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S Nielsen

Publications and source records attributed to S Nielsen.

At least 19 recordsLinked to original sources
PubMed1992

Novel functional M1 selective muscarinic agonists. Synthesis and structure-activity relationships of 3-(1,2,5-thiadiazolyl)-1,2,5,6-tetrahydro-1-methylpyridines .

A series of novel 3-(3-substituted-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro- 1-methylpyridines (substituted-TZTP; 5a-l, 7a-h, 8, 9c-n, 11, 13j) were synthesized and tested for central muscarinic cholinergic receptor affinity by using [3H]-oxotremorine-M (Oxo-M) and [3H]-pirenzepine (Pz) as ligands. The potency and efficacy of the compounds for the pharmacological defined M1 and M2 muscarinic receptors were determined on isolated electrically stimulated rabbit vas deferens and on spontaneously beating isolated guinea pig atria, respectively. Selected compounds were also tested for M3 activity in the isolated guinea pig ileum. The C1-8 alkoxy-TZTP 5a-l analogues all displaced [3H]-Oxo-M and [3H]-Pz with low nanomolar affinity. Depicting chain length against Oxo-M binding and against Pz binding the unbranched C1-8 alkoxy-TZTP (5a-h) derivatives produced U-shaped curves with butoxy- (5d) and (pentyloxy)-TZTP (5e) as the optimum chain length, respectively. This U-shaped curve was also seen in the ability of the compounds 5a-h to inhibit the twitch height in the vas deferens preparation. The (pentyloxy)- (5e) and the (hexyloxy)-TZTP (5f) analogues produced an over 90% inhibition of the twitch height with IC50 values in the low picomolar range. In both the atria and in the ileum preparations 5f had low efficacy and potency. With the (alkylthio)-TZTP (7a-h) analogues the structure-activity relationship was similar to the one observed with the alkoxy (5a-h) analogues, but generally 7a-h had higher receptor affinity and was more potent than the corresponding 5a-h. However, the C3-8 alkyl-TZTP (9c,e,g,h) analogues had 10-100 times lower affinity for the central muscarinic receptors than the corresponding alkoxy and alkylthio derivatives, and their efficacy in the vas deferens preparation was too low to obtain IC50 values. The unsubstituted TZTP (11) compound was a potent but nonselective muscarinic agonist. The two 3-(3-butoxy/(hexyloxy)-1,2,5-oxadiazol-4-yl)-1,2,5,6-tetrahy dro-1- methylpyridines (butoxy/hexyloxy)-OZTP; 19a/b) were also synthesized and tested. Both 19a and 19b had much lower affinity for the central muscarinic receptors than 5d and 5f, and the efficacy of 19a,b was too low to give IC50 values in the vas deferens preparation. Therefore, the C5-6 (alkyloxy)/(alkylthio)-TZTP's represent a unique series of potent functional M1 selective muscarinic agonists.

Animals↗
PubMed1992

Time course and kinetics of proximal tubular processing of insulin.

The present study was undertaken to determine the time courses and kinetics of the subcellular processing of 125I-insulin in isolated and in vitro perfused proximal tubules. Morphometric analysis demonstrated well-preserved ultrastructure after 90 min of perfusion. After luminal perfusion for 90 min the absorption was constant with time and reached steady state within 5 min (177 +/- 7 fg.min-1.mm-1). Also the hydrolysis rate and tubular accumulation rate were constant and averaged 84 +/- 8 and 93 +/- 10 fg.min-1.mm-1, respectively. Free 125I appeared already within 5 min of perfusion and reached steady state within 10 min. From proximal tubules perfused with 125I-insulin for 30 min and chased for 60 min, a compartmental analysis revealed two compartments; half time (t1/2) for delivery of insulin to the lysosomes was determined to be 8.5 min, and t1/2 for lysosomal degradation was 72 min. The results demonstrated that internalization by endocytic invaginations, incorporation in endocytic vacuoles, fusion with lysosomes, and hydrolysis were rapid processes and reached maximum rates within few minutes. A significant transtubular transport of insulin to the peritubular compartment was determined to be a constant rate of 11.2 +/- 0.7 fg.min-1.mm-1. Perfusion of tubules with insulin at high concentrations in the perfusate revealed that the transport was dependent on the absorbed amount and not on the perfused load, compatible with transport through the cells and not via a paracellular mechanism. The intactness of the tight junctions was supported by the following: 1) [14C]inulin leak did not increase with time and 2) enzyme-free intercellular spaces were evident after perfusion for only 5 min with microperoxidase (mol wt of 1,700). The transported 125I-insulin was trichloroacetic acid precipitable and immunoprecipitable.

Animals↗
PubMed1992

The press-fit Kinemax knee arthroplasty. High failure rate of non-cemented implants.

We report the results of 75 consecutive primary press-fit Kinemax arthroplasties with an average follow-up of 14 months (three to 28). We reviewed 26 cemented and 49 non-cemented tibial components implanted into 72 patients (30 men and 42 women, median age 70 years). At the latest follow-up the overall evaluation (Hospital for Special Surgery knee rating scale) for cemented cases was excellent in 54%, good in 42% and poor in 4%. No cemented prosthesis loosened. Of the non-cemented cases 55% were excellent, 23% good, and 2% fair. Ten tibial implants (20%) loosened and required revision. Residual pain marred the result in 24% of the non-cemented prostheses and in 4% of the cemented group. We do not recommend the press-fit, smooth-surfaced Kinemax prosthesis for non-cemented use.

Adult↗
PubMed1992

Microalbuminuria in non-insulin-dependent diabetes.

According to international consensus, microalbuminuria is defined as an elevated urinary albumin excretion rate (UAER) of 20-200 micrograms/min, which is below the proteinuric range. Nephropathy is a major complication in IDDM, seen in about 30% of patients after many years of diabetes. Increasing microalbuminuria is an excellent marker of subsequent nephropathy in these patients. End-stage diabetic nephropathy is also important in NIDDM, but in most Western countries this serious complication eventually develops in only 5 to 10% of cases, whereas the majority of patients die before this from cardiovascular disease. In completely healthy individuals there is no clear correlation between age and UAER, at least up to about 70 years of age. The mean excretion rate is around 5 micrograms/min, with a considerable range, but excretion only rarely exceeds 15 micrograms/min. In population studies among middle-aged and elderly individuals, higher values are seen. In newly diagnosed NIDDM about 40% of patients show an excretion rate above 15-20 micrograms/min. There is a significant but not precise correlation between albumin excretion rate and glycemic control, and usually UAER is reduced by standard antidiabetic treatment. In a considerable number of patients, high values cannot be reduced. In the course of NIDDM about 20-30% of patients show microalbuminuria. In patients with known diabetes, microalbuminuria is related not only to subsequent diabetic proteinuria, but even more strongly to early death, mainly from cardiovascular disease. Even slight microalbuminuria (15-40 mg/l in early morning urines) is clearly associated with increased mortality. In subjects with newly detected elevated blood glucose (by screening) microalbuminuria also predicts early mortality. The mechanisms are not established, but several arteriosclerosis-related risk factors are seen more frequently in patients with microalbuminuria, e.g. lipid abnormalities, elevated systolic blood pressure (BP), hemostatic measures, as well other markers of cardiovascular disease. Usually there is a significant but not precise correlation between BP and UAER in groups of patients throughout the course of diabetes. New studies document that also in the elderly background population microalbuminuria is a significant risk factor for early death, maybe even stronger than the established risk markers, which thus may be confounded with the presence of microalbuminuria.

Adult↗
PubMed1991

Membrane traffic after inhibition of endocytosis in renal proximal tubules.

This study was performed to examine quantitatively the cellular organelles involved in membrane recycling after inhibition of luminal endocytosis in renal proximal tubules. Paraffin oil was microinfused into rat renal proximal convoluted tubules to prevent luminal endocytosis. After 1-2 hr the kidneys were fixed by perfusion and prepared for electron microscopy. Segment 1 proximal tubules infused with paraffin oil and control tubules from the same kidney were studied. In addition we examined proximal tubules from kidneys fixed by immersion 30 sec after removal of the kidney. In the oil-infused tubules the large endocytic vacuoles (greater than 0.5 micron) disappeared, the amount of small endocytic vacuoles (less than 0.5 micron) was reduced to about 10%, and the amount of dense apical tubules was significantly increased. The dense apical tubules were very seldom seen connected to the apical plasma membrane in controls but this was occasionally observed in tubules fixed by immersion and relatively often in oil-infused tubules. An ultrastructural morphometric analysis substantiated and extended the qualitative observations and provided quantitative estimates of volumes and surface areas for large endocytic vacuoles, lysosomes, mitochondria, small endocytic vacuoles, and dense apical tubules in control and experimental tubules. The results strongly support the suggestion that the dense apical tubules located in the apical cytoplasm represent the vehicle for the recycling of membrane from endocytic vacuoles back to the plasma membrane, and show that in renal proximal tubule cells small and large endocytic vacuoles are transformed into dense apical tubules when endocytosis is stopped.

Animals↗
PubMed1991

Peptide YY luminal processing and axial heterogeneity of basolateral binding in renal proximal tubules.

This study investigates the definite location of peptide YY (PYY) binding sites on the basolateral membranes in proximal tubules. S1, S2, and S3 segments were dissected, perfused in vitro, and exposed to [125I-Tyr36]monoiodo-PYY either in the bath fluid or in the perfusate. S1 segments exposed to [125I-Tyr36]PYY in the bath fluid were fixed and prepared for electron microscope autoradiography. The results demonstrated a high degree of axial heterogeneity of basolateral binding of PYY, since only S1 bound PYY, 0.59 +/- 0.09 pg/mm after 15 min; 89.1% could be displaced with unlabeled PYY. PYY was not internalized, 90% of the grains were associated with the basolateral membranes, and no accumulation of grains was observed over the vacuolar apparatus. After luminal perfusion with PYY, 79.3 +/- 7.2% was processed, 61.7 +/- 6.3% was degraded at the brush border, and no tubular accumulation was detected. Thus PYY is not taken up by endocytosis. Unexpectedly, a very large fraction of processed PYY was transported from lumen to bath as trichloroacetic acid (TCA)-precipitable label constituting 41.6 +/- 4.7%. There was no axial heterogeneity in the luminal handling of PYY. In conclusion, this study reveals a high density of PYY binding sites at the basolateral membranes from S1 segments, indicating a selective function of S1 segments on stimulation with PYY. In contrast to other proteins PYY was not internalized from the basolateral membranes.

Animals↗
PubMed1991

Anterolateral instability in the anterior cruciate ligament deficient knee. A cadaver study.

Knee instability was evaluated in 13 normal osteoligamentous knee preparations after transection of the anterior cruciate ligament. Abduction-adduction rotation, coupled tibial translatory movement, and coupled tibial axial rotation were recorded continuously and simultaneously during flexion or extension while applying a well defined valgus directed moment and during extension while applying an anterior tibial force. As a result of the valgus-directed moment, an increase was found in abduction rotation, in coupled anterior tibial translation, and in coupled internal tibial axial rotation. Coupled rotatory and translatory instabilities were larger, and maximum instability was observed at a smaller knee angle during the extension movement than during the flexion movement. The pattern of the instability, excited as a result of the valgus moment, was different from the instability excited as a result of an anterior tibial force.

Aged↗
PubMed1990

A simple calf muscle ergometer for use in a standard whole-body MR scanner.

A calf muscle ergometer, designed for use in a standard whole-body MR scanner, is described. The instrument allows isotonic or isometric calf muscle exercise over a continuous range of work loads from 0 to individual maximum work output. Work output may be recorded on a strip chart recorder. A sound encoding provides an effective guidance for the subject tested to accurately reproduce his performance in each contraction cycle at a given work load. The FID recording may be triggered from the ergometer at any point during the contraction cycle. Nonmetal materials are used for the instrument construction in order to eliminate potentially disturbing eddy currents. The force resistance of the ergometer is obtained by a combined hydraulic-pneumatic system, which is loaded by coupling to an outside source of compressed air equipped with a suitable pressure regulator. When varying the time of data sampling within a repeated 6-s contraction cycle it was found that the recorded Pi/PCr ratio remained essentially constant at low and moderate work loads. However, at work loads at or above 70% of individual Vmax a pronounced dependence of the time of sampling with the contraction cycle was observed.

Equipment Design↗
PubMed1990

Long-term bone loss in insulin-dependent diabetes mellitus.

The bone mineral content (BMC) in patients with insulin-dependent diabetes is reduced by 10% early in the disease, but due to a lack of long-term longitudinal studies it is unknown whether this diabetic osteopenia develops further through life. Over a time period of 11 years we examined the BMC in a group of seven adult insulin-dependent diabetics, in whom physiological and pathological factors affecting bone metabolism had been excluded; the patients were well regulated without diabetic complications. The BMC was not significantly decreased at the initial examination. The longitudinal study revealed a small but statistically significant fall in BMC, mainly in trabecular bone. The narrow (95%) confidence interval of median end value (93.3-99.0% of initial BMC) indicates that the annual decrease in BMC in such patients is of the order of 0.5%, a reduction that is probably clinically insignificant.

Adult↗
PubMed1990

Reversible somatotropin deficiency (psychosocial dwarfism) presenting as conduct disorder and growth hormone deficiency.

The syndrome of reversible somatotropin deficiency (psychosocial dwarfism) is characterized by environment-related impairment of stature and mental growth and growth-hormone secretion. The syndrome is well illustrated by this case report of an eight-year-old boy with psychosocial dwarfism since the third year of life. It was undetected for four years, despite his having been in regular contact with a number of health workers. After he was removed from the deleterious environment, both his growth and behaviour improved markedly, and at follow-up he had maintained this progress.

Child↗
PubMed1990

The epidemiology of anorexia nervosa in Denmark from 1973 to 1987: a nationwide register study of psychiatric admission.

A nationwide register study of psychiatric admission for anorexia nervosa in Denmark yielded average incidence rates of 1.9 per 100,000 per year for females and 0.17 per 100,000 per year for males. The prevalence was 6.7 per 100,000 per year for females and 0.6 per 100,000 per year for males. The female-male ratio for first admissions was 11.8:1. The incidence of anorexia nervosa showed no trend in the general population, but an increase was found among psychiatric inpatients. This increase was explained by a reduction by one third in all psychiatric first admissions and in available psychiatric beds and augmented by an increase in readmissions of anorectic patients. Males were younger than females at first admission. Females were older at first admission from 1973 to 1977 than in later periods. Of males readmitted for non-eating disorders, more were psychotics and fewer psychopaths than among females. Age-period and age-cohort analysis of the 10- to 24-year-old females showed that only age exerted a significant independent influence on first-admission rates, whereas all 3 factors exerted significant independent influence on readmission rates. This might reflect changes in admission policy, greater diagnostic vigilance and changes in attitude towards weight, shape and fitness.

Adolescent↗
PubMed1990

Distal humeral migration as a component of multidirectional shoulder instability. An anatomical study in autopsy specimens.

The object of the present study of autopsy specimens was to evaluate distal humeral migration during abduction allowed by sequential severance of capsular and ligamentous structures stabilizing the shoulder joint. A kinesiologic testing device continuously registered distal humeral migration, abduction angle, rotation, and flexion-extension. No distally directed force was applied to the humerus except the weight of the apparatus. Significant distal migration was recorded in the entire range of abduction (0 degrees -60 degrees) after solitary severance of the coracohumeral ligament as well as the proximal part of the anterior joint capsule. Further sectioning of the proximal part of the posterior capsule did not significantly increase distal humeral migration. Maximum distal migration (25 mm) was measured at 20 degrees of abduction. Applying an internal torque to the humerus significantly prevented distal migration as long as the posterior capsule was kept intact. Clinical testing for distal humeral migration should be performed with the shoulder joint at 20 degrees of abduction and neutral rotation. Furthermore, distal humeral migration can be significantly reduced by internal rotation of the humerus when the posterior joint capsule is intact.

Aged↗
PubMed1989

Cachectin/tumor necrosis factor and interleukin-1 show different modes of combined effect on lipoprotein lipase activity and intracellular lipolysis in 3T3-L1 cells.

Cachectin/tumor necrosis factor (cachectin/TNF) and interleukin-1 (IL-1) share many effects in various tissues and cells, including suppression of lipoprotein lipase (LPL) activity and enhancement of intracellular lipolysis. A possible interaction between cachectin/TNF and IL-1 in these lipase systems was studied in 3T3-L1 adipocytes. The two cytokines showed marked synergy in their suppression of LPL activity in these adipocytes. The least effective dose of cachectin/TNF or IL-1 was at around 5 x 10(-11) or 2.5 x 10(-12) M, respectively. However, when present in combination in amounts as small as 1/20 or 1/100 of the minimum effective dose for either cytokine alone (2.5 x 10(-12) M cachectin/TNF and 2.5 x 10(-14) M IL-1), the cytokines showed marked suppression of LPL activity. In marked contrast, such synergism was not seen for enhancement of intracellular lipolysis. This discrepancy in the combined effects of the two monokines on the two different enzyme systems in the same cells suggests that synergism between cachectin/TNF and IL-1 is unlikely at the level of their receptors on the surface of 3T3-L1 cells. Because the two monokines are considered to be secreted from macrophages under similar conditions, their effect on LPL suppression in many pathophysiological situations would be much greater than that of either monokine alone.

Adipose Tissue↗