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P Hougaard

Publications and source records attributed to P Hougaard.

At least 55 records · Page 3Linked to original sources
PubMed1987

Soluble, prolonged-acting insulin derivatives. I. Degree of protraction and crystallizability of insulins substituted in the termini of the B-chain.

Hydrophilic insulins, more positively charged than human insulin at neutral pH, have been prepared by substitution with basic amino acids at the termini of the B-chain and by blocking the C-terminal carboxyl group of the B-chain. The isoelectric pH of the insulin is thereby moved from 5.4 towards physiological levels. Slightly acid solutions of derivatives, in which charge has been added in the C-terminus of the B-chain, have a prolonged action in vivo, in particular if the carboxyl group is blocked. It is found that the prolonged-acting hydrophilic insulins crystallize instantly when the pH is adjusted to 7. The prolonged action is ascribed to this readiness to crystallization combined with a low solubility, which may be further decreased by increased concentration of zinc ions. Hydrophobic insulins have a prolonged action independent of the site of substitution even if the derivative is soluble at physiological pH. Some derivatives were prepared from porcine insulin by tryptic transpeptidation. N-terminal B-chain substituted insulins were prepared by alkylation of a biosynthetic single-chain insulin precursor, followed by tryptic transpeptidation rendering the double chain insulin derivative. The observed blood glucose lowering in the rabbits implies that neither N- nor C-terminal B-chain substitution results in substantial deterioration of biological potency. An index for the degree of protraction based on the blood glucose data is used to compare the insulins.

Animals↗
PubMed1987

Soluble, prolonged-acting insulin derivatives. II. Degree of protraction and crystallizability of insulins substituted in positions A17, B8, B13, B27 and B30.

It has previously been found that insulins, to which positive charge has been added by substitutions in position B30, thus raising the isoelectric point towards pH 7, had a prolonged action when injected as slightly acidic solutions because such derivatives crystallize very readily upon neutralization. Positive charge has now been added by substituting the B13 and A17 glutamic acid residues with glutamines and B27 threonine with lysine or arginine. These substitutions were introduced by site-specific mutagenesis in a gene coding for a single-chain insulin precursor. By tryptic transpeptidation the single-chain precursors were transformed to the double-chain insulin structure, concomitantly with incorporation of residue B30. Thus insulins combining B13 glutamine, A17 glutamine and B27 lysine or arginine with B30 threonine, threonine amide or lysine amide were synthesized. The time course of blood glucose lowering effect and the absorption were studied after subcutaneous injection in rabbits and pigs. The prolonged action of B30-substituted insulins was markedly enhanced by B27 lysine or arginine substitutions and by B13 glutamine. The B27 residue is located on the surface of the hexamer, so a basic residue in this position presumably promotes the packing of hexamers at neutral pH. The B13 residues cluster in the centre of the hexamer. When the electrostatic repulsive forces from six glutamic acid residues are abolished by substitution with glutamine, a stabilization of the hexamer can be envisaged.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1985

Comparison of the working formulation of non-Hodgkin's lymphoma with the Rappaport, Kiel, and Lukes & Collins classifications. Translational value and prognostic significance based on review of 658 patients treated at a single institution.

Six hundred fifty-eight cases of previously untreated non-Hodgkin's lymphoma seen between 1970 and 1979 at the Medical Department, the Finsen Institute, were the basis for a comparative study of the prognostic value of the Rappaport, Kiel, and Lukes & Collins classifications and the new translation system, the Working Formulation of Non-Hodgkin's Lymphoma. Each histopathologic system proved equally effective in separating patients into subgroups with a spectrum of prognoses ranging from a median survival of less than 1 year to greater than 7 years. The established classifications were compared with the Working Formulation in order to evaluate its translational value. The Working Formulation was more similar to the Rappaport and the Lukes & Collins systems than to the Kiel system, since 82%, 89%, and 75% of the cases, respectively, were translatable following the guidelines outlined in the National Cancer Institute (NCI)-sponsored study. Similarities among the four systems were demonstrated in lymphomas with follicular growth pattern, and in diffuse lymphomas composed of small mature appearing lymphocytes or small cleaved lymphocytes. Incongruity among the systems was more marked in lymphomas composed of large lymphoid cells or in lymphomas of mixed cellular composition. A comparison was performed for each classification against the Working Formulation. All such subdivided subsets were tested for prognostic heterogeneity and the following conclusions were reached: the diffuse poorly differentiated lymphocytic category of Rappaport was separated into two subgroups (malignant lymphoma [ML] small cleaved cell and ML lymphoblastic) with different prognoses (P = 0.01); the diffuse "histiocytic" lymphomas were prognostically homogeneous, since none of the newer systems were able to identify subpopulations with significantly different prognoses; the subtypes of the Kiel classification were prognostically homogeneous; the only weakness of the Lukes & Collins classification was the undefined cell subtype, encompassing two populations with different prognoses; and (5) the importance of follicular growth pattern was confirmed for small cleaved cell and mixed cell cytology, whereas large cell cytology implied a poor prognosis regardless of pattern. By the use of the Cox regression model it could be demonstrated that the Working Formulation can substitute any of the established classifications in terms of prognostic value.

Female↗
PubMed1985

Relative mortality of type 1 (insulin-dependent) diabetes in Denmark: 1933-1981.

The relative mortality of Type 1 (insulin-dependent) diabetes in Denmark during the period 1933-1981 was studied using a modification of Cox's regression model on the basis of two patient populations, ascertained in different ways and independently of each other. Initial analysis showed that the two groups could be combined completely into one common analysis. Relative mortality was the same for both sexes. The additional variables studied were age at diagnosis, current age, calendar year at diagnosis and calendar time during follow-up. All these interrelated variables were accounted for in the analysis. The analysis showed that relative mortality decreased with increasing age at diagnosis; increased from 1933 to a maximum in about 1965, after which it decreased; increased with increased duration of diabetes to a maximum at 15-25 years, after which it declined.

Adolescent↗
PubMed1985

Prognostic significance of architectural patterns in non-Hodgkin lymphomas.

Clinical data and lymphoma biopsies were analyzed in 651 patients with non-Hodgkin lymphoma in order to describe the prognostic influence of different grades of follicular architecture compared to diffuse architecture. The follicularity was graded qualitatively according to the distinctness of the pattern (intra-follicular, infiltrative follicular and traceably follicular patterns). The partially follicular pattern, with co-existence of follicular and diffuse areas in the same biopsy, was graded quantitatively according to the proportion of these areas. The median survival of patients with diffuse pattern was 1.2 years, while that of patients with follicular patterns ranged from 2.5 to 7.3 yr. The prognosis for those with partially follicular pattern was not affected, whether or not more or less than 50% of the lymphoma was diffuse. For cytologically identical lymphomas, only the intra- and infiltrative follicular patterns influenced the prognosis favourably. This conclusion was further substantiated by means of multivariate analysis.

Humans↗
PubMed1985

Circadian variation in mitotic influx in a keratinized epithelium. The stathmokinetic technique used in vivo on the hamster cheek pouch epithelium and analyzed by periodic regression analysis.

An in vivo study of the hamster cheek pouch epithelium using the stathmokinetic technique (Colcemid) demonstrated a circadian variation in mitotic influx. Based on measurements of all nucleated epithelial cells the diurnal mean was estimated in two separate experiments as 0.34%/h +/- 0.02 (SE) and 0.27%/h +/- 0.02 (SE) respectively. 3HTdR was injected in the latter study (a double labelling experiment). The significant difference between the two experiments is, however, probably due to biological variations. The maximal values for the mitotic rate were found during the light (resting) period, as were the maximal values for the mitotic index. The mean mitotic influx for the 'light period' was estimated as 0.5-0.4%/h, and for the 'dark period' as 0.2%/h. Independent analyses demonstrated the necessity of a circadian-dependent correction of the 1 and 4 h values of accumulated metaphases. The 1 h value was significantly too high during the light as well as the dark period. The 4 h value was found to be too low, but only significantly so during the dark period. Basing the estimation of mitotic rate on the 3 h accumulation value produced only very similar results to those found by using all four accumulation periods. The use of overlapping experiments proved that only cells entering mitosis after Colcemid application were arrested, so that when arrested metaphases were counted the accumulation line was correctly drawn through the origin. In the latter study (the double labelling experiment) both S- (Møller and Keiding 1982) and mitotic influx were estimated, the estimates being 0.55%/h +/- 0.03 (SE) and 0.27%/h +/- 0.02 (SE) respectively. Even considering possible methodological problems, the discrepancy between the S efflux and the mitotic influx indicates cell death and/or differentiation from G2.

Anaphase↗
PubMed1985

A Cox regression model for the relative mortality and its application to diabetes mellitus survival data.

A Cox-type regression model for the ratio between the mortality in a cohort and that in a reference population is introduced. By means of the model it is possible to include in the survival analysis both individual (possibly time-dependent) characteristics for the study cohort and changing trends in the mortality in the reference population. This is particularly relevant in long-term follow-up studies where there may be considerable changes in the mortality in the reference population. Estimation procedures in the model are discussed and large-sample properties of the estimators are outlined. The model is applied to the analysis of two sets of data concerning the survival among insulin-dependent diabetics in Denmark.

Adolescent↗
PubMed1984

Epidemiological studies of diabetes mellitus in Denmark: 5. Mortality and causes of death among insulin-treated diabetic patients.

A 7-year follow-up study is reported on the prevalent population of all insulin-treated diabetic patients (n = 1499) as of 1 July 1973 in the Funen County, Denmark. The analysis of mortality was based on data from 395 dead and the remaining 1104 living patients. Males had a significantly higher mortality than females and a lower age at onset was associated with a significantly higher mortality. An analysis of the causes of death revealed a higher than expected number of deaths in all categories studied, although the excess mortality was highest for diabetes mellitus itself and cardiovascular diseases. Diabetes mellitus was not notified on 15% of the death certificates, and this under-reporting varied according to duration of the disease and place of death. It is concluded that studies based solely on death certificates will underestimate the mortality of diabetes mellitus, and that further longitudinal studies of well-defined, population-based patient groups are needed to evaluate the determinants of mortality in diabetes.

Adolescent↗
PubMed1983

Epidemiological studies of diabetes mellitus in Denmark: 4. Clinical characteristics of insulin-treated diabetes.

We report the clinical characteristics of all insulin-treated diabetic patients (783 males and 716 females) living on July 1 1973 in a Danish county. In 18 patients diabetes was believed to be secondary to another disease or condition. Of all patients, 43% of the males and 55% of the females were greater than age 50 years and 42% and 36% of males and females, respectively, had a disease duration of less than 10 years. The overall proportion of patients treated permanently with insulin from diagnosis was 85% and 79% in males and females, respectively, but within the subgroup of patients with current age less than 30 years these proportions were 99% and 96%, respectively. Statistical analysis indicated that insulin-treated diabetes is a clinically heterogeneous group of diseases; thus, low age at onset combined with immediate and permanent insulin treatment delineate one subtype, while relatively high age at onset and late start and/or interruption of insulin treatment delineate other subtype(s). It is estimated that the proportion of patients with truly Type 1 (insulin-dependent) diabetes is greater than 50% in this cross-sectional population of insulin-treated patients.

Adolescent↗
PubMed1983

Dynamic evaluation of prognosis from time-dependent variables in acute myocardial infarction.

For predicting the 3 endpoints death, cardiac arrest, and cardiogenic shock within 44 days after admission for acute myocardial infarction (MI), a competing risk variant of the Cox multivariate model was developed. The population consisted of 1,140 patients with definite MI admitted within 24 hours of onset of symptoms. Prognostic variables from the entire hospitalization period were assessed. The time-dependent variables (occurrence of complications) were evaluated with occurrence up through the day before the actual prediction period started. The important prognostic variables for the endpoint death were ventricular fibrillation, age, congestive heart failure, and asystole. Variables for the endpoint cardiac arrest were congestive heart failure, ventricular premature beats, supraventricular tachycardia, extension of MI, and age. Variables for the endpoint cardiogenic shock were cardiac arrest, age, congestive heart failure, previous MI, and nodal rhythm. By using a hazard function for each endpoint and the coefficients for the variables entered, it is possible to estimate a total risk of death, cardiac arrest, or cardiogenic shock for the individual patient. This prediction can be updated during the course of hospitalization according to the occurrence of the new complications. The model can be directly utilized to assess risk.

Adult↗
PubMed1983

Treatment of nickel dermatitis with Antabuse; a double blind study.

A double blind, placebo-controlled treatment with Antabuse was carried out in 24 patients with hand eczema and nickel allergy. The amount of Antabuse given was gradually increased from 50 to 200 mg daily. The maximum dose was given for 6 weeks. During the treatment period, the dermatitis of 5 out of 11 patients in the group treated with Antabuse healed, compared with 2 out of 13 in the group receiving the placebo. A statistical analysis was made of changes observed during the study, through the parameters: scaling, frequency of flares, erythema, area involved and number of vesicles. Differences in results obtained with Antabuse and the placebo were statistically significant only for the parameters scaling and frequency of flares (p less than 0.05). The difference between the sums of parameters following the 2 forms of treatment was not statistically significant (p = 0.11). 2 patients treated with Antabuse showed signs of hepatic toxicity; 1 of them had toxic hepatitis. No other significant side effects were seen.

Adult↗
PubMed1983

Blood pressure in children with diabetes mellitus.

Blood pressure measurements were evaluated in 151 children aged 2-19 years old with insulin-dependent diabetes mellitus (DM) of a duration of few months to 15 1/2 years. Compared with a reference group, the diabetic children had lower diastolic blood pressure (DBP) shortly after start of DM. There was no difference for the systolic blood pressure (SBP). After duration of diabetes of 5 years there were no significant differences in SBP and only significantly lower DBP in girls (median difference 5 mmHg, p less than 0.01), while the difference in boys is insignificant (median difference 2 mmHg, p = 0.32). In a model describing the intraindividual variation in blood pressure and its dependence on age, weight and height it was found that age was insignificant when weight and height were included. For DBP height was also insignificant when weight was included. For the 9 children with retinal microaneurysms the average SBP was significantly higher than expected for diabetic children of that weight and height.

Adolescent↗
PubMed1983

Tracking of blood pressures in diabetic children.

Repeated blood pressure measurements in 127 diabetic children, obtained at intervals of 6 months, were studied. Tracking of measurements described by the correlation between repeated observations of systolic blood pressure showed highest degree of tracking between consecutive measurements (0.38-0.76), while there was a lower degree of tracking between measurements at longer time intervals, and lower degree of tracking in the observations of diastolic blood pressure than of systolic blood pressure. After adjustment for changes in height and weight, the tracking correlations are slightly smaller on the whole. The tracking correlations are generally rather small and repeated measurements of blood pressure are necessary.

Adolescent↗
PubMed1983

The length of hospitalization after acute myocardial infarction determined by risk calculation.

The feasibility of the use of a Cox model for risk assessment of individualized hospital discharge after myocardial infarction was evaluated. First, a previously developed prognostic index computed at the fifth day after admission was tested on a new population of 1140 patients. It was confirmed that after 5 days half of the patients (52%) could be discharged with low risk. Second, a new competing risk variant of the Cox model that updates prognosis according to the occurrence of complications was developed that describes the risk of death, cardiac arrest, and cardiogenic shock within 44 days after hospital admission. With a risk of one of these events being below 2% during a 14 day period after proposed discharge, 453 patients of 966 survivors (47%) could be discharged after only 5 days. A longer stay (of up to 30 days) was proposed for 338 patients (35%) to achieve the same level of risk. The savings in hospitalization days would be 15%. These results were confirmed in a new sample of 197 patients from the same institution who were discharged according to the proposed system. Of the 169 day 5 survivors, 67% were discharged on days 6 through 15 and this resulted in only two unexpected deaths and a 20% savings in hospitalization days. We conclude that individually determined discharge time is feasible without increased risk of death of severe complications after early discharge.

Age Factors↗
PubMedDate not supplied

Dynamic evaluation of short-term prognosis after myocardial infarction.

The risk of cardiac arrest, cardiogenic shock or death in the first 44 days after myocardial infarction is evaluated using a version of the Cox regression model. The (time-dependent) covariates include complications that have occurred, making it possible to give an individual assessment of prognosis that can be updated each day. Low risk patients can be discharged from hospital after a few days, whereas high risk patients must remain in hospital until their risk has fallen to an acceptable level. For the former group of patients it is possible to reduce the number of days in hospital without increased mortality and for the latter group mortality can be reduced by longer hospitalization.

Female↗
PubMedDate not supplied

A 6-year nationwide cohort study of glycaemic control in young people with type 1 diabetes. Risk markers for the development of retinopathy, nephropathy and neuropathy. Danish Study Group of Diabetes in Childhood.

The study aimed to identify risk markers (present at the start of the study in 1989) for the occurrence and progression of microvascular complications 6 years later (in 1995) in a Danish nationwide cohort of children and adolescents with Type 1 diabetes (average age at entry 13.7 years). Probabilities for the development of elevated albumin excretion rate (AER), retinopathy, and increased vibration perception threshold (VPT) could then be estimated from a stepwise logistic regression model. A total of 339 patients (47% of the original cohort) were studied. Sex, age, diabetes duration, insulin regimen and dose, height, weight, HbA(1c), blood pressure, and AER were recorded. In addition, information on retinopathy, neuropathy (VPT), and anti-hypertensive treatment was obtained at the end of the study. HbA(1c) (normal range 4.3-5.8, mean 5.3%) and AER (upper normal limit <20 microg min(-1)) in two, timed overnight urine collections were analysed centrally. Eye examination was performed by two-field fundus photography. Determination of VPT was assessed by biothesiometry. Increased AER (> or =20 microg min(-1)) was found in 12.8% of the patients in 1995, and risk markers for this were increased AER and high HbA(1c), in 1989 (both p<0.001). Retinopathy was present in 57.8% of patients in 1995, for which the risk markers were long duration of diabetes (p<0.0001), age (p<0.01), and high HbA(1c) (p<0.0001) in 1989. Elevated VPT (>6.5 V) was found in 62.5% of patients in 1995, for which the risk markers were male sex (p<0.05), age (p<0.0001), and increased AER (p<0.05) in 1989. This study confirms that hyperglycaemia plays a major role for the development of microvascular complications in kidneys and eyes, and emphasises the need for optimal glycaemic control in children and adolescents with Type 1 diabetes.

Adolescent↗