Whiplash-Associated Disorders : Clinical and medico-legal guidelines on the methods of ascertainment.

The manuscript presents the International Guidelines developed by the Working Group on Personal Injury and Damage under the patronage of the International Academy of Legal Medicine (IALM) regarding the Methods of Ascertainment of any suspected Whiplash-Associated Disorders (WAD).The document includes a detailed description of the logical and methodological steps of the ascertainment process as well as a synoptic diagram in the form of Flow Chart.

Reproducibility and responsiveness of a Danish Pedi-IKDC subjective knee form for children with knee disorders.

The modified International Knee Documentation Committee Subjective Knee Form (Pedi-IKDC) is a widely used patient-reported tool ranging on a scale from 0 to 100. We aimed to translate Pedi-IKDC into Danish and assess its reproducibility and responsiveness in children with knee disorders. The translation complied with the international guidelines. Reproducibility was assessed in 53 children (15 years) responding Pedi-IKDC at baseline and after 3-14 days. For analysis of responsiveness, 94 children (15 years) responded Pedi-IKDC again after 3 months. Test-retest reliability was excellent. Intraclass correlation coefficient was 0.9, standard error of measurement was 4.1 points, and smallest detectable change (SDC) was 11.3 points. Evaluating responsiveness as a large effect was found in children reporting improvement compared with children reporting deterioration. The change score was correlated to the external anchor Global Rating Scale consisting of 15 answers from -7 "A very great deal worse" to +7 "A very great deal better," with a Spearmen's rho of 0.45 (P > 0.001). The minimal clinically important changes was 12.0. In conclusion, excellent test-retest reproducibility was found at group level, but at individual level the SDC was high. The Pedi-IKDC showed adequate responsiveness and is suitable for assessing improvement or deterioration in children with knee disorders.

Two cases of acute severe flaccid myelitis associated with enterovirus D68 infection in children, Norway, autumn 2014.

Enterovirus D68 (EV-D68), phylogenetic clade B was identified in nasopharyngeal specimens of two cases of severe acute flaccid myelitis. The cases were six and five years-old and occurred in September and November 2014. EV-D68 is increasingly associated with acute flaccid myelitis in children, most cases being reported in the United States. Awareness of this possible neurological complication of enterovirus D68 infection is needed.

Danish military fatalities in international operations 2002-2018.

INTRODUCTION: This study describes deaths among Danish soldiers in international operations 2002-2018. Having been part of UN and later NATO forces in ex-Yugoslavia, in 2002 the first Danish contingent took part in the International Security Assistance Force mission in Afghanistan as well as Iraq. The changing role of the Danish military in international operations meant casualties, in numbers that had not yet been experienced, and necessitated a review of our procedures for handling fatalities in the military. METHODS: The study is a retrospective review of autopsy reports, Military Police reports and medical reports, and the purpose is to examine all Danish fatalities in international operations in 2002-2018 to identify potential areas of improving treatment and protection and to review the contribution of the autopsies. The mechanism of injury, the fatal injuries and causes of death and the time of death within the chain of evacuation were identified. Casualties dying at any time from site of injury until definitive care were included. RESULTS: A total of 53 soldiers died from injuries during international operations in the years 2002-2018. The majority of these (43) died from combat injuries and 10 from accidents. Four of the victims with combat injuries were not autopsied. The majority (36) of the combat deaths were caused by blast/explosions (improvised explosive devices, rocket propelled grenades, fragments), while 7 were caused by bullets. 39 combat victims died instantly on the site or at the arrival to the field hospital, 4 were treated in field hospital and 2 of these were transported back to Denmark. CONCLUSIONS: Most combat fatalities result from fragmentation and blast injury. Forensic autopsies provide valuable information regarding injuries, weaponry, the efficiency of protective equipment and the quality of medical intervention in military fatalities and are recommended in all military fatalities in order to prevent avoidable casualties in the future.

Vitamin D deficiency as a risk factor for cystic fibrosis-related diabetes in the Scandinavian Cystic Fibrosis Nutritional Study.

AIMS/HYPOTHESIS: Many cystic fibrosis patients are vitamin D-insufficient. Cystic fibrosis-related diabetes is a major complication of cystic fibrosis. The literature suggests that vitamin D might possess certain glucose-lowering properties. We aimed to assess the relationship between vitamin D and cystic fibrosis-related glucose intolerance. METHODS: We enrolled 898 cystic fibrosis patients from Sweden, Norway and Denmark. Vitamin D intake was assessed using a seven-day food record. Serum 25-hydroxyvitamin D (s25OHD) and HbA(1c) were measured, and an OGTT was carried out. Multiple linear and logistic regressions were used for HbA(1c) and cystic fibrosis-related diabetes/OGTT result as outcome variables, respectively. Each model was controlled for country, and for known cystic fibrosis-related diabetes risk factors: age, sex, genotype, liver dysfunction, long-term corticosteroid treatment, and lung and pancreatic function. RESULTS: Degree of vitamin D insufficiency (OR 1.36; p = 0.032) and s25OHD < 30 nmol/l (OR 1.79; p = 0.042) were significant risk factors for cystic fibrosis-related diabetes. Accordingly, HbA(1c) value was positively associated with s25OHD < 30 nmol/l and < 50 nmol/l, as well as with degree of vitamin D insufficiency (adjusted R (2) = 20.5% and p < 0.05 in all). In subgroup analyses, s25OHD < 30 nmol/l determined the HbA(1c) value in paediatric patients (adjusted R (2) = 20.2%; p = 0.017), but not in adults. CONCLUSIONS/INTERPRETATION: Vitamin D status is associated with HbA(1c) and diabetes in cystic fibrosis, particularly in children. The study justifies prospective studies on the proposed role of vitamin D deficiency in the pathophysiology of diabetes mellitus.

Patient safety incidents involving transdermal opioids: data from the Danish Patient Safety Database.

Background Transdermal opioids are widely used among elderly adults with chronic pain. However, transdermal patches may be involved in a significant proportion of opioid-related patient safety incidents, as the application process includes several subprocesses, each associated with an individual risk of error. Objective The aim was to obtain specific knowledge on patient safety incidents related to transdermal opioid treatment within both the primary care sector and the hospital sector in Denmark. Setting The study is descriptive with data provided by the Danish Patient Safety Database. Methods We manually retrieved all patient safety incidents concerning transdermal opioids reported for 2018 from (1) the hospital sector and (2) the primary care sector. Study data were collected and managed using REDCap electronic data capture tools. Main outcome measure The available information for each incident was sorted into the following categories: location, medication process, type of problem, outcome at time of reporting, and outcome classification. Results A total of 866 patient safety incidents involving transdermal opioids were reported to the Danish Patient Safety Database in 2018. No fatal incidents were present in the database. In 386 cases, the incidents were reported as harmful, and these 386 cases were analysed. Most reports came from the primary care sector (nursing home, home care or social housing). The majority of incidents were related to the administration of the patch in the medication process, and the most prevalent problem was the omission of doses. Conclusion This study has demonstrated that the administration of transdermal opioids is challenging and may cause harm, particularly in the primary care sector. To improve patient safety, optimized systems, including guidelines on drug management and the continuing education of healthcare personnel in transdermal opioid management, are necessary. These guidelines should preferably incorporate reminders and checklists, since the omission of doses was the most reported problem.

Vision guides the adjustment of auditory localization in young barn owls.

Barn owls raised with one ear plugged make systematic errors in auditory localization when the earplug is removed. Young owls correct their localization errors within a few weeks. However, such animals did not correct their auditory localization errors when deprived of vision. Moreover, when prisms were mounted in front of their eyes, they adjusted their auditory localization to match the visual error induced by the prisms, as long as the visual and auditory errors were within the same quadrant of directions. The results demonstrate that, during development, the visual system provides the spatial reference for fine-tuning auditory localization.

Direct method for detecting small quantities of hepatitis B virus DNA in serum and plasma using the polymerase chain reaction.

Serum components inhibit DNA polymerase, thereby obviating direct detection of serum viral DNA sequences by the polymerase chain reaction (PCR). This has necessitated extraction of nucleic acid from sera before performing PCR and has resulted in loss of sensitivity. By adsorbing virus to a solid surface (microcentrifuge tubes or antibody coated microparticles) followed by proteinase K digestion, as little as three viruses per 200 microliters serum may be directly detected by PCR without nucleic acid extraction. The sensitivity is dependent on the surface area of the adsorptive surface and is increased by having antibodies on the adsorptive surface. The nucleic acid sequence of the amplified DNA fragments may be directly determined by the dideoxy method. Of 24 plasma samples from HBsAg+ volunteer blood donors, HBV DNA was detected in 7 by dot blot assay, 7 by liquid hybridization, and 9 by PCR. PCR detected DNA in every sample that was positive by another assay. Analysis of serial samples of two patients with acute self-limited hepatitis B found detectable HBsAg and pre-S2 antigenemia before HBV DNA by the PCR method. These results suggest that surface antigenemia may precede viremia during acute hepatitis.

Multidrug-resistant tuberculosis in Norway: a nationwide study, 1995-2014.

SETTING: The management of multidrug-resistant tuberculosis (MDR-TB) is strictly regulated in Norway. However, nationwide studies of the epidemic are lacking. OBJECTIVE: To describe the MDR-TB epidemic in Norway over two decades. DESIGN: Retrospective analysis of data on MDR-TB cases in Norway, 1995-2014, obtained from the national registry, patient records and the reference laboratory, with genotyping and cluster analysis data. Data for non-MDR-TB cases were collected from the national registry. RESULTS: Of 4427 TB cases, 89 (2.0%) had MDR-TB, 7% of whom had extensively drug-resistant TB (XDR-TB) and 24% pre-XDR-TB. Of the 89 MDR-TB cases, 96% were immigrants, mainly from the Horn of Africa or the former Soviet Union (FSU); 37% had smear-positive TB; and 4% were human immunodeficiency virus co-infected. Of the 19% infected in Norway, the majority belonged to a Delhi/Central Asian lineage cluster in a local Somali community. Among the MDR-TB cases, smear-positive TB and FSU origin were independent risk factors for XDR/pre-XDR-TB. Treatment was successful in 66%; 17% were lost to follow-up, with illicit drug use and adolescence being independent risk factors. Forty-four per cent of patients treated with linezolid discontinued treatment due to adverse effects. CONCLUSION: MDR-TB is rare in Norway and is predominantly seen in immigrants from the Horn of Africa and FSU. Domestic transmission outside immigrant populations is minimal.

Iodine intake and the pattern of thyroid disorders: a comparative epidemiological study of thyroid abnormalities in the elderly in Iceland and in Jutland, Denmark.

Thyroid abnormalities are common in all populations, but it is difficult to compare results of epidemiological studies, because different methods have been used for evaluation. We studied the importance of the population iodine intake level for the prevalence rate of various thyroid abnormalities in elderly subjects. Random samples of elderly subjects (68 yr) were selected from the central person registers in Jutland, Denmark, with low (n = 423) and, in Iceland, with longstanding relatively high (n = 100) iodine intake. Females from Jutland had a high prevalence of goiter or previous goiter surgery (12.2%), compared with males from Jutland (3.2%) and females (1.9%) and males (2.2%) from Iceland. Abnormal thyroid function was very common in both areas, with serum TSH outside the reference range in 13.5% of subjects from Jutland and 19% of those from Iceland. In Jutland, it was mainly thyroid hyperfunction (9.7% had low, 3.8% had high serum TSH), whereas in Iceland, it was impaired thyroid function (1% had low, 18% had high serum TSH). All subjects with serum TSH more than 10 mU/L had autoantibodies in serum, but antibodies were, in general, more common in Jutland than in Iceland. Thus, thyroid abnormalities in populations with low iodine intake and those with high iodine intake develop in opposite directions: goiter and thyroid hyperfunction when iodine intake is relatively low, and impaired thyroid function when iodine intake is relatively high. Probably, mild iodine deficiency partly protects against autoimmune thyroid disease. Thyroid autoantibodies may be markers of an autoimmune process in the thyroid or secondary to the development of goiter.

Amelioration of some pregnancy-associated variations in thyroid function by iodine supplementation.

Knowledge of the effect of differences in iodine intake levels on public health in areas with no endemic goiter is limited. Groups at risk when iodine intake is relatively low are pregnant and lactating women and their newborns. A prospective randomized study was performed to evaluate the effect of iodine supplementation in an area where the median daily iodine excretion in urine is around 50 micrograms. Fifty-four normal pregnant women were randomized to be controls or to receive 200 micrograms iodine/day from weeks 17-18 of pregnancy until 12 months after delivery. In the control group, serum TSH, serum thyroglobulin (Tg), and thyroid size showed significant increases during pregnancy. These variations were ameliorated by iodine supplementation. Iodine did not induce significant variations in serum T4, T3, or free T4. Cord blood Tg was much lower when the mother had received iodine, whereas TSH, T4, T3, and free T4 levels were unaltered. The results suggest that a relatively low iodine intake during pregnancy leads to thyroidal stress, with increases in Tg release and thyroid size. However, the thyroid gland is able to adapt and keep thyroid hormones in the mother and the child normal, at least under normal circumstances, as evaluated in the present study. It is not known whether this stress is sufficient to be of importance for late development of autonomous thyroid growth and function.

Polymorphism of the glycogen synthase gene in hypertensive and normotensive subjects.

Hypertension and non-insulin-dependent diabetes mellitus (NIDDM) are characterized by a strong genetic component and impaired ability to store glucose as glycogen in skeletal muscle. Impaired insulin activation and altered genetic control of muscle glycogen synthase, the rate-limiting enzyme for glucose storage in skeletal muscle, could provide an explanation for this insulin resistance. We examined whether there is an association between the glycogen synthase gene (Xba I polymorphism) and hypertension in 304 nondiabetic subjects. We examined glucose tolerance with an oral glucose tolerance test and glucose storage in skeletal muscle with the euglycemic insulin clamp technique in combination with indirect calorimetry. The Xba I A2 allele of the glycogen synthase gene was enriched in subjects with hypertension and a family history of NIDDM (48%) compared with normotensive subjects without a family history of NIDDM (6%, P < .0001). The presence of the A2 versus the A1 allele was associated with decreased rates of insulin-stimulated glucose storage in hypertensive subjects (11.2 +/- 2.3 versus 16.9 +/- 2.6 mumol/kg lean body mass per minute, P = .029) but not in normotensive subjects (28.0 +/- 4.6 versus 29.6 +/- 3.7 mumol/kg lean body mass per minute). In conclusion, Xba I polymorphism of the glycogen synthase gene identifies a subgroup of hypertensive subjects with a family history of NIDDM. The data suggest that a locus in the glycogen synthase gene region on chromosome 19 may serve as a "thrifty gene," increasing susceptibility for insulin resistance when exposed to other environmental or genetic factors.

Space-mapped auditory projections from the inferior colliculus to the optic tectum in the barn owl (Tyto alba).

The optic tectum of the owl contains a topographic representation of auditory space. We have investigated the source of this space-mapped auditory activity by using retrograde tracing with horseradish peroxidase. The major source of auditory input to the optic tectum is the ipsilateral external nucleus of the inferior colliculus (ICX), which is known to contain a map of auditory space also. Additional minor projections originate in the superficial nucleus of the inferior colliculus and the nucleus isthmi parvocellularis. There is no apparent projection to the optic tectum from the contralateral ICX or any other brainstem auditory nucleus. The projection from the ICX to the optic tectum is point-to-point: rostral ICX projects to rostral tectum, caudal ICX to caudal tectum, dorsal ICX to dorsomedial tectum, and ventral ICX to ventral tectum. Thus, the space-mapped organization that exists in the ICX is passed on by topographic projections to the optic tectum.

Genetic variation in the amino-terminal part of apolipoprotein B: studies in hyperlipidemic patients.

Hypertriglyceridemia is a heterogeneous lipid disorder often running in families. Variation in the apolipoprotein B (apo B) gene has been associated with serum triglyceride levels. Recently, a role of the amino-terminal end of apo B in binding with lipoprotein lipase (LPL) has been suggested. We screened the 5' end of the apo B gene in 76 Finnish severely hypertriglyceridemic (> 6 mmol/l) patients, using a single-strand conformation polymorphism (SSCP) screening method. We detected a previously unreported polymorphic C2316-->A change, causing a Val703-->Ile substitution. The minor 703 Ile allele frequency was 0.04 in hypercholesterolemic and normolipidemic population samples. This allele was associated with lower serum triglyceride levels in a normolipidemic population sample. Analysis of two previously reported polymorphisms also located in the amino-terminal domain of apo B (Thr71-->Ile and Val591-->Ala) revealed elevating effects on serum apo B concentrations in hypertriglyceridemic individuals. The 591 Ala allele was associated with elevated apo B (P=0.011), and individuals with both minor alleles (apo B 591 Ala + and apo B 71 Ile +) had higher apo B levels compared to subjects homozygous for both common alleles (P=0.004). Although no DNA sequence change seemed to be the cause of hypertriglyceridemia in our patients, genetic variation in the 5' end of the apo B gene may contribute to changes in serum apo B levels in hypertriglyceridemic patients.

LDL particle size in mildly hypertriglyceridemic subjects: no relation to insulin resistance or diabetes.

We examined 18 Type 2 diabetic and 19 non-diabetic subjects in order to determine the association between insulin resistance and LDL particle size distribution in mildly hypertriglyceridemic and hyperinsulinemic subjects with and without Type 2 diabetes. Insulin sensitivity of the patients was characterized by their insulin-stimulated glucose uptake rate determined by euglycemic clamp technique. LDL particle size distribution was determined by nondenaturing polyacrylamide gradient gel electrophoresis. Type 2 diabetic and non-diabetic subjects had closely similar serum lipid and lipoprotein concentrations as well as the mean particle diameters of the major LDL peak (246 +/- 6 A and 244 +/- 6 A, respectively). To evaluate the effect of insulin resistance on LDL particle size the participants were categorized into two subgroups using the median of their insulin-stimulated glucose uptake rate (14.67 mumol/kg/min) as a cut-off point. Neither lipid and lipoprotein concentrations nor the LDL particle size distributions differed between the more insulin resistant group (nine diabetic and nine non-diabetic subjects) and less insulin resistant group (nine diabetic and ten non-diabetic subjects). LDL particle size was not associated with the insulin-stimulated glucose uptake rate or with the mean 24-h concentration of serum insulin. Mean 24-h concentration of serum triglycerides was the strongest discriminator for LDL particle size (r = -0.44, P < 0.01). In conclusion, neither Type 2 diabetes nor insulin resistance seem to have any direct effect on LDL particle size in mildly hypertriglyceridemic subjects. The fact that LDL particle size was associated with serum triglycerides indicates that the effect of diabetes and insulin resistance on LDL particle size could be explained by the effects of insulin resistance and/or hyperinsulinism on VLDL metabolism.

Heterozygous hepatic lipase deficiency, due to two missense mutations R186H and L334F, in the HL gene.

Hepatic lipase (HL) is an endothelial enzyme involved in the metabolism of intermediate density lipoproteins (IDL) and high density lipoproteins (HDL) in plasma. In a Finnish pedigree consisting of 18 members belonging to three generations two missense mutations RI86H and L334F in exons 5 and 7 of the HL gene co-segregated with low post-heparin HL activity. Haplotype analysis of the HL gene in family members revealed a high degree of genetic variation and demonstrated that the two missense mutations reside on the same chromosome. In vitro site-directed mutagenesis and expression of the cDNA constructs in COS-1 cells revealed that the R186H mutation leads to a protein that is not secreted while the L334F mutation results in the production of a HL protein that is secreted but has only about 30% of wild type HL activity. Carriers of the mutated HL gene exhibited clearly reduced HL activity and mass in post-heparin plasma. Probably due to their heterozygous carrier status they had only moderate elevation of total triglycerides, IDL, and LDL-triglycerides. The LDL-particles were enriched in triglycerides and depleted of cholesterol. Also their HDL2- and HDL3-particles were enriched in triglycerides.

Psoralenamines. 3. Synthesis, pharmacological behavior, and DNA binding of 5-(aminomethyl)-8-methoxy-, 5-[[(3-aminopropyl)oxy]methyl]-, and 8-[(3-aminopropyl)oxy]psoralen derivatives.

A series of derivatives of 5-(aminomethyl)-8-methoxypsoralens, 8-[(3-aminopropyl)oxy]psoralens, and 5-[[[3-(tri-methylammonio)propyl]methyl]-8-methoxypsoralen has been synthesized and their potential as PUVA reagents examined. While the DNA association constants of selected psoralens were found to be 10(5)-10(6)L mol-1, corresponding to efficient binding, flow linear dichroism studies indicated that only the 8-substituted psoralens bind to DNA by intercalation. Furthermore, the ability to photoinduce interstrand cross-links in calf thymus DNA, in vitro, was as efficient as that of 8-methoxypsoralen for the 8-substituted psoralens, which were up to 25 times as efficient as the 5-substituted psoralens. Four of the psoralens studied were radiolabeled and used to study photobinding to DNA. Analogously to the cross-binding results, the 8-substituted psoralens were more efficiently photobound than the 5-substituted, while only slight differences were found in the photobinding-cross-linking ratio. The photoreactivity of the aminopsoralens toward cyclohexene and 2'-deoxythymidine was enhanced compared to that of 8-methoxypsoralen, the effect being most pronounced when the amino group is close to the furocoumarin ring system. Most of the new compounds were less photocytotoxic than 8-methoxypsoralen to NHIK 3025 cells, in vitro, and they caused less light-induced DNA interstrand cross-linking, in situ, in these cells. A clear correlation between the photocytotoxicity and the DNA cross-linking ability of the psoralens was observed. Several of the derivatives showed more pronounced effects in the light-dependent skin thickening (inflammatory) test on mice than 8-methoxypsoralen. No correlation between DNA cross-linking capacity, in vitro, and skin phototoxicity was found for this series of psoralens.

Rapid analysis and quantitation of PCR products by high-performance liquid chromatography.

HPLC utilizing a high efficiency anion-exchange column provides a rapid and easily automated technique for the qualitative and quantitative analysis of subnanogram to microgram amounts of DNA fragments generated by the PCR. The accuracy, precision and linearity of this method exceed those attainable with electrophoretic techniques. In addition, because of the nondestructive nature of HPLC, the desired PCR amplification product can be purified for subsequent utilization. Thus, liquid chromatography extends the utility of the PCR technique to those applications requiring precise quantitation.

A monoclonal antibody that recognizes the alpha chain of HLA-DR antigens.

A monoclonal antibody, HC2.1, has been generated that specifically reacts with both the denatured and the in vitro translated alpha chain of the DR antigen. Although HC2.1 antibody reacted with the alpha chain of protein immunoprecipitated by two DR-specific monoclonal antibodies, L227 and LB3.1, it did not react with the alpha chain of the DQ1 antigen immunoprecipitated by the monoclonal antibody, Genox 3.53. The isoelectric focusing pattern of the alpha chain precipitated by HC2.1 antibody was invariant across a range of DR specificities within a panel of lymphoblastoid cells. The alpha chain of DR antigen from a B cell line was purified by HC2.1-Sepharose immunoaffinity chromatography and limited amino acid sequence analysis was carried out with Staphylococcus aureus SV8 protease fragments purified by high-pressure liquid chromatography. The sequence analysis confirmed that the antigen reactive with HD2.1 antibody is encoded by the DR alpha chain gene.