Impaired performance of female APP/PS1 mice in the Morris water maze is coupled with increased Aß accumulation and microglial activation.

BACKGROUND: Alzheimer's disease (AD) is characterized by progressive neuronal loss and cognitive decline. Epidemiological studies suggest that the risk of AD is higher in women even when data are adjusted for age. OBJECTIVE: We set out to compare changes in 9-month-old male and female mice which overexpress amyloid precursor protein (APP) with presenilin (PS1; APP/PS1 mice) and to evaluate whether any changes were coupled with deficits in spatial learning. METHODS: APP/PS1 mice were assessed for their ability to learn in the Morris water maze and Aß burden assessed by Congo Red and Aß triple ultrasensitive assay. Neuroinflammatory changes were examined in brain tissue along with expression of Aß-generating and Aß-degrading enzymes. RESULTS: A deficit in reversal phase learning in the Morris water maze was observed in female mice and was paralleled by evidence of increased accumulation of Aß, microglial activation and expression of IL-1ß. Accumulation of Aß was coupled with an increase in expression of BACE-1 and a decrease in insulin-degrading enzyme (IDE). CONCLUSION: The results indicate that the observed impairment in spatial memory in female APP/PS1 mice correlated with increased Aß burden and the changes in Aß may have occurred as a result of enhanced BACE-1 and decreased IDE expression.

Porcine bladder extracellular matrix for closure of a large defect in a burn contracture release.

Porcine bladder extracellular matrix (PBEM) is an innovative wound healing alternative to traditional wound closure and reconstruction. By stimulating blood vessel formation and chemotaxis of progenitor cells to the site of injury, it promotes a unique healing environment favouring regeneration of native tissue over scar formation. This is the first clinical report describing the novel use of PBEM scaffold material to close a large defect resulting from a burn contracture release. The benefits of this method are the improved functional and cosmetic result. PBEM-moderated tissue regeneration may serve a valuable role in burn reconstruction.

Metabolic effects of Troglitazone in patients with diet-controlled type 2 diabetes.

BACKGROUND: In order to study the mechanisms of action of Troglitazone (TGZ) in vivo in Type 2 diabetes, its effects were studied on glucose metabolism, lipolysis and very low-density lipoprotein (VLDL) apolipoprotein B100 (apoB) kinetics. MATERIALS AND METHODS: A placebo-controlled, double-blind study was performed in 24 diet-treated patients randomized to receive TGZ 600 mg day(-1), TGZ 200 mg day(-1) or placebo for 8 weeks. Glucose and glycerol turnover were assessed after an overnight fast, and during sequential low-dose insulin infusions (0.01 U kg(-1) h(-1) followed by 0.015 U kg(-1) h(-1)) using 6,6-2H Glucose and 1,2,3-2H Glycerol. Very low-density lipoprotein apoB secretion was measured using l-13C-leucine, monitoring isotopic enrichment by gas chromatography-mass spectrometry. Treatment effects were analyzed by analysis of covariance, adjusting for baseline. RESULTS: Therapy resulted in a significant group differences in fasting plasma glucose adjusting for baseline (P=0.039). This was most evident at TGZ 600 mg daily [glucose decrease from (mean +/- SD) 9.2 +/- 2.7 to 6.6 +/- 0.9 mmol L(-1)]. HbA1c and insulin levels did not change significantly. Plasma nonesterified fatty acid (NEFA) levels decreased (P=0.045), most evidently at TGZ 200 mg daily, but glycerol was not significantly affected. Although no significant effects were observed on VLDL apoB or triglyceride concentrations, there were treatment differences in the absolute secretion rate of VLDL apoB of borderline (P=0.056) statistical significance, with a decrease observed at TGZ 600 mg daily [geometric mean, SD range, 0.94 (0.41-2.15) to 0.40 (0.14-1.13 mg kg(-1) h(-1))]. Very low-density lipoprotein apoB fractional secretion rate and pool size were unaffected. The VLDL triglyceride: apoB molar ratio differed between treatment groups (P=0.013), being higher in the TGZ 600 mg group [5714 (4128-7741) to 8092 (5669-11552)]. Neither glucose nor glycerol rates of appearance were significantly altered by TGZ and nor did TGZ affect their suppression by insulin. DISCUSSION: The PPARgamma agonist, troglitazone, decreases fasting glucose and NEFA levels in diet-treated Type 2 diabetes. It may also decrease VLDL particle secretion. These effects would be considered beneficial. The biological importance of the increase in VLDL-triglyceride enrichment warrants further study.

Hypogastric artery embolization in endovascular abdominal aortic aneurysm repair.

PURPOSE: Iliac artery anatomy is a central factor in endoluminal abdominal aortic aneurysm therapy. It serves as the conduit for graft deployment and as the region of distal graft seal. Thirty-eight percent of iliac vessels in our patients require special treatment because of aneurysms, tortuosity, or small size. Bilateral hypogastric artery exclusion has been avoided because of concerns of colorectal ischemia, hip/buttock claudication, and impotence. We suggest that elective, staged, bilateral hypogastric embolization can be performed safely with reasonably low morbidity and can expand the anatomic boundaries for stent-graft abdominal aortic aneurysm repair. METHODS: This study was performed as a retrospective chart review of patients requiring hypogastric artery embolization for endovascular repair of abdominal aortic aneurysms between June 1998 and June 2000. Patients with otherwise appropriate anatomy and common iliac artery aneurysms were informed of the option for stent-graft repair with internal iliac artery embolization with its risks of impotence, hip/buttock claudication, and bowel ischemia. Patients underwent unilateral or staged bilateral coil embolizations of their proximal hypogastric arteries with an approximate 1-week interval between procedures. Hospital and office records were reviewed; phone interviews were performed. Follow-up ranged from 1 to 12 months. RESULTS: During a 24-month period, 65 patients underwent endovascular abdominal aortic aneurysm repair; 18 patients (28%) required hypogastric artery embolization. Seven (39%) of these patients underwent bilateral embolization. There were no episodes of clinically evident bowel ischemia. Lactate levels were normal in all measured patients. Postoperative fevers (> 101.0 degrees F) were documented in 10 (56%) of 18 patients. The average white blood cell count was 12.8 x 10(9)/L (range, 8.5-22.9). There were no positive blood culture results. The return to the full preoperative diet occurred in 1 to 3 days. Hip/buttock claudication occurred in approximately 50% of patients with persistent but improved symptoms at 6 months. Eighty-seven percent of patients had preoperative erectile dysfunction. Only two patients noted worsening of erectile function postoperatively. CONCLUSIONS: Preliminary results indicate that bilateral hypogastric artery embolization can be performed, when necessary, with reasonable morbidity in patients undergoing stent-graft abdominal aortic aneurysm repair.

Effects of growth hormone treatment on very-low density lipoprotein apolipoprotein B100 turnover in adult hypopituitarism.

Adult hypopituitarism is associated with hyperlipidemia, mainly due to an increase of very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) levels. Recent studies have shown that such patients exhibit increased hepatic secretion of VLDL apolipoprotein B100 (VLDL apo B100). To examine the effects of growth hormone (GH) replacement on VLDL apo B100 turnover, 13 GH-deficient hypopituitary patients (8 women and 5 men; aged 47 +/- 3 years, mean +/- SEM; body mass index [BMI], 30 +/- 2 kg/m2) entered a double-blind placebo-controlled study for 6 months (GH 0.125 IU/kg/wk for 4 weeks, and then 0.25 IU/kg/wk). GH was subsequently used in all patients for a further 6 months. A 6-hour [1-13C] leucine infusion was administered at baseline and at 6 months. The secretion rate of VLDL apo B100 was derived by kinetic analysis following quantitation of isotopic enrichment by gas chromatography/mass spectrometry. The GH-treated group (6 patients) demonstrated a similar fractional secretion rate (FSR) for VLDL apo B100 at 0 and 6 months. The pool size and absolute secretion rate (ASR) also were unaffected significantly by GH therapy. No significant changes were observed in the placebo group (7 patients). Treatment with GH for 6 months caused an increase in the high-density lipoprotein (HDL) cholesterol concentration (13 patients, 1.27 +/- 0.13 v 1.16 +/- 0.10 mmol/L, respectively, P = .05), whereas total cholesterol and triglyceride concentrations did not change. Nonesterified fatty acids (NEFAs) increased during GH therapy (471 +/- 43 micromol/L at 6 months v 349 +/- 49 micromol/L at baseline, P < .0005). The data suggest that GH does not affect VLDL apo B100 turnover in a significant way.

Two tails of the normal curve. Similarities and differences in the study of mental retardation and giftedness.

Professionals in the fields of mental retardation and giftedness have much to teach each other as well as the field of human development in general. Examining the commonalities and differences between the fields in social issues, definitions, developmental differences from the norm, values and policy issues, and educational and long-term implications deepens insights about both normal and deviant development. The authors stress the importance of individual differences in the differential design of educational strategies and the application of approaches developed with specialized populations to normally developing children. Current social inequalities affect both of these fields in particular ways. Finally, numerous research agendas can be enhanced by including representatives of both ends of the normal curve.

Very-low-density lipoprotein apolipoprotein B100 kinetics in adult hypopituitarism.

Hypopituitarism is associated with hyperlipidemia, the mechanisms of which are not fully known. One possible mechanism is an increased hepatic secretion of very-low-density lipoprotein (VLDL) apolipoprotein B100 (apo B100). To investigate this, 13 hypopituitary patients (seven women and six men; age, 46 +/- 3 years [mean +/- SEM]; body mass index [BMI], 29 +/- 2 kg/m2) and 13 matched controls (seven women and six men; age, 43 +/- 3 years; BMI, 28 +/- 2 kg/m2) were investigated in a stable-isotope study. [1-(13)C]leucine (1 mg/kg body weight) was administered, followed by a continuous 6-hour infusion of [1-(13)C]leucine (at a rate of 1 mg/kg/h). Patients had a similar fractional secretion rate (FSR) of VLDL apo B100 versus controls (0.37 +/- 0.05 v 0.38 +/- 0.06 pools/h, respectively), but they had a significantly larger pool size (3.4 +/- 0.3 v 1.9 +/- 0.3 mg/kg) and higher absolute secretion rate ([ASR] 27.8 +/- 2.9 v 16.0 +/- 2.5 mg/kg/d). The increase in hepatic VLDL production may explain the lipid abnormalities found in hypopituitarism. Fasting circulating nonesterified fatty acids (NEFAs) were decreased in the patients (284 +/- 26 v 664 +/- 92 micromol/L, P < .001) despite the increase in VLDL secretion. An inverse relationship was observed between the NEFA level and VLDL apo B100 FSR in the patients (r(s) = -.85, P < .005).

Prognostic importance of scintigraphic left ventricular cavity dilation during intravenous dipyridamole technetium-99m sestamibi myocardial tomographic imaging in predicting coronary events.

Left ventricular (LV) cavity dilation during stress myocardial perfusion imaging has been associated with multivessel disease, and may be an independent prognostic marker in addition to perfusion defects. The present study examines the predictive value for future cardiac events of transient or fixed LV dilation during dipyridamole technetium-99m (Tc-99m) sestamibi single-photon emission computed tomography (SPECT) imaging. The study included 512 consecutive patients who underwent SPECT imaging with Tc-99m sestamibi after dipyridamole infusion. Transient LV dilation was seen in 70 patients (14%) and 74 had fixed cavity dilation (14%); cavity size was normal in 368 patients (72%). Each perfusion scan was classified as normal or abnormal, and if abnormal, defects were categorized as transient or fixed, and as small, medium, or large (depending upon the number of abnormal vascular territories). Events during a mean follow-up of 12.8 +/- 6.8 months were tabulated by direct review of hospital charts and death certificates. The cardiac event rate (cardiac death or nonfatal infarction) was 1.9% in patients with normal cavity size, 11.4% with transient LV dilation, and 13.5% with fixed LV dilation (p < 0.01). Compared with patients with normal cavity size, those with transient LV dilation were more likely to sustain a myocardial infarction (p < 0.01) and those with fixed dilation more frequently suffered cardiac death (p < 0.01) and hospitalization for heart failure (p < 0.01). The group with the highest risk had both a large perfusion defect and cavity dilation. By Cox proportional hazard regression analysis, both transient and fixed LV dilation were strong independent predictors of cardiac events. Transient or fixed LV dilation are commonly seen during dipyridamole Tc-99m sestamibi SPECT imaging (14% incidence for each) and are useful predictors of cardiac events.

Arteriographic embolization of visceral artery pseudoaneurysms.

The purpose of this study was to determine the safety and efficacy of transcatheter embolization in the management of bleeding visceral artery pseudoaneurysms. Eight patients (four women and four men) whose mean age was 61.0 years (range 44 to 77 years) underwent emergency transcatheter embolization for acute hemorrhage from a visceral artery pseudoaneurysm. Arteriographic technique was used to localize and selectively embolize these seven visceral artery pseudoaneurysms (three inferior pancreaticoduodenal, one gastroduodenal, two hepatic, and one splenic) by means of intravascular steel coils. Arteriography demonstrated visceral artery pseudoaneurysms in all eight patients. Acute hemorrhage was documented by endoscopy, falling hematocrit levels, CT scans, and arteriography. Successful embolization of these visceral artery pseudoaneurysms was achieved in seven (88%) of eight patients. In one patient embolization was not attempted because of a worsening clinical status, and this patient subsequently underwent emergency surgical resection. There was no significant morbidity associated with the procedures and seven patients remain asymptomatic with no further bleeding at a mean follow-up of 21.1 months (range 11 to 46 months). Arteriographic embolization of visceral artery pseudoaneurysms is a safe and highly successful technique for the effective identification and treatment of hemorrhage even in critically ill patients.

Does the presence of the 3500 mutant apolipoprotein B-100 in low density lipoprotein particles affect their atherogenicity?

Apolipoprotein B-100 (apo B-100) is the protein component of low density lipoprotein (LDL) responsible for its binding and clearance by LDL receptors (LDL-R). In familial defective apo B-100 (FDB), a mutation in apo B-100 at residue 3500 markedly reduces its affinity for LDL-R, often causing accumulation of defective LDL particles, and an increased proneness to coronary artery disease (CAD). In FDB heterozygotes, about 70% of the LDL particles are mutant, which may alter their atherogenicity relative to LDL containing normal apo B. Therefore, we compared CAD in heterozygous FDB with CAD in heterozygous familial hypercholesterolemia (FH), since raised LDL is usually present from birth in both conditions, and in FH the LDL particles that accumulate have normal apo B, as the inherited defect involves the LDL-R. The clinical presentation of coronary atherosclerosis and its angiographic appearance were examined in FDB and FH patients matched for conventional cardiac risk factors (hypertension, smoking, sex) and serum lipid levels. There was no significant difference between the FDB and FH patients (n=11 pairs) in the type of cardiac symptoms or their ages of onset (50 +/- 9 vs. 45 +/- 11 years). Coronary angiographic appearance was also similar in both groups (n=9 pairs). These observations suggest that LDL particles with the 3500 mutation in apo B have the same atherogenicity as LDL particles with normal apo B.

The affinity of low-density lipoproteins and of very-low-density lipoprotein remnants for the low-density lipoprotein receptor in homozygous familial defective apolipoprotein B-100.

We have identified two familial defective apo B-100 (FDB) homozygotes by DNA sequencing and have measured affinity of low-density lipoproteins (LDL) and very-low-density lipoprotein (VLDL) remnants for the LDL receptor in vitro. The patients were a 66-year-old man with coronary heart disease (plasma cholesterol level, 9.5 mmol/l before treatment) and his 69-year-old sister, without signs of cardiovascular disease (plasma cholesterol, 12.0 mmol/l before treatment). In both patients, treatment with statins caused a marked fall in plasma cholesterol level. Binding affinity of LDL from the two patients was 10%-20% of normal at 4 degrees C and 37 degrees C. Binding affinity of VLDL remnants was normal. We conclude that (1) residual affinity of LDL in homozygous FDB is high enough to permit significant catabolism via the LDL-receptor pathway, and (2) normal affinity of VLDL remnants permits normal hepatic clearance of precursors of LDL and increased clearance of LDL precursors when receptor activity is stimulated by statins. Residual affinity of LDL and normal affinity of remnants could explain why expression of the FDB mutation is generally milder than that of LDL receptor mutations causing familial hypercholesterolaemia.

Intra-arterial thrombolytic therapy in the initial management of thrombosed popliteal artery aneurysms.

Case reports of three patients presenting with acute limb-threatening lower extremity ischemia as a result of thrombosed popliteal artery aneurysms are described. Intra-arterial urokinase was administered to each patient prior to definitive surgery. This improved the infrapopliteal runoff in each case, allowing for successful arterial reconstruction without limb loss.

Indicators of developmental and functional status of Mexican-American and Puerto Rican children.

The overall purpose of this study was to describe the developmental and functional status of young Latino children. We analyzed data from the Hispanic Health and Nutrition Examination Survey and estimated the percentages of young Mexican-American and mainland Puerto Rican children with indicators of developmental need for special services, i.e., low birth weight, use of neonatal intensive care, congenital problems, chronic conditions of developmental concern, functional limitations, and physician diagnoses of medical conditions. Estimates suggest that Puerto Rican children had substantially poorer status than Mexican-American children who, in turn, have indicators that are comparable with those reported for the general population. The difference in status between the two Latino groups merits further investigation.

Mobile cardiac catheterization registry: report of the first 1,001 patients.

The purpose of this study was to evaluate prospectively the efficacy and safety of mobile cardiac catheterization. Mobile cardiac catheterization was introduced into clinical practice in 1989, but there has been no systematic study of its performance and safety. A registry was established in 1989 to monitor outcomes with mobile cardiac catheterization and is reported here. Patients were screened for eligibility for mobile cardiac catheterization using the joint AHA/ACC criteria for outpatient angiography. Eligible patients underwent mobile catheterization at eight hospitals within 120 miles of the base tertiary center. Helicopter evacuation services were available at each mobile site. The indications, findings, dispositions, and complications of mobile cardiac catheterization were recorded by means of a checklist, telephone follow-up and chart review. A total of 1,001 consecutive patients were entered into the registry in the first 20 months of operation, including 436 females and 565 males aged 22 to 84 years. Angina (Canadian Classes II-IV) was the most frequent primary indication for catheterization (46.4%), followed by atypical chest pain (36.9%), or a positive exercise stress test (25.6%). Infrequent indications for catheterization included a history of myocardial infarction (5.6%), congestive heart failure (7.1%), arrhythmias (4.1%), and valvular heart disease (0.7%). Catheterization was accomplished in 99.9% of patients. Angiographically normal studies were observed in 22.8%, and mild (< or = 50%) coronary artery disease in 13.6% of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Mobile cardiac catheterization: comparison with outpatient and inpatient catheterization at tertiary facilities.

The study group included 1,553 consecutive patients from areas serviced by our mobile catheterization laboratories: 719 procedures were performed in the mobile unit at their local hospitals, 277 were performed at a tertiary hospital with less than a 24 hr hospital stay, and 557 were performed at a tertiary hospital as inpatients. The indications for mobile catheterization were predominantly atypical chest pain, angina pectoris, or positive treadmill stress test, whereas patients with less than 24 hr hospitalization at the tertiary center had their catheterization performed for additional reasons. The majority of the inpatient indications were for recent myocardial infarction or unstable angina. Using the American College of Cardiology/American Heart Association (ACC/AHA) criteria for outpatient catheterization, the mobile catheterizations were performed safely with a complication rate of only 0.7% compared to a complication rate of 3.1% for inpatients demonstrating that a low risk group of patients can be prospectively identified and catheterized safely in the mobile setting. An extremely high risk group of patients with ongoing unstable angina and recent myocardial infarction was also identified which should undergo catheterization only at a tertiary center.

Intravascular extraction of chronic pacemaker leads: efficacy and follow-up.

Extraction of chronic pacemaker leads has been recommended for infections, prevention of venous thrombosis, migration, and possible perforation. Success with constant traction techniques has been variable, and the cost and morbidity of open chest surgical procedures are prohibitive. Efficacy of a new system for lead extraction using intravascular techniques was analyzed. The system (Cook Pacemaker) uses a locking stylet, which is secured at the distal electrode by counterclockwise rotation to reinforce the lead and facilitate traction, and dilator sheaths that are used to free the lead from adhesions in the venous system. In a series of 56 patients (ages 19-88) who presented for lead extraction because of erosion (5), infection (14), lead replacement (35), or other (2), 86 leads were extracted. Thirty-two were atrial leads and 54 ventricular; 23 had active fixation and 63 passive. Average duration of implant was 58 +/- 42 months (range 1-264). Eighty-four leads were totally removed and two partially removed. For these two leads, the distal tip was not removed; in both cases the locking stylet was not secured at the distal electrode due to obstruction within the lead. Two patients developed arm edema following the procedure, which resolved with elevation. One patient developed a subclavian thrombosis, which resolved with warfarin anticoagulation. Four patients have expired due to unrelated causes. In conclusion, this intravascular approach for extraction of chronic leads is effective, and the procedure is safe when performed by experienced personnel.

The binding of very low density lipoprotein remnants to the low density lipoprotein receptor in familial defective apolipoprotein B-100.

We have compared the affinity for low density lipoprotein (LDL) receptors of LDL and very low density lipoprotein (VLDL) remnants from patients with familial defective apo B-100 (FDB) with that of LDL and VLDL remnants from normal subjects. The binding affinity of FDB LDL was markedly reduced in all 14 FDB patients examined, hut the affinity of FDB remnants did not differ significantly from that of remnants prepared from normal subjects. Since the mutant form of apo B-100 present in FDB is recognized by LDL receptors with greatly reduced efficiency, we suggest that apo B plays only a minor role in the receptor-mediated uptake of VLDL remnants by the liver in man. These results are consistent with our previous suggestion that the ability of drugs that stimulate hepatic receptor activity to lower the plasma LDL level in FDB is due in part to increased hepatic uptake of lipoprotein precursors of LDL, including remnant particles with normal apo B-100 and those with mutant apo B-100.

Variable expression of the mutation in familial defective apolipoprotein B-100.

Although most subjects with familial defective apolipoprotein B-100 (FDB) have raised plasma low-density lipoprotein (LDL) levels, a few have LDL levels within the normal range. We have previously identified two normocholesterolemic FDB heterozygotes in an affected family. Results obtained from a study of this family are compatible with a major genetic contribution to the normocholesterolemia in the two heterozygotes. However, our findings are not compatible with inheritance of a variant normal allele at the apolipoprotein B locus in this family that neutralizes the effect of an FDB allele on the plasma LDL level. Polymorphic variations at the apolipoprotein E and LDL receptor loci did not explain the presence of normal LDL levels in the two heterozygous FDB subjects.