F8 gene dosage defects in atypical patients with severe haemophilia A

Summary. We performed molecular analysis of the factor 8 gene (F8) in 272 unrelated Spanish patients with haemophilia A (HA) and detected a mutation by routine analysis in 267 of them (98.1%). No mutation was detected in the remaining five patients despite clinical and laboratory confirmation of HA. The aim is to describe the molecular alterations in F8 discovered by gene dosage methodologies in three of these patients. For methodology, F8 sequencing, intragenic marker analysis, multiplex ligation-dependent probe amplification and quantitative real time-PCR were followed. One patient had Klinefelter syndrome (47,XXY) and a large deletion spanning exons 1-12 masked by the other F8 allele; the second patient showed a large duplication spanning exons 2-10 and the third patient revealed a non-contiguous double duplication of exons 14 and 23-25. The remaining two patients had mild HA and dosage results were normal. The application of gene dosage methods is useful to define haemophilic patients in whom mutations are not detected using other routine methods. Nevertheless, in a small percentage of patients (<1%), no molecular pathology can be identified after testing several genetic methodologies.     

Racial Differences in the Effect of a Telephone-Delivered Hypertension Disease Management Program

BACKGROUND

African Americans are significantly more likely than whites to have uncontrolled hypertension, contributing to significant disparities in cardiovascular disease and events.

OBJECTIVE

The goal of this study was to examine whether there were differences in change in blood pressure (BP) for African American and non-Hispanic white patients in response to a medication management and tailored nurse-delivered telephone behavioral program.

PARTICIPANTS

Five hundred and seventy-three patients (284 African American and 289 non-Hispanic white) primary care patients who participated in the Hypertension Intervention Nurse Telemedicine Study (HINTS) clinical trial.

INTERVENTIONS

Study arms included: 1) nurse-administered, physician-directed medication management intervention, utilizing a validated clinical decision support system; 2) nurse-administered, behavioral management intervention; 3) combined behavioral management and medication management intervention; and 4) usual care. All interventions were activated based on poorly controlled home BP values.

MAIN MEASURES

Post-hoc analysis of change in systolic and diastolic blood pressure. General linear models (PROC MIXED in SAS, version 9.2) were used to estimate predicted means at 6-month, 12-month, and 18-month time points, by intervention arm and race subgroups (separate models for systolic and diastolic blood pressure).

KEY RESULTS

Improvement in mean systolic blood pressure post-baseline was greater for African American patients in the combined intervention, compared to African American patients in usual care, at 12?months (6.6?mmHg; 95?% CI: -12.5, -0.7; p?=?0.03) and at 18?months (9.7?mmHg; -16.0, -3.4; p?=?0.003). At 18?months, mean diastolic BP was 4.8?mmHg lower (95?% CI: -8.5, -1.0; p?=?0.01) among African American patients in the combined intervention arm, compared to African American patients in usual care. There were no analogous differences for non-Hispanic white patients.

CONCLUSIONS

The combination of home BP monitoring, remote medication management, and telephone tailored behavioral self-management appears to be particularly effective for improving BP among African Americans. The effect was not seen among non-Hispanic white patients.     

Foot education improves knowledge and satisfaction among patients at high risk for diabetic foot ulcer

PURPOSE: The purpose of this study was to evaluate an intensive diabetes foot education program for veterans at high risk for foot ulcer. METHODS: We invited 100 consecutive patients with diabetes from a Department of Veterans Affairs Medical Center clinic who were insensate to the Semmes-Weinstein 5.07 monofilament to participate in a foot care education program. Two sessions were conducted by a nurse diabetes educator 3 months apart. Multiple educational approaches were used to teach patients foot self-examination, foot washing, proper footwear, and encouragement in enlisting proper physician foot care. Knowledge and satisfaction with care was measured before and after each visit. RESULTS: The 34 patients who attended both education sessions improved their foot care knowledge over the course of the program. After the second session, the mean improvement over baseline was 14%. These patients also reported improved satisfaction with foot care; mean improvement was 33%. CONCLUSIONS: An intensive education program improved the foot care knowledge and behavior of high-risk patients. Those who adhered to a foot care education program were more satisfied with their foot care than prior to the program. Ways to improve accessibility of education sessions must be explored.     

Systemic and Hepatic Hemodynamics in Hepatosplenic Manson's Schistosomiasis with and Without Propranolol

Systemic and hepatic hemodynamics wereprospectively studied in 11 patients with Manson'sschistosomiasis and portal hypertension, as well asalterations resulting from the use of propranolol. Itwas decided that patients whose portal pressure was reducedby 30% with the use of the drug would not undergosurgery and that treatment would consist of the chronicuse of propranolol, associated with sclerosis of esophageal varices. This objective was not metby any of the patients whose portal pressure wasmeasured and the study was interrupted. Results showthat patients with Manson's schistosomiasis and portal hypertension have hyperdynamic circulation,mild pulmonary hypertension, greatly increased splenicblood flow, and preservation of total hepatic bloodflow. Administration of propranolol correctshyperdynamic circulation, aggravates pulmonary hypertension,does not alter portal pressure and reduces the sectorialportal blood flows, especially of the azygos vein, withmaintenance of total hepatic blood flow. These data favor the hypothesis of portaloverflow in the physiopathology of portal hypertensionof schistosomiasis.     

The usage and diagnostic yield of the implantable loop-recorder in detection of the mechanism of syncope and in guiding effective antiarrhythmic therapy in older people.

OBJECTIVES: To evaluate the usage and diagnostic yield of the implantable loop-recorder (ILR) in detection of the mechanism of syncope and in guiding therapy in patients aged >/=65 years and comparing them with those <65 years. DESIGN: This was a two-hospital, observational, prospective study in consecutive patients with unexplained syncope who underwent an ILR implantation. Between November 1997 and December 2002, a total of 2052 patients with syncope were evaluated (local population of 590,000 inhabitants). The diagnosis remained unexplained in 371 (18%). Of these, 103 patients (5% of the total, 28% of those with unexplained syncope) received an ILR. RESULTS: There were 70 (76%) patients aged >/=65 years and 25 (24%) <65 years. ILR implantation was 110 and 9 per million inhabitants per year, respectively. During a mean follow-up of 14+/-10 months, syncope was recorded in 52 patients. Compared with younger patients those older had a 2.7 higher syncope recurrence rate (56% vs 32%, P=0.03); arrhythmias were 3.1 times more likely to be responsible for syncope (44% vs 20%, P=0.03). More patients >/=65 years finally received ILR-guided therapy (42% vs 20%, P=0.04). Among the 29 patients (25 of those >/=65 years) who received specific antiarrhythmic therapy, only one (3%), had recurrence of syncope during the subsequent follow-up of 40+/-18 months. CONCLUSIONS: In patients referred for investigation of unexplained syncope, the older subjects are more likely to have an indication for ILR implantation than those younger, ILR has a higher diagnostic value, an arrhythmia is more likely to be detected and successfully treated.     

Shear stress is required for the endocytic uptake of the factor VIII‐von Willebrand factor complex by macrophages

Summary. Background: Low‐density lipoprotein (LDL) receptor family members contribute to the cellular uptake of factor VIII. How von Willebrand factor fits into this endocytic pathway has remained poorly understood. Objectives: It has been suggested that macrophages contribute to the clearance of the factor VIII (FVIII)‐von Willebrand factor (VWF) complex. We now assessed the mechanisms of uptake employing human monocyte‐derived macrophages. Methods: A confocal microscopy study was employed to study the uptake by monocyte‐derived macrophages of a functional green fluorescent FVIII‐GFP derivative in the presence and absence of VWF. Results: The results revealed that FVIII‐GFP is internalized by macrophages. We found that FVIII‐GFP co‐localizes with LDL receptor‐related protein (LRP), and that the LRP antagonist Receptor Associated Protein (RAP) blocks the uptake of FVIII‐GFP. However, FVIII‐GFP was not detected in the macrophages in the presence of VWF, suggesting that the FVIII‐VWF complex is not internalized by these cells at all. Apart from static conditions, we also investigated the effect of shear stress on the uptake of FVIII‐GFP in presence of VWF. Immunofluorescence studies demonstrated that VWF does not block endocytosis of FVIII‐GFP under flow conditions. Moreover, VWF itself was also internalized by the macrophages. Strikingly, in the presence of RAP, endocytosis of FVIII‐GFP and VWF was inhibited. Conclusion: The results show that shear stress is required for macrophages to internalize both constituents of the FVIII‐VWF complex.     

Understanding racial variation in the use of carotid endarterectomy: the role of aversion to surgery.

Previous studies indicate that African-American patients undergo carotid endarterectomy at one fourth the rate of white patients. This study was undertaken to determine if differences in aversion to carotid endarterectomy might account for some of the racial difference in utilization of this procedure. A sample of 185 African-American and white patients was selected from a cohort of patients hospitalized for stroke or transient ischemic attack at four Veterans Affairs medical centers. Of these patients, 115 (62%) were able to be contacted by telephone and 95 (83%) agreed to be interviewed. The interview included assessments of functional status, patient preferences for their current health status, and risk aversion to a hypothetical carotid endarterectomy. Patients from both racial groups were similar in age, marital status, level of education, and comorbid medical illnesses. All respondents were male. Functional status for both groups was high and not statistically different. There were no significant racial differences in patients'' perceptions of their current health state. However, African-American patients expressed more aversion to the hypothetical surgery than whites. The median excess risk of death accepted to avoid surgery was 20% for African Americans versus 2.5% for whites. These results indicate that racial differences in the utilization of carotid endarterectomy may be due in part to differences in patients'' levels of aversion to this surgery.