Cerebrospinal fluid biomarkers for predicting development of multiple sclerosis in acute optic neuritis: a population-based prospective cohort study.

BACKGROUND: Long-term outcome in multiple sclerosis (MS) depends on early treatment. In patients with acute optic neuritis (ON), an early inflammatory event, we investigated markers in cerebrospinal fluid (CSF), which may predict a diagnosis of MS. METHODS: Forty patients with acute ON were recruited in a prospective population-based cohort with median 29 months (range 19-41) of follow-up. Paired CSF and serum samples were taken within 14 days (range 2-38), prior to treatment. Prospectively, 16/40 patients were by a uniform algorithm diagnosed with MS (MS-ON) and 24 patients continued to manifest isolated ON (ION) during follow-up. Levels of cytokines and neurofilament light chain (NF-L) were measured at the onset of acute ON and compared to healthy controls (HC). Significance levels were corrected for multiple comparisons ("q"). The predictive value of biomarkers was determined with multivariable prediction models using nomograms. RESULTS: CSF TNF-α, IL-10, and CXCL13 levels were increased in MS-ON compared to those in ION patients (q = 0.021, 0.004, and 0.0006, respectively). MS-ON patients had increased CSF pleocytosis, IgG indices, and oligoclonal bands (OCBs) compared to ION (q = 0.0007, q = 0.0058, and q = 0.0021, respectively). CSF levels of IL-10, TNF-a, IL-17A, and CXCL13 in MS-ON patients correlated with leukocyte counts (r > 0.69 and p < 0.002) and IgG index (r > 0.55, p < 0.037). CSF NF-L levels were increased in ON patients compared to those in HC (q = 0.0077). In MS-ON, a progressive increase in NF-L levels was observed at 7 to 14 days after disease onset (r = 0.73, p < 0.0065). Receiver-operating characteristic (ROC) curves for two multivariable prediction models were generated, with IL-10, CXCL13, and NF-L in one ("candidate") and IgG index, OCB, and leukocytes in another ("routine"). Area under the curve was 0.89 [95% CI 0.77-1] and 0.86 [0.74-0.98], respectively. Predictions of the risk of MS diagnosis were illustrated by two nomograms. CONCLUSIONS: CSF TNF-α, IL-10, CXCL13, and NF-L levels were associated with the development of MS, suggesting that the inflammatory and neurodegenerative processes occurred early. Based on subsequent diagnosis, we observed a high predictive value of routine and candidate biomarkers in CSF for the development of MS in acute ON. The nomogram predictions may be useful in the diagnostic work-up of MS.

A population-based prospective study of optic neuritis.

BACKGROUND: Optic neuritis (ON) is often associated with multiple sclerosis (MS). Early diagnosis is critical to optimal patient management. OBJECTIVE: To estimate the incidence of acute ON and the rates of conversion to MS and antibody-mediated ON. METHOD: Population-based prospective study was performed in patients with ON from three ophthalmological departments and 44 practicing ophthalmologists from 2014 to 2016. Ophthalmological and neurological examination, magnetic resonance imaging (MRI), determination of aquaporin-4(AQP4)-IgG and myelin-oligodendrocyte glycoprotein (MOG)-IgG were investigated blindly. RESULTS: In all, 63 patients were evaluated and 51 fulfilled the criteria for ON. All were Caucasian, with female:male ratio of 2.2:1 and a median age of 38 years (16-66); 44 (86%) had a single episode of ON (four bilateral), while 7/51 (14%) had recurrent ON. The overall age-specific incidence was 3.28 (2.44-4.31) per 100,000 person years, 2.02 for men and 4.57 for women. At follow-up, 20 patients met the diagnostic criteria for MS, MRI lesions disseminated in space and time in 17/20 patients. AQP4-IgG was detected in none, MOG-IgG was detected in two patients. CONCLUSION: The prospective incidence of ON was estimated. MRI enabled a diagnosis of MS in a subgroup of patients. Antibody-mediated ON with specificity for MOG was detected in 4% of cases.

VEGFA variants are associated with pre-school lung function, but not neonatal lung function.

BACKGROUND: Vascular endothelial growth factor (VEGF) is implicated in airway remodelling and asthma development. We studied VEGFA gene variants and plasma levels and the development of lung function, bronchial hyperresponsiveness and asthma in childhood. METHODS: We analysed 13 SNPs in the VEGFA gene in 411 children from the COPSAC2000 high-risk birth cohort. Asthma was diagnosed prospectively, and lung function measurements were obtained at birth and 6 years of age. Plasma VEGF levels were measured at 18 months of age. We used a Bonferroni adjusted significance level. Findings were replicated in the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort at age 8. RESULTS: At age six, three SNPs from the same linkage block were associated with FEV1 (rs699947, P = 1.31E-05), independent of asthma, and there were suggestive associations between FEV1/FVC ratio and rs833052 and maximal mid-expiratory flow and rs6900017. Replication in the PIAMA cohort showed borderline association between FEV1 and rs699947 and significant meta-analysis result. SNPs upstream and nearby rs699947 were nominally associated with VEGF plasma levels. VEGF levels were not associated with asthmatic symptoms or lung function measures. CONCLUSIONS AND CLINICAL RELEVANCE: VEGF gene variants are associated with lung function at school age, but not at birth, suggesting a role of VEGF in post-natal lung function development.

Circulating miR-141 and miR-375 are associated with treatment outcome in metastatic castration resistant prostate cancer.

Metastatic castration resistant prostate cancer (mCRPC) is associated with high mortality, where monitoring of disease activity is still a major clinical challenge. The role of microRNAs (miRs) has been widely investigated in prostate cancer with both diagnostic and prognostic potential. The aim of this study was to investigate the relationship between circulating miRs and treatment outcome in mCRPC patients. The relative expression of five miRs (miR-93-5p, -125b-1-5p, -141-3p, -221-3p, and miR-375-3p) was investigated in plasma samples from 84 mCRPC patients; 40 patients were treated with docetaxel (DOC cohort) and 44 patients with abiraterone (ABI cohort). Blood was sampled at baseline before treatment start and at radiological progression. The plasma levels of four miRs; miR-93-5p, -141-3p, -221-3p, and miR-375-3p decreased significantly after treatment initiation in patients receiving docetaxel, and for miR-141-3p and miR-375-3p the level increased again at the time of radiological progression. In the patients treated with abiraterone, the plasma level of miR-221-3p likewise decreased significantly after the first treatment cycle. High baseline levels of both miR-141-3p and miR-375-3p were significantly associated with a shorter time to radiological progression in both cohorts. Additionally, high baseline levels of miR-141-3p and miR-221-3p were significantly associated with a shorter overall survival (OS) in the ABI cohort, while high levels of miR-141-3p and miR-375-3p were significantly associated with shorter OS in the DOC cohort. Plasma levels of miR-141-3p and miR-375-3p may predict time to progression in mCRPC patients treated with docetaxel or abiraterone. The clinical impact of these findings is dependent on validation in larger cohorts.

Highly sensitive quantification of optic neuritis intrathecal biomarker CXCL13.

BACKGROUND: Elevation of CXCL13, a key regulator of B-cell recruitment in cerebrospinal fluid (CSF) is implicated in multiple sclerosis (MS). OBJECTIVE: to evaluate if measurement of CXCL13 using a highly sensitive assay is of value in acute optic neuritis (ON) patients for the prediction of later MS. METHOD: CXCL13 was measured by Simoa in two independent treatment-naïve ON cohorts, a training cohort (TC, n = 33) originating from a population-based cohort, a validation cohort (VC, n = 30) consecutively collected following principles for population studies. Prospectively, 14/33 TC and 12/30 VC patients progressed to MS (MS-ON) while 19/33 TC and 18/30 VC patients, remained as isolated ON (ION). RESULTS: CXCL13 was detectable in all samples and were higher in ON compared with healthy controls (HC) (p = 0.012). In the TC, CSF levels in MS-ON were higher compared with ION patients and HC (p = 0.0001 and p<0.0001). In the VC, we confirmed the increase of CXCL13 in MS-ON compared to ION (p = 0.0091). Logistic regression analysis revealed an area under receiver operating characteristic curve of 0.83 [95% C.I: 0.73-0.93]. CONCLUSIONS: The highly sensitive CXCL13 Simoa assay demonstrated ability to identify ON patients and separate MS-ON from ION, and predictive diagnostic values indicates a promising potential of this assay.

No association between hip geometry and four common polymorphisms associated with fracture: the Danish osteoporosis prevention study.

Both osteoporosis and hip geometry are independently associated with fracture risk. There is a significant genetic contribution to the risk of osteoporosis, and evidence provided by twin studies has suggested that hip geometry may also in part be genetically programmed. Polymorphisms in a number of genes, including those coding for methylene-tetrahydrofolate reductase (MTHFR c.677C > T), the purinergic P2X(7) receptor (Glu496Ala and Ile568Asn), and the low-density lipoprotein receptor-related protein 5 (LRP5 exon 9 [c.266A > G]), have been associated with an increased fracture incidence and/or reduced bone mineral density (BMD). The aim of the present study was to test whether these polymorphisms influence hip structural geometry in perimenopausal women. The four polymorphisms were genotyped in 800 healthy recently perimenopausal women never using hormone replacement therapy. BMD of the femoral neck was measured using a Hologic QDR-2000 densitometer and femoral neck axis length, neck width, neck shaft angle, and femoral head diameter were measured from the screen images. Genotype frequencies were compatible with Hardy-Weinberg equilibrium. No significant differences between homozygotes for the minor allele and carriers of the common allele regarding parameters of hip geometry were demonstrated. According to the anthropometric characteristics of the subjects, only body height in the MTHFR TT genotype group was significantly different from the combined CT/CC genotype group (P < 0.05). The geometric dimensions of the proximal femur in perimenopausal women are not associated with the MTHFR c.677C > T, P2X(7) (Glu496Ala), P2X(7) (Ile568Asn), and LRP5 exon 9 (c.266A > G) polymorphisms.

Validation of the PHEEM instrument in a Danish hospital setting.

The Postgraduate Hospital Educational Environment Measure (PHEEM) has been translated into Danish and then validated with good internal consistency by 342 Danish junior and senior hospital doctors. Four of the 40 items are culturally dependent in the Danish hospital setting. Factor analysis demonstrated that seven items are interconnected. This information can be used to shorten the instrument by perhaps another three items.

Positive impact of hormone replacement therapy on the fibrinolytic system: a long-term randomized controlled study in healthy postmenopausal women.

BACKGROUND: The mechanisms by which postmenopausal hormone replacement therapy (HRT) may influence risk of cardiovascular disease are still unclear. Impaired fibrinolytic function is associated with an enhanced risk of cardiovascular disease and therefore the effect of HRT on fibrinolysis may be of importance. OBJECTIVES: To investigate the prolonged effect of HRT on the fibrinolytic system and to determine whether two common polymorphisms in the plasminogen activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (t-PA) genes modulate this effect. METHODS: Healthy postmenopausal women (n = 248) were randomized to HRT (n = 122) or no substitution (n = 126) 5 years prior to investigation. RESULTS: Significantly higher values of t-PA activity and lower values of PAI-1 activity and PAI-1 antigen were found in the HRT group compared with the control group. This effect was independent of smoking and without influence from the two common polymorphisms PAI-1 -675(4G/5G) and t-PA intron8ins311. Furthermore, no difference between opposed estrogen (with norethisterone acetate as the gestagen component) and unopposed estrogen therapy was found. Both an intention-to-treat and a per-protocol analysis were performed and similar results were obtained. CONCLUSIONS: Long-term treatment with HRT in healthy postmenopausal women was found to be associated with a beneficial fibrinolytic profile. This effect was found independent of smoking status, opposed and unopposed estrogen therapy had equal effect, and no influence of the two common polymorphisms PAI-1-675(4G/5G) and t-PA intron8ins311 was found. This effect of HRT on fibrinolytic capacity may be one of the beneficial effects of HRT in relation to cardiovascular diseases.

Effect of long-term hormone replacement therapy on tissue factor pathway inhibitor and thrombin activatable fibrinolysis inhibitor in healthy postmenopausal women: a randomized controlled study.

It was recently reported from the Women's Health Initiative that healthy women using combined hormone replacement therapy (HRT) for 5 years have an increased cardiovascular risk. We hypothesize that the increased risk is confined to subgroups of atherosclerotic women. Such women may have higher arterial tissue factor expression and higher thrombin formation, and changes in tissue factor pathway coagulation inhibitor (TFPI) and thrombin activatable fibrinolysis inhibitor (TAFI) may be deleterious. Healthy postmenopausal women (n = 719) were randomized to hormone therapy [n = 357; opposed (n = 290) and unopposed (n = 67)] or no treatment (n = 362). Plasma TFPI and TAFI and the TFPI -287T/C and TAFI -438G/A polymorphisms were measured 5-6 years after randomization. Concentrations of TFPI were significantly lower in the hormone group than in the control group (P < 0.001) and in all genotypes of the TFPI polymorphism. Overall, concentrations of TAFI did not differ between the two groups but were reduced by hormone therapy in homozygotes for the rare TAFI -438 A allele (P < 0.05). The hormone effects on TFPI and TAFI were similar in smokers and non-smokers and in women using unopposed and opposed therapy. The observed decrease in TFPI may contribute to the increased cardiovascular risk associated with HRT.

Procollagen type-III aminoterminal peptide in serum and synovial fluid of dogs with hip dysplasia and coxarthrosis.

Hip dysplasia is an affection of the coxofemoral joint that progresses until stabilization is caused by fibrosis and osteoarthritic changes. This stabilization process can be examined by clinical and radiographic methods. The capability of evaluating the procollagen concentrations in liquids, such as serum and synovial fluid, has further offered the basis for an objective biochemical evaluation of the stabilization process. Our study was performed to evaluate whether determination of procollagen concentrations was suitable for the use in practice. The procollagen type-III aminoterminal peptide (P-III-NP) concentration was measured in serum and in synovial fluid from coxofemoral joints in 20 dogs. Dogs were grouped on the basis of evidence of dysplasia and osteoarthritic changes of the hip: (1) a control group of 6 dogs without clinical or radiographic signs of hip dysplasia, and (2) dysplastic group of 14 dogs, which was further grouped with respect to the coxofemoral joint laxity, as determined by the Ortolani test. Synovial fluid concentration of P-III-NP was significantly (P less than 0.05) higher in fluid from dysplastic joints than in fluid from normal joints. Serum concentrations of P-III-NP were significantly (P less than 0.05) higher in dogs in which results of the Ortolani test were positive.

The joint capsule and joint laxity in dogs with hip dysplasia.

Present knowledge of the complexity of joint diseases makes it difficult to investigate the causes and early pathogenesis of canine hip dysplasia. Clinical signs of canine hip dysplasia including joint laxity may be a result of primary or secondary alterations of the joint. We already know that joint laxity is related to effusive synovitis (ie, accumulation of synovial fluid) and to other primary collagenous diseases. Canine hip dysplasia may be a third collagenous disease associated with joint laxity. This paper summarizes some of the studies that investigated the relationship between joint laxity and a defect in collagen metabolism and the influence that alterations in transsynovial flow have on joint laxity.

Arthroscopic treatment of shoulder instability: current concepts and techniques.

The incidence of glenohumeral joint instability is estimated to effect between 2 and 8% of the population. It represents at least one third of all shoulder related emergency room visits. When one considers the spectrum of shoulder instability, including transient subluxation, the true incidence of glenohumeral instability is probably grossly under-reported. Although any age group can be affected, shoulder instability is primarily a disease of the young. The occurrence of instability is inversely proportional to the age of the patient and the time of original injury. A patient who dislocates for the first time as a teen can expect a redislocation rate approaching 90% in his or her lifetime. Therefore, many authors recommend early surgical treatment to repair the lesion.

Inclination and anteversion of collum femoris in hip dysplasia and coxarthritis.

Femoral neck angles were measured radiographically in 41 dogs examined for hip dysplasia. Steep femoral neck inclination was found to be a phenomenon of hip dysplasia and coxofemoral joint laxity. The altered biomechanics of a steep femoral neck inclination may be a factor in the pathogenesis of hip dysplasia and secondary osteoarthritis.

[Questions as evident key to knowledge: teaching medical students evidence-based medicine]. / Spørgsmålet som (e)vidensnøgle: undervisning af medicinstuderende i evidensbaseret medicin.

INTRODUCTION: In Denmark, as in other countries, there is an increasing focus on evidence-based medicine (EBM) as a necessary tool for using modern sources of information, but until now EBM training has not been incorporated in our undergraduate curriculum. MATERIAL AND METHODS: This course is given in the ninth semester (out of 13) and the subject matter is clinical biochemistry. The course consists of seven (one-hour) lectures over three weeks. First, the EBM method is introduced, then the students split up into small groups, choose their own diagnostic problem, and carry out a structured search. The search leads to the choice of a scientific article, which is subsequently presented to and discussed by all the students. We asked about their opinion of the course by questionnaire. RESULTS: The answers to the questionnaire confirmed that the students have improved their ability to read and assess scientific articles and to seek information, and it has stimulated them to understand concepts instead of memorising details. DISCUSSION: Although the assessment of this course was positive, it can no doubt be improved and further developed. In our opinion the use of EBM should not be confined to one course. The medical students should be introduced to EBM at an early stage, thereby abling them to practice it throughout their training.

[Evidence-based use of clinical biochemistry]. / Evidensbaseret anvendelse af klinisk biokemi.

Evidence-based use of clinical biochemistry integrates into clinical decision-making the best research evidence with the clinical expertise of the physician and the expectations and concerns of the patient. The best research evidence for the clinical use of a biochemical test should be appraised in close collaboration between clinicians and specialists in clinical biochemistry, as familiarity with both the clinical problem and the analytical performance of the test is necessary. At present, it is difficult to ensure an evidence-based use of biochemical tests. More and methodologically better studies of the clinical value of biochemical tests are needed, and methods should be developed that make it possible to assess the results of such studies by systematic reviews and meta-analyses. Clinical biochemistry is an interdisciplinary specialty, and papers on the clinical value of biochemical tests are published in a vast number of journals of different clinical specialties as well as those of clinical biochemistry. It is thus almost impossible to keep abreast of the subject. The establishment of a system for literature surveillance focusing on methodologically sound studies of the clinical value of biochemical tests would be advantageous. Lastly, training and education on how to find and assess the existing evidence for the clinical use of biochemical tests are needed.

Procalcitonin as a marker of postoperative complications.

OBJECTIVE: Procalcitonin (PCT) is a 116 amino acid peptide that functions as a pro-hormone for calcitonin in the C cells of the thyroid gland. Large quantities of intact PCT are present in the blood of patients with sepsis, particularly when organ dysfunction occurs. PCT has been proposed as an early marker of postoperative complications. The aim of this study was to examine the diagnostic accuracy of PCT as a marker of postoperative complications by systematically reviewing the existing literature. MATERIAL AND METHODS: The databases PubMed, Embase and the Cochrane Library were searched to find studies on the diagnostic accuracy of PCT in the postoperative phase. Primary studies were retrieved using specific inclusion and exclusion criteria. RESULTS: A total of nine studies were included. These studies were heterogeneous regarding the spectrum of patients, complications, design and methodological quality according to QUADAS (quality assessment of studies of diagnostic accuracy). This could explain the marked variation in diagnostic accuracy. Considering all types of complications the sensitivity ranged from 37% to 100% and the specificity from 70% to 100%. On examining the infectious complications separately, it was found that the sensitivity ranged from 70% to 86% and the specificity from 45% to 98%. CONCLUSIONS: Owing to a pronounced heterogeneity among the existing studies, the diagnostic accuracy of PCT as a marker for postoperative complications is not yet sufficiently clarified.

Angiotensin converting enzyme inhibitor therapy and acute pancreatitis.

Angiotensin converting enzyme (ACE) inhibitors are generally well tolerated. Worldwide, only few reports have been published associating pancreatitis with ACE inhibitor therapy. We report a case in whom there was no other likely explanation for the acute pancreatitis than enalapril therapy, which was temporally associated with the symptoms. Possible mechanisms underlying the induction of pancreatitis by ACE inhibitors are discussed. With the increasing use of ACE inhibitors, the incidence of rare adverse effects such as potentially lethal pancreatitis is likely to increase. Clinicians need to be aware of this association.

Association of a common allelic polymorphism (C677T) in the methylene tetrahydrofolate reductase gene with a reduced risk of osteoporotic fractures. A case control study in Danish postmenopausal women.

Twin studies indicate a substantial genetic component in the development of osteoporosis. One of the latest studied candidate genes is the one coding for methylene tetrahydrofolate reductase (MTHFR) (C677T) in which a point mutation gives rise to a thermolabile variant of MTHFR. The aim of this study was to investigate the influence of this mutation on peripheral measures of bone density and on the odds ratios (OR) for hip and lower forearm fracture in a case control study of Danish postmenopausal women. A total of 74 women with lower forearm fracture, 41 women with hip fracture, and 207 age-matched controls were included. All had broadband ultrasound attenuation (BUA) and speed of sound (SOS) measured at the heel as well as bone mineral density (BMD) measured by dual X-ray absorptiometry at the distal forearm. The MTHFR (C677T) genotypes were determined using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Only 2 of 21 individuals with the TT genotype had sustained a fracture as opposed to 46 of 142 with the CT genotype and 67 of 159 with the CC genotype (P = 0.007). Using logistic regression, the following odds ratios were found when comparing the individuals homozygotic for the C-allele with those homozygotic for the T-allele: lower forearm fracture OR = 3.93 (1.25; 12.40, P = 0.02), hip fracture OR = 6.99 (l.35; 36.92, P = 0.02) and the fractures combined OR = 4.33 (1.73; 10.81, P = 0.002). In this study, the MTHFR (C677T) genotypes were not significantly associated with BMD at the lower forearm or with ultrasound parameters measured at the calcaneus. However, a significant increase in the odds ratio of fracture was found for the wild-type C-allele.