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Biomedical subjects

J Møller

Publications and source records attributed to J Møller.

At least 109 records · Page 6Linked to original sources
PubMed1990

Effects of growth hormone on body composition in adults.

GH replacement therapy in GH-deficient adults has recently been shown to increase (normalize) muscle volume and decrease adipose tissue volume as measured by means of CT scan and skinfold thickness. Also in adults with acquired GH deficiency in adulthood, GH replacement has been shown to significantly influence body composition with an increase in lean body mass and a reduction in skinfold thickness. Preliminary results from an open long-term trial indicate that 12 months of GH substitution result in a further normalization of the muscle/fat ratio. The fluid-retaining effect, with a significant increase in extracellular-fluid volume demonstrated during GH administration to normal subjects, seems to be of little clinical importance if a replacement dose around 2 IU/m2/day is chosen for young GH-deficient adults. Long-term trials are needed to finally establish the indication of GH replacement therapy in GH-deficient adults.

Adipose Tissue↗
PubMed1990

Pharmacological aspects of growth hormone replacement therapy: route, frequency and timing of administration.

Two or three weekly, daytime intramuscular injections of GH has been the traditional treatment of GH deficiency since the first studies. A recent reevaluation of the feasibility of subcutaneous GH injections revealed no side-effects, but a very strong preference by the patients for the subcutaneous route, and also an increase in growth rate in studies where the patients received daily injections given in the evening. That could indicate that the route, frequency and timing of GH administration may be of clinical importance. Subcutaneous injections result in a slower absorption, a smaller peak value, and a prolonged serum disappearance phase compared to intramuscular injections. This extends the periods of elevated serum GH levels in the patient, which might be advantageous. On the other hand, a reduced bioavailability of GH by the subcutaneous route has also been reported. The frequency of subcutaneous injections correlates positively with growth rate in animal studies. This is commonly ascribed to a closer resemblance to the endogenous pulsatile pattern. However, frequent subcutaneous injections do not induce a pulsatile pattern, but a pattern which is intermediary between continuous and true pulsatile administration. In a short-term patient study, we observed that pulsatile and continuous intravenous administration of GH generated identical increases in serum insulin-like growth factor I, which suggests that both pulsatory and constant, small elevations in serum GH are important for its actions. Concerning the time of administration, evening GH injections yield a more physiological pattern, and it has been shown that evening GH administration induces increased nitrogen retention and is more successful in normalizing circadian patterns of pertinent hormones and metabolites.(ABSTRACT TRUNCATED AT 250 WORDS)

Drug Administration Routes↗
PubMed1990

Lack of effects of hyperglycemia on the disposal of 3-hydroxybutyrate in insulin-dependent diabetic patients.

There is evidence that hyperketonemia in insulin-dependent diabetes may be aggravated by a decreased disposal rate for ketone bodies. To test the hypothesis that this decrease may be induced by concomitant hyperglycemia through substrate competition at the acetyl-CoA level, 5 young insulin-dependent diabetic subjects received at 2-h iv infusion of 0.9 mmol 3-hydroxybutyrate.kg-1.h-1 at clamped 1. euglycemia (5 mmol/l) and 2. hyperglycemia (11 mmol/l) on separate occasions. To ensure similar metabolic conditions, a low-dose hyperinsulinemic euglycemic clamp was performed during the 5 h preceding the actual studies. Substrate fluxes in muscle were assessed through the forearm technique. The glucose infusion rate was 4.9 and 2.9 mg.kg-1.min-1, and the forearm arteriovenous difference for glucose was 0.72 during hyperglycemia and 0.39 mmol/l (p less than 0.05), during euglycemia. Hyperglycemia did not affect circulating levels of free insulin, glucagon, non-esterified fatty acids, 3-hydroxybutyrate (hyperglycemia: 665, euglycemia: 770 mumol/l, p greater than 0.05) or acetoacetate, nor forearm uptake of 3-hydroxybutyrate (hyperglycemia, 152, euglycemia: 168 mumol/l, p greater than 0.05). In conclusion, our results do not suggest any inhibitory role for hyperglycemia in the disposal of ketone bodies. In as much as extrapolation from the present well insulinized state is appropriate, the data indicate that alternative mechanisms may be involved in the observed impairment of ketone body clearance in hyperketonemic insulin-dependent diabetic patients.

3-Hydroxybutyric Acid↗
PubMed1990

Growth hormone (GH) therapy in GH-deficient patients, the plasma factor VIII-von Willebrand factor complex, and capillary fragility. A double-blind, placebo-controlled crossover study.

It has been suggested that growth hormone (GH) plays a role in the regulation of Factor VIII-von Willebrand factor complex and other parameters associated with haemostasis and vascular integrity. However, limited information is available on these features in GH-deficient patients. We therefore examined, in a double-blind, placebo-controlled crossover design, the effects of 4 months' replacement therapy with biosynthetic human GH in 22 GH-deficient adults on circulating haemostatic parameters and capillary fragility. A non-significant increase in the plasma levels of von Willebrand factor antigen (p = 0.09), Factor VIII antigen (p = 0.6), fibrinogen (p = 0.4) and fibronectin (p = 0.2) was observed at the end of the GH treatment period along with a non-significant decrease in tissue-type plasminogen activator (p = 0.2). Capillary fragility tended to decrease during GH therapy (p = 0.2). All variables remained within the reference range following both the placebo and the GH treatment period. It is concluded that GH-deficient patients display normal levels of the haemostasis parameters recorded, and that 4 months of GH therapy in a conventional replacement dose does not significantly affect these values.

Adolescent↗
PubMed1990

Methylmalonic acid concentrations in serum of normal subjects: biological variability and effect of oral L-isoleucine loads before and after intramuscular administration of cobalamin.

The clinical value of measuring concentrations of methylmalonic acid in serum (S-MMA) as an aid in the diagnosis of cobalamin deficiency has recently aroused interest. In 58 healthy subjects, ages 40-68 years, we found a 0.95 reference interval of 0.05-0.37 mumol/L (mean 0.21, SD 0.094). In 33 of the subjects, who were studied further, day-to-day variation (SD) was 0.031 mumol/L. Intake of food had no effect. Weekly and three-monthly intra-individual variations were both 0.038 mumol/L. In all seven subjects with S-MMA greater than 0.30 mumol/L, the concentrations declined significantly after intramuscular administration of cobalamin. No significant difference was found between mean serum cobalamin concentrations in these seven and in the remaining subjects. We have also established the normal response of S-MMA to standardized oral loading of L-isoleucine: 100 mmol caused a significant average S-MMA increase of 0.072 mumol/L before cobalamin administration vs 0.013 mumol/L after cobalamin, without significant relation to initial S-MMA values. Our results provide a necessary background for interpretation of S-MMA measurements in clinical studies.

Administration, Oral↗
PubMed1989

False positive results in an enzyme immunometric assay for the ovarian cancer associated antigen CA 125.

A commercially available two-site, solid phase enzyme immunoassay was used for measuring CA 125. Samples from six healthy subjects with known false positive CA 125 results (range 42-895 U/ml) were retested after addition of murine serum. A decrease ranging from 45 to 81% in the CA 125 levels was seen after addition of 63 ml/l murine serum. After addition of 500 ml/l three out of six samples had antigen levels below 35 U/ml. It is concluded that in the present study false positive CA 125 results could be diminished by addition of murine serum to the sample and may be due to human antibodies against murine immunoglobulins. Addition of murine serum to samples from persons with no evidence of disease and increased CA 125 levels is recommended.

Animals↗
PubMed1989

Specific depletion of mature T lymphocytes from human bone marrow.

An effective method for specific depletion of mature T lymphocytes from human bone marrow mononuclear cells (BMMC) with preservation of prethymic T cells and natural killer (NK) cells is presented. The BMMC were incubated with F101.01, a monoclonal antibody recognizing an epitope of the T-cell receptor-CD3 complex, and subsequently with immunomagnetic beads. Flow cytometric analysis demonstrated that mature T cells were efficiently depleted and that NK cells and prethymic T cells were preserved in the BMMC. Furthermore, T cell-mediated immune reaction as measured by thymidine incorporation after stimulation with phytohaemagglutinin was abolished, whereas NK activity as measured by 51Cr release using K562 as target cells was preserved. Recovery of colony-forming units of granulocyte-macrophages was 60-70%.

Bone Marrow↗
PubMed1989

Immunodeficiency after allogeneic bone marrow transplantation in man. Effect of phorbol ester (phorbol myristate acetate) and calcium ionophore (A23187) in vitro.

This study was undertaken to clarify the mechanism behind the severely decreased lymphocyte proliferative response upon stimulation with mitogens and antigens seen after allogeneic bone marrow transplantation (BMT) in man. We investigated eight BMT patients and eight controls and found that the proliferative response of patient cells was reduced both when the cells were stimulated with phytohaemagglutinin (PHA) and when they were stimulated with a combination of phorbol myristate acetate (PMA), which is an activator of protein kinase C (PKC), and the calcium ionophore A23187, which irreversibly opens for calcium transport into the cell (median relative responses were 41 and 37%, respectively). However, the PHA-induced increase in the concentration of intracellular free calcium in post-BMT cells was not significantly different from the values found in control cells and the expression of interleukin 2 (IL-2) receptors (CD25) was only slightly decreased. However, the production of IL-2 was severely decreased in patient cells after stimulation with A23187/PMA (median 3541 units), although it was higher than in PHA-stimulated control cells (median 354 units). These results show that a direct activation of PKC by PMA combined with an increase in intracellular free calcium by A23187 cannot overcome the lymphocyte proliferation deficiency in cells from patients after allogeneic BMT. The data suggests that the defect is affecting the diacylglycerol pathway considerably more than the inositol triphosphate pathway.

Adolescent↗
PubMed1989

Growth hormone administration by means of an injection pen.

We have evaluated the pharmacokinetics, reliability and patient tolerability of a newly developed injection pen for cartridged growth hormone (GH). The cartridge contains 25 IU GH in 2 ml solvents. The pen, which is basically a needle, syringe and vial in one piece, is operated by a turning movement and allows doses from 0.25-4 IU. Nine GH deficient patients were hospitalized twice for overnight bloodsampling following subcutaneous injections (at 8 p.m.) of GH: i.e. when using traditional syringe and vial and after 6 weeks of use of the pen. Serum GH antibodies were measured immediately prior to, and 3 and 6 months following pen treatment. GH containers were collected regularly from the patients for chemical analysis. A questionnaire was completed during and at the end of the study. The absorption rate and bioavailability of GH tended to be higher with syringe and vial (2 P = 0.07) but there were no differences in the profiles of IGF-I, insulin, glucagon or pertinent metabolic parameters following the 2 injection modes. No GH antibodies occurred during 6 months of pen treatment. The content of polymeric GH was lower in the cartridges (2 P less than 0.001). Seven of the patients reported less injection pain when using the injection pen, which they all strongly preferred and wished to continue using. We conclude that the GH injection pen is a reliable tool which seems to be more convenient for the patients.

Growth Hormone↗
PubMed1988

Effect of thapsigargin on cytoplasmic Ca2+ and proliferation of human lymphocytes in relation to AIDS.

The tumor-promoting sesquiterpene lactone, thapsigargin, induced a dose-dependent increase of the cytoplasmic Ca2+ concentration ([ Ca2+]i) in human lymphocytes from a resting level between 100 and 150 nM up to about 1 microM. Half-maximum response was found at about 1 nM of thapsigargin, full response at 100 nM. The effect of thapsigargin on [Ca2+]i exceeded that of phytohaemagglutinin (PHA) which raised [Ca2+]i to maximum 300 nM. In combination with phorbol 12-myristate 13-acetate (PMA), thapsigargin stimulated the proliferation of normal lymphocytes to the same extent as did PHA, whereas the thapsigargin/PMA treatment could not restore the defective proliferation of AIDS lymphocytes in spite of the increased [Ca2+]i. Thapsigargin or PMA added separately had no stimulatory effects on cell proliferation. The thapsigargin/PMA treatment caused an increase in the interleukin-2 (IL-2) production of the lymphocytes, which was much higher than that caused by the PHA treatment, even in AIDS lymphocytes. Moreover, the thapsigargin/PMA treatment stimulated the expression of the IL-2 receptors on both normal and AIDS lymphocytes, similar to the effect of PHA. It is concluded that thapsigargin exerts its effects on lymphocyte proliferation by increasing [Ca2+]i, and that the general defect of AIDS lymphocytes, rather than being ascribed to the initiating signal systems, is associated with later events related to DNA synthesis and proliferation.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Phosphoenzymes formed from Mg.ATP and Ca.ATP during pre-steady state kinetics of sarcoplasmic reticulum ATPase.

We have investigated here the pre-steady state kinetics of sarcoplasmic reticulum ATPase incubated under conditions where significant amounts of Mg.ATP and Ca.ATP coexist, both of them being substrates for the ATPase. We confirmed that these two substrates are independently hydrolyzed by the ATPase, which thus apparently catalyzes Pi production by two simultaneous and separate pathways. External calcium (or the Ca2+/Mg2+ ratio) determines the extent to which Ca2+ or Mg2+ is bound at the phosphorylation site, while internal calcium controls the rate of processing of both the slow, calcium-containing and the fast, magnesium-containing phosphoenzyme. Time-dependent binding of calcium at the catalytic site is correlated with the observed burst of Pi liberation, which therefore results from reequilibration during pre-steady state of magnesium- and calcium-containing phosphoenzyme pools. Independently of direct exchange of metal at the catalytic site, ADP produced by the hydrolysis reaction contributes to reequilibration of these pools through reversal of phosphorylation by the ATP-ADP exchange pathway.

Adenosine Diphosphate↗
PubMed1988

Complete amino acid sequence of human intestinal aminopeptidase N as deduced from cloned cDNA.

The complete primary structure (967 amino acids) of an intestinal human aminopeptidase N (EC 3.4.11.2) was deduced from the sequence of a cDNA clone. Aminopeptidase N is anchored to the microvillar membrane via an uncleaved signal for membrane insertion. A domain constituting amino acid 250-555 positioned within the catalytic domain shows very clear homology to E. coli aminopeptidase N and contains Zn2+ ligands. Therefore these residues are part of the active site. However, no homology of the anchor/junctional peptide domain is found suggesting that the juxta- and intra-membraneous parts of the molecule have been added/preserved during development. It is speculated that this part carries the apical address.

Amino Acid Sequence↗
PubMed1987

Nephrotoxicity of cyclosporin A in humans: effects on glomerular filtration and tubular reabsorption rates.

The contention that cyclosporin A (CyA) nephrotoxicity may be due to renal afferent arteriolar constriction was inferred from rat studies showing CyA to increase renal vascular resistance, to reduce glomerular filtration rate (GFR) and delivery of tubular fluid from the end of the proximal tubule to the loop of Henle (Vprox), and to increase proximal fractional reabsorption. In order to test whether the mechanism of human CyA nephrotoxicity is similar to its rat analogue, and whether CyA treatment causes prolonged renal malfunction after drug withdrawal, renal function was investigated with clearance techniques including lithium clearance (CLi) as a measure of Vprox. The subjects were patients (n = 11) with previously normal renal function, given CyA in the treatment of ocular manifestation of extrarenal disease, or bone-marrow transplant recipients. Nine out of these eleven patients were investigated before and during CyA treatment: GFR (P less than 0.05) and Vprox (P less than 0.005) decreased while proximal fractional reabsorption increased (P less than 0.01). In six patients investigated before CyA was given, and re-examined a mean of 273 days (range 84-384 days) after CyA withdrawal, CLi was reduced (P less than 0.05) while mean GFR was not significantly lowered (0.5 greater than P greater than 0.2). In one of these six patients GFR was reduced to a subnormal value of 26 ml min-1 (1.73 m2 body surface)-1. In conclusion, human and rat CyA nephrotoxicity have the same pattern of renal functional deterioration. Cyclosporin A nephrotoxicity was evident in patients investigated a mean of 9 months after CyA withdrawal.

Absorption↗
PubMed1987

The immunodeficiency of bone marrow-transplanted patients. II. CD8-related suppression by patient lymphocytes of the response of donor lymphocytes to mitogens, antigens, and allogeneic cells.

Lymphocytes from 21 patients sampled 1-6 months after bone marrow transplantation (BMT) were tested for functional suppressor activity against marrow-donor lymphocytes in the lymphocyte transformation test. Suppression of donor responses to allogeneic (i.e. mixed lymphocyte reaction, MLR) and antigenic stimulation by irradiated (7600 rad) post-BMT cells was observed in about two-thirds of the combinations tested (N = 20 and N = 9). The suppression of donor MLR and antigen responses ranged between 5-52% and 10-46%, respectively. Irradiated post-BMT cells significantly suppressed donor responses to suboptimal concentrations of phytohaemagglutinin (PHA) (median suppression: 28%; P less than 0.05; N = 7) and concanavalin A (Con A) (median suppression: 31%; P less than 0.05; N = 6). A clearly suppressive effect of post-BMT cells was observed when the ratios of CD4+/CD8+ post-BMT cells were lower than 0.5 (P less than 0.01). In three experiments, the depletion of the CD8- but not of the CD4-positive subset abrogated the suppression of the donor MLR by post-BMT cells. The suppression by post-BMT cells (irradiated) of MLR and mitogen responses was comparable whether the responding cells were derived from the donor or from HLA-DR-incompatible, unrelated individuals. The proliferative capacity of post-BMT cells compared to that of donor cells was assayed in the MLR with unrelated, HLA-DR-incompatible stimulator cells. A significantly decreased proliferative capacity (median 20% of that of donor cells) was found (P less than 0.01; N = 16). A weak inverse correlation (P less than 0.05; N = 16) between the proliferative and the suppressive capacity of post-BMT cells in the MLR was observed. These findings indicate that the decreased proliferative capacity upon mitogen, antigen, and alloantigen stimulation observed in most patients within 1-6 months after BMT may be partly due to non-specific suppression by CD8+ cells.

Adolescent↗
PubMed1987

HLA-DP and bone marrow transplantation: DP-incompatibility and severe acute graft versus host disease.

Thirteen recipients of HLA-haploidentical, DR compatible bone marrow (BM) and the corresponding BM donors were HLA-DP typed using primed lymphocyte typing (PLT). Severe acute GVHD (greater than or equal to grade 2) developed within 3 months after BM-transplantation in all of eight recipients of DP incompatible BM, but in none of five recipients of DP-compatible BM. This difference was highly significant (p less than 0.001, Fisher's exact test). Moreover, severe acute GVHD was significantly increased in recipients of haploidentical, DR compatible, but DP incompatible BM as compared to severe acute GVHD in 88 recipients of HLA-identical BM (p less than 0.0001). In contrast, there was no difference in acute GVHD between recipients of haploidentical, DR and DP compatible BM and recipients of HLA-identical BM. The data presented here provide strong evidence for the first time that HLA-DP antigens play a role as transplantation antigens.

Bone Marrow Transplantation↗
PubMed1987

Pretreatment with atracurium: the influence on neuromuscular transmission and pulmonary function.

The influence of pretreatment with atracurium on neuromuscular transmission was evaluated in 60 healthy volunteers using train-of-four (TOF) nerve stimulation and measurement of respiratory rate (RR), vital capacity (VC), inspiratory force (IF), and peak expiratory flow (PEF). The subjects were randomly allocated to one of four groups: Group I received atracurium 0.02 mg/kg, Group II 0.03 mg/kg, Group III 0.04 mg/kg, and Group IV atracurium 0.05 mg/kg. TOF ratio decreased significantly in all four groups. There was, however, no difference between the groups after injection. PEF decreased significantly in all four groups, VC decreased in Groups I and IV, and RF increased significantly only in Group IV. Three subjects (5%) had shallow, frequent respiration; however, none needed respiratory support. The majority of the volunteers experienced blurring of vision and heavy eyelids: 82% and 67%, respectively. All subjects were able to sustain head lift for 10 s or more after atracurium. Careful observation of respiration is necessary, especially when using the higher doses of atracurium.

Anesthesia↗