Evidence for a Type 1 diabetes‐specific mechanism for the insulin gene‐associated IDDM2 locus rather than a general influence on autoimmunity

Aims The Type 1 diabetes susceptibility locus, IDDM2, has been mapped to a variable number of tandem repeats (VNTR) region 5′ upstream of the insulin (INS) and insulin‐like growth factor (IGF2) genes on chromosome 11p15. The function of the VNTR is uncertain; however, it may influence the thymic expression of the insulin gene and affect the development of immune self‐tolerance. The aim of this study was to investigate whether the INS VNTR region is a Type 1 diabetes‐specific locus or acting as a general autoimmunity gene. Methods We genotyped the INS‐IGF2 VNTR [using the surrogate INS?23 HphI single nucleotide polymorphism (SNP)] in 823 Graves’ disease (GD)/multiple sclerosis (MS) families, 1433 GD/MS patients and 837 healthy control subjects. Results We found no evidence of excess transmission of the allele associated with Type 1 diabetes to individuals affected by GD or MS within the families. Analysis of the case–control dataset showed no genotypic or allelic difference between the two populations. Conclusions These data suggest that the INS‐IGF2 VNTR is acting as a Type 1 diabetes‐specific susceptibility gene rather than as an influence on general autoimmunity.     

Orthostatic blood pressure control and ageing*

Reflex haemodynamic responses to orthostatic stress are attenuated with ageing, the extent of attenuation increasing with advancing age. In 15–20% of individuals aged >65 years, the attenuation may be so marked that there is an excessive fall of blood pressure (BP) on assumption of the upright posture, sufficient on occasions to cause symptomatic cerebral hypoperfusion - this is known as ‘ageing-related’ orthostatic hypotension (AOH), a major risk factor for morbidity and mortality. Comparison of the cardiovascular responses to a variety of physiological and pharmacological stresses in healthy young and elderly subjects and in those with AOH suggests that the predominant site of the ageing-related change in cardiovascular reflex function is in the central connections of the arterial baroreflex, affecting particularly the BP buffering response. There is no evidence for ageing-related impairment of the efferent limb of the baroreflex, i. e. there is no significant ageing change in sympathetic vasomotor function or cardiac drive. Ageing-related impairment of baroreflex function also does not appear to result from either attenuation of arterial compliance or the presence of systolic hypertension, despite the epidemiological association between systolic hypertension and AOH. Better understanding of this important problem has the potential to improve the health of all elderly people.     

Unregulated proliferation of primitive neoplastic progenitor cells in long-term polycythemia vera marrow cultures

Marrow cells from seven untreated patients with polycythemia vera (PV) were used to initiate standard single inoculum long-term marrow cultures. The numbers, erythropoietin independence, and cycling behavior of all detectable classes of erythroid, granulopoietic, and multilineage progenitors were then evaluated and the results obtained compared with preculture values. Time course studies showed that the long-term marrow culture system supports the continuous proliferation of primitive neoplastic progenitor cells from PV patients for many weeks. However, these progenitors fail to respond to signals from the adherent layer that return their counterparts in normal long-term marrow cultures to a quiescent state 5-7 d after each medium change. This abnormal cycling behavior of PV cells in the long-term culture system appears to mimic that operative in vivo, where primitive hemopoietic progenitors are also in a continuous state of turnover, in contrast to similar primitive progenitor compartments in normal individuals, which are quiescent. The long-term marrow culture system thus offers new possibilities for the further analysis of abnormal cellular and molecular mechanisms underlying clonal expansion at the stem cell level in PV.     

Uroscopy in the 21st century: high-field NMR spectroscopy

From the experiments described, it can be seen that there are different research approaches that can be taken and these are summarized in Table 1. Whereas much scientific research is principally hypothesis led, there remains, nevertheless, an important place for exploratory research. High resolution NMR can measure, directly and simultaneously, a wide range of endogenous metabolites in biological fluids and has the unique capability of providing structural information on the metabolites detected. It has proved to be a powerful research tool with which to study inherited metabolic diseases, renal disease, drug metabolism, and toxicity, and can be used to monitor the effects of drug therapy. For instance, by using a library of experimental toxins one can map the metabolic profile of site-specific nephron injury. With this approach in man one could eventually take an unknown disease such as Balkan nephropathy and predict the initial site of tubular injury, the mode of injury and therefore the kind of toxin capable of producing that injury. NMR spectroscopic techniques are still advancing rapidly, with ever increasing sensitivity and sophistication of NMR pulse sequences to enhance structural elucidation in complex mixtures. Given the advances in directly coupled HPLC-NMR and even HPLC-NMR-mass spectroscopy it is likely that these technologies in conjunction with pattern recognition will make major contribution to our understanding of renal processes and provide new diagnostic insights in the 21st century.      

The genetic epidemiology of phobias in women. The interrelationship of agoraphobia, social phobia, situational phobia, and simple phobia.

In 2163 personally interviewed female twins from a population-based registry, the pattern of age at onset and comorbidity of the simple phobias (animal and situational)--early onset and low rates of comorbidity--differed significantly from that of agoraphobia--later onset and high rates of comorbidity. Consistent with an inherited "phobia proneness" but not a "social learning" model of phobias, the familial aggregation of any phobia, agoraphobia, social phobia, and animal phobia appeared to result from genetic and not from familial-environmental factors, with estimates of heritability of liability ranging from 30% to 40%. The best-fitting multivariate genetic model indicated the existence of genetic and individual-specific environmental etiologic factors common to all four phobia subtypes and others specific for each of the individual subtypes. This model suggested that (1) environmental experiences that predisposed to all phobias were most important for agoraphobia and social phobia and relatively unimportant for the simple phobias, (2) environmental experiences that uniquely predisposed to only one phobia subtype had a major impact on simple phobias, had a modest impact on social phobia, and were unimportant for agoraphobia, and (3) genetic factors that predisposed to all phobias were most important for animal phobia and least important for agoraphobia. Simple phobias appear to arise from the joint effect of a modest genetic vulnerability and phobia-specific traumatic events in childhood, while agoraphobia and, to a somewhat lesser extent, social phobia result from the combined effect of a slightly stronger genetic influence and nonspecific environmental experiences.     

Fibrinogen adsorption and platelet adhesion at the surface of modified polypropylene glycol/polysiloxane networks

The protein film adsorbed at an artificial surface ultimately affects platelet adhesion and activation. This study examines the role of fibrinogen in platelet adhesion at the surface of crosslinked polypropylene glycol (PPG)/polyglycidoxy propyl methyl siloxane (PGPMS) networks which contain polyethylene glycol monomethyl ether (PEGME) chains. These crosslinked networks were produced by reacting the epoxy groups of PGPMS with the hydroxyl groups of the polyethers. PEGME chains were attached covalently to the network at only one end while PPG chains were attached at both ends. The incorporation of PEGME resulted in a substantial reduction in fibrinogen adsorption as compared to the model network (PPG + PGPMS only), but the expected concomitant decrease in platelet adhesion was not observed.     

A twin-family study of self-report symptoms of panic-phobia and somatization

Self-report symptoms of anxiety are widely used in mental health and social science research as an index of current psychiatric state. Previous twin studies have suggested that genetic factors account for a significant proportion of the variance in these symptoms. To replicate and extend these findings, we examined self-report symtoms of panic-phobia and somatization in the “Virginia 30,000” twin-family sample. Model fitting applied to 80 unique relationships in the twin-family pedigree produced the following major results: (i) genetic effects were significant for both symptom factors, accounting for between 25 and 49% of the total variance, with the exception of symptoms of panic-phobia in females, where they accounted for 15–16% of the variance; (ii) familial environmental effects were absent for symptoms of somatization, while for symptoms of panic-phobia they accounted for a very small proportion of variance in males (≤1.2%) and a modest proportion in females (6–17%) (iii) spousal correlations were present for both factors, ranging from +0.05 to +0.20; (iv) genetic factors which influenced symptoms were generally the same in males and females, although their effect was greater in males; (v) heritability estimates were lower in the population-based than in the volunteer sample; and (vi) when test-retest reliability was included in the model, results suggest that genetic factors account for at least half of the stable variance for all symptom factors, except panic-phobia in females. Our results support the validity of previous twin studies of self-report symptoms of anxiety and suggest that genetic factors significantly influence these symptoms but familial-environmental factors play little or no etiologic role.     

Comparison of Chlamydia psittaci isolates by restriction endonuclease and DNA probe analyses.

DNAs from eight Chlamydia psittaci isolates (koala conjunctivitis, avian psittacosis, avian ornithosis, ovine abortion, ovine polyarthritis, sporadic bovine encephalomyelitis, and feline conjunctivitis) and one Chlamydia trachomatis isolate (lymphogranuloma venereum) were compared by restriction endonuclease and DNA probe analyses. Digestion with HindIII yielded a series of discrete fragments which allowed the differentiation of most isolates. A gene probe, pFEN207, which encodes the chlamydia-specific component of the lipopolysaccharide group antigen was used in Southern hybridizations. The probe was chlamydia specific and hybridized to a single BamHI fragment and multiple HindIII fragments in each isolate. The variation in size of the hybridizing fragments allowed easy differentiation of the isolates and may eventually lead to a meaningful subgrouping of the diverse group of disease agents presently included in the species C. psittaci.