, ∼25.5 E% protein, ∼41.0 E% carbohydrate, ∼33.5 E% fat). Energy expenditure was measured at baseline and six times postprandially, each lasting 25 min. Additionally, appetite sensations were measured every half hour. Arterialized venous blood samples were drawn every 20 min until an ad libitum buffet-style lunch was served 3.5 h later. DIT did not differ between test meals (P > 0.05), and there were no differences in appetite sensations or ad libitum EI (all, P > 0.05). Meal-time interactions were found for glucose and insulin (P = 0.04 and P < 0.001). Pairwise comparisons revealed that glucose and insulin peaks were higher after the meals with high GI carbohydrates. No differences were found between meals with cod or veal in combination with carbohydrates with low or high GI on DIT, appetite sensations, or EI in overweight men and women. However, as expected meals with high GI carbohydrates resulted in higher glucose and insulin responses compared to meals with low GI carbohydrates regardless of protein source.

Emergence of a vancomycin-variable Enterococcus faecium ST1421 strain containing a deletion in vanX.

Background: Primary screening for VRE with PCR directed against vanA allowed identification of vanA+ samples from which VRE could not be isolated when selective culture methods were used. From such a sample a vancomycin-susceptible, vanA+ Enterococcus faecium, Efm-V1511, was isolated, when vancomycin selection was not used during culture. Similar isolates with variable susceptibility to vancomycin were obtained in the following months. Objectives: To characterize Efm-V1511 and investigate the causes of variable susceptibility to vancomycin. Methods: All strains were sequenced using Illumina technology. Plasmids containing vanA were reconstructed by scaffolding to known plasmids or plasmids were sequenced using Oxford Nanopore MinION. Derived structures were verified by PCR and sequencing. Furthermore, selected vanA+ vancomycin-susceptible isolates were passaged in the presence of vancomycin and vancomycin-resistant variants obtained were sequenced. Results: Efm-V1511 belonged to ST1421 and contained a 49 696 bp plasmid pHVH-V1511 carrying a Tn1546-derived genetic element. Within this element vanX was truncated by a 252 bp 3' deletion explaining the susceptibility of Efm-V1511. Between March 2016 and April 2017, 48 isolates containing pHVH-V1511 were identified. All were ST1421. In isolates resistant to vancomycin, resistance could be attributed to changes in ddl disrupting gene function sometimes accompanied by changes in vanS, increased pHVH-V1511 copy number or the existence of an additional vanA-containing plasmid encoding a functional vanX. Conclusions: E. faecium carrying pHVH-V1511 is capable of nosocomial transmission and may develop clinical resistance to vancomycin. Strains may not be detected using standard culture methods for VRE.

Analytical performance of the Hologic Aptima HBV Quant Assay and the COBAS Ampliprep/COBAS TaqMan HBV test v2.0 for the quantification of HBV DNA in plasma samples.

BACKGROUND: Quantification of HBV DNA is used for initiating and monitoring antiviral treatment. Analytical test performance consequently impacts treatment decisions. OBJECTIVES: To compare the analytical performance of the Aptima HBV Quant Assay (Aptima) and the COBAS Ampliprep/COBAS TaqMan HBV Test v2.0 (CAPCTMv2) for the quantification of HBV DNA in plasma samples. STUDY DESIGN: The performance of the two tests was compared on 129 prospective plasma samples, and on 63 archived plasma samples of which 53 were genotyped. Linearity of the two assays was assessed on dilutions series of three clinical samples (Genotype B, C, and D). RESULTS: Bland-Altman analysis of 120 clinical samples, which quantified in both tests, showed an average quantification bias (Aptima - CAPCTMv2) of -0.19 Log IU/mL (SD: 0.33 Log IU/mL). A single sample quantified more than three standard deviations higher in Aptima than in CAPCTMv2. Only minor differences were observed between genotype A (N = 4; average difference -0.01 Log IU/mL), B (N = 8; -0.13 Log IU/mL), C (N = 8; -0.31 Log IU/mL), D (N = 25; -0.22 Log IU/mL), and E (N = 7; -0.03 Log IU/mL). Deming regression showed that the two tests were excellently correlated (slope of the regression line 1.03; 95% CI: 0.998-1.068). Linearity of the tests was evaluated on dilution series and showed an excellent correlation of the two tests. Both tests were precise with %CV less than 3% for HBV DNA ≥3 Log IU/mL. CONCLUSIONS: The Aptima and CAPCTMv2 tests are highly correlated, and both tests are useful for monitoring patients chronically infected with HBV.

Weight loss decreases self-reported appetite and alters food preferences in overweight and obese adults: Observational data from the DiOGenes study.

People with obesity often struggle to maintain their weight loss after a weight loss period. Furthermore, the effect of weight loss on appetite and food preferences remains unclear. Hence this study investigated the effect of weight loss on subjective appetite and food preferences in healthy, overweight and obese volunteers. A subgroup of adult participants (n = 123) from the Diet Obesity and Genes (DiOGenes) study (subgroup A) was recruited from across six European countries. Participants lost ≥8% of initial body weight during an 8-week low calorie diet (LCD). Subjective appetite and food preferences were measured before and after the LCD, in response to a standardized meal test, using visual analogue rating scales (VAS) and the Leeds Food Choice Questionnaire (FCQ). After the LCD, participants reported increased fullness (p < 0.05), decreased desire to eat (p < 0.05) and decreased prospective consumption (p < 0.05) after consuming the test meal. An interaction effect (visit x time) was found for hunger ratings (p < 0.05). Area under the curve (AUC) for hunger, desire to eat and prospective consumption was decreased by 18.1%, 20.2% and 21.1% respectively whereas AUC for fullness increased by 13.9%. Preference for low-energy products measured by the Food Preference Checklist (FPC) decreased by 1.9% before the test meal and by 13.5% after the test meal (p < 0.05). High-carbohydrate and high-fat preference decreased by 11.4% and 16.2% before the test meal and by 17.4% and 22.7% after the meal (p < 0.05). No other effects were observed. These results suggest that LCD induced weight loss decreases the appetite perceptions of overweight volunteers whilst decreasing their preference for high-fat-, high-carbohydrate-, and low-energy products.

Protein from Meat or Vegetable Sources in Meals Matched for Fiber Content has Similar Effects on Subjective Appetite Sensations and Energy Intake-A Randomized Acute Cross-Over Meal Test Study.

Higher-protein meals decrease hunger and increase satiety compared to lower-protein meals. However, no consensus exists about the different effects of animal and vegetable proteins on appetite. We investigated how a meal based on vegetable protein (fava beans/split peas) affected ad libitum energy intake and appetite sensations, compared to macronutrient-balanced, iso-caloric meals based on animal protein (veal/pork or eggs). Thirty-five healthy men were enrolled in this acute cross-over study. On each test day, participants were presented with one of four test meals (~3550 kilojoules (kJ) 19% of energy from protein), based on fava beans/split peas (28.5 g fiber), pork/veal or eggs supplemented with pea fiber to control for fiber content (28.5 g fiber), or eggs without supplementation of fiber (6.0 g fiber). Subjective appetite sensations were recorded at baseline and every half hour until the ad libitum meal three hours later. There were no differences in ad libitum energy intake across test meals (p > 0.05). Further, no differences were found across meals for hunger, satiety, fullness, prospective food consumption, or composite appetite score (all p > 0.05). Iso-caloric, macronutrient-balanced, fiber-matched meals based on vegetable protein (fava beans/split peas) or animal protein (veal/pork or eggs) had similar effects on ad libitum energy intake and appetite sensations.

Analytical and clinical performance of the Hologic Aptima HCV Quant Dx Assay for the quantification of HCV RNA in plasma samples.

BACKGROUND: Chronic hepatitis C virus (HCV) infection can be effectively treated with directly acting antiviral (DAA) therapy. Measurement of HCV RNA is used to evaluate patient compliance and virological response during and after treatment. OBJECTIVES: To compare the analytical performance of the Aptima HCV Quant Dx Assay (Aptima) and the COBAS Ampliprep/COBAS TaqMan HCV Test v2.0 (CAPCTMv2) for the quantification of HCV RNA in plasma samples, and compare the clinical utility of the two tests in patients undergoing treatment with DAA therapy. STUDY DESIGN: Analytical performance was evaluated on two sets of plasma samples: 125 genotyped samples and 172 samples referred for quantification of HCV RNA. Furthermore, performance was evaluated using dilutions series of four samples containing HCV genotype 1a, 2b, 3a, and 4a, respectively. Clinical utility was evaluated on 118 plasma samples obtained from 13 patients undergoing treatment with DAAs. RESULTS: Deming regression of results from 187 plasma samples with HCV RNA >2 Log IU/mL indicated that the Aptima assay quantified higher than the CAPCTMv2 test for HCV RNA >4.9 Log IU/mL. The linearity of the Aptima assay was excellent across dilution series of four HCV genotypes (slope of the regression line: 1.00-1.02). The Aptima assay detected significantly more replicates below targeted 2 Log IU/mL than the CAPCTMv2 test, and yielded clearly interpretable results when used to analyze samples from patients treated with DAAs. CONCLUSIONS: The analytical performance of the Aptima assay makes it well suited for monitoring patients with chronic HCV infection undergoing antiviral treatment.

Efficacy of a liquid low-energy formula diet in achieving preoperative target weight loss before bariatric surgery.

A preoperative weight loss of 8 % is a prerequisite to undergo bariatric surgery (BS) in Denmark. The aim of the present study was to evaluate the efficacy of a 7- or an 11-week low-energy diet (LCD) for achieving preoperative target weight before BS. A total of thirty obese patients (BMI 46·0 (sd 4·4) kg/m(2)) followed an LCD (Cambridge Weight Plan(®), 4184 kJ/d (1000 kcal/d)) for 7 or 11 weeks as preparation for BS. Anthropometric measurements including body composition (dual-energy X-ray absorptiometry), blood parameters and blood pressure were assessed at weeks 0, 7 and 11. At week 7, the majority of patients (77 %) had reached their target weight, and this was achieved after 5·4 (sem 0·3) weeks. Mean weight loss was 9·3 (sem 0·5) % (P < 0·01) and consisted of 41·6 % fat-free mass (FFM) and 58·4 % fat mass. The weight loss was accompanied by a decrease in systolic and diastolic blood pressure (7·1 (sem 2·3) and 7·3 (sem 1·8) mmHg, respectively, all P < 0·01) as well as an improved metabolic profile (8·2 (sem 1·8) % decrease in fasting glucose (P < 0·01), 28·6 (sem 6·4) % decrease in fasting insulin (P < 0·01), 23·1 (sem 2·2) % decrease in LDL (P < 0·01), and 9·7 (sem 4·7) % decrease in TAG (P < 0·05)). Weight, FFM and fat mass continued to decrease from week 7 to 11 (all P < 0·01), whereas no additional improvements was observed in the metabolic parameters. Severely obese patients can safely achieve preoperative target weight on an LCD within 7 weeks as part of preparation for BS. However, the considerable reduction in FFM in severely obese subjects needs further investigation.

Hepatocytes respond differently to major dietary trans fatty acid isomers, elaidic acid and trans-vaccenic acid.

BACKGROUND: It has been discussed if the adverse health effect associated with the ingestion of trans fatty acids correlates with the food source, as the composition of the isomers varies in different foods. We have investigated the hepatocellular responses to the predominant trans fatty acid isomers in industrially produced partially hydrogenated vegetable oils (elaidic acid) and products of ruminant origin (trans-vaccenic acid). RESULTS: The responses of HepG2-SF cells exposed to 100 µM fatty acids during 7 days were examined. Elaidic acid decreased the cellular proliferation rate while trans-vaccenic acid had no effect. Analysis of cellular triacylglycerol fractions showed, that both trans fatty acids were metabolized by HepG2-SF cells, although elaidic acid, to a higher degree than trans-vaccenic, accumulated in the triacylglycerol fraction. Proteome analysis revealed that the overlap of differentially regulated proteins only contained four proteins, suggesting that the two trans fatty acid isomers affect the cells in different ways. The data are available via ProteomeXchange with identifier PXD000760. CONCLUSIONS: Our investigations revealed that the hepatocellular response to the two most abundant dietary positional C18:1 trans fatty acid isomers differ substantially. In addition, the results suggest that trans-vaccenic acid does not affect cholesterol metabolism adversely compared to elaidic acid.

Effects of elaidic acid on lipid metabolism in HepG2 cells, investigated by an integrated approach of lipidomics, transcriptomics and proteomics.

Trans fatty acid consumption in the human diet can cause adverse health effects, such as cardiovascular disease, which is associated with higher total cholesterol, a higher low density lipoprotein-cholesterol level and a decreased high density lipoprotein-cholesterol level. The aim of the study was to elucidate the hepatic response to the most abundant trans fatty acid in the human diet, elaidic acid, to help explain clinical findings on the relationship between trans fatty acids and cardiovascular disease. The human HepG2 cell line was used as a model to investigate the hepatic response to elaidic acid in a combined proteomic, transcriptomic and lipidomic approach. We found many of the proteins responsible for cholesterol synthesis up-regulated together with several proteins involved in the esterification and hepatic import/export of cholesterol. Furthermore, a profound remodeling of the cellular membrane occurred at the phospholipid level. Our findings contribute to the explanation on how trans fatty acids from the diet can cause modifications in plasma cholesterol levels by inducing abundance changes in several hepatic proteins and the hepatic membrane composition.

Neurorehabilitation with versus without resistance training after botulinum toxin treatment in children with cerebral palsy: a randomized pilot study.

OBJECTIVE: To compare the effects of physical rehabilitation with (PRT) and without (CON) progressive resistance training following treatment of spastic plantarflexors with botulinum toxin type A (BoNT) in children with cerebral palsy (CP). METHODS: Fourteen children with CP performed supervised PRT (n=7) or CON (n=7) two times per week for 12 weeks, following the BoNT-treatment. Outcome measurements were performed at baseline (pre BoNT), and 4 and 12 weeks post BoNT. They consisted of: ankle muscle function (maximal torque and submaximal torque steadiness of isometric ankle dorsi- and plantarflexion and associated ankle muscle [EMG] activity), gait function (3-dimensional gait analysis), balance function (sway analysis), gross motor function (GMFM-66), and spasticity (modified Ashworth). RESULTS: Submaximal torque control (torque steadiness) of isometric dorsiflexion improved similarly in the two groups, and the improvement was related to the reduction in antagonist (soleus) co-activity (P< 0.05). Maximal plantarflexion torque increased after PRT, whereas a reduction was seen after CON (P< 0.05). No changes in function were observed. CONCLUSIONS: Both types of physical rehabilitation in combination with BoNT-treatment improved antagonist (ankle dorsiflexion) torque-control to the same extent - which was related to the reduction in antagonist co-activity - but only rehabilitation with PRT increased maximal plantarflexion torque.

Identification of a potential biomarker panel for the intake of the common dietary trans fat elaidic acid (trans∆9-C18:1).

Trans fatty acid intake has been correlated to an unfavorable plasma lipoprotein profile and an increased cardiovascular disease risk. The present study aimed to identify a plasma protein biomarker panel related to human intake of elaidic acid. The human liver cell line HepG2-SF was used as a model system, and the cells were maintained for seven days in serum-free medium containing 100 µM elaidic acid (trans∆9-C18:1), oleic acid (cis∆9-C18:1) or stearic acid (C18:0). The secretomes were analyzed by stable isotope labeling of amino acids in cell culture (SILAC), difference in gel electrophoresis (DIGE) and gene expression microarray analysis. Twelve proteins were found to be differentially regulated based on SILAC data (>1.3 fold change, P-value<0.05), 13 proteins were found to be differentially regulated based on DIGE analysis (>1.3 fold change, P-value<0.05), and 17 mRNA transcripts encoding extracellular proteins were determined to be affected (>1.3 fold change, P-value<0.01) following the addition of elaidic acid compared to oleic acid or stearic acid. The results revealed that 37 proteins were regulated specifically in response to elaidic acid exposure, and nine of these proteins were confirmed to be regulated in this manner by using selected reaction monitoring mass spectrometry.

Absence of hematopoietic tissue factor pathway inhibitor mitigates bleeding in mice with hemophilia.

Tissue factor pathway inhibitor (TFPI) blocks thrombin generation via the extrinsic blood coagulation pathway. Because the severe bleeding in patients with hemophilia occurs from deficiency of intrinsic blood coagulation pathway factor VIII or IX, pharmacological agents that inactivate TFPI and, therefore, restore thrombin generation via the extrinsic pathway, are being developed for treatment of hemophilia. Murine models of combined TFPI and factor VIII deficiency were used to examine the impact of TFPI deficiency on bleeding and clotting in hemophilia. In breeding studies, Factor VIII null (F8(-/-)) did not rescue the embryonic death of TFPI null (Tfpi(-/-)) mice. Tfpi(+/-) did not alter the bleeding phenotype of F8(-/-) mice. However, total inhibition of intravascular TFPI through injection of anti-TFPI antibody mitigated tail vein bleeding. Interestingly, tail blood loss progressively decreased at doses greater than needed to totally inhibit plasma TFPI, suggesting that inhibition of a sequestered pool of TFPI released at the injury site mitigates bleeding. Because TFPI is sequestered within platelets and released following their activation, the function of platelet TFPI was examined in F8(-/-) mice lacking hematopoietic cell TFPI that was generated by fetal liver transplantation. Blood loss after tail transection significantly decreased in Tfpi(+/-);F8(-/-) mice with hematopoietic Tfpi(-/-) cells compared with Tfpi(+/-);F8(-/-) mice with Tfpi(+/+) hematopoietic cells. Additionally, following femoral vein injury, Tfpi(+/-);F8(-/-) mice with Tfpi(-/-) hematopoietic cells had increased fibrin deposition compared with identical-genotype mice with Tfpi(+/+) hematopoietic cells. These findings implicate platelet TFPI as a primary physiological regulator of bleeding in hemophilia.

Stereocontrolled synthesis of 2-substituted-1,3-azasilaheterocycles.

Chiral alpha-silylsulfinamides, prepared by the treatment of an alkyldiphenylsilane with lithium followed by its addition to a sulfinimine, can be applied to the synthesis of 1,3-azasilaheterocycles as derivatives of cyclic alkaloids. This synthetic route, which involves intramolecular substitution of an amino alcohol or cyclization of an amino acid promoted by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), represents a convenient means for accessing these silicon-containing heterocycles.

Single nucleotide polymorphisms in inflammatory genes and the risk of early onset of lone atrial fibrillation.

BACKGROUND: Systemic low-grade inflammation is a prognostic risk factor of atrial fibrillation (AF). OBJECTIVE: We hypothesized that genetic polymorphisms, which determine the rate of inflammatory cytokines, are associated with the risk of AF, independently of comorbidity. METHODS AND RESULTS: We included 192 patients with so-called lone AF and age 40 years or below, and 188 healthy controls. All patients were genotyped for single nucleotide polymorphisms (SNPs) in inflammatory genes using fluorescence-based real-time polymerase chain reaction (PCR). A case-control analysis of the C/C, C/T and T/T genotypes on IL1A-889 revealed a significant difference in both the frequency of genotypes (p = 0.03) and in the allelic frequency (p = 0.015). These differences were not significant after Bonferroni corrections. For IL1B-511, IL10-592, IL10-1082, IL18-137, IL18-607 and TNF-308 there were no significant differences, neither in genotype frequency, nor in allelic frequency between the lone AF patients and the controls. CONCLUSION: Our study failed to show an association between polymorphisms in inflammatory genes and early onset of lone AF. It remains to be established whether polymorphisms in inflammatory genes play a causative role in the pathophysiology of AF.

Further studies toward the stereocontrolled synthesis of silicon-containing peptide mimics.

Further studies are reported on the utilization of the versatile reaction between chiral sulfinimines and alkyldiphenylsilyl lithium reagents with the goal of preparing a wide range of silanediol-based protease inhibitors. In particular, focus has been placed to demonstrate how a number of genetically encoded amino acid side chains such as serine, threonine, tyrosine, lysine, proline, arginine, aspartate and asparagine might be incorporated into the overall approach. Efforts to apply this synthetic methodology for accessing biologically relevant silanediol dipeptide mimics are also described. This includes the synthesis of a potential inhibitor of the human neutrophil elastase, as well as a diphenylsilane mimic of a hexapeptide fragment of the human islet amyloid polypeptide.