Presymptomatic testing for Huntington's disease in the United Kingdom. The United Kingdom Huntington's Disease Prediction Consortium.

OBJECTIVE--To evaluate the United Kingdom Huntington''s disease presymptomatic testing programme. DESIGN--Postal questionnaire survey to collect data on all tests performed by clinical genetics centres between 1987 and 1990. SETTING--Genetic centres providing presymptomatic testing in the United Kingdom. SUBJECTS--248 subjects at risk of Huntington''s disease who had presymptomatic testing at their request. MAIN OUTCOME MEASURES--Sex, age, prior risk, and risk after testing. RESULTS--The risk of carrying the Huntington disease gene was reduced for 151 (61%) of the applicants and raised for 97 (39%). 158 (64%) of the subjects were female and 90 (36%) male. The median age at which the results were given was 32.5 years. CONCLUSIONS--The demand for testing was lower than expected and may have reached its peak in 1990. The excess of low risk results was not fully explained by the age effect. All the genetics centres concerned have agreed a common service protocol which requires extensive pre-test counselling and post-test follow up. The worth of the procedure remains to be decided. The availability of a large body of pooled data from all the United Kingdom testing centres, which individually are likely to have only a few results, will form a valuable resource for monitoring the long term psychosocial impact of testing.     

Morphogenesis of the respiratory bronchiole in rhesus monkey lungs

The epithelium of the respiratory bronchiole in the adult rhesus monkey consists of two populations: a pseudostratified epithelium with basal, mucous goblet, and ciliated cells located near the pulmonary artery (PA); and a simple cuboidal epithelium composed only of nonciliated bronchiolar epithelial (or Clara) cells in areas away from the PA. This study describes the pattern of differentiation of these two epithelial populations, and their relationship to the PA and to the time of appearance of alveoli in the respiratory bronchiole of the rhesus monkey during the period of 90-125 days gestational age (DGA). These events were related to changes in the adjacent parenchyma. Dissected airways of infusion-fixed, critical-point-dried lungs were evaluated by scanning microscopy followed by light microscopy of the same airways. At 54% of gestation (90 DGA), the distal airway was lined by a mixture of ciliated and nonciliated cells. By 67% of gestation (110 DGA), the ciliated cells were confined to the epithelium over the PA. The underlying connective tissue initially was cellular containing few fibers but was fibrous by 76% of gestation (125 DGA). Alveolarization began near the most distal cartilage at 57% of gestation (95 DGA), the same period at which secondary septation occurred in the distal acinus. Thus, alveolarization occurred simultaneously in two centers: 1) the proximal centriacinar region in the vicinity of the most distal cartilage and 2) the distal lung parenchyma. The duration of centriacinar alveolarization was short, approximately 5 days.     

Ultrastructure of the frontal organ in Convoluta and Macrostomum spp.: significance for models of the turbellarian archetype

Present models of turbellarian evolution depict the organism with a frontal organ — a complex of glands whose necks emerge at the anterior tip of the body — and therefore imply that this organ is homologous throughout the Turbellaria. However, comparisons of representatives of the Acoela and Macrostomida, two putatively primitive orders of the Turbellaria, show that frontal organs in these two are not similar in ultrastructure or histochemistry. The acoel Convoluta pulchra had a prominent cluster of frontal mucous glands whose necks emerged together in a frontal pore at the exact apical pole of the organism, and an array of smaller glands of at least five other types opened at the anterior end, separately from and ventral to this pore. The frontal organs (Stirndrüsen) of two species of Macrostomum on the other hand, comprised an array of discretely emerging necks of at least two gland types including one with rhabdiform (rhammite) and one with globular mucous secretion granules neither of which emerge at the apical pole. In neither species did the organ appear to be sensory. Our findings indicate a low probability of homology between the frontal glands of the Acoela and Macrostomida.     

Genetic basis for altered pathogenesis of an immune-selected antigenic variant of reovirus type 3 (Dearing).

In this paper we provide a step by step comparison of the pathogenesis of murine infection caused by reovirus type 3 (Dearing) and an antigenic variant (K) selected by its resistance to neutralization with a monoclonal antibody (G5) directed against the T3 hemagglutinin. To show that specific changes in the biologic properties of variant K were due to mutation in the S1 double-stranded RNA segment (gene), which encodes the viral hemagglutinin, we generated a reassortant virus ("1 HA K") containing the variant K S1 gene and compared its properties to variant K and to a reassortant ("1 HA 3") containing the T3 (Dearing) S1 gene. These studies, in conjunction with our previous nucleotide sequence analysis of the S1 genes of variant K and T3 (Dearing) [R. Bassel-Duby, A. Jayasuriya, D. Chatterjee, N. Sonenberg, J. V. Maizel, Jr., and B. N. Fields, Nature (London) 315:421-423, 1985; R. Bassel-Duby, D. R. Spriggs, K. L. Tyler, and B. N. Fields, submitted for publication], indicate that a single amino acid change in the T3 hemagglutinin can alter viral growth and tropism within the central nervous system without affecting either its primary replication in the intestine or its pattern of spread to or within the central nervous system.     

Reflex cardiovascular responses caused by stimulation of pulmonary C-fibers with capsaicin in dogs

The purpose of these studies was to determine quantitatively the reflex cardiovascular responses to stimulation of the pulmonary C-fibers in dogs. We used a preparation in which the airway, pulmonary artery, and the pulmonary veins to the left lung were cannulated in situ. Ventilation and perfusion of the right lung maintained the animal in relatively normal homeostasis. Capsaicin, a decylenic acid amide of vanillylamine that selectively stimulates nerve endings of unmyelinated fibers (C-fibers), was injected into the left pulmonary artery in 5-ml boluses. Maximal reflex responses were obtained with concentrations as low as 0.8-1.6 X micrograms-1 X kg-1. Heart rate, hindlimb resistance, and left ventricular contractility were lowered transiently (the maximal responses showing declines of 40, 13, and 15.2%, respectively). As a result of these changes, combined with vasodilation in other resistance vessels, cardiac output fell 28% and blood pressure fell 35%. Interrupting the afferent neural pathway by severing the ipsilateral cervical vagus nerve eliminated these responses, confirming the distribution of their reflex origin. Although the role of these reflexes in homeostasis has not been decided, the results of this study suggest that the lungs of dogs, if appropriately stimulated, potentially can exert a major inhibitory influence on the neural regulation of cardiovascular function.     

Influence of restricted food intake on brown adipose tissue function in genetically obese mice (genotype, ob/ob)

Measurements were made of cytochrome c oxidase activity and the GDP-binding capacity of mitochondria in brown adipose tissue of genetically obese mice and wild-type siblings, to estimate the thermogenic capacity of the tissue. The binding capacity was decreased in ad libitum fed obese animals compared with wild-type animals. Limited feeding of obese animals to restrict their body weight caused a large increase in the binding capacity of the tissue, which was greater than that in wild-type animals fed either ad limitum or on a limited diet. The decreased binding capacity of brown adipose tissue mitochondria in obese mice appears to be a consequence of ad libitum feeding and therefore not a cause of the obesity. Limit feeding of obese animals also corrected their characteristic hypothermia at low ambient temperature. The large increase in the thermogenic capacity of brown adipose tissue in obese animals, induced by limited feeding, may account for the vital improvement of their thermoregulation. However, close similarities were found between obesity hypothermia and hypothermia induced in wild-type animals by restraint. It is suggested that changes in posture caused by obesity, resulting in increased loss of body heat, may be important in the development of obesity hypothermia. Obese animals fed less than wild-type grained more weight than wild-type animals, indicating that the high thermogenic capacity of their brown adipose tissue did not function to regulate their calorie intake.     

Growth of Acinetobacter sp. strain HO1-N on n-hexadecanol: physiological and ultrastructural characteristics.

The growth of Acinetobacter sp. strain HO1-N on hexadecanol results in the formation of intracytoplasmic membranes and intracellular rectangular inclusions containing one of the end products of hexadecanol metabolism, hexadecyl palmitate. The intracellular inclusions were purified and characterized as "wax ester inclusions" consisting of 85.6% hexadecyl palmitate, 4.8% hexadecanol, and 9.6% phospholipid, with a phospholipid-to-protein ratio of 0.42 mumol of lipid phosphate per mg of inclusion protein. The cellular lipids consisted of 69.8% hexadecyl palmitate, 22.8% phospholipid, 1.9% triglyceride, 4.7% mono- and diglyceride, 0.1% free fatty acid, and 0.8% hexadecanol, as compared with 98% hexadecyl palmitate and 1.9% triglyceride, which comprised the extracellular lipids. Cell-associated hexadecanol represented 0.05% of the exogenously supplied hexadecanol, with hexadecyl palmitate accounting for 14.7% of the total cellular dry weight. Acinetobacter sp. strain HO1-N possesses a mechanism for the intracellular packaging of hexadecyl palmitate in wax ester inclusions, which differ in structure and chemical composition from "hydrocarbon inclusions" isolated from hexadecane-grown cells.     

GH3 cell secretion of growth hormone and prolactin increaseases spontaneously during perfifusion

Summary GH₃ cell secretory activity was studied in long-term perifusion to define previously reported spontaneous increases in growth hormone (GH) and prolactin production (PRL). Mechanically harvested cells (1×10⁷/column) were perifused at 4 ml/h for 72 h. A basal period of variable duration (8 to 12 h), during which hormone secretion was stable, was followed by steadily increasing secretion rates. Changes in cell number were not sufficient to acount for increased jormone secretion rates: a) there was no significant change in cell count after 72 h (0.97±0.03×10⁷;n=18); b) mean cell column DNA content increased 25.5% above the base value, whereas GH secretion rose 385% and PRL rose 178% (n=5). Observed differences in the duration of the basal secretion period, the basal secretory rate, and the magnitude of secretory rate increase were associated with several variables: a) variablility within a subline was a function of passage number: GH secretion decreased and PRL secretion increased with subculture number; b) cells with identical lot and freeze numbers, but received at different times, behaved differently; c) the presence of an antifungal agent (nystatin) altered hormone secretion reproducibly. Conclusions: a) rates of GH and PRL secretion rise spontaneously in perifusion without a proportional increase in GH₃ cell number; b) fluctuations in the rate of GH₃ cell secretion of GH and PRL are not entirely random but are determined by several definable variables. Supported by a grant to MES from the National Institutes of Health (AM33388) and in part by the Medical Research Service of the Veterans Administration.