Translational neuroscience of basolateral amygdala lesions: Studies of Urbach-Wiethe disease.

Urbach-Wiethe disease (UWD) is an extremely rare autosomal recessive disorder characterized by mutations in the extracellular matrix protein 1 gene on chromosome 1. Typical clinical manifestations include voice hoarseness in early infancy and neuropsychiatric, laryngeal, and dermatological pathologies later in life. Neuroimaging studies have revealed a pattern of brain calcification often but not exclusively leading to selective bilateral amygdala damage. A large body of work on amygdala lesions in rodents exists, generally employing a subregion model focused on the basolateral amygdala (BLA) and the central-medial amygdala. However, human work usually considers the amygdala as a unified structure, not only complicating the translation of animal findings to humans but also providing a unique opportunity for further research. To compare data from rodent models with human cases and to complement existing data from Europe and North America, a series of investigations was undertaken on UWD subjects with selective BLA damage in the Namaqualand region, South Africa. This review presents key findings from this work, including fear processing, social-economic behavior, and emotional conflict processing. Our findings are broadly consistent with and support rodent models of selective BLA lesions and show that the BLA is integral to processing sensory stimuli and exhibits inhibitory regulation of responses to unconditioned innate fear stimuli. Furthermore, our findings suggest that the human BLA mediates calculative-instrumental economic behaviors and may compromise working memory via competition for attentional resources between the BLA salience detection system and the dorsolateral prefrontal cortex working memory system.

Extracellular matrix protein 1 inhibits the activity of matrix metalloproteinase 9 through high-affinity protein/protein interactions.

Extracellular matrix protein 1 (ECM1), an approximately 85-kDa glycoprotein with broad tissue distribution, harbors mutations in lipoid proteinosis (LP), a heritable disease characterized by reduplication of basement membranes and hyalinization of dermis, associated with neurologic disorders. The mechanisms leading from ECM1 mutations to LP phenotype are unknown. In this study, we explored ECM1 protein-protein interactions utilizing yeast two-hybrid genetic screen of human placental library, which identified nine interacting proteins, including matrix metalloproteinase 9 (MMP9). The interactions were confirmed by beta-galactosidase assay with isolated clones and by co-immunoprecipitation which narrowed the interacting segment in ECM1 to the C-terminal tandem repeat 2 (amino acids 236-361). This peptide segment also inhibited MMP9 activity in a gelatin-based ELISA assay. We propose that ECM1-mediated reduction in MMP9 proteolytic activity may have relevance to pathogenesis of LP.

Hemorheology in complicated hypertension.

During essential and secondary arterial hypertension it is possible to observe changes in microcirculation perfusion associated with a reduction in tissue oxygenation due in part to hemorheological changes such as an increase in blood viscosity or the formation of the red blood cell "rouleaux" which favour an increase in peripheral resistance and can cause or worsen arterial hypertension. We studied 21 healthy subjects (11 male and 10 female aged 42 +/- 4) and 26 hypertensive subjects (14 male and 12 female aged 49 +/- 3). The patients were non smokers and non suffering from respiratory or haemathological pathologies. They were not undergoing antihypertensive or vasodilatory pharmaceutical treatment. The patients suffered from mild hypertension (II WHO) with Peripheral Occlusive Arterial Disease (POAD II "a" acc. to Leriche-Fontaine class.). The patients showed an increase in cholesterolaemia (6.42 +/- 0.81 mmol/l) and trygliceridaemia (2.73 +/- 0.09 mmol/l) at an average level. The patients were studied in standard conditions with a constant temperature of 22 degrees C. We measured SBP, DBP, MBP, and the HR. We also measured the elongation index (EI) (with shear stress range 0.30 to 30 pascals) using LORCA, acc. to Hardeman method (1994), in order to study the erythrocyte deformability and aggregation kinetics in dynamic condition. To evaluate deformability in static conditions we calculated the Erythrocyte Morphologic Index (EMI), acc. to Forconi method, via the bowl/discocyte ratio (for 100 red blood cells fixed in glutaraldehyde at 0.3% and observed with an optical microscope under immersion in glycerol). Peripheral oxygenation was taken transcutaneously (TcpO2). To establish the level of vascular disease we used the Regional Perfusion Index (RPI = TcpO2 foot/TcpO2 subclavean) and doppler guided Winsor Index (WI). The Student "t" test and linear regression were used for the statistical analysis. Our data confirm a reduction in peripheral tissue oxygenation in hypertensives especially if suffering from vascular disease which correlates significantly (p < 0.01) with a reduction in red blood cell deformability. This itself can increase peripheral resistances and favour the onset of hemorheological complications, at a cerebral-vascular level, which are frequent in hypertensives.

Cutaneous deposition diseases. Part I.

The cutaneous deposition disorders are a group of unrelated conditions characterized by the presence of either endogenous or exogenous substances within the dermis or the subcutis. Part I of this two-part series will focus on metabolic processes involved in the endogenous deposition in the various forms of amyloidosis, porphyria, colloid milium, and lipoid proteinosis. We will also review the clinical, histologic, biochemical, and ultrastructural findings relevant to each disorder. Basic mechanisms of pathogenesis, diagnostic modalities, and treatment options are also discussed.

[Lipoprotein metabolism disturbances in patients with kidney diseases]. / Zaburzenia metabolizmu lipoproteiny(a) u chorych z chorobami nerek.

Lipoprotein(a) was discovered over 30 years age and it is an independent risk factor for atherosclerosis, coronary artery disease and peripheral vascular diseases. Among patients with end stage renal failure lipoprotein(a) levels are higher than in general population and being independent of the type of treatment. Cardiovascular diseases are the most important cause of mortality in ESRD patients. Moreover we have interesting information about possibility of influence of Lp(a) serum levels.

Dyslipoproteinemia in murine systemic lupus erythematosus.

Dyslipoproteinemia, a feature of systemic lupus erythematosus may contribute to premature atherosclerosis. In order to develop an experimental model for this dyslipoproteinemia we measured plasma concentrations of lipoproteins in juvenile NZB/W (lupus) and NZB/B (control) mice. Additionally to evaluate the effects of a diet rich in n - 3 fatty acids we measured lipoprotein concentrations in mice on normal or menhaden oil-enriched diets. The lupus mice had elevated triglycerides compared to the controls, similar to that seen in human SLE patients (161 +/- 31 vs 113 +/- 13 mg/dl, P less than 0.003). In contrast, the menhaden oil diet fed NZB/W mice had triglycerides similar to the NZB/B control fed group. In the NZB/W murine SLE model, dyslipoproteinemia is an early sign of disease as has been shown in man, therefore this model will be useful in elucidating the mechanism of dyslipoproteinemia in SLE.

Pulmonary alveolar phospholipoproteinosis: experience with 34 cases and a review.

A retrospective review of Mayo Clinic records through 1983 revealed 84 patients (24 male and 10 female; mean age, 41 years) with the diagnosis of pulmonary alveolar phospholipoproteinosis. The major clinical features were dyspnea, cough, fever, and chest pain. Chest roentgenograms usually showed bilateral symmetric alveolar infiltrates, but asymmetric, unilateral, and chronic patchy patterns were also noted. Diagnosis was established by thoracotomy-lung biopsy in 26 patients. Histologic analysis revealed uniform filling of the alveoli by periodic acid-Schiff-positive material and maintenance of normal alveolar architecture. Electron microscopy showed enlarged alveolar macrophages with lamellar osmiophilic inclusions, dense granules, and myeloid bodies. Of the 21 patients who underwent therapeutic bronchoalveolar lavage, 13 had no recurrence of the disease during a mean follow-up of 8.8 years. In patients who underwent pulmonary function testing both before and after lavage, significant restrictive dysfunctions present before the procedure were alleviated afterward. Three deaths occurred among the 34 patients. Pulmonary alveolar phospholipoproteinosis may result from defective clearance of phospholipids by the alveolar macrophages, excessive production of phospholipids by type II pneumocytes, or both. It is likely a nonspecific response to a variety of injuries to the alveolar macrophage or type II pneumocyte or both, including exposure to certain dusts and chemicals and occurrence of hematologic diseases or infections. The uncommon occurrence of this disorder suggests individual susceptibility.

Pulmonary alveolar lipoproteinosis in rats following intratracheal injection of pyrite particles.

Wistar rats were injected intratracheally with pyrite particles and after 6 and 12 mo, lungs were evaluated for histological changes. Results were compared with rats that were given particles of galena, lead silicate, travertine, and quartz. Under the light microscope no significant changes were observed in the lungs from animals treated with galena, lead silicate, and travertine. In the lungs from animals that received quartz, a typical nodular fibrosis was observed. Moreover, both pyrite-treated rats and quartz-treated rats developed pulmonary alveolar lipoproteinosis; the lesions were much less prominent and severe in animals injected with pyrite than with quartz. These results indicate that pyrite, like only a few other types of dust that are different from quartz, can evoke the development of pulmonary alveolar lipoproteinosis in rats.

Lipoid proteinosis. A case report.

A 31-year-old Coloured man was admitted to Tygerberg Hospital in 1981 with hoarseness, hyperkeratotic skin lesions and nodules on the eyelids. There was a history of an episode of loss of consciousness. Skull radiographs demonstrated bilateral symmetrical calcifications in the temporal region. Skin biopsy was consistent with a diagnosis of lipoid proteinosis.

[Hyalinosis cutis et mucosae (Urbach-Wiethe lipoidproteinosis)]. / Hyalinosis cutis et mucosae (Lipoid-Proteinose Urbach-Wiethe).

Hyalinosis cutis et mucosae is a rare, probably autosomal-recessively inherited disease, which begins in the first weeks of life with a remarkable hoarseness due to deposits of hyaline material in the larynx. Later on alterations of the mucous membranes and the skin are involved. Etiology and pathogenesis are unknown. An effective treatment does not exist. We present a Turkish family whose 4 children show the typical picture of hyalinosis cutis et mucosae. The skin alterations at the mother's eyelids, however, cannot be submitted to the lipoid proteinosis Urbach-Wiethe with certainty. The occurrence of hyalinosis cutis et mucosae in the 4 children makes the hitherto presumed autosomal-recessive heredity of the disease questionable.

Hyalinosis cutis et mucosae. Defective digestion and storage of basal lamina glycoprotein synthesized by smooth muscle cells.

Electron microscopy revealed accumulation of fibrogranular materials associated with laminated basal lamina around the smooth muscle cells of tunica dartos (most strikingly) and of blood vessels, vascular endothelial cells, pericytes, myofibroblasts (not usual fibroblasts) as well as Schwann cells and perineuria. Around the presumably regressive and slightly shrunken sweat duct, a network of basal lamina containing fibrogranular materials was found in a configuration indicating that it would have surrounded the remnants of cells (involuted cells) of the sweat duct, probably consisting of old, undegradated, residual basal lamina. Consequently, it was suggested that hyalinosis cutis et mucosae might be caused by accumulation and invasion of basal lamina glycoprotein involving the type IV (plusV?) collagen into normal collagen fibers (bundles) due to defective degradation.