Alternatively spliced tissue factor promotes breast cancer growth in a β1 integrin-dependent manner

Full-length tissue factor (flTF), the coagulation initiator, is overexpressed in breast cancer (BrCa), but associations between flTF expression and clinical outcome remain controversial. It is currently not known whether the soluble alternatively spliced TF form (asTF) is expressed in BrCa or impacts BrCa progression. We are unique in reporting that asTF, but not flTF, strongly associates with both tumor size and grade, and induces BrCa cell proliferation by binding to β1 integrins. asTF promotes oncogenic gene expression, anchorage-independent growth, and strongly up-regulates tumor expansion in a luminal BrCa model. In basal BrCa cells that constitutively express both TF isoforms, asTF blockade reduces tumor growth and proliferation in vivo. We propose that asTF plays a major role in BrCa progression acting as an autocrine factor that promotes tumor progression. Targeting asTF may comprise a previously unexplored therapeutic strategy in BrCa that stems tumor growth, yet does not impair normal hemostasis.     

Endocrine tumors of the pancreas.

Neuroendocrine tumors of the pancreas are rare neoplasms of the heterogeneous group of neuroendocrine gastroenteropancreatic tumors that originate from totipotential stem cells or preexisting endocrine cells within the pancreas. Most neuroendocrine tumors of the pancreas are benign or show an indolent course of disease.A subset of them shows a very aggressive behavior, becomes highly malignant, and metastasizes early with life-limiting consequences. An effective disease-management includes the diagnostic approach with hormonal testing and localization and surgical treatment with histologic classification in combination with biotherapy, chemotherapy, or therapy with radionucleotides, de-pending on the individual behavior of the tumor. The primary goal is the improvement of symptoms leading to an acceptable quality of life in the individual patient.     

Mortality‐risk‐based apnea–hypopnea index thresholds for diagnostics of obstructive sleep apnea

The severity of obstructive sleep apnea is clinically assessed mainly using the apnea–hypopnea index. Based on the apnea–hypopnea index, patients are classified into four severity groups: non‐obstructive sleep apnea (apnea–hypopnea index < 5); mild (5 ≤ apnea–hypopnea index < 15); moderate (15 ≤ apnea–hypopnea index < 30); and severe obstructive sleep apnea (apnea–hypopnea index ≥ 30). However, these thresholds lack solid clinical and scientific evidence. We hypothesize that the current apnea–hypopnea index thresholds are not optimal despite their global use, and aim to assess this clinical shortcoming by optimizing the thresholds with respect to the risk of all‐cause mortality. We analysed ambulatory polygraphic recordings of 1,783 patients with suspected obstructive sleep apnea (mean follow‐up 18.3 years). We simulated 79,079 different threshold combinations in 100 randomized subgroups of the population and studied the relative risk of all‐cause mortality corresponding to each combination and randomization. The optimal thresholds were chosen according to three criteria: (a) the hazard ratios increase linearly between severity groups towards more severe obstructive sleep apnea; (b) each group includes at least 15% of the study population; (c) group sizes decrease with increasing obstructive sleep apnea severity. The risk of all‐cause mortality varied greatly across simulations; the threshold defining non‐obstructive sleep apnea group having the largest effect on the hazard ratios. The apnea–hypopnea index threshold combination of 3‐9‐24 was optimal in most of the subgroups. In conclusion, the assessment of obstructive sleep apnea severity based on the current apnea–hypopnea index thresholds is not optimal. Our novel approach provides methods for optimizing apnea–hypopnea index‐based severity classification, and the revised thresholds better differentiate patients into severity groups, ensuring that an increase in the severity corresponds to an increase in the risk of all‐cause mortality.     

Association of CHRM2 with IQ: Converging Evidence for a Gene Influencing Intelligence

The cholinergic neurotransmitter system is thought to be involved in many aspects of memory, attention, and higher cognition. In the Collaborative Study on the Genetics of Alcoholism (COGA) sample, we have previously reported linkage and association to the cholinergic muscarinic 2 receptor gene (CHRM2) on chromosome 7 with evoked EEG oscillations (Jones et al. 2004), providing evidence that this gene may be involved in human brain dynamics and cognition. In addition, a small number of genetic markers were genotyped in CHRM2 in the Minnesota Twin and Family Study (Comings et al. 2003) and a Dutch family study (Gosso et al. 2006, in press) and both research groups found evidence that this gene may be involved in intelligence. In the COGA sample, we have extensively genotyped SNPs within and flanking the CHRM2 gene. We find evidence of association with multiple SNPs across CHRM2 and Performance IQ, as measured by the Wechsler Adult Intelligence Scale-Revised (WAIS-R). These results remain significant after taking into account alcohol dependence and depression diagnoses in the sample. Edited by Danielle Posthuma Henri Begleiter—Deceased     

Vaccine knowledge in students in Paris,France, and surrounding regions

INTRODUCTION:

In France, young adults are legally freed from parental authority at the age of 18 years and are, thus, responsible for their own vaccine record. This young adult population is more frequently exposed to vaccine-preventable infectious diseases.

OBJECTIVE:

To determine the factors associated with students’ knowledge of the interval between two antitetanus boosters and their report of having up-to-date vaccinations.

METHODS:

In April 2009, a survey was conducted involving a random sample of students between 18 and 25 years of age eating lunch at university dining facilities in Paris and its suburbs (Ile de France).

RESULTS:

Among the 677 students approached, 583 agreed to participate. Only 207 (36%) of respondents knew the recommended dosing interval between two doses of tetanus vaccine booster (10 years). The majority of students (69%) reported having up-to-date vaccinations. Declaring having up-to-date vaccinations was significantly associated with having a general practitioner (OR 3.03 [95% CI 1.69 to 5.55]). Health care students were significantly more likely to know the decennial interval between two antitetanus boosters (OR 2 [95% CI 1.28 to 3.25]). Most of responding students (n=519 [89%]) believed that vaccines were very useful.

CONCLUSIONS:

An overall lack of knowledge of vaccines was observed among this student population. Health care providers, such as GPs and university medical practice staff, who interact with these young individuals have an essential role to promote better vaccination coverage in this population.     

HLA haplotype study of 53 juvenile insulin-dependent diabetic (I.D.D.) families

Fifty-three families with at least one IDD patient were genotyped for 5 markers of the HLA complex including Bf and DR. In 8 families one of the parents was also affected and in 12 families more than two children were diseased. In total, 76 patients were genotyped. Their haplotypes were compared with those of 106 unrelated controls (the parents of 53 genotyped families).

• 1) 

  Three haplotypes or segments of them (A2, Cw3, B15, BfS, DR4; Aw30, Cw5, B18, BfF I, DR3; and Al, Cw7, B8, BfS, DR3) were found more frequently in IDD patients.
• 2) 

  Measured by the 6 formula, the association of the postulated IDD susceptibility gene was very strong with the D-end of two of these haplotypes: BfF1, DR3 and BfS, DR4. However, the association was weak with the DR3 of the haplotype Al, Cw7, B8, BfS, DR3.
• 3) 

  An excess of HLA-identical affected siblings was found.
• 4) 

  An excess of DR3/DR4 heterozygotes was observed. By contrast, the observed frequency of patients homozygous for DR3 or DR4 was not increased, but even slightly decreased.

The data support a model of inheritance comprising at least two closely linked specifically "diabetic" loci (most of the time marked by B18, BfFl, DR3 and B15, BfS, DR4) and a non-specifically "diabetic" haplotype favouring auto-immunisation (most of the time marked by B8, BfS, DR3). This model is discussed in the light of the presented data and of those of the literature.     

Predicting prolonged duration of fever in children: a cohort study in primary care

Background

Fever in children in primary care is commonly caused by benign infections, but often worries parents. Information about the duration of fever and its predictors may help in reassuring parents, leading to diminished consultation of health care.

Aim

To determine which signs and symptoms predict a prolonged duration of fever in febrile children in primary care and evaluate whether C-reactive protein (CRP) measurement has an additive predictive value for these symptoms.

Design and setting

A prospective cohort study at a GPs’ cooperative (GPC) out-of-hours service.

Method

Children (aged 3 months to 6 years) presenting with fever as stated by the parents were included. Exclusion criteria were no communication in Dutch possible, previous enrolment in the study within 2 weeks, referral to the hospital directly after visiting the GPC, or no informed consent. The main outcome measure was prolonged duration of fever (>3 days) after initial contact.

Results

Four-hundred and eighty children were analysed, and the overall risk of prolonged duration was 13% (63/480). Multivariate analysis combined model of patient history and physical examination showed that ‘sore throat’ (OR 2.8; 95% CI = 1.30 to 6.01) and ‘lymph nodes palpable’ (OR 1.87; 95% CI = 1.01 to 3.49) are predictive for prolonged duration of fever. The discriminative value of the model was low (AUC 0.64). CRP had no additive value in the prediction of prolonged duration of fever (OR 1.00; 95% CI = 0.99 to 1.01).

Conclusion

The derived prediction model indicates that only a few signs and symptoms are related to prolonged duration of fever. CRP has no additional value in this model. Overall, because the discriminative value of the model was low, the duration of fever cannot be accurately predicted.     

Gain‐of‐Function Mutation in STIM1 (P.R304W) Is Associated with Stormorken Syndrome

Stormorken syndrome is a rare autosomal dominant disorder characterized by a phenotype that includes miosis, thrombocytopenia/thrombocytopathy with bleeding time diathesis, intellectual disability, mild hypocalcemia, muscle fatigue, asplenia, and ichthyosis. Using targeted sequencing and whole‐exome sequencing, we identified the c.910C > T transition in a STIM1 allele (p.R304W) only in patients and not in their unaffected family members. STIM1 encodes stromal interaction molecule 1 protein (STIM1), which is a finely tuned endoplasmic reticulum Ca²⁺ sensor. The effect of the mutation on the structure of STIM1 was investigated by molecular modeling, and its effect on function was explored by calcium imaging experiments. Results obtained from calcium imaging experiments using transfected cells together with fibroblasts from one patient are in agreement with impairment of calcium homeostasis. We show that the STIM1 p.R304W variant may affect the conformation of the inhibitory helix and unlock the inhibitory state of STIM1. The p.R304W mutation causes a gain of function effect associated with an increase in both resting Ca²⁺ levels and store‐operated calcium entry. Our study provides evidence that Stormorken syndrome may result from a single‐gene defect, which is consistent with Mendelian‐dominant inheritance.     

High prevalence of hepatitis C virus type 5 in central France evidenced by a prospective study from 1996 to 2002

From 1996 to 2002, hepatitis C virus (HCV) typing was prospectively performed for 1,281 unselected HCV-infected and viremic patients, irrespective of their clinical status. Eighty-three patients (6.5%) were coinfected with human immunodeficiency virus (HIV) and HCV. A total of 1,195 strains were identified by a serotype screening (Murex HCV Serotyping 1-6 assay) and/or genotyping (Inno-LiPA HCV II) test. The distribution of HCV types showed an unusually high rate of type 5 (14.2%) that was stable over time and was the third most frequent type, after type 1 (59.1%) and type 3 (15.1%). HCV type 5 was more frequent in patients who were older than 50 (P = 10(-6)), but its frequency did not differ significantly by gender (P = 0.21). Serotyping was performed for 1,160 strains but failed for 30.2% of them. The efficiency depended on HIV status (for HCV-HIV-coinfected patients, half of the strains were untypeable) and HCV type. Genotyping was performed for 428 samples, with an overall efficiency of 99.3%. It failed in three cases, which were subsequently identified as HCV type 2. Serotyping and genotyping results for 39 patients showed discrepancies between the two methods for 4 patients, who had HCV type 2, type 6, or mixed infections. Thus, HCV type 5 may also be encountered frequently in Western countries. Its apparent confinement to a restricted area raises the question of how it emerged and underscores the need for further studies of HCV type prevalence, routes of transmission, pathogenicity, and responses to treatment.