Dimerization leads to changes in APP (amyloid precursor protein) trafficking mediated by LRP1 and SorLA.

Proteolytic cleavage of the amyloid precursor protein (APP) by α-, ß- and γ-secretases is a determining factor in Alzheimer's disease (AD). Imbalances in the activity of all three enzymes can result in alterations towards pathogenic Aß production. Proteolysis of APP is strongly linked to its subcellular localization as the secretases involved are distributed in different cellular compartments. APP has been shown to dimerize in cis-orientation, affecting Aß production. This might be explained by different substrate properties defined by the APP oligomerization state or alternatively by altered APP monomer/dimer localization. We investigated the latter hypothesis using two different APP dimerization systems in HeLa cells. Dimerization caused a decreased localization of APP to the Golgi and at the plasma membrane, whereas the levels in the ER and in endosomes were increased. Furthermore, we observed via live cell imaging and biochemical analyses that APP dimerization affects its interaction with LRP1 and SorLA, suggesting that APP dimerization modulates its interplay with sorting molecules and in turn its localization and processing. Thus, pharmacological approaches targeting APP oligomerization properties might open novel strategies for treatment of AD.

Negative impact of cardiac evaluation before vascular surgery.

The optimal preoperative evaluation of cardiac risk in patients with peripheral vascular disease is controversial. In developing a paradigm for preoperative cardiac workup, potential adverse effects of evaluation and cardiac intervention must be considered. This study analyzed the deleterious outcomes of extensive, comprehensive cardiac evaluation and intervention before planned vascular surgery in patients treated at the Denver Department of Veterans Affairs Medical Center. Over a 12-month period between 1994 and 1995, 161 patients were scheduled to undergo major vascular operations; 153 patients came to operation. The decision to pursue a cardiac evaluation was variously made by a combination of surgeons, cardiologists, and anesthesiologists. No defined protocol was followed. Cardiac history, chest X-rays and ECGs were obtained for all patients. Extended cardiac evaluation included these studies plus special tests, including echocardiography (echo), radionuclide ventriculography (RNVG), dipyridamole thallium scintigraphy (DTS), and cardiac catheterization (CC). Extended cardiac evaluations were undertaken in 42 patients. Complications related to percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass grafting (CABG) were also recorded. Cardiac mortality and morbidity after vascular interventions were itemized in all 153 patients. Forty-two male patients, aged 68 +/- 9 years, underwent extended cardiac evaluations before planned vascular operations. The median elapsed time for cardiac workup was 14 days (mean 30 +/- 59 days). The median and mean times from cardiac workup to vascular surgery were 25 days and 76 +/- 142 days, respectively. Eighteen (43%) patients had echo or RNVG; 22 (52%) patients had DTS; 27 (64%) had CC; 9 (21%) had PTCA; 7 (17%) had CABG. Sixteen (38%) patients had untoward events related to cardiac evaluation. Eight patients (19%: one with cerebrovascular disease, and seven with aortic aneurysms) refused vascular surgery after extended cardiac workup. Complications attributable to CC, PTCA, and CABG included prosthetic graft infection, pseudoaneurysms (two), sternal wound infections (two), renal failure and brain anoxia. Two patients with severe limb ischemia who were candidates for revascularization ultimately required amputations because of delay due to cardiac evaluations. Extensive cardiac evaluation prior to vascular operations can result in morbidity, delays, and refusal to undergo vascular surgery. The underlying indication for vascular operations and the local iatrogenic cardiac complication rates must be considered before ordering special studies.

Evaluation of Helicobacter pylori in gastric MALT-type lymphoma: differences between histologic and serologic diagnosis.

Helicobacter pylori provides the pathogenic background for the development of gastric MALT-type lymphoma. The assessment of H. pylori is limited by the accuracy of the detection method used. Especially in patients with low-grade MALT-type lymphoma, the H. pylori status is the crucial question for therapeutic management. In this study, 60 patients with gastric MALT-type lymphoma. (lowgrade, 22; high-grade, 38) were investigated for the presence of H. pylori by histologic and serologic means. In 98% of the patients with MALT-type lymphoma, H. pylori-specific IgG serum antibodies were detected. In contrast, on histologic examination, H. pylori was found only in 78% of the patients (low-grade, 77%; high-grade, 79%). In this study, a discrepancy between serologic and histologic evaluation of the H. pylori status in gastric MALT-type lymphoma was found. Therefore, a H. pylori eradication therapy in low-grade MALT-type lymphoma, which often leads to a complete tumor regression, should not be excluded as a first line therapy because of a negative H. pylori status on histologic examination.

Important role of carotid afferents in control of breathing.

The purpose of the present study was to determine the effect on breathing in the awake state of carotid body denervation (CBD) over 1-2 wk after denervation. Studies were completed on adult goats repeatedly before and 1) for 15 days after bilateral CBD (n = 8), 2) for 7 days after unilateral CBD (n = 5), and 3) for 15 days after sham CBD (n = 3). Absence of ventilatory stimulation when NaCN was injected directly into a common carotid artery confirmed CBD. There was a significant (P < 0.01) hypoventilation during the breathing of room air after unilateral and bilateral CBD. The maximum PaCO2 increase (8 Torr for unilateral and 11 Torr for bilateral) occurred approximately 4 days after CBD. This maximum was transient because by 7 (unilateral) to 15 (bilateral) days after CBD, PaCO2 was only 3-4 Torr above control. CO2 sensitivity was attenuated from control by 60% on day 4 after bilateral CBD and by 35% on day 4 after unilateral CBD. This attenuation was transient, because CO2 sensitivity returned to control temporally similar to the return of PaCO2 during the breathing of room air. During mild and moderate treadmill exercise 1-8 days after bilateral CBD, PaCO2 was unchanged from its elevated level at rest, but, 10-15 days after CBD, PaCO2 decreased slightly from rest during exercise. These data indicate that 1) carotid afferents are an important determinant of rest and exercise breathing and ventilatory CO2 sensitivity, and 2) apparent plasticity within the ventilatory control system eventually provides compensation for chronic loss of these afferents.

[Diagnostic value of stomach biopsy in comparison with surgical specimen in gastric B-cell lymphomas of the MALT type]. / Diagnostische Aussagekraft der Magenbiopsie im Vergleich zum Resektat bei primären gastralen B-Zell-Lymphomen vom MALT-Typ.

Diagnostic und therapeutic management of gastric lymphomas of the mucosa-associated lymphoid tissue type (MALT-type lymphomas) is often based exclusively on the evaluation of biopsy material. To evaluate the diagnostic value of gastric biopsies in gastric MALT-type lymphomas, biopsies--on average six per patient--and subsequent surgical specimens of 64 patients were compared at the Institute of Pathology, University of Würzburg. Tumor diagnosis and tumor gradind were assessed. Using biopsy specimens, primary gastric MALT-type lymphomas were correctly diagnosed by local pathologists in 69% of cases, but correctly graded as low-grade, high-grade or secondary high-grade lymphomas in only 41%. When immunohistochemistry and molecular biological techniques were applied in addition to conventional histology, diagnosis of gastric MALT-type lymphoma was achieved in biopsies in 95% of cases at the Institute of Pathology Würzburg, but correct grading in only 73%. In secondary high-grade MALT-type lymphomas, both components--the high-grade and the low-grade component--were identified in gastric biopsies in only 33% of cases. Diagnostic accuracy in gastric lymphomas based on biopsies is limited by biopsy artefacts, but improved by using immunohistochemistry and molecular biological techniques. Particularly in secondary high-grade MALT-type lymphomas the correct diagnosis is often missed when using biopsies, due to a low number of biopsy specimens.

Contemporary management of isolated iliac aneurysms.

OBJECTIVE: Because isolated common iliac artery aneurysms are infrequent, are difficult to detect and treat, and have traditionally been associated with high operative mortality rates in reported series, we analyzed the outcomes of operative repair of 31 isolated common iliac artery aneurysms in 21 patients to ascertain morbidity and mortality rates with contemporary techniques of repair. METHODS: A retrospective review study was conducted in a university teaching hospital and a Department of Veterans Affairs Medical Center. Perioperative mortality and operative morbidity rates were examined in 17 men and four women with isolated common iliac artery aneurysms between 1984 and 1997. Ages ranged from 38 to 87 years (mean 69 +/- 8 years). Slightly more than half of the cases were symptomatic, with abdominal pain, neurologic, claudicative, genitourinary, or hemodynamic symptoms. One aneurysm had ruptured and one was infected. There was one iliac artery-iliac vein fistula. All aneurysms involved the common iliac artery. Coexistent unilateral or bilateral external iliac aneurysms were present in four patients; there were three accompanying internal iliac aneurysms. Overall, 52% of patients had unilateral aneurysms and 48% had bilateral aneurysms. Aneurysms ranged in maximal diameter from 2.5 to 12 cm (mean 5.6 +/- 2 cm). No patients were unavailable for follow-up, which averaged 5.5 years. RESULTS: Nineteen patients underwent direct operative repair of isolated iliac aneurysms. One patient had placement of an endoluminal covered stent graft; another patient at high risk had percutaneous placement of coils within the aneurysm to occlude it in conjunction with a femorofemoral bypass graft. Patients with bilateral aneurysms underwent aortoiliac or aortofemoral interposition grafts, whereas unilateral aneurysms were managed with local interposition grafts. There were no deaths in the perioperative period. Only one elective operation (5%) resulted in a significant complication, compartment syndrome requiring fasciotomy. The patient treated with the covered stent required femorofemoral bypass when the stent occluded 1 week after the operation. The patient treated with coil occlusion of a large common iliac aneurysm died 2 years later when the aneurysm ruptured. CONCLUSIONS: Isolated iliac artery aneurysms can be managed with much lower mortality and morbidity rates than aneurysm previously been reported by using a systematic operative approach. Percutaneous techniques may be less durable and effective than direct surgical repair.