Citations

Background and Purpose— Risk for both intracranial aneurysms (IAs) and aortic aneurysms (AAs) is thought to be heritable with mounting evidence for genetic predisposition. The concept of shared risk for these conditions is challenged by differences in age of diagnosis and demographic characteristics. We performed a genomewide linkage analysis in multiplex families with both IA and AA from the Familial Intracranial Aneurysm study. Methods— Available medical records of subjects who reported IA or abdominal/thoracic AA were reviewed with adjudication as definite/probable, possible, or not a case. To identify genes contributing to the susceptibility for IA and AA, genomewide linkage analysis was performed in the 26 multiplex IA families who had members who also had thoracic or abdominal AA. Individuals (n=91) were defined as affected if they had an IA (definite/probable) or an aortic or thoracic AA (definite/probable). Results— Maximum logarithm of odds (LOD) scores were found on chromosomes 11 (144 cM; LOD=3.0) and 6 (33 cM; LOD=2.3). In both chromosomal regions, analyses of these same 26 families considering only IA as the disease phenotype produced LOD scores of 1.8 and 1.6, respectively. Conclusions— Our linkage analysis in these 26 families using the broadest disease phenotype, including IA, abdominal AA, and thoracic AA, supports the concept of shared genetic risk. The chromosome 11 locus appears to confirm earlier independent associations in IA and AA. The chromosome 6 finding is novel. Both warrant further investigation.

AbstractThe survival of patients with Waldenstrom macroglobulinemia (WM) varies enormously. The development of prognostic models in WM has been fraught by limited follow-up in current studies. Here, we update the outcome of a prospective WM trial with a median follow-up of 10 years for live patients. Of the 59 previously untreated patients who initially were observed, only 12 patients (21%) required therapy at a median follow-up of 100 months. Multivariate analysis among the 183 patients requiring therapy reaffirmed age 70 years or greater, previous nonprotocol therapy, and β-2 microglobulin (B2M) of 3 mg/dL or greater as prognostic factors. Importantly, increased serum lactate dehydrogenase (LDH) was identified as an additional independent variable, which improved risk assessment beyond the recent WM international prognostic scoring system (ISSWM). By using age, previous therapy, B2M, and LDH, we identified 3 risk groups with 8-year survival estimates of 55%, 33%, and 5% (P < .001). These data provide novel insights into factors predicting long-term outcome in WM. This trial has been registered with www.cancer.gov under ID 4852904.

SummaryBoth genetic and environmental factors contribute to autoimmune disease development. Previously, we evaluated genetic factors in a humanized mouse model of Hashimoto's thyroiditis (HT) by immunizing human leucocyte antigen DR3 (HLA-DR3) and HLA-DQ8 transgenic class II-knock-out non-obese diabetic (NOD) mice. DR3+ mice were susceptible to experimental autoimmune thyroiditis (EAT) induction by both mouse thyroglobulin (mTg) and human (h) Tg, while DQ8+ mice were weakly susceptible only to hTg. As one environmental factor associated with HT and tested in non-transgenic models is increased sodium iodide (NaI) intake, we examined the susceptibility of DR3+ and/or DQ8+ mice to NaI-induced disease. Mice were treated for 8 weeks with NaI in the drinking water. At 0·05% NaI, 23% of DR3+, 0% of DQ8+ and 20% of DR3+DQ8+ mice had thyroid destruction. No spleen cell proliferation to mTg was observed. Most mice had undetectable anti-mTg antibodies, but those with low antibody levels usually had thyroiditis. At 0·3% NaI, a higher percentage of DR3+ and DR3+DQ8+ mice developed destructive thyroiditis, but it was not statistically significant. However, when DR3+ mice had been depleted of CD4+CD25+ regulatory T cells prior to NaI treatment, destructive thyroiditis (68%) and serum anti-mTg antibodies were exacerbated further. The presence of DQ8 molecules does not alter the susceptibility of DR3+DQ8+ mice to NaI-induced thyroiditis, similar to earlier findings with mTg-induced EAT. Susceptibility of DR3+ mice to NaI-induced EAT, in both the presence and absence of regulatory T cells, demonstrates the usefulness of HLA class II transgenic mice in evaluating the roles of environmental factors and immune dysregulation in autoimmune thyroid disease.

Background— We previously reported the feasibility of an acute, orally delivered, newly developed, conjugated form of human B-type natriuretic peptide (hBNP) in normal animals. The objective of the present study was to extend our findings and to define the chronic actions of an advanced oral conjugated hBNP (hBNP-054) administered for 6 days on sodium excretion and blood pressure. We also sought to establish the ability of this new conjugate to acutely activate cGMP and to reduce blood pressure in an experimental model of angiotensin II (ANG II) –mediated hypertension. Methods and Results— First, we developed additional novel conjugated forms of oral hBNP that were superior to our previously reported hBNP-021 in reducing blood pressure in 6 normal dogs. We then tested the new conjugate, hBNP-054, chronically in 2 normal dogs to assess its biological actions as a blood pressure–lowering agent and as a natriuretic factor. Second, we investigated the effects of acute oral hBNP-054 or vehicle in 6 dogs that received continuous infusion of ANG II to induce hypertension. After baseline determination of mean blood pressure (MAP) and blood collection for plasma hBNP and cGMP, all dogs received continuous ANG II infusion (20 ng · kg −1 · min −1 , 1 mL/min) for 4 hours. After 30 minutes of ANG II, dogs received oral hBNP-054 (400 μg/kg) or vehicle in a random crossover fashion with a 1-week interval between dosing. Blood sampling and MAP measurements were repeated 30 minutes after ANG II administration and 10, 30, 60, 120, 180, and 240 minutes after oral administration of hBNP-054 or vehicle. In the chronic study in normal dogs, oral hBNP-054 effectively reduced MAP for 6 days and induced a significant increase in 24-hour sodium excretion. hBNP was not present in the plasma at baseline in any dogs, and it was not detected at any time in the vehicle group. However, hBNP was detected throughout the duration of the study after oral hBNP-054, with a peak concentration at 30 minutes of 1060±818 pg/mL. In the acute study, after ANG II administration, plasma cGMP was not activated after vehicle, whereas it was significantly increased after oral hBNP-054 ( P =0.01 between the 2 groups). Importantly, MAP was significantly increased after ANG II throughout the acute study protocol. However, although no changes occurred in MAP after vehicle administration, oral hBNP-054 reduced MAP for >2 hours (from 138±1 mm Hg after ANG II to 124±2 mm Hg at 30 minutes, 124±2 mm Hg at 1 hour, and 130±5 mm Hg at 2 hours after oral hBNP-054; P <0.001). Conclusions— This study reports for the first time that a novel conjugated oral hBNP possesses blood pressure–lowering and natriuretic actions over a 6-day period in normal dogs. Furthermore, hBNP-054 activates cGMP and reduces MAP in a model of acute hypertension. These findings advance the concept that orally administered chronic BNP is a potential therapeutic strategy for cardiovascular diseases such as hypertension.

OBJECTIVE. The goal of this study was to evaluate the effect of antibiotic administration before lumbar puncture on cerebrospinal fluid profiles in children with bacterial meningitis. METHODS. We reviewed the medical records of all children (1 month to 18 years of age) with bacterial meningitis who presented to 20 pediatric emergency departments between 2001 and 2004. Bacterial meningitis was defined by positive cerebrospinal fluid culture results for a bacterial pathogen or cerebrospinal fluid pleocytosis with positive blood culture and/or cerebrospinal fluid latex agglutination results. Probable bacterial meningitis was defined as positive cerebrospinal fluid Gram stain results with negative results of bacterial cultures of blood and cerebrospinal fluid. Antibiotic pretreatment was defined as any antibiotic administered within 72 hours before the lumbar puncture. RESULTS. We identified 231 patients with bacterial meningitis and another 14 with probable bacterial meningitis. Of those 245 patients, 85 (35%) had received antibiotic pretreatment. After adjustment for patient age, duration and severity of illness at presentation, and bacterial pathogen, longer duration of antibiotic pretreatment was not significantly associated with cerebrospinal fluid white blood cell count, cerebrospinal fluid absolute neutrophil count. However, antibiotic pretreatment was significantly associated with higher cerebrospinal fluid glucose and lower cerebrospinal fluid protein levels. Although these effects became apparent earlier, patients with ≥12 hours of pretreatment, compared with patients who either were not pretreated or were pretreated for &lt;12 hours, had significantly higher median cerebrospinal fluid glucose levels (48 mg/dL vs 29 mg/dL) and lower median cerebrospinal fluid protein levels (121 vs 178 mg/dL). CONCLUSIONS. In patients with bacterial meningitis, antibiotic pretreatment is associated with higher cerebrospinal fluid glucose levels and lower cerebrospinal fluid protein levels, although pretreatment does not modify cerebrospinal fluid white blood cell count or absolute neutrophil count results.

Background Observational studies and small clinical trials suggested that hormone replacement therapy (HRT) decreases risk of cognitive loss and Alzheimer's disease (AD) in postmenopausal women and may have value in primary prevention. Purpose A clinical trial was designed to determine if HRT delays AD or memory loss. This report describes the rationale and original design of the trial and details extensive modifications that were required to respond to unanticipated findings that emerged from other studies during the course of the trial. Methods The trial was designed as a multi-center, placebo-controlled primary prevention trial for women 65 years of age or older with a family history of dementia. Recruitment from local sites was supplemented by centralized efforts to use names of Medicare beneficiaries. Inclusion criteria included good general health and intact memory functioning. Participants were randomized to HRT or placebo in a 1:1 ratio. Assignment was stratified by hysterectomy status and site. The primary outcomes were incident AD and memory decline on neuropsychological testing. Results Enrollment began in March 1998. In response to the Women's Health Initiative (WHI) May 2002 report of increased incidence of heart disease, stroke, pulmonary embolism, and breast cancer among women randomized to HRT, participants were re-consented with a revised consent form. Procedural modifications, including discontinuation of study medication and a modification of the planned primary outcome based on a final enrollment below the target enrollment (N = 477), were enacted in response to the subsequent WHI Memory Study report of increased risk of dementia and poorer cognitive function with HRT. The mean length of treatment exposure prior to discontinuation was 2.14 years. Participants' mean age at baseline was 72.8; mean education was 14.2 years. Minority participation was 19% and 34% had a hysterectomy. The study continues to follow these participants for a total of 5 years blind to the original medication assignment. Limitations Results reported from the WHI during the course of this study mandated extensive procedural modifications, including discontinuing recruitment before completion and halting study medication. Alternative strategies for study redesign that were considered are discussed. Clinical Trials 2008; 5: 523—533. http://ctj.sagepub.com

Background— Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease characterized by a diverse clinical and phenotypic spectrum. This study reports the prevalence, morphology, clinical course, and management of an underrecognized subgroup of HCM patients with left ventricular apical aneurysms. Methods and Results— Of 1299 HCM patients, 28 (2%) were identified with left ventricular apical aneurysms, including a pair of identical twins. Aneurysms were recognized at a wide age range (26 to 83 years), including 12 patients (43%) who were ≤50 years of age. Apical aneurysms varied considerably in size (maximum dimension, 10 to 66 mm), were dyskinetic/akinetic with thin rims, and were associated with transmural (and often more extensive) myocardial scarring identified by late gadolinium enhancement cardiovascular magnetic resonance. Apical aneurysms were recognized by echocardiography in only 16 of 28 patients (57%) but by cardiovascular magnetic resonance in the 12 patients undetected by echocardiography. Left ventricular chamber morphology varied; however, 19 patients (68%) showed an “hourglass” contour, with midventricular hypertrophy producing muscular narrowing and intracavitary gradients in 9 patients (74±42 mm Hg). Sarcomeric protein missense mutations known to cause other phenotypic expressions of HCM were present in 3 patients. Over 4.1±3.7 years of follow-up, 12 patients (43%) with left ventricular apical aneurysms experienced adverse disease complications (event rate, 10.5%/y), including sudden death, appropriate implantable cardioverter-defibrillator discharges, nonfatal thromboembolic stroke, and progressive heart failure and death. Conclusions— Patients with left ventricular apical aneurysms represent an underappreciated subset in the heterogeneous HCM disease spectrum with important clinical implications, often requiring a high index of suspicion and cardiovascular magnetic resonance for identification. Apical aneurysms in HCM are associated with substantial cardiovascular morbidity and mortality and raise novel treatment considerations.