Morbidity and mortality following poliomyelitis - a lifelong follow-up.

BACKGROUND AND PURPOSE: In the world today 10-20 million people are still living with late effects of poliomyelitis (PM), but the long-term consequences of the disease are not well known. The aim of this study was to describe lifelong morbidity and mortality among Danes who survived PM. METHODS: Data from official registers for a cohort of 3606 Danes hospitalized for PM in the period 1940-1954 were compared with 13 762 age- and gender-matched controls. RESULTS: Compared with controls, mortality was moderately increased for both paralytic as well as non-paralytic PM cases; Hazard Ratio, 1.31 (95% confidence interval, 1.18-1.44) and 1.09 (95% confidence interval, 1.00-1.19), respectively. Hospitalization rates were approximately 1.5 times higher among both paralytic and non-paralytic PM cases as compared with controls. Discharge diagnoses showed a broad spectrum of diseases. There were no major differences in morbidities between paralytic and non-paralytic PM cases. CONCLUSIONS: Poliomyelitis has significant long-term consequences on morbidity and mortality of both paralytic and non-paralytic cases.

Multiple sclerosis and risk of Parkinson's disease: a Danish nationwide cohort study.

BACKGROUND AND PURPOSE: Case reports have observed a co-occurrence of multiple sclerosis (MS) and Parkinson's disease (PD) and it has been hypothesized that MS lesions could affect dopaminergic pathways causing parkinsonism. Our aim was to examine the association between MS and PD in a historically prospective cohort study using Danish nationwide register data. METHODS: Multiple sclerosis patients identified in the Multiple Sclerosis Registry were followed for PD from 1977 to 2011 in the National Patient Register. As measures of relative risk, ratios of observed to expected incidence rates of first hospitalization for PD amongst persons with MS were used, i.e. standardized incidence ratios (SIRs) with 95% confidence intervals (CIs). RESULTS: Amongst 15,557 MS patients 26 cases of PD were observed versus 26.51 expected, reflecting no overall increased risk of PD (SIR 0.98, 95% CI 0.67-1.44). Similar estimates were seen for female (SIR 0.99, 95% CI 0.58-1.67) and male MS patients (SIR 0.97, 95% CI 0.55-1.72). Likewise, no increased risk of PD amongst MS patients was observed in a robustness analysis backdating the date of diagnosis of PD by 5 years to account for the time lag between disease onset and first hospital contact with PD (SIR 0.57, 95% CI 0.32-1.00). CONCLUSION: Our data do not suggest an increased risk of PD amongst patients with MS.

Socio-demographic factors, reproductive history and risk of osteoarthritis in a cohort of 4.6 million Danish women and men.

OBJECTIVE: Studies addressing possible socio-demographic and reproductive factors in the aetiology of osteoarthritis (OA) are few. We studied possible influences of educational level, household income, marital status and parenting patterns on OA risk overall and at anatomical sites. METHOD: We linked national register data about socio-demographic variables, reproductive histories and OA hospital contacts to a cohort of 4.6 million Danes. Ratios of first OA hospitalisation rates (RRs) were calculated using Poisson regression. RESULTS: Overall, 100,437 women and 92,020 men had a first OA hospital contact during 91.5 million person-years between 1982 and 2008. Short education, low income and married status were significantly associated with increased OA risk, and persons with children were at higher risk of OA(overall) (RR=1.10 in women; RR=1.22 in men), OA(knee) (RRs 1.14; 1.28), OA(back) (RRs 1.18; 1.33), and OA(hand) (RRs 1.21; 1.43), but not of OA(hip) (RRs 0.96; 1.00) than persons without children. The RR of OA(overall) increased by a factor of 1.05 in women and 1.04 in men per additional child, most notably for OA(knee) in women (1.10 per child). CONCLUSION: Risk of OA hospitalisation was highest among married persons and persons with short education or low income. The similar or even stronger associations with reproductive factors in men than women suggest that unmeasured lifestyle factors rather than biological factors associated with pregnancy might explain the higher OA risk in persons with children. However, the particularly strong association between parity and risk of OA(knee) in women is compatible with a role of pregnancy-associated factors.

Autoimmune diseases in patients with multiple sclerosis and their first-degree relatives: a nationwide cohort study in Denmark.

BACKGROUND: Multiple sclerosis (MS) and other autoimmune diseases might cluster. Our aim was to estimate the relative risk (RR) of other autoimmune diseases among MS patients and their first-degree relatives in a population-based cohort study. METHODS: Using the Danish Multiple Sclerosis Register, the Danish Hospital Discharge Register, and the Danish Civil Registration System, we estimated RRs for 42 different autoimmune diseases in a population-based cohort of 12 403 MS patients and 20 798 of their first-degree relatives. Ratios of observed to expected numbers of autoimmune diseases, based on national sex-, age-, and period-specific incidence rates, served as measures of the RRs. RESULTS: Compared with the general population, MS patients were at an increased risk of developing ulcerative colitis (RR = 2.0 (95% confidence interval (CI): 1.4-2.8), n = 29) and pemphigoid (RR = 15.4 (CI: 8.7-27.1), n = 12) but at reduced risk of rheumatoid arthritis (RR = 0.5 (CI: 0.4-0.8), n = 28) and temporal arteritis (RR = 0.5 (CI: 0.3-0.97), n = 11). First-degree relatives of MS patients were at increased risks of Crohn's disease (RR = 1.4 (CI: 1.04-1.9), n = 44), ulcerative colitis (RR = 1.3 (CI: 0.99-1.7), n = 51), Addison's disease (RR = 3.4 (CI: 1.3-9.0), n = 4), and polyarteritis nodosa (RR = 3.7 (CI: 1.4-10.0), n = 4). PATIENTS: with MS and their first-degree relatives seem to be at an increased risk of acquiring certain other autoimmune diseases.

Characterization of rotavirus strains in a Danish population: high frequency of mixed infections and diversity within the VP4 gene of P[8] strains.

We characterized the G and P types from 162 rotavirus-positive stool specimens collected from 162 persons in Denmark (134 children and 28 adults) with acute diarrhea in 1998, 2000, and 2002. Samples were obtained during outpatient consultations (73%) and from hospitalized patients (27%). Although more than 20 different G-P combinations were identified, only 52% represented the globally most common types G1P[8], G2P[4], and G4P[8]. The G9 genotype, which is emerging worldwide, was identified in 12% of all samples. Twenty-one percent of the samples were of mixed genotypic origin, which is the highest frequency reported in any European population. The standard reverse transcription-PCR methods initially failed to identify a considerable fraction of the rotavirus P strains due to mutations at the VP4 primer-binding sites of P[8] strains. The application of a degenerate P[8] primer resulted in typing of most VP4 strains. There was considerable year-to-year variation among the circulating G-P types, and whereas G1P[8] was predominant in 1998 (42% of samples) and 2002 (26%), G2P[4] was the strain that was most frequently detected in 2000 (26% of samples). Our findings might implicate challenges for rotavirus vaccine implementation in a European population and underscore the importance of extensive strain surveillance prior to, during, and after introduction of any vaccine candidate.

Age at bacille Calmette-Guérin vaccination and risk of allergy and asthma.

BACKGROUND: It has been proposed that early age at bacille Calmette-Guérin (BCG) vaccination protects against the development of allergy. OBJECTIVE: To study whether early age at BCG vaccination was associated with a decreased risk of atopy, allergic rhinitis, and asthma compared to BCG vaccination at later ages in childhood. METHODS: The occurrence of atopy, allergic rhinitis, and asthma was studied in nearly 2000 women participating in the Danish National Birth Cohort study. Detailed information on age at BCG vaccination (age 0-15 years) was available from school health records. Atopic status was assessed serologically by a specific response to 11 common inhalant allergens using serum samples obtained from the women during the period 1997-2001. Information on allergic rhinitis and asthma was available from telephone interviews. RESULTS: Approximately 85% of the women had been BCG-vaccinated. Age at BCG vaccination was not associated with risk of atopy, allergic rhinitis, or asthma. The odds ratio of atopy, allergic rhinitis, and asthma associated with being vaccinated during the first year of life was 1.05 (95% CI 0.71-1.56), 1.42 (95% CI 0.85-2.36), and 1.71 (95% CI 0.91-3.20), respectively, compared with being vaccinated at the age of 7 years. Adjustment for birth cohort, sibship size, age of the woman's mother at birth, and social class in childhood did not affect the results. CONCLUSION: Our findings suggest that age at BCG vaccination in childhood does not influence the development of allergy or asthma.

Intensive exposure as a risk factor for severe polio: a study of multiple family cases.

To examine the importance of intensity of exposure for the outcome of the poliomyelitis infection 429 polio cases were identified belonging to families with 2, 3 or 4 polio cases, all hospitalized in Copenhagen from 1919 to 1953. Furthermore, 87 pairs of polio cases living on the same stairway, but not in the same household, were identified. Severity among multiple cases in families analysed according to time of appearance showed a U-shaped curve. Initial cases had a higher risk of developing paralysis [relative risk (RR) = 1.5, 95% confidence interval (CI) 1.2-1.91 and of dying (RR = 2.5, 95% CI 0.9-6.9). Decreased severity was observed among subsequent cases appearing within 11 d after the initial case (RR = 1.0); however, severity increased again, with higher mortality for cases likely to have been infected by the initial case (cases appearing more than 11 d later) (RR = 5.7, 95% CI 1.8-17.8). The pattern described among multiple family cases was not found among cases from the same stairway. Since family cases appearing within 11 d were probably infected simultaneously, a short incubation period is associated with severe disease and a prolonged incubation period with milder infections. Furthermore, intensive exposure from being infected in the household increased severity. These observations therefore suggest that intensity of exposure and dose of infection are important factors in the severity of poliomyelitis.

Cancer risk in a cohort of polio patients.

Poliomyelitis has hypothetically been associated with an increased risk of central nervous system (CNS) tumors. The present study was performed to examine not only the risk of CNS tumors but also the overall risk of cancer among a cohort of 5,883 polio patients. Patients diagnosed with acute poliomyelitis in the Danish capital, Copenhagen, between 1919 and 1954 were identified and followed with respect to cancer. Information on vital status and cancer diagnoses was obtained through linkage with the Danish Civil Registration System and the Danish Cancer Registry, respectively. The ratio of observed number of cancers to the number expected from population-based incidence rates, i.e., the standardized incidence ratio (SIR), served as measure of the relative cancer risk. Overall, 717 cases of cancer were observed among 5,883 polio patients during 249,084 person-years of follow-up vs. an expected number of 645 (SIR = 1.11 [95% confidence interval 1.03 to 1.20])). The increased risk was restricted to female polio patients (SIR = 1.18 [1.07 to 1.30]), among whom the risk was particularly high for breast cancer (SIR = 1.35 [1.12 to 1.61]) and for skin cancer (SIR = 1.66 [1.32 to 2.07]). The risk of breast cancer was highest among women with a history of paralytic polio (SIR = 1.62 [1.24 to 2.10]). The observed number of CNS tumors did not exceed the expected (SIR = 1.09 [0.72 to 1.60]). Women diagnosed with poliomyelitis, in particular paralytic polio, may be at increased risk of breast cancer. There was no association between malignancies of the CNS and poliomyelitis.

Intensity of exposure and severity of whooping cough.

OBJECTIVE: To study the association between intensity of exposure and mortality due to pertussis. METHODS: Overall 3233 historical records from the main fever hospital in Copenhagen were examined. Exposure status of the whooping cough cases was coded as primary, secondary or multiple cases according to information in the hospital records. Primary cases, infected outside the home, were presumably exposed less intensively to the infectious agent compared to secondary cases, who were infected in the family. Multiple cases were from families with several simultaneous cases, but no clear information on transmission between cases. RESULTS: Case fatality was strongly related to age, being highest among the infants. Other risk factors were sibship size, exposure status and calendar period. In a multivariate analysis, period, age, and exposure status remained significant. Compared to primary cases, secondary cases and multiple cases had a 2.8 [RR = 2.76 (1.37 - 5.56)] and a two-fold [(RR = 1.99 (1.33 - 2.96)] higher risk of dying. CONCLUSION: Intensity of exposure may be a major determinant of the severity of pertussis infection.

Multiple sclerosis and poliomyelitis. A Danish historical cohort study.

OBJECTIVE: To evaluate whether persons with a history of poliomyelitis are at an increased risk of developing multiple sclerosis (MS). MATERIAL AND METHODS: All patients diagnosed with acute poliomyelitis in the greater capital area of Copenhagen, Denmark, between 1919 and 1954 were identified and followed with respect to MS. Information on vital status and diagnosis of sclerosis was obtained through linkage with the Danish Civil Registration System and The Danish Multiple Sclerosis Registry, respectively. Follow-up started on the date of the establishment of the Danish Civil Registration System (April 1, 1968) until death, emigration or December 31, 1996, whichever came first. The observed incidence of MS among polio patients was compared with the expected incidence calculated according to national gender, age and period specific rates of MS. RESULTS: During 149,364 years of follow-up, 19 cases of multiple sclerosis were observed among 5652 polio patients compared with 11.0 expected (SIR = 1.73 (1.04-2.74)). The increased risk of MS was most pronounced in polio patients hospitalized during adolescence. Neither gender nor the acute severity of poliomyelitis modified the risk of MS. CONCLUSION: Our results are based on small numbers of events, however the findings suggest that the polio patients might be at an increased risk of MS.

HPV detection in children prior to sexual debut.

Knowledge of the epidemiology of infection with human papillomavirus (HPV) in childhood is important, since HPV infection early in life could represent a risk factor for later development of anogenital cancer. A random sample of Danish children aged 0 to 17 years was tested for the presence of HPV in the anal region and the oral cavity by the polymerase chain reaction using a consensus HPV L1 primer. Only 4 of 249 anal beta-globin-positive samples and one of 392 oral beta-globin-positive samples were HPV-positive. All HPV-positive samples were of unknown types. We conclude that the prevalence of anogenital HPV infection in childhood is very low indeed and that the oral cavity does not seem to act as a reservoir for HPV infection in childhood. This indicates that anogenital types of HPV are not transmitted to any measureable degree by non-sexual routes and further supports the notion that HPV infection takes place mainly later in life.

Estimation of the effect of salmon calcitonin in established osteoporosis by biochemical bone markers.

We reviewed data on 42 postmenopausal women with established osteoporosis (forearm fracture or a low bone mass) who had been randomly treated for 1 year with either rectal salmon calcitonin (sCT), 100 IU daily (n = 25) or nasal sCT, 200 IU daily (n = 17) applying an estimation algorithm for bone loss rates. Both groups received a daily calcium supplement of 500 mg. A group of 18 age-matched women who received no treatment served as controls. The bone mineral content of the distal forearm (BMCarm) was measured every 3 months by single photon absorptiometry. The individual rates of change during the 1-year period were calculated by linear regression analysis (alpha BMCarm). Bone loss rates were estimated initially and after 1 year of therapy by measurements of serum alkaline phosphatase, plasma bone Gla protein, and fasting urinary hydroxyproline and calcium (both corrected for creatinine excretion) according to the estimation algorithm. Both administration forms revealed significant control group-corrected decreases in serum and urine markers of bone turnover of 15-40% (P < 0.05-0.01) and positive outcomes of 2% in alpha BMCarm (P < 0.01). The estimated effect on bone mass was expressed as the difference between the bone loss estimated after 1 year and initially (delta ESTBIO). A significant correlation was seen between alpha BMCarm and delta ESTBIO (r = 0.5, P < 0.0001). We conclude that the effect of sCT on bone can be followed up by biochemical markers for bone turnover, i.e., by an annual blood and fasting urine sample, applying an estimation algorithm for the rate of bone loss.

Fusogenic activity of SIV (simian immunodeficiency virus) peptides located in the GP32 NH2 terminal domain.

Peptides of 12, 16 and 24 amino acids length corresponding to the NH2 terminal sequence of SIV gp32 were synthesized. Fluorescence energy transfer studies have shown that those peptides can induce lipid mixing of SUV (Small Unilamellar Vesicles) of various compositions at pH 7.4 and 37 degrees C. LUV (Large Unilamellar Vesicles) were shown to undergo fusion, provided they contained PE in their lipid composition. This work is an attempt to determine how the fusogenic activity depends on the structure of the peptide inserted into a lipidic environment. The peptides secondary structure and orientation in the lipid bilayer were determined using Fourier Transform infrared spectroscopy (FTIR). They adopt mainly a beta-sheet conformation in the absence of lipids. After interaction with DOPC SUV, the beta-sheet is partly converted into alpha-helix oriented obliquely with respect to the membrane interface. We bring here evidence that this oblique orientation is a prerequisite to the fusion process.

Evaluation of glycolamide esters and various other esters of aspirin as true aspirin prodrugs.

A series of glycolamide, glycolate, (acyloxy)methyl, alkyl, and aryl esters of acetylsalicylic acid (aspirin) were synthesized and evaluated as potential prodrug forms of aspirin. N,N-Disubstituted glycolamide esters were found to be rapidly hydrolyzed in human plasma, resulting in the formation of aspirin as well as the corresponding salicylate esters. These in turn hydrolyzed rapidly to salicylic acid. The largest amount of aspirin formed from the esters were 50 and 55% in case of the N,N-dimethyl- and N,N-diethylglycolamide esters, respectively. Similar results were obtained in blood with the N,N-dimethyl- and N,N-diethylglycolamide esters. Unsubstituted and monosubstituted glycolamide esters as well as most other esters previously suggested to be aspirin prodrugs were shown to hydrolyze exclusively to the corresponding salicylic acid esters. Lipophilicity parameters and water solubilities of the esters were determined, and structural factors favoring ester prodrug hydrolysis at the expense of deacetylation to yield salicylate ester are discussed. The properties of some N,N-disubstituted glycolamide esters of aspirin are highlighted with respect to their use as potential aspirin prodrugs.

Facile plasma-catalysed degradation of penicillin alkyl esters but with no liberation of the parent penicillin.

The methyl ester and some glycolamide esters of benzylpenicillin and ampicillin were shown to be rapidly degraded by human plasma at 37 degrees C with no parent penicillin being produced. The plasma-catalysed degradation which was also observed in rat plasma proceeds most likely through hydrolytic cleavage of the beta-lactam bonds of the penicillin esters and is suggested to be due to the presence of an ester-specific beta-lactamase in plasma. The results show that the failure of simple alkyl esters of penicillins to function as prodrugs is not due to a high enzymatic stability of the esters, as widely believed, but rather to a pronounced susceptibility to undergo hydrolytic cleavage of their beta-lactam ring in-vivo. Since double ester prodrugs of penicillins, such as the pivaloyloxymethyl ester of ampicillin, are readily hydrolysed in plasma to yield the parent penicillin although at a rate lower than e.g. that of inactivation of a simple methyl ester, the plasma enzyme apparently attacking the beta-lactam bond of penicillin esters appears to have a high degree of specificity for the ester structure.

Glycolamide esters as biolabile prodrugs of carboxylic acid agents: synthesis, stability, bioconversion, and physicochemical properties.

Benzoic acid esters of various substituted 2-hydroxyacetamides (glycolamides) were found to be hydrolyzed extremely rapidly in human plasma solutions, the half-lives of hydrolysis being less than 5 s in 50% plasma solutions for some N,N-disubstituted glycolamide esters. The rapid rate of hydrolysis could be largely attributed to cholinesterase (also called pseudocholinesterase) present in plasma. From a study of a variety of substituted glycolamide esters and structurally related esters, the most prominent structural requirement needed for a rapid rate of hydrolysis was found to be the glycolamide ester structure combined with the presence of two substituents on the amide nitrogen atom. A structural similarity of such esters with benzoylcholine, a good substrate for cholinesterase, was put forward. Esters of N,N-disubstituted glycolamides are suggested to be a useful biolabile prodrug type for several carboxylic acid agents. The esters combine a high susceptibility to undergo enzymatic hydrolysis in plasma with a high stability in aqueous solution. Furthermore, as demonstrated with the benzoic acid model esters, it is feasible to obtain ester derivatives with almost any desired water solubility or lipophilicity with retainment of marked lability to enzymatic hydrolysis.