Do bone turnover markers reflect changes in bone microarchitecture during treatment of patients with thyroid dysfunction?

PURPOSE: This study aimed to compare changes in the bone turnover markers (BTMs)-C-terminal telopeptide of type I collagen (CTX-I) and procollagen I N-terminal peptide (PINP)-with changes in the bone microarchitecture, assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT), during treatment of patients with thyroid dysfunction. METHODS: In women with newly diagnosed hypo- or hyperthyroidism, HR-pQCT variables, obtained from the tibia and the radius, were compared with BTMs. Data were collected at diagnosis and after at least 12 months of euthyroidism. RESULTS: 73 women completed the study (hypothyroidism, n = 27; hyperthyroidism, n = 46). Among hyperthyroid patients, correlations were found between changes in BTMs and HR-pQCT variables, primarily for cortical variables in the tibia, i.e. cortical thickness (CTX-I, p < 0.001; PINP, p < 0.001), and volumetric bone mass density (vBMD) (CTX-I, p < 0.001; PINP, p < 0.001). Moreover, correlations between BTMs and estimated bone strength were found. In the hypothyroid subgroup, no significant findings existed after adjustment. Following treatment, less decrease in tibial vBMD was seen among patients with increasing CTX-I compared to those with a decreasing CTX-I level (p = 0.009). Opposite findings applied to PINP, as patients with decreasing PINP showed an increase in tibial vBMD, in contrast to a decline in this parameter among patients with increasing PINP (p < 0.001). CONCLUSION: Changes in CTX-I and PINP correlated with HR-pQCT variables during the treatment of women with thyroid dysfunction. To some extent, these BTMs reflected the restoration of bone microarchitecture. CTX-I seems to be the most sensitive BTM in treatment-naïve thyroid diseases, while PINP is more useful for monitoring during treatment. TRIAL REGISTRATION NUMBER: NCT02005250. Date: December 9, 2013.

Identification of a novel mutation in the factor VIII gene causing severe haemophilia A.

BACKGROUND: Deficiency in coagulation factor VIII encoded by F8 results in the X-linked recessive bleeding disorder haemophilia A (HEMA). Here we describe the identification of a novel variant in the factor VIII gene, F8, in an adult male patient with severe haemophilia A. CASE PRESENTATION: The patient was diagnosed in early childhood and subsequently co-infected with Hepatitis C and HIV acquired during early blood transfusion for haemophilia in the 1980ies. The identified F8 deletion, c.5411_5413delTCT, p.F1804del lies within a conserved part of the molecule, is predicted by bioinformatic software to be deleterious by the loss of Phenylalanine, and has not been previously described in any database. CONCLUSION: This novel F8 deletion as a cause of haemophilia A did not result in generation of inhibitory antibodies to Factor VIII treatment and may have impact on (prenatal) diagnosis, genetic counselling, and treatment decisions in the affected family as well as in other families diagnosed with this F8 mutation. Finally, this novel mutation should be included in the panel of known genetic variants in F8 when searching for the genetic etiology in patients suspected of HEMA.

Safety and efficacy of BAY 94-9027, a prolonged-half-life factor VIII.

Essentials Recombinant factor VIII BAY 94-9027 conjugates in a site-specific manner with polyethylene glycol. BAY 94-9027 was given to patients with severe hemophilia A as prophylaxis and to treat bleeds. BAY 94-9027 prevented bleeds at dose intervals up to every 7 days and effectively treated bleeds. BAY 94-9027 treatment was mainly well tolerated and no patient developed factor VIII inhibitors. Click to hear Dr Tiede's perspective on half-life extended factor VIII for the treatment of hemophilia A SUMMARY: Background BAY 94-9027 is a B-domain-deleted prolonged-half-life recombinant factor VIII (FVIII) that conjugates in a site-specific manner with polyethylene glycol. Objective Assess efficacy and safety of BAY 94-9027 for prophylaxis and treatment of bleeds in patients with severe hemophilia A. Patients/methods In this multinational, phase 2/3, partially randomized, open-label trial, men aged 12-65 years with FVIII < 1% and ≥ 150 exposure days to FVIII received BAY 94-9027 for 36 weeks on demand or prophylactically at intervals determined following a 10-week run-in period on 25 IU kg-1 body weight two times per week. Patients with > 1 bleed during the run-in subsequently received 30-40 IU kg-1 two times per week; patients with ≤ 1 bleed were eligible for randomization to every-5-days (45-60 IU kg-1 ) or every-7-days (60 IU kg-1 ) prophylaxis (1 : 1) for 26 additional weeks until randomization arms were filled. Patients who were eligible but not randomized continued twice-weekly prophylaxis. The primary efficacy outcome was annualized bleeding rate (ABR). Results The intent-to-treat population included 132 patients (prophylaxis, n = 112; on demand, n = 20). Median ABR (quartile [Q1; Q3]) for patients treated two times per week who were not eligible for randomization (n = 13) improved after dose increase (17.4 [14.3; 26.0] to 4.1 [2.0; 10.6]). Median ABR for patients randomized to every-5-days treatment (n = 43) was 1.9 (0; 4.2), similar to patients eligible for randomization but who continued treatment two times per week (n = 11). Median ABR for 32/43 patients (74%) who continued every-7-days prophylaxis until study end was 0.96 (0.0; 4.3). Six hundred and thirty-six of 702 bleeds (90.6%) were controlled with ≤ 2 infusions. No patient developed a FVIII inhibitor. Conclusions BAY 94-9027 prevented bleeding across three individually tailored dose regimens and was effective for treatment of bleeds.

Progression of haemophilic arthropathy in children: a Lithuanian--Danish comparative study.

Recurrent bleeding into joints initiates a sequence of events leading to a progressive joint damage in people with severe haemophilia. This is a continuous process during childhood and adolescence, therefore joint abnormalities may be minimal on physical examination in very young children - even those receiving on-demand treatment. The aim of our study was to quantify the burden of arthropathy in Lithuanian patients who had been treated exclusively by on-demand substitution and compare their physical joint health with age-matched Danish patients who received prophylaxis from an early age. Boys, aged 4-17 years, with severe haemophilia and no signs of inhibitors were included in the study. Joint outcome based on the Haemophilia Joint Health Score (HJHS) was analysed in two different treatment groups and compared within the matched pairs. In total, 32 (16 in each treatment group) patients were enroled. A total of 192 joints were evaluated. Joint status according to treatment strategy was strikingly different: 27.4 for on-demand vs. 3.3 for prophylaxis (<0.001) group. Significance of the difference in joint status comparing different treatment strategies was equally strong both in younger (4-9 years) and older (10-17 years) patient groups: 2.2 vs. 12.5 (P = 0.0002) and 3.9 vs. 36.3 (P < 0.0001) respectively. The results further demonstrate the unequivocal effect of prophylaxis on joint status and give an insight into early and late manifestations of joint impairment based on the HJHS in haemophilia patients with treatment on-demand compared with joint changes that may develop over the time with the preventative treatment.

Assessing peristomal skin changes in ostomy patients: validation of the Ostomy Skin Tool.

BACKGROUND: Peristomal skin problems are common and are treated by a variety of health professionals. Clear and consistent communication among these professionals is therefore particularly important. The Ostomy Skin Tool (OST) is a new assessment instrument for the extent and severity of peristomal skin conditions. Formal tests of reliability and validity are necessary for its use in clinical practice, research, and education. OBJECTIVES: To estimate inter- and intra nurse assessment variability of the OST and validity by comparison to a 'gold standard' (GS) defined by an expert panel. METHODS: Thirty photographs of peristomal skin were presented twice to 20 ostomy care nurses--10 from Denmark (DK) and 10 from Spain (ES)--to determine intra- and inter nurse assessment variability. The same photographs were presented to an international group of experts (dermatologist and ostomy care nurses), to establish a GS for comparison and validation of the results. RESULTS: A high intra-nurse assessment agreement, κ=0·84, was found with no differences in the intra-nurse assessments from the two groups of nurses (DK and ES). The inter-nurse assessment agreement was 'moderate to good', κ=0·54, with the agreement between the experts higher, κ=0·70. A high correlation between the scores from the nurses and the GS were seen in the lower part of the two scales [Discoloration, Erosion, Tissue overgrowth (DET) score<7)]. CONCLUSION: The study supported the validity of the OST. It is suggested that a categorical scale can be used to illustrate the severity of the DET scores.

Assay discrepancy in mild haemophilia A: entire population study in a National Haemophilia Centre.

Assay discrepancy in mild haemophilia, here defined by a significantly higher factor VIII (FVIII):C response by the one-stage procoagulant assay as compared with a two-stage enzymatic method, has repeatedly been reported in literature. The purpose of this study was to determine the overall prevalence of this phenomenon amongst mild haemophilia families from a population of 2.95 million inhabitants in the Western Danish region. Information was collected retrospectively through a thorough search of archives of the National Haemophilia Centre in Aarhus. We identified 109 patients with mild haemophilia A amongst whom 92 were eligible to enter the study. These represent a total of 53 unrelated families. Our data illustrate that this assay discrepancy pattern is found quite frequently amongst our mild haemophilia A families. While the ratio of FVIII:C chromogenic/FVIII:C clot values was quite consistent amongst patients belonging to same family pattern, ratios in the entire cohort of families ranged from 0.18 to 1.00. Selecting a cut-off level for the FVIII:C chromogenic/FVIII:C clot ratios at 0.7, 0.6 and 0.5, respectively, we found that 38 (72%), 27 (51%) and 19 (36%) of families, respectively, displayed this assay discrepancy. In 10 patients, the FVIII:C chromogenic level was inside the category of moderate haemophilia at >0.01-<0.05 IU mL(-1), pointing to a class-shift in the biochemical phenotype. In conclusion, our data illustrate a substantial prevalence of the assay discrepancy phenomenon amongst mild haemophilia A patients in our geographical area.

Late puerperal thrombohemorrhagic complications in a patient with antiphospholipid syndrome.

In this study, we present a case of late-puerperal onset of thrombohemorrhagic complications in a 33-yr-old woman with known antiphospholipid syndrome (APS) and heterozygosity for factor V Leiden gene mutation. Antithrombotic prophylaxis with low-molecular-weight (LMW) heparin was given since the 12th gestational week. Pregnancy and cesarean delivery were uncomplicated. Five weeks postpartum, the patient developed a severe hemorrhagic diathesis with marked thrombocytopenia accompanied by vaginal, nasal and cutaneous bleeding. A variety of autoimmune phenomena were also detected, partly at clinical presentation and partly later on, despite ongoing steroid treatment. Platelet counts recovered to normal values within a few weeks secondary to high-dose steroids and intravenous immunoglobulin administration. An ultrasound of both legs, performed because of persistent complaint of moderate calf pain, revealed bilateral deep venous thromboses (DVT). The clinical and biochemical findings were not consistent with thrombotic thrombocytopenic purpura (TTP), heparin-induced thrombocytopenia (HIT) or the 'hemolysis, elevated liver enzymes and low platelet syndrome' (HELLP). The diagnostic criteria for systemic lupus erythematosus (SLE) were not fulfilled either. The complex of thrombohemorrhagic complications and autoimmune phenomena seen in this case is unusual and not previously described in the late puerperal stage of APS-related pregnancies.

Potential role of the dynamic properties of whole blood coagulation in assessment of dosage requirements in haemophilia.

In the clinical setting, patients suffering from haemophilia are classified according to the residual level of the deficient coagulation factor. Patients suffering from the severe form of haemophilia (critical factor level <0.01 IU mL-1) display some heterogeneity in their tendency to bleeding despite the uniform factor level. Utilizing a new thrombelastographic method in which coagulation is activated by very small amounts of tissue factor and where resulting data are processed with new software, we studied the whole blood coagulation profile in 11 patients with severe haemophilia A and 11 patients with moderate haemophilia. In both groups of patients, we found a considerable degree of heterogeneity in the coagulation signal. In moderate haemophilia with factor VIII (FVIII):C levels between 0.01 and 0.05 IU mL-1, variance was expected, whereas a quite substantial diversity had not been forecasted in patterns of the whole blood coagulation profiles in patients with the severe form of haemophilia A. Ex vivo substitution to patient's blood to reach various theoretical levels of recombinant factor VIII (rFVIII) revealed that the coagulation response to FVIII supplementation varied substantially. In some severely affected patients levels of FVIII:C close to 0.05 IU mL-1 was sufficient to normalize the coagulation profile, while others required a dose giving >0.50 IU mL-1 of FVIII to achieve a normal whole blood clotting profile. In conclusion, our study revealed that severe haemophilia A seems not to be a single entity, but rather several different clinical and biochemical phenotypes, and that the response to added FVIII varies amongst patients.

Exposure to teachers smoking and adolescent smoking behaviour: analysis of cross sectional data from Denmark.

OBJECTIVE: To determine whether adolescent smoking behaviour is associated with their perceived exposure to teachers or other pupils smoking at school, after adjustment for exposure to smoking at home, in school, and best friends smoking. DESIGN: Logistic regression analysis of cross sectional data from students in Denmark. SUBJECTS: 1515 grade 9 students (mean age 15.8) from 90 classes in 48 Danish schools. OUTCOME MEASURE: Self reported smoking behaviour; daily smoking and heavy smoking, defined as those smoking more than 20 cigarettes per week. RESULTS: Of the students in this study, 62% of boys and 60% of girls reported being exposed to teachers smoking outdoors on the school premises. The proportion of boys and girls reporting to have been exposed to teachers smoking inside the school building were 86% and 88%, respectively. Furthermore, 91% of boys and 92% of girls reported that they had seen other students smoking outdoors on the school premises. Adolescents' perceived exposure to teachers smoking outdoors on the school premises was significantly associated with daily smoking, having adjusted for sex, exposure to teachers smoking indoors at school and pupils smoking outdoors at school, as well as the smoking behaviour of mother, father, and best friend (odds ratio (OR) 1.8, 95% confidence interval 1.2 to 2.8). Adolescents' perceived exposure to teachers smoking inside the school building was not associated with daily smoking (OR 0.9, 95% CI 0.5 to 1.6) and perceived exposure to pupils smoking outdoors was not associated with daily smoking (adjusted OR 1.5, 95% CI 0.5 to 4.4). There were similar findings with heavy smoking as the outcome variable. CONCLUSIONS: Teachers smoking during school hours is associated with adolescent smoking. This finding has implications for future tobacco prevention strategies in schools in many countries with liberal smoking policies where it might provide support for those working to establish smokefree schools.

Prognostic value of renal biopsy and clinical variables in patients with lupus nephritis and normal serum creatinine.

OBJECTIVE: To evaluate factors with possible influence on the renal outcome in patients with lupus nephritis but without chronic renal insufficiency (CRI). METHODS: Renal biopsies from 94 patients were re-assessed with regard to WHO class, activity, chronicity and tubulointerstitial indices without knowledge of clinical features. The outcome parameters were CRI defined as irreversibly increased serum creatinine and renal end stage disease. RESULTS: The risk ratios (RR) of developing CRI were 2.6 for active urinary sediment, 3.1 for hyaline thrombi and 7.3 for glomerular leukocyte exudation. The RR of renal end stage disease was 5.0 when the duration of renal disease exceeded one year at the time of biopsy and 4.3 when biopsy disclosed a class IV lesion. Glomerular sclerosis was also associated to renal end stage disease. CONCLUSION: Early renal biopsy and the abovementioned signs of active renal disease carry prognostic information that may have significant therapeutic implications.

Mortality and causes of death of 513 Danish patients with systemic lupus erythematosus.

A multicentre cohort of 513 clinic attenders with systemic lupus erythematosus (SLE) was retrospectively identified, representing 4185 patient-years of follow-up. Expected numbers of death were calculated by means of age- and sex-specific mortality rates of the general Danish population. The observed number of deaths was 122. The survival rates were 97%, 91%, 76%, 64% and 53% after 1, 5, 10, 15, and 20 years respectively. The overall mortality rate was 2.9% per year (95% CI 2.4-3.5), and the standardized mortality rate (SMR) was 4.6 (95% CI 3.8-5.5). The causes of death included active SLE (n = 19), end stage organ failure due to SLE (n = 16), infections (n = 25), malignancy (n = 9), cardiovascular disease (n = 32), and other causes (n = 21). SLE was directly related to one third of the excess mortality. In conclusion, SLE patients in the present cohort had a 4.6-fold increased mortality compared with the general population and half of the deaths were caused by SLE manifestations or infections, especially in young patients during the early period of the disease.

A multicentre study of 513 Danish patients with systemic lupus erythematosus. I. Disease manifestations and analyses of clinical subsets.

A Danish multicentre study was undertaken of the manifestations, infections, thrombotic events, survival and predictive factors of survival in 513 Danish patients with systemic lupus erythematosus (SLE) according to the 1982 classification criteria of the American College of Rheumatology. The mean duration of follow-up was 8.2 years from diagnosis and 12.8 years from first symptom. This paper describes the most common clinical and laboratory manifestations and their relationship to sex and age at the time of onset and diagnosis. Cluster analysis revealed three clinically defined clusters at the time of disease onset. Cluster 1 (57% of patients) consisted of relatively elderly patients without nephropathy or malar rash, but with a high prevalence of discoid lesions. Cluster 2 (18%) consisted of patients with nephropathy, a third of whom also developed serositis and lymphopenia. The patients of the third cluster (25%) all had malar rash and half were photosensitive. Follow-up showed that the patients of cluster 2 developed azotaemia, large proteinuria, arterial hypertension and myositis significantly more often than did the rest of the patients, but the mortality was not increased. The risk of developing renal end-stage disease was highest in men with early-onset disease.

A multicentre study of 513 Danish patients with systemic lupus erythematosus. II. Disease mortality and clinical factors of prognostic value.

In this Danish multicentre study, predictive clinical factors of mortality and survival were calculated for 513 patients with systemic lupus erythematosus (SLE), 122 of whom died within a mean observation period of 8.2 years equalling a mortality rate of 2.9% per year. Survival rates were 97%, 91%, 76% and 64% after 1, 5, 10 and 15 years, respectively. The direct causes of death included SLE (n = 35), infections (n = 25), malignancy (n = 9), cardiovascular disease (n = 32) and other causes (n = 21). Uni- and multivariate analyses of survival and mortality were performed for all deaths and for SLE-related deaths. Azotaemia (one-fifth of the patients) was a strong predictor of increased overall and SLE-related mortality, but nephropathy per se (one-half of the patients) and large proteinuria (one-sixth of the patients) were unrelated to survival. Haemolytic anaemia had a significant negative influence on survival related to mortality caused by infections. Diffuse central nervous system disease and myocarditis were related to increased SLE-related mortality, whereas photosensitivity predicted a decreased mortality. Non-fatal infections and thrombotic events predicted a decreased overall survival. Since 1980 the mortality caused by SLE manifestations has decreased significantly.

Valproate for treatment of chronic central pain after spinal cord injury. A double-blind cross-over study.

Chronic central pain is a frequent complication after spinal cord injury. Anticonvulsant drugs, among them valproate, have been recommended for treatment. In this paper we conducted a double-blind, cross-over study comparing valproate and placebo for severe chronic central pain. During the study, serum concentration of valproate, pain and side effects were registered and the dose was adjusted according to these. No significant analgesic effects of valproate could be demonstrated although serum concentration and dose reached a high level. Few studies of pain following spinal cord injury exist and we recommend that further studies be performed.

McGill Pain Questionnaire translated into Danish: experimental and clinical findings.

OBJECTIVE: To develop a methodology for translating the McGill Pain Questionnaire (MPQ) into a Danish version, and to make comparisons to studies of patients speaking other languages. DESIGN: Finding suitable Danish adjectives using the same methodology as that in the original MPQ. Comparison of Danish descriptors to the words in the English version of MPQ. Survey in healthy subjects and patients with rheumatoid arthritis (RA) and fibromyalgia (F). SETTING: The general public and hospital outpatients. PATIENTS: A random sample of 186 healthy volunteers, 20 patients with rheumatoid arthritis and 41 patients with fibromyalgia. MAIN OUTCOME MEASURES: Danish words translated as closely as possible to the descriptors in the original McGill Pain Questionnaire. A pain-assessment instrument making international pain description possible. RESULTS: A Danish version of the McGill Pain Questionnaire was developed with scale values of Danish descriptors not differing more than 5 x SEM from the 'patient' words in the English version. The subdivision into classes and subclasses was respected. In the reliability experiment, the same rank values were found in 85% of subclasses. In a study using two experimental pain stimulus intensities, seven of 10 subjects obtained higher MPQ scores following the high-intensity stimulus. In the clinical study, the pain profiles of patients with RA and F in English, Italian, and Danish patients were almost the same. CONCLUSION: The present methodology of translating the McGill Pain Questionnaire permits comparison of studies from English-speaking and non-English-speaking populations, thus facilitating international research exchange.