Familial dyslipidemic hypertension. Evidence from 58 Utah families for a syndrome present in approximately 12% of patients with essential hypertension

Population-based sibships with essential hypertension diagnosed before the age of 60 years are being screened in Utah to find two or more hypertensive siblings with the same biochemical abnormality as a clue to an inherited cause for their specific type of hypertension. Among 131 hypertensive subjects in 58 sibships, concordant abnormalities in fasting serum lipid concentrations were observed in two or more siblings in 48% of the sibships. After adjusting for effects of antihypertensive medications, abnormal values reported in only 10% of the Lipid Research Clinics data were observed in 30% of patients for serum triglycerides, 19% for serum low-density lipoprotein cholesterol, and 39% for high-density lipoprotein cholesterol. More than one lipid level was abnormal in almost all concordant sibships, suggesting an association between hypertension and a syndrome of mixed lipid abnormalities, probably familial combined hyperlipidemia (renamed "familial combined dyslipidemia" because of common low high-density lipoprotein cholesterol levels). We conclude that familial dyslipidemic hypertension may be a specific syndrome with lipid abnormalities more severe than blood pressure elevations.     

Localization and Quantitative Autoradiography of Glutamatergic Ligand Binding Sites in Chick Brain

The anatomical localization of glutamate receptor subtype-selective ligand binding sites was investigated in 1-day-old chick brain using quantitative autoradiography. Under the conditions used, the regional distributions of [3H]glutamate, [3H]AMPA (a selective quisqualate receptor ligand) and [3H]kainate binding sites are manifestly different. [3H]l-glutamate binding is densely localized in the telencephalon, particularly in the neostriatum (2.8 pmol/mg protein). In addition, [3H]l-glutamate labels the thalamus, the nucleus mesencephalicus lateralis pars dorsalis, the superficial layers of the optic tectum and the molecular layer of the cerebellum. [3H]AMPA binding sites are most densely localized in the hippocampus (0.90 pmol/mg protein), with an otherwise relatively uniform distribution of binding within the telencephalon. [3H]AMPA also labels the striatum griseum et fibrosum superficiale of the optic tectum and the molecular layer of the cerebellum. [3H]Kainate binding sites are extremely densely packed in the molecular layer of the cerebellum (10 pmol/mg protein). Other regions of [3H]kainate binding include the hyperstriatum and the thalamus. The binding of the NMDA receptor channel blocker [3H]MK-801 is increased in the presence of 1 mM l-glutamate. [3H]MK-801 binding is generally widespread in the telencephalon but is notably absent from the ectostriatum. No evidence of [3H]MK-801 binding sites was detected in the cerebellum, even in the presence of 1 mM l-glutamate. The relatively high densities and the well-defined localizations of the glutamate receptor subtype binding sites suggest that chick brain provides a useful system for the further study of excitatory amino acid receptors.     

The mechanism of action of retrograde oxygen persufflation in renal preservation

Vascular perfusion of gaseous oxygen has been used to prolong the in vitro survival of a number of isolated organs, and has been shown to improve the hypothermic preservation of ischemically injured kidneys that were subsequently transplanted. We have investigated the mechanism of this effect. Rabbit kidneys were subjected to 60 min of warm ischemia prior to preservation for 24 hr with Ross, Marshall, and Escott's hypertonic citrate solution, with or without retrograde oxygen persufflation (ROP) via the renal vein. It was found that adenine nucleotide levels were almost doubled in the ROP-preserved kidneys, principally due to higher adenosine triphosphate (ATP) concentrations. It was shown that cytochrome oxidase activity was unaffected by ischemia or preservation method, but studies with the metabolic inhibitors ouabain and a mixture of cyanide and iodoacetate suggested that ATP was being synthesized during the storage period but was also being utilized to power the active volume-regulating pump. Morphological examination revealed a much greater degree of cell swelling and cytological injury in the kidneys not subject to ROP, and the interstitial space appeared much reduced in the latter group. At the ultrastructural level, the ROP-treated kidneys showed generally well-preserved mitochondria, mostly in the energized "orthodox" configuration. In contrast, the mitochondria in the nonpersufflated kidneys were generally in the "condensed" deenergized state. We conclude that the provision of sufficient oxygen by ROP allows the continued production of ATP in sufficient quantities to permit improved maintenance of cellular volume and morphology under the conditions of low-temperature storage that we have studied.     

Effects of laminin on the attachment of glioma cells to type IV collagen

The interaction of tumour cells with basement membrane components is thought to be important in influencing their invasive and metastatic properties. This paper describes the effect of laminin on the attachment of radiolabelled glioma and B16 murine melanoma cells to tissue culture plastic and type IV collagen. With the exception of the non-metastatic B16 F1 variant, laminin (and fibronectin) stimulated cell attachment to tissue culture plastic. Although laminin stimulated the attachment of the B16 BL6 metastatic variant to type IV collagen, it consistently inhibited the attachment of the glioma cells under the same conditions. Laminin appeared to exert its effect by adsorption to the collagen and was not cytotoxic to the glioma cells. In contrast, fibronectin had very little effect on cell attachment to type IV collagen. One of the most unusual features of glioma is the rarity of metastasis to extraneural sites. However, the effect of laminin observed here may not be the only factor involved in the metastatic inefficiency of this tumour type.     

Radical-mediated damage to parasites and erythrocytes in Plasmodium vinckei infected mice after injection of t-butyl hydroperoxide.

Intravenous injection of t-butyl hydroperoxide rapidly killed Plasmodium vinckei in mice, and caused haemolysis. The same dose seemed harmless to unparasitized mice. Many parasites disintegrated inside circulating erythrocytes, so parasite death was not simply a passive consequence of haemolysis. Injection of desferrioxamine, which removes the traces of free iron that promote the dissociation of t-butyl hydroperoxide into radical species, prevented both parasite death and haemolysis. Lipid peroxidation, as measured by accumulation of malonyldialdehyde over 2 h in vitro, occurred in erythrocytes exposed to t-butyl hydroperoxide, and was particularly marked in erythrocytes from parasitized mice. These erythrocytes accumulated appreciable malonyldialdehyde even without exposure to t-butyl hydroperoxide. Desferrioxamine inhibited the accumulation of malonyldialdehyde, but did not prevent depletion of reduced glutathione by t-butyl hydroperoxide. This suggests that t-butyl hydroperoxide damaged parasites and erythrocytes by dissociating into radical species, rather than by decreasing intraerythrocyte anti-oxidant capacity. In earlier experiments we suggested that intraerythrocytic parasite death and haemolysis caused by alloxan were mediated by radical species, and these experiments with t-butyl hydroperoxide add weight to this interpretation. We regard both of these systems as models for macrophage-induced parasite death and host pathology in acute malaria.     

Loss of heterozygosity mutations of tumor suppressor genes in cytologically atypical areas in chronic lymphocytic thyroiditis

The relationship between chronic lymphocytic thyroiditis (CLT) and papillary thyroid carcinoma (PTC) is a subject of controversy. Some investigators suggest a causal relationship, whereas others regard the two as only a coincidental occurrence. An additional complicating factor is the presence of atypical nuclei frequently found within lymphoid infiltrates in CLT, which resemble those in PTC. The finding of the RET-PTC translocations in CLT has been reported by two independent groups of investigators, suggesting that the areas of nuclear atypia in CLT are neoplastic rather than reactive. In the present study, we report additional molecular findings that support the hypothesis that the atypical nuclear changes in CLT may be preneoplastic or neoplastic. We microdissected small areas with atypical nuclei in glands with CLT and observed loss-of-heterozygosity mutations of tumor suppressor genes. These genetic mutations are evidence of clonal preneoplastic or neoplastic changes in the follicular cells of CLT. The clinical malignant potential of these minute foci is likely to be very small but remains to be determined.     

Molecular alterations in atypical adenomatous hyperplasia occurring in benign and cancer-bearing lungs.

Atypical adenomatous hyperplasia (AAH) is considered to be a precursor lesion of the lung adenocarcinoma. Several genetic abnormalities have been reported in AAH associated with adenocarcinoma, but little is known about AAH associated with benign lung lesions. To address this we compared the molecular characteristics of AAH present in benign conditions to those coexisting with carcinoma. Seven cases of AAH from resected non-neoplastic lungs (AAH-B) and 12 cases from lungs resected for primary lung carcinoma (AAH-M) were analyzed for loss of heterozygosity (LOH) using 21 polymorphic microsatellite markers situated in proximity to known tumor suppressor genes on chromosomes 3p, 5q, 7p, 9p, 10q, and 17p. Direct DNA sequencing for K-ras mutation was also performed. There was a broad range of LOH in both groups. No LOH was identified in 3 cases (25%) of AAH-M, but all cases of AAH-B showed LOH (P=0.26). Six cases (50%) of AAH-M and 3 cases (43%) of AAH-B showed loss at 1 marker (P=0.99). LOH at 2 or more markers was identified in 3 (25%) cases of AAH-M and 4 (57%) cases of AAH-B (P=0.32). LOH was most frequently detected on chromosomes 3p and 10q in both groups. The difference in overall fractional allelic loss between the 2 groups did not reach statistical significance. K-ras mutations were not identified in either group. Our results showed a significant overlap in LOH patterns between AAH with or without coexistent lung malignancy. Therefore, AAH may represent a smoking induced low-grade neoplastic lesion that may be a precursor lesion of only a subset of invasive lung adenocarcinoma.     

A test of the assumptions of the transtheoretical model in a post-traumatic stress disorder population

Prior reports suggest an ambivalence regarding treatment in individuals with Post-Traumatic Stress Disorder (PTSD). A model that accommodates such ambivalence is the Transtheoretical Model of Behavior Change (TTM, also known as the Stages-of-Change Model). Fifty veterans presenting for treatment completed self-report measures (94% response rate) that assessed disorder variables and constructs relating to the TTM. While the relationships between the components of each specific construct were found to be consistent with the findings of other studies and a number of predicted relationships between variables were confirmed, many results were inconsistent with the TTM. Notwithstanding questions about the suitability of the self-report measures, the unique characteristics of the veteran sample and the small sample size, the results suggest that the assumptions of the TTM were not met in veterans with PTSD. Copyright © 2005 John Wiley & Sons, Ltd.