Epstein-Barr virus infection after adolescence and human herpesvirus 6A as risk factors for multiple sclerosis.

BACKGROUND AND PURPOSE: Infections with human herpesvirus 6A (HHV-6A) and Epstein-Barr virus (EBV) have been linked to multiple sclerosis (MS) development. For EBV, late infection has been proposed as a risk factor, but serological support is lacking. The objective of this study was to investigate how age affects the EBV and HHV-6A associated risks of developing MS. METHODS: In this nested case-control study, Swedish biobanks were accessed to find pre-symptomatically collected blood samples from 670 individuals who later developed relapsing MS and 670 matched controls. A bead-based multiplex assay was used to determine serological response against EBV and HHV-6A. Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals. RESULTS: Seropositivity against EBV exhibited a pattern where associations switched from a decreased risk of developing MS in the group below 20 years of age to an increased risk amongst individuals aged 20-29 and 30-39 years (p for trend 0.020). The age of transition was estimated to be 18.8 years. In contrast, HHV-6A was associated with increased MS risk in all age groups (total cohort odds ratio 2.1, 95% confidence interval 1.6-2.7). CONCLUSIONS: This study suggests EBV infection after adolescence and age independent HHV-6A infection as risk factors for MS.

Guidelines for the use of magnetic resonance imaging in diagnosing and monitoring the treatment of multiple sclerosis: recommendations of the Swedish Multiple Sclerosis Association and the Swedish Neuroradiological Society.

Multiple sclerosis (MS) is associated with inflammatory lesions in the brain and spinal cord. The detection of such inflammatory lesions using magnetic resonance imaging (MRI) is important in the consideration of the diagnosis and differential diagnoses of MS, as well as in the monitoring of disease activity and predicting treatment efficacy. Although there is strong evidence supporting the use of MRI for both the diagnosis and monitoring of disease activity, there is a lack of evidence regarding which MRI protocols to use, the frequency of examinations, and in what clinical situations to consider MRI examination. A national workshop to discuss these issues was held in Stockholm, Sweden, in August 2015, which resulted in a Swedish consensus statement regarding the use of MRI in the care of individuals with MS. The aim of this consensus statement is to provide practical advice for the use of MRI in this setting. The recommendations are based on a review of relevant literature and the clinical experience of workshop attendees. It is our hope that these recommendations will benefit individuals with MS and guide healthcare professionals responsible for their care.

Characteristics in childhood and adolescence associated with future multiple sclerosis risk in men: cohort study.

BACKGROUND AND PURPOSE: Associations with multiple sclerosis (MS) of living conditions in childhood and characteristics in adolescence including physical fitness, cognitive function and psychological stress resilience were investigated. METHODS: A cohort of male Swedish residents born 1952-1956 who were included in the Swedish Military Conscription Register was used to create a nested case-control study comprising 628 MS cases and 6187 controls matched on birth year, county of residence and vital status at time of diagnosis. Conscription examination records were linked with other national register data. Conditional logistic regression was used to evaluate associations with MS subsequent to the conscription examination. RESULTS AND CONCLUSIONS: Men with MS were less likely to be from more crowded households in childhood (>two persons per room) with an adjusted odds ratio of 0.67 (95% confidence interval 0.51-0.86, P = 0.023). They had lower physical working capacity in adolescence with adjusted odds ratio of 0.94 (95% confidence interval 0.89-0.99, P = 0.026). Cognitive function and stress resilience scores displayed no significant differences between cases and controls. Parental occupation in childhood and body mass index in adolescence were not associated with future MS risk. The inverse association of MS risk with higher levels of household crowding may reflect environmental factors such as the pattern of exposure to microorganisms. Lower physical fitness in men at MS risk may indicate a protective effect of exercise or could be due to prodromal disease activity, although there was no association with cognitive function. Poor psychological stress resilience (and thus risk of chronic stress arousal) was not associated with MS.

High tau levels in cerebrospinal fluid predict rapid decline and increased dementia mortality in Alzheimer's disease.

OBJECTIVE: Cerebrospinal fluid (CSF) amyloid ß42 (Aß42), total tau (t-tau) and phosphorylated tau (p-tau) are useful as predictors of conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD) dementia. However, results are contradictory as to whether these biomarkers reflect the future rate of clinical decline. METHODS: This is a retrospective study on 196 patients with AD [mild/moderate AD (n = 72) or AD-MCI (n = 124) at baseline] with a follow-up period of 2-9 years' duration (median 6 years). Lumbar punctures were performed at baseline as a part of the diagnostic procedure. RESULTS: We found an increased risk of rapid cognitive decline defined as a drop in the Mini-Mental State Examination score of ≥ 4 points/year in patients with CSF t-tau concentrations above the median (OR 3.31, 95% CI 1.53-7.16) and CSF p-tau above the median (OR 2.53, 95% CI 1.21-5.26). Patients with CSF t-tau in the highest quartile had a higher risk of dying in severe dementia (HR 4.67, 95% CI 1.16-18.82). CONCLUSIONS: In this large AD cohort, we found an association between high levels of CSF t-tau and p-tau and a more aggressive course of the disease, measured as a rapid cognitive decline and a higher risk of dying in severe dementia.

Effectiveness of first generation disease-modifying therapy to prevent conversion to secondary progressive multiple sclerosis.

BACKGROUND: The use of disease-modifying therapies (DMTs) in multiple sclerosis (MS) has been associated with reduced relapse rates and accumulation of disability. However, studies examining impact of DMT on risk of transition to secondary progressive MS (SPMS) leveraging population-based nationwide data are still rare. Here, we determine the population incidence of conversion to SPMS using two consecutive nation-wide cohorts, one immediately before and one after the introduction of DMT in Sweden. METHODS: We included two consecutive population cohorts of relapsing-remitting MS (RRMS) from the Swedish national MS register for the periods 1975-1994 (n = 2161), before DMT availability, and 1995-2011 (n = 3510), in which DMTs, mainly first generation DMT (injectables), became available and eventually were used by 70% of patients. We explored the risk of transition to SPMS as a calendar year function encompassing the two cohorts. In addition, we determined the incidence of transition to SPMS through age strata below and above 50 years in untreated and treated patient subgroups. RESULTS: The risk of conversion to SPMS (adjusted for current age, current time since onset, calendar year and sex) was significantly lower in the second compared with the first population cohort (hazard ratio 0.58; CI 0.48, 0.70). The risk of SPMS conversion per calendar year decreased by 2.6% annually (p < 0.001) after 1995. The risk of SPMS conversion increased with age until age 50. Thereafter, it was unchanged or decreased among those with early MS onset age (<35 years), but continued to increase with onset at higher age, with similar trends in treated and untreated subgroups. CONCLUSION: The incidence of SPMS conversion significantly decreased at the population level after introduction of first generation DMTs by 1995. DMT efficiency was confirmed by a downward turn of the annual trajectory of the risk of SPMS conversion after 1995. An onset age determined pattern of variable SPMS incidence in higher age appeared in both treated and untreated strata. While first generation DMT delayed conversion to SPMS, their long-term effect was only moderate.

Pittsburgh compound-B and Alzheimer's disease biomarkers in CSF, plasma and urine: An exploratory study.

BACKGROUND: The positron emission tomography (PET) radiotracer Pittsburgh Compound-B (PIB) is an in vivo ligand for measuring beta-amyloid (Abeta) load. Associations between PET PIB and cerebrospinal fluid (CSF) Abeta1-42 and apolipoprotein E epsilon4 (APOE epsilon4) have been observed in several studies, but the relations between PIB uptake and other biomarkers of Alzheimer's disease (AD) are less investigated. METHOD: PET PIB, PET 18Fluoro-2-deoxy-D-glucose and different AD biomarkers were measured twice in CSF, plasma and urine 12 months apart in 10 patients with a clinical diagnosis of mild to moderate AD. RESULTS: PIB retention was constant over 1 year, inversely related to low CSF Abeta1-42 (p = 0.01) and correlated positively to the numbers of the APOE epsilon4 allele (0, 1 or 2) (p = 0.02). There was a relation between mean PIB retention and CSF ApoE protein (r = -0.59, p = 0.07), and plasma cystatin C (r = -0.56, p = 0.09). CONCLUSION: PIB retention is strongly related to CSF Abeta1-42, and to the numbers of the APOE epsilon4 allele.

Optimization of energy and directional response of a small 4π silicon dosemeter for quality control of CT/CBCT-units - A 3D CAD, Monte-Carlo, AM approach.

A 4π radiation dosemeter for use in medical radiology was designed. It is based on a solid state silicon detector, a sensor wafer, a flex card, a 3D plastic holder and a spherical stainless steel filter with a distribution of holes around the detector. The detector is attached to the wafer using only low Z material. To achieve an energy and directional response which is as uniform as possible for various radiation qualities and beam directions, the filter was designed using a series of Monte Carlo calculations. The energy filter and its hole pattern were created using Additive Manufacturing (AM) in the form of metal 3D printing. The functionality of the dosemeter was designed to fulfill the quality criteria of a combined energy and angular dependence of less than 5% for the IEC beam qualities RQR and RQT in the range of 65-145 kV. This is a major improvement to the existing solutions that may need software corrections to be used for the same beam quality range.

Glucose metabolism and the risk of Alzheimer's disease and dementia: a population-based 12 year follow-up study in 71-year-old men.

AIMS/HYPOTHESIS: Accumulating evidence suggests that diabetes increases the risk of dementia, but few studies have addressed possible mechanisms underlying this relationship. The aim of our study was to investigate the longitudinal association of glucose metabolism, insulin secretion and insulin action with the development of Alzheimer's disease and vascular dementia. METHODS: The Uppsala Longitudinal Study of Adult Men is an ongoing observational study in Sweden in which 1,125 men aged 71 years and free from dementia underwent an OGTT and a euglycaemic insulin clamp between 1990 and 1995. During a median follow-up of 12 years, 257 persons developed dementia or cognitive impairment, of whom 81 had Alzheimer's disease and 26 vascular dementia. Associations were analysed with the Cox proportional hazards method. RESULTS: Low early insulin response to oral glucose challenge, but not low insulin sensitivity, was associated with a higher risk of Alzheimer's disease (HR for 1 SD decrease 1.32; 95% CI 1.02, 1.69) after adjustment for diabetes, blood pressure, body mass index, cholesterol, smoking and educational level. Low insulin sensitivity was associated with a higher risk of vascular dementia (HR for 1 SD decrease 1.55; 95% CI 1.02, 2.35), but not after multiple adjustments. Diabetes increased the risk of any dementia and cognitive impairment by 63%. CONCLUSIONS/INTERPRETATION: In this community-based study, low early insulin response was associated with increased risk of subsequent Alzheimer's disease, whereas low insulin sensitivity was not. Vascular dementia was not related to early insulin response. We suggest that glucometabolic disturbances are linked differentially to the pathogenesis of these two main dementia subtypes.

Effective dose of cone beam CT (CBCT) of the facial skeleton: a systematic review.

OBJECTIVE: To estimate effective dose of cone beam CT (CBCT) of the facial skeleton with focus on measurement methods and scanning protocols. METHODS: A systematic review, which adhered to the preferred reporting items for systematic reviews (PRISMA) Statement, of the literature up to April 2014 was conducted. Data sources included MEDLINE®, The Cochrane Library and Web of Science. A model was developed to underpin data extraction from 38 included studies. RESULTS: Technical specifications of the CBCT units were insufficiently described. Heterogeneity in measurement methods and scanning protocols between studies made comparisons of effective doses of different CBCT units and scanning protocols difficult. Few studies related doses to image quality. Reported effective dose varied across studies, ranging between 9.7 and 197.0 µSv for field of views (FOVs) with height ≤5 cm, between 3.9 and 674.0 µSv for FOVs of heights 5.1-10.0 cm and between 8.8 and 1073.0 µSv for FOVs >10 cm. There was an inconsistency regarding reported effective dose of studies of the same CBCT unit with the same FOV dimensions. CONCLUSION: The review reveals a need for studies on radiation dosages related to image quality. Reporting quality of future studies has to be improved to facilitate comparison of effective doses obtained from examinations with different CBCT units and scanning protocols. A model with minimum data set on important parameters based on this observation is proposed. ADVANCES IN KNOWLEDGE: Data important when estimating effective dose were insufficiently reported in most studies. A model with minimum data based on this observation is proposed. Few studies related effective dose to image quality.

Guidelines for prophylactic radical lymph node dissection in cases of carcinoma of the external ear.

All cases of squamous-cell carcinoma of the external ear that were treated at the ENT Clinic, University Hospital, Lund, Sweden, between 1970 and 1977 were analyzed retrospectively to determine parameters for predicting the development of metastases. These cases included 62 males and 3 females, with a mean age of 77 years. The frequency of metastases for these patients was 16.4%. The carcinomas were graded according to four parameters: depth of growth, mode of invasion, cellular differentiation, and cellular plasmolymphocytic response. We concluded that depth of growth and mode of invasion were the most useful of these parameters and that prophylactic lymph node dissection should be performed in cases of tumors larger than 4 cm in diameter, of tumors infiltrating the cartilage, and of smaller tumors with maximum scores for depth of growth and mode of invasion.

Distribution and tissue expression of semenogelin I and II in man as demonstrated by in situ hybridization and immunocytochemistry.

Semenogelin I and II (Sgl, Sgll) are two separate gene products of chromosome 20 with extensive (80%) identity in primary structure. They are mainly responsible for immediate gel formation of freshly ejaculated semen. Degradation of Sgl and Sgll is due to the proteolytic action of prostate-specific antigen (PSA); it results within 5-15 minutes in liquefaction of semen and release of progressively motile spermatozoa. By means of cDNA cloning and Northern blots, Sgl and Sgll transcripts have previously been shown to be abundant in human seminal vesicles, but Sgll alone is suggested to be expressed at low levels in the epididymis. To characterize the expression and tissue distribution of Sgl and Sgll in greater detail, we produced monoclonal immunoglobulin Gs (lgGs for immunocytochemistry (lCC) and specific [35S]-, digoxigenin-, or alkaline phosphatase-labeled 30-mer antisense probes to Sgl and Sgll for in situ hybridization (lSH). Immunocytochemical staining for both Sgl and Sgll, and lSH detection of both Sgl and Sgll transcripts, were demonstrated in the cytoplasm of seminal vesicle epithelium. lSH showed Sgll alone to be expressed in the epithelium of the epididymal cauda. Neither lCC nor lSH yielded any evidence of Sgl or Sgll expression in caput or corpus epithelium or in any stromal cells of the epididymis. Consistent with our previous findings using polyclonal lgG, monoclonal anti-Sgll Sgll lgGs identified epitopes on the posterior head, midpiece, and tail of ejaculated spermatozoa. Spermatozoa in the epididymal cauda were also immunoreactive, but those in the caput or corpus region of the epididymis as well as those in the testis were negative. As shown by lCC, neither Sgl nor Sgll were expressed in the testis, the prostate, the female genital tract, or other normal human tissue specimens. Although the significance of Sg attachment to epididymal and ejaculated spermatozoa remains to be established, monoclonal anti-Sg lgG might prove useful in establishing the origin of seminal vesicle tissue components in prostate core biopsies or other biopsy specimens.

Aberrant forms of alpha(2)-macroglobulin purified from patients with multiple sclerosis.

The biochemical properties of alpha(2)-macroglobulin were investigated in four patients with multiple sclerosis and compared to alpha(2)-macroglobulin from healthy controls. An impaired stability of alpha(2)-macroglobulin from the multiple sclerosis patients was demonstrated as a spontaneous conversion to an electrophoretic"fast" form of alpha(2)-macroglobulin upon purification and storage, with a concomitant decrease in functional capacity to inhibit proteinases. The ability to form complexes with proteinases was significantly reduced in alpha(2)-macroglobulin purified from the multiple sclerosis patients. The aberrant molecular arrangements of the protein were not due to proteinase cleavages in the bait regions of alpha(2)-macroglobulin, as demonstrated by gel electrophoresis and protein sequencing. The number of functional thiol esters, however, was reduced in alpha(2)-macroglobulin purified from the multiple sclerosis patients, an observation compatible with the impaired proteinase binding property. Furthermore, differences in isoelectric points were observed between alpha(2)-macroglobulin from the multiple sclerosis patients and alpha(2)-macroglobulin from healthy controls. The results suggest that aberrant forms of alpha(2)-macroglobulin may be present in patients with multiple sclerosis.

Conformational state and receptor recognition of the C-terminal domain of human alpha(2)-macroglobulin after dissociation into half-molecules.

BACKGROUND: Dissociation of native human alpha(2)-macroglobulin (alpha(2)M) by sodium thiocyanate generates stable half-molecules with intact thiol esters. Significant conformational changes occur by the dissociation, which are similar to those occurring by transformation from native to methylamine-treated alpha(2)-macroglobulin. METHODS: The conformational state of the receptor-binding domain of the half-molecules was investigated by receptor binding and clearance studies, and by use of a panel of 11 monoclonal antibodies (mAbs) specific for the 18-kDa C-terminal receptor-binding fragment of alpha(2)-macroglobulin. RESULTS: The half-molecules simultaneously express epitopes specific for native, as well as epitopes specific for transformed alpha(2)-macroglobulin. While it is possible to immunochemically discriminate between the different forms of tetrameric protein, the half-molecules retain a conformational state with no observed conformational changes in the C-terminal domain following cleavage of thiol esters or bait regions. The in vivo clearance rate in mice was consequently significantly slower for the half-molecules than for the tetrameric receptor-recognized forms of alpha(2)-macroglobulin. Furthermore, half-molecules demonstrate lower affinity for binding to mouse macrophages than methylamine-treated tetrameric alpha(2)-macroglobulin in competition studies. CONCLUSIONS: It is suggested that contact zones are functionally important for mediating conformational switches, which result in trapping and exposure of the receptor-binding sites.

No radiation protection reasons for restrictions on 14C urea breath tests in children.

Traditional (14)C urea breath tests are normally not used for younger children because the radiation exposure is unknown. High sensitivity accelerator mass spectrometry and an ultra-low amount (440 Bq) of (14)C urea were therefore used both to diagnose Helicobacter pylori (HP) infection in seven children, aged 3-6 years, and to make radiation dose estimates. The activity used was 125 times lower than the amount normally used for older children and 250 times lower than that used for adults. Results were compared with previously reported biokinetic and dosimetric data for adults and older children aged 7-14 years. (14)C activity concentrations in urine and exhaled air per unit administered activity for younger children (3-6 years) correspond well with those for older children (7-14 years). For a child aged 3-6 years who is HP negative, the urinary bladder wall receives the highest absorbed dose, 0.3 mGy MBq(-1). The effective dose is 0.1 mSv MBq(-1) for the 3-year-old child and 0.07 mSv MBq(-1) for the 6-year-old child. For two children, the 10 min and 20 min post-(14)C administration samples of exhaled air showed a significantly higher amount of (14)C activity than for the rest of the children, that is 6% and 19% of administered activity exhaled per hour compared with 0.3-0.9% (mean 0.5%) of administered activity exhaled per hour indicating that these two children that is were HP positive. For a 3-year-old HP positive child, absorbed dose to the urinary bladder wall was 0.3 mGy MBq(-1) and effective dose per unit of administered activity was 0.4 mSv MBq(-1). Using 55 kBq, which is a normal amount for older children when liquid scintillation counters are used for measurement, the effective dose will be approximately 6 micro Sv to a 3-year-old HP negative child and 20 microSv to a HP positive child. Thus there is no reason for restrictions on performing a normal (14)C urea breath test, even on young children.

Local corticosteroid treatment of caustic injuries of the esophagus. A preliminary report.

So far, no therapy has been shown to reduce the incidence of strictures in the esophagus after ingestion of caustic agents. Two patients with pronounced caustic ingestion injuries were treated locally with solutions of corticosteroids normally used for inhalation therapy in lung diseases. Serious strictures did not appear, and their swallowing returned to normal. Further studies are needed.

Mucolytic agents and mucociliary activity.

The three substances bromhexine, NA 872 (bromhexine metabolite VIII) and the beta 2-receptor agonist NAB 365 (clenbuterol) and their effect on the mucociliary activity have been studied in vivo in rabbits. The substances were given parenterally in increasing dosages and 519 records were obtained from 12 rabbits. Not even at dosages in excess of recommended human dosages has any effect on the mucociliary activity been observed for any of the substances during the first 30 minutes after administration. The conclusion to be drawn is that the three substances have no effect on the mucociliary activity in rabbit in vivo, but that this does not exclude an effect on mucociliary transport or clearance.

Fewer problems with dry nasal mucous membranes following local use of sesame oil.

Many people experience problems with a dry nasal mucous membrane, often without wondering why. Their noses itch and burn and dried mucus collects there. These problems are exacerbated during the winter, in air-conditioned environments and after nasal irradiation. Twenty patients experiencing problems with dryness of the nose were selected from outpatient clinics, together with twenty patients who had previously undergone nasal irradiation. During the first five days no treatment was administered. For the following twenty days the patients sprayed sesame oil into each nostril three times a day. For the last five days no treatment was given. When both groups received treatment and sprayed sesame oil (Nozoil) in their noses, the nasal problems decreased significantly. The greatest effect is exerted on dryness. The side effects from using this oil are few in number and mild.

Circumvaginal surface electromyography in women with urinary incontinence and in healthy volunteers.

In this study we developed a probe for surface EMG investigation of the circumvaginal muscle function in women with various forms of urinary incontinence. 69 women were investigated, 20 healthy volunteers, 25 patients with stress incontinence, 11 with urge incontinence and 13 with a mixed type of incontinence. We found that the circumvaginal surface EMG activity at short lasting (2 sec) maximum contraction was significant lower in patients with incontinence compared to healthy volunteers. We also found that the ability to hold a maximum contraction during one minute was significant reduced in all the patient groups compared to controls. The results suggest that patients with stress, urge or mixed incontinence all seem to have a defective function of the circumvaginal musculature. A common aetiology for stress, urge and mixed incontinence seems to be a reasonable working hypothesis for future investigations.

Re-evaluation of clinical dementia diagnoses with pittsburgh compound B positron emission tomography.

OBJECTIVES: There is an overlap regarding Pittsburgh compound B (PIB) retention in patients clinically diagnosed as Alzheimer's disease (AD) and non-AD dementia. The aim of the present study was to investigate whether there are any differences between PIB-positive and PIB-negative patients in a mixed cohort of patients with neurodegenerative dementia of mild severity regarding neuropsychological test performance and regional cerebral glucose metabolism measured with [(18)F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET). METHODS: Eighteen patients clinically diagnosed as probable AD or frontotemporal dementia were examined with PIB PET, FDG PET and neuropsychological tests and followed for 5-9 years in a clinical setting. RESULTS: The PIB-positive patients (7 out of 18) had slower psychomotor speed and more impaired visual episodic memory than the PIB-negative patients; otherwise performance did not differ between the groups. The initial clinical diagnoses were changed in one third of the patients (6 out of 18) during follow-up. CONCLUSIONS: The subtle differences in neuropsychological performance, the overlap of hypometabolic patterns and clinical features between AD and non-AD dementia highlight the need for amyloid biomarkers and a readiness to re-evaluate the initial diagnosis.