Novel TAP1 polymorphisms in indigenous Zimbabweans: their potential implications on TAP function and in human diseases

Because of the essential role of transporter associated with antigen processing (TAP1 or TAP2) molecule in antigen processing, the implication of its polymorphism as a factor involved in human diseases and the possible genetic variation at this locus among ethnically diverse populations, we underwent a study to analyze the full extent of TAP1 polymorphism in an indigenous Zimbabwean population (Shona ethnic group). Using single-stranded conformation polymorphism and DNA direct sequencing procedures, we detected the presence of 11 nucleotide sequence variations in the entire coding region of TAP1. Of these variants, eight are nonconservative substitutions with respect to amino acid composition and are located in a critical part of the protein that could modulate its function. Five new polymorphic sites were identified in exon 1 (codons 7 Pro --> Ser, 17 Gly --> Arg, 141 Val --> Val), exon 6 (codon 419 Gly --> Cys), and exon 7 (codon 487 Arg --> Arg). Significant differences were seen in the distribution of TAP1*0201 and TAP1*0401 alleles, and codon 333 (Ile --> Val) polymorphism among African and non-African populations. Thus, TAP1 polymorphism has evolved differently among populations presumably because of the evolutionary pressures generated by prevalent pathogens in these geographically distinct regions.     

Physical activity improves gaze and posture control in the elderly

Ageing is associated with a decrease in the quality of balance regulation, in particular through dysfunctions of gaze control and postural stabilization, which results in an increased risk of falling. Conversely, the practice of physical and sporting activities has been shown to improve every level of postural regulation. This study is to assess the effects of the practice of physical activities on vestibulospinal reflex and ocular movements of visual and vestibular origins in elderly people. Gaze control and posture stabilization were evaluated in 13 healthy aged women who regularly practised physical activities and in 13 healthy aged sedentary women of a similar age, by dynamic posturographic test with electromyography, as well as electronystagmography with caloric and rotational vestibular tests, ocular saccades, smooth pursuit and optokinetic tests. The gaze and posture control performance of the active group was better; the proprioceptive and vestibular sensitivities were higher, visual detection quality was good, and reaction time was low. Regular physical activity develops or maintains the efficiency of the reflexes involved in postural control, especially through adequate neurosensorial information, which allows the central integrative structures to generate a more appropriate motor response.     

Physical activity, aerobic fitness, and seven-year changes in adiposity in the Canadian population.

Associations among baseline physical activity, aerobic fitness, changes in physical activity, and 7-y changes in adiposity were determined. The sample consisted of 602 males and 644 females, aged 20-69 y, from the 1981 Canada Fitness Survey and the 1988 Campbell's Survey. Questionnaire-derived measures of physical activity level consisted of activity energy expenditure (AEE) and time spent on physical activity. Participants were grouped into physical activity level categories by AEE and physical activity intensity (based on MET values), and physical activity level changes were determined from movement between tertiles of AEE from baseline to follow-up. Aerobic fitness levels at baseline were determined using the Canadian Aerobic Fitness Test. Changes in body mass, the sum of five skinfolds (SF5), and waist circumference (WC) were used as indicators of adiposity change. ANCOVA and multiple regression analyses indicated that neither baseline physical activity levels, intensity, physical activity change categories, nor aerobic fitness levels were significant predictors of changes in adiposity. In conclusion, physical activity was not predictive of 7-y changes in indicators of adiposity in this sample.     

An “all-season” mammoplasty

A reduction mammoplasty must produce a reduction in volume, a natural lasting shape, and minimal residual scarring. Many attempts to achieve this goal have been developed in recent years. The author described, in 1970, a vertical technique achieving an important reduction and a good shape but with the appearance of the end of the vertical scar below the brassiere line. In 1977, the author [3] modified the technique by the adjunction of a small horizontal scar to eliminate the inconvenience of the visible part of the vertical scar. In this article the author describes his technique which appears to be suitable for most types of breast deformities.     

Dopamine in the conscious dog with chronic heart-block

Summary The chronotropic effects of dopamine were studied in the conscious dog with chronic A-V block. Dopamine at 12.5–200 g/kg and 12.5–50 g/kg/min lowered atrial rate independently of dose. After blockade of muscarine receptors or alpha-adrenoceptors, it raised atrial rate. After blockade of dopamine receptors, dopamine still lowered atrial rate, and did so dose-relatedly after blockade of beta-adrenoceptors. It raised ventricular rate, and at high doses also induced ventricular rhythm disorders. Blockade of muscarine receptors enhanced the ventricular cardioaccelerator effect of dopamine (P<0.025) at 100 g/kg, while blockade of alpha-adrenoceptors reduced it (P<0.05). Blockade of dopamine receptors did not modify this effect, but blockade of beta-adrenoceptors reversed it. Dopamine at 25–200 g/kg raised mean blood pressure. This effect was enhanced by blockade of muscarine receptors, reversed by blockade of alpha-adrenoceptors, and was unaffected by blockade of beta-adrenoceptors or dopamine receptors. These results show that the atrial cardiomoderator effect of dopamine is a vagal reflex response to its hypertensive action, and that it is limited by its direct beta-adrenergic stimulating action. They also show that the ventricular cardioaccelerator effect of dopamine is attenuated by a reflex vagal depressor effect consequent to the induced hypertension. No evidence was found for the existence of positive chronotropic dopamine receptors in either atria or ventricles.A preliminary report of these findings was presented at the Symposium on Peripheral Dopaminergic Receptors, July 1978, in Strasbourg, France (Boucher et al. 1979b)     

Human platelets after their contact with influenza virus activate the complement system in autologous serum

Guinea pig erythrocytes that have been exposed to influenza virus activate the alternative pathway through virus-induced desialation of the cells. Neuraminidase treatment of rabbit platelets enhance their clearancein vivo. Washed human platelets were labeled with⁵¹Cr exposed to Influenza virus, and resuspended in autologous serum that had been dialyzed against Veronal-buffered saline containing Ca⁺⁺ and Mg⁺⁺ (VBS⁺⁺), VBS containing 8 mM EGTA and 2 mM Mg⁺⁺ (VBS-MgEGTA) or VBS containing 20 mM EDTA (VBS-EDTA) for 60 min at 37°C. Three per cent⁵¹Cr release and no complement consumption were observed in VBS-EDTA serum. In contrast, 6%⁵¹Cr release with 37 and 54% decrease in C3 and B hemolytic activities respectively occurred in VBS-MgEGTA serum and 14%⁵¹Cr release with 50% decrease in C2 hemolytic activity occurred in VBS⁺⁺ serum. These results suggest that influenza virus may alter the platelet surface in such a way that both complement pathways might be recruited and the cells be lyzed in autologous serum.The human complement system is activated by a number of viruses and virus-infected cells through antibody-dependent and independent mechanisms. Guinea pig erythrocytes that have been treated with influenza virus are lyzed in human serum through activation of the classical and of the alternative pathways: activation of the alternative pathway is dependent on an acquired resistance of the cell-bound C3 amplification convertase to control mechanisms that are directly related to desialation of the cells by viral neuraminidase [1]. Since,in vivo, clearance of desialated platelets is enhanced in animal models and since human platelets do not express the C3b receptor-associated inhibitory activity of the complement system, we investigated whether human platelets, after contact with influenza virus, acquire the ability to activate complement in autologous serum.     

Coloanal anastomosis after resection of low rectal cancer in the elderly

Twenty-two patients had coloanal anastomoses performed after resection of low rectal tumors (16 adenocarcinomas and 6 large degenerated villous adenomas). The patients had an average age of 72 years (range: 62–85). A hand-sewn anastomosis was performed between a J-shaped colonic reservoir and the anal sphincter, except in 3 patients who underwent a straight end-to-end coloanal suture without pouch. A defunctionalized stoma was made in 18 cases. Mortality within 30 days of operation was 9%. Specific complications occurred in 2 patients (9%). Mean follow-up in this series was 20.2±11.7 months (± standard deviation). Fifteen patients were alive and free of disease up to 54 months after surgery. One patient was found to have local recurrence at 19 months. The actuarial 3-year survival rate was 73% in the whole group (operative mortality included). Functional results were good in 16 of 19 patients, with an average 1.8–2.9 stools/24 hours and the continence rate was good. Three patients had complications requiring a permanent colostomy. From these preliminary results, coloanal anastomosis appears to be satisfying in regard to oncologic results and affords good anal function, even in the elderly patient (over 62 years of age).

---

Resumen Veintidos pacientes fueron sometidos a anastomosis después de la resecciôn de tumores rectales bajos (16 adenocarcinomas y 6 grandes adenomas vellosos con degeneración carcinomatosa), con edad promedio de 72 años (rango: 62–85). Se practicó anastomosis manual entre un reservorio colónico construído en forma de J y el esfínter anal, excepto en 3 pacientes sometidos a sutura colo-anal términoterminal sin construcción de bolsa. Se practicó un estoma de funcionante en 18 casos. La mortalidad en los primeros 30 días después de la operación fue 9%. Se presentaron complicaciones específicas en 2 pacientes (9%). El seguimiento promedio en la serie fue de 20.2±11.7 meses (± de). Quince pacientes se encuentran vivos y libres de enfermedad hasta por 54 meses. Un paciente demostró recurrencia local a los 19 meses. La tasa actuarial de sobrevida a 3 anos es de 73% para el grupo total (incluyendo la mortalidad operatoria). Los resultados funcionales fueron buenos en 16 de 19 pacientes, con un promedio de 1.8 a 2.9 deposiciones/24 horas y buena continencia. Tres pacientes presentaron complicaciones que requirieron colostomía permanente. Según estos resultados preliminares, la anastomosis colo-anal aparece como un procedimiento satisfactorio en relación con los resultados oncológicos y provee buena función anal aun en el paciente anciano (mayor de 62 años).

---

Résumé Vingt-deux patients ont eu une anastomose coloanale après résection d'une tumeur rectale basse (16 adénocarcinomes et 6 tumeurs villeuses larges dégénérées). L'âge moyen des patients était de 72 ans (extrêmes 62 et 85 ans). Dix-neuf patients ont eu une anastomose manuelle entre un réservoir colique en J et le canal anal, alors que 3 ont eu une anastomose manuelle termino-terminale coloanale sans réservoir. Une colostomie de décharge a été ajoutée dans 18 cas. La mortalité des 30 premiers jours postopératoires a été de 9%. Deux patients (9%) ont eu des complications spécifiques. La survie moyenne a été de 20.2±11.7 mois (± ET). A 54 mois, 15 patients sont en vie et sans maladie. Une récidive locale a été décelée chez un patient à 19 mois. La survie actuarielle à 3 ans est de 73% pour l'ensemble des patients (mortalité opératoire incluse). Les résultats fonctionnels étaient bons chez 16 des 19 patients. Ces patients avaient en moyenne 1.8 à 2.9 selles par 24 heures et la continence était bonne. Trois patients avaient des complications nécessitant une colostomie permanente. D'après ces premiers résultats, il semble que l'anastomose coloanale donne de bons résultats du point de vue oncologique avec conservation d'une fonction sphinctérienne satisfaisante, même chez le patient âgé (plus de 62 ans).

---

---

Presented at the Société Internationale de Chirurgie in Toronto, Ontario, Canada, September, 1989.     

The structure of human S-phase chromosome fibres

Recentin situ hybridization studies suggested that within the range of 0.1–1.0 Mb, human interphase chromosomes follow a random walk model (i.e. they behave as flexible polymers without major constraints). However, chromosome structure may differ in the G1, S, and G2 phases, and phase-specific constraints may be masked if the chromosome analysis does not discriminate between the phases. Therefore, using confocal microscopy, we examined the structure of S-phase chromosomes labelled with 5-iododeoxyuridine after prolonged treatment with 5-fluorodeoxyuridine. In the S-phase, labelled 0.32 µ chromosome fibres mostly appear as semi-circles with an average diameter of 0.83 ±0.03 µ. These semi-circles are joined together to form different 3D structures, and two semicircles frequently adopt s- or-like conformations involving about 2.5 µ of the chromosome contour length (L). Morphometric analysis of the S-phase fibres suggests that our data fit both the random flexible polymer model and also a model in which two constrained semi-circles are attached to each other by a flexible joint, thus eliminating constraints at long distances (L more than 2 µ).     

Monitoring pathological assembly of tau and β-amyloid proteins in Alzheimer's disease

This double-labelling confocal microscopy study of the neuropathology of Alzheimer's disease (AD) reports the use of a fluorescent dye, thiazin red, which has staining properties similar to thioflavin-S. Thiazin red fluorescence can be visualised selectively in the red channel, and we have used this property to compare it with the labelling seen using monoclonal antibody (mAb) 423, which detects tau protein C-terminally truncated at Glu-391, and mAb 4G8, which detects -amyloid protein. Thiazin red is shown to recognized the typical histopathological deposits associated with both proteins. However, not all deposits containing these proteins are stained. Specifically, diffuse -amyloid plaques and severely degraded extracellular tangles are unlabelled. Likewise a characteristic mAb 423-reactive granular plaque-like structure, typically present in cases with abundant extracellular tangels, is unlabelled by thiazin red. Such plaques can be shown to be continuous with the basal dendrites of degraded tanglebearing pyramidal cells. These findings suggest that paired helical filaments (PHFs) continue to undergo degradation in the extracellular space, which is associated with loss of thiazin red binding sites, but preservation of mAb 423 immunoreactivity. This epitope appears to be characteristic of a stable core element of the PHF which is highly resistant to proteolysis. Compounds such as thiazin red with high affinity for -pleated protein structures can be used to monitor the state of pathological assembly of amyloidogenic protein species found in AD.Supported in part by CONACyT grant #1624-N9208 (to R.M.), the Medical Research Council (U.K.), Zeneca Pharmaceuticals and the Alzheimer Disease Research Fund and the Leopold Muller Estate