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Study design Preclinical studies: Efficacy and toxicological studies on lactic acid (LA)-induced sclerozation in pig lumbar discs. Clinical study: Prospective, randomised, double-blinded, placebo-controlled, single ascending dose study investigating the safety and local tolerability of LA. Objective To determine if LA produces sclerozation of the porcine NP followed by a phase Ib study to evaluate preliminary safety, tolerability and efficacy of LA in patients with chronic discogenic low back pain. Summary of background data Surgical stabilization of a motion segment harboring a painful degenerated disc often affords symptomatic relief. In the present study, the hypothesis was tested that LA can produce sclerozation and stabilization of the nucleus pulposus (NP). Methods LA (0.2 mL; 60, 120 or 240 mg/mL) or vehicle was injected into the NP or close to the extra spinal region of spinal nerves of young female pigs. The size of the NP, MRI changes, flexural stiffness and histology of the disc was studied after up to 84 days of survival. Fifteen patients injected intra discally with placebo (iohexol, 1.5 mL, n = 6) or iohexol plus LA (30, 60 or 120 mg/mL; 3 patients in each group) were followed for up to 12 months. Results Injection of LA in the pig reproducibly induced sclerozation of the NP and increased flexural rigidity. Histological changes included generation of connective tissue and increased expression of collagen I. No safety concerns were raised. Adverse events in patients were limited to transiently increased low back pain with no obvious difference between treatment groups. There was indication of lower water content of NP injected with the 2 highest doses of LA. Conclusions LA has a sclerozing effect on the NP in pigs and patients and is therefore a candidate for further clinical studies powered to determine its potential as a treatment of chronic discogenic low back pain. Level of evidence 2.

Purpose Women with congenital adrenal hyperplasia (CAH) may develop a virilized voice due to late diagnosis or suboptimal suppression of adrenal androgens. Changes in the vocal folds due to virilization have not been studied in vivo. The purpose was to investigate if the thyroarytenoid (TA) muscle is affected by virilization and correlate findings to fundamental frequency (F0). Method A case-control study using magnetic resonance imaging and voice recordings. Four women with CAH with virilized voices (26–40 years), and 5 female and 4 male controls participated. Measurements of cross-sectional TA muscle area, vocal fold length, vocal tract length, and acoustic analyses of F0 were performed. Results Women with CAH had larger cross-sectional TA muscle area than female control subjects and smaller than male controls. A significant negative correlation was found between TA muscle area and mean F0. The patients had a smaller physiological voice range than both female and male controls. Conclusion Data from our small study suggest that a larger TA muscle area is strongly associated with a lower F0 and thus the anatomical explanation for a female virilized voice, suggesting an androgen effect on the vocal folds. The findings from the present study need to be confirmed in a larger study.

Background: Studies of extraocular muscle (EOM) by magnetic resonance imaging (MRI) need to be extended to normal subjects of different ages to obtain data on the muscle thickness, cross-sectional area, and the volume of EOM and other orbital tissues. Methods: Forty-two orbits of 21 normal subjects in three age groups with an age range of 19–70 years were examined with surface-coil MRI. The transverse and sagittal images were used to measure the thickness of the four rectus muscles during fixation in different gaze positions. The coronal images with eyes in the primary position were used to calculate the cross-sectional areas. The volumes of all six EOM, orbital fatty tissue, the optic nerve and the eyeball were measured in the coronal plane and in either the transverse or the sagittal plane. Results: The horizontal muscles were thinner than vertical muscles. Muscle volume was larger in SR (superior rectus) than in IR (inferior rectus), larger in SO (superior oblique) than in IO (inferior oblique), and the same in LR (lateral rectus) as in MR (medial rectus). No significant differences were found in the values of the cross-sectional area in any image plane between the three age groups. There were no significant differences in muscle thickness and size and fatty tissue volume between age groups. The muscle thickness was linearly correlated to the angle of the eye deviation for all four rectus muscles, both in the ”on” and ”off” directions of the muscles. Conclusions: The study provides quantitative data, in normal subjects of different ages, on the thickness and size of EOM and the volume of other orbital tissues by MRI, to serve as a basis for further studies on the morphological changes of EOM in various orbital diseases.

A 26-year-old previously healthy woman developed granulomatous pneumonitis, encephalitis, and genital ulceration during primary Epstein-Barr virus (EBV) infection. EBV DNA was demonstrated by polymerase chain reaction analysis of serum, lung tissue, and genital ulcer specimens. Serology verified primary EBV infection. The patient lacked lymphocytes cytotoxic to autologous EBV-transformed B lymphocytes. No spontaneous or in vitro EBV-induced interferon gamma (IFN-gamma) production was evident in peripheral blood. The cells had normal IFN-gamma production when stimulated with Staphylococcus aureus exotoxin A. In the bone marrow and peripheral blood, the number of large granular CD56+ lymphocytes (natural killer cells) increased 39%-55%, but no CD4 or CD8 cell lymphocytosis was initially found. A partial clinical response was achieved with treatment with acyclovir, corticosteroids, and intravenous gamma-globulin. Because of persistent granulomatous central nervous system and lung involvement, subcutaneous IFN-gamma therapy was started but was discontinued after 3 months because of development of fever, pancytopenia, and hepatitis. This therapy initiated a complete clinical recovery, which occurred parallel to development of EBV-specific cytotoxic CD8+ T lymphocytes and normalization of natural killer cell lymphocytosis. These findings provide evidence for an EBV-induced lymphoproliferative disorder due to a T lymphocyte dysfunction associated with a selective lack of IFN-gamma synthesis.

To analyse the influence of apolipoprotein E (APOE) genotype on the extent of white matter lesions (WMLs) in Alzheimer's disease (AD), we examined 60 AD patients with magnetic resonance imaging. The WMLs were rated visually in different brain regions. The patients with the APOE genotype sigma4/4 had more extensive WMLs in the deep white matter than patients with genotypes sigma3/3 and sigma3/4. There was a correlation with age for WMLs in the deep white matter in patients with the APOE sigma3/3 genotype. In patients carrying at least one sigma4 allele, the WMLs showed no age correlation. The results could imply that in APOE allele sigma4 carriers, the WMLs represent a pathological process related to the aetiology of the disease.

We assessed the reliability of an interactive 3-dimensional methodology for magnetic resonance imaging (MRI) brain tissue segmentation and volumetry using a 3-dimensional magnetization prepared rapid gradient echo pulse sequence (3D MP-RAGE). The methodology was intended to be practically useful to study structural brain changes in larger groups of patients investigated for suspected dementia. The pulse sequence combines volume acquisition, excellent tissue contrast and short patient scan-time. The volumetric method is fully interactive, requiring a minimum of image pre-processing. Ten healthy controls and 10 patients with dementia were included in the study. Six healthy controls were scanned twice. The method is based on thresholding combined with manual tracing in a 3D volume. The 3-dimensional measurement method reduces the measurement time considerably compared to that of slice by slice measurement and permits 3-dimensional display of measured volumes. For different brain regions the intra-study (0.5-1.3%), study-study (1.8-4.7%) and inter-operator (7.1%) variability of this method compared favourably with other manual or automated methods reported. The major advantages of the method are its simplicity and speed, which permits measurement and display of regional brain volumes and tissues in larger patient groups.

Skeletal muscle adaptations to high intensity knee extensor strength and/or endurance training in patients with chronic heart failure were investigated. Eleven patients with chronic heart failure were randomized into two groups and exercised the m. quadriceps femoris 3 days/week for 8 weeks. After training, the maximal exercise intensity tolerated on the ergometer cycle was raised from 99 (32) to 114 (40) watts (W, P

Purpose: The aim of our prospective study was to determine the diagnostic accuracy of MR mammography (MRM) in detecting malignant disease. Material and Methods: In 231 consecutive patients scheduled for surgery because of mammographic or palpable lesions suspected of malignancy, the breasts were examined with T1-weighted transversal images using a 3-D fast low angle shot (FLASH) sequence. One pre- and 2 post-contrast images were obtained. Histological examination of the surgical specimens showed carcinoma in 155 breasts, of which 138 were invasive and 17 in situ. Results: MRM detected 144 of the 155 malignancies and was false-negative in 11 cases. Eight of these MRM-missed tumours were invasive and 3 were in situ cancers. Benign lesions were found at microscopy in 95 breasts, of which MRM correctly diagnosed 69. The cellular composition of the 26 false-positive lesions (myxomatous stromal change, high vascularity, and epithelial or apocrine hyperplasia) might explain the false positivity. The sensitivity and specificity of MRM were 93% and 73%, respectively. Conclusion: MRM should be interpreted with caution, and supplemented with e.g. mammography and ultrasonography.

Background context A reduced frequency of discographies might be the result of increasing concern with long-term effects of discography such as disc degeneration. More knowledge is needed in what patient discography is most likely to influence the surgical decision. Purpose This study was aimed at highlighting how discography affects surgical decisions when performed on one of four different indications in a complicated subgroup of patients with chronic low back pain assumed to be associated with degenerative disc disease (DDD). Study design Prospective before-after study to analyze how frequently a prediscography preliminary decision was changed and in what direction by adding information from discography in a subgroup of patients with DDD. Patient sample One hundred thirty-eight patients admitted to a spine clinic more than 4 years with the DDD diagnosis (15% of all) were referred for discography because it was considered that medical history, clinical findings, and magnetic resonance imaging (MRI) were insufficient to make a final assessment on whether to propose surgery/recommend against surgery or what segments to operate on. Outcome measures These were the recorded changes to prediscography preliminary decisions after information was added from discography. Methods Before these patients were referred to provocative discography, the surgeon had to select one of four alternative questions/indications being the reason for the discography and choose what decision would have been made if discography would not have been available. The questions/indications were as follows: surgery decided discography to establish whether to treat adjacent segment as well (n=17); several segments degenerated on MRI, pain likely to be discogenic, discography to evaluate what segments to treat (n=56); uncertainty whether pain is discogenic but one suspected segment on MRI (n=38); uncertainty whether pain is discogenic and several segments degenerated in MRI (n=27); the decision after discography was then compared with the prediscography decision and the changes affected by the result of the discography were analyzed. Results Changes were made to the prediscography decision in 71% of the patients in total. When the surgeon was assured that the pain was discogenic, one segment was added or subtracted in 58% of the patients compared with original prediscography decision. When the surgeon was uncertain if pain was discogenic, the final decision changed from surgery to no surgery in 8%, from no surgery to surgery in 42%, and in cases that were planned for surgery prediscography, one segment was added or subtracted in 17% of the patients. The more certain the surgeon was before discography that the patient's pain was indeed discogenic, the fewer changes between surgical treatment and no surgical treatment took place. The more uncertain the surgeon was before discography that the patient's pain was discogenic, the fewer changes in segments to treat took place in patients who went on to surgery. Changes of involved segments were made to all the 27 patients with a preliminary decision for surgical treatment of the L5–S1 segment solely. The corresponding figure for L4–L5 and L4–L5–S1 was 70% and 53%, respectively. Conclusions A high frequency of decisions was altered in this group of surgeons when using discography as an additional examination in patients where uncertainty remains in how to treat after clinical examination, questioning, and MRI.

Purpose: To assess extraocular muscle (EOM) involvement in thyroid-associated orbitopathy (TAO) of different stages with magnetic resonance imaging (MRI) and ultrasound techniques. Methods: A total of 32 patients with TAO were divided into three groups according to whether they had mild active, pronounced active or longstanding inactive disease. Six patients with Graves' disease but no clinical signs of TAO and 10 healthy control subjects were also studied. Muscle volume and cross-sectional area were measured with MRI. A-scan ultrasound was used to measure muscle thickness. Results: The average MRI volume and maximal cross-sectional area of the EOM were significantly larger in patients with pronounced active and longstanding inactive TAO than in control subjects. Increased average muscle thickness measured by ultrasound was found mainly in patients with longstanding disease. Muscle enlargement was seen with MRI and ultrasound in individual patients in all patient groups, including those with Graves' disease but no TAO. Bilateral muscle enlargement was revealed by MRI in about two-thirds of patients with mild active TAO and in all patients with pronounced active and longstanding inactive TAO. Bilateral involvement estimated with ultrasound was less common in all patient groups. The MRI and ultrasound findings were not well correlated in any patient group. Conclusions: Extraocular muscle enlargement was seen in all patient groups with TAO of differing levels of severity. Measurements with MRI of muscle volume or maximal cross-sectional area are considered good indicators of muscle enlargement in TAO.

Long-term heart failure may affect both skeletal muscle strength and endurance as a result of fiber atrophy, decreased percentage of oxidative muscle fibers, lowered oxidative enzyme capacity and a reduced number of capillaries per fiber found in patients with chronic congestive heart failure (CHF).1–4 Isometric strength of the musculus quadriceps femoris in patients with CHF has been shown to be markedly lower,5,6 but also unaltered,7 in comparison with healthy subjects. In addition, patients with CHF have a lower muscular endurance in the forearm, as well as postural muscles, than in healthy subjects.5,7,8 Although Minotti et al7 showed a greater force reduction after an anaerobic, short-lasting bout of knee extensions in patients with CHF, it remains to be shown that patients respond in the same way after a challenge that activates the metabolism to a higher degree. The aim of the present study was to investigate whether muscular strength and endurance are lower in patients with CHF, and if so, to determine the degree and manner in which functional capacity is altered. Specifically, this study examined the force velocity relation of musculus quadriceps femoris during single isometric, concentric and eccentric, as well as repeated, muscular contractions. Furthermore, the muscle cross-sectional area was measured to study specific tension and possible atrophy of the muscles of patients with CHF in relation to healthy subjects.

Background: Muscle volume investigation by different imaging techniques has proven useful in the diagnosis and follow up of treatment in dysthyroid ophthalmopathy. However, no study on muscle volume measurement by magnetic resonance imaging (MRI) has been done in this disease. Methods: Six patients with monocular or asymmetric binocular dysthyroid ophthalmopathy and eight controls were examined with orbital MRI using a surface coil. In the muscle volume study, 2 mm coronal slices were used for measuring the six extraocular muscles (EOM), i.e., medial rectus (MR), lateral rectus (LR) superior rectus (SR), inferior rectus (IR), superior oblique (SO), and inferior oblique (IO) muscles, as well as the orbital fatty tissue (OFT). In the muscle thickness study, 3 mm transverse and sagittal images were used for measuring the four rectus muscles during fixation in different gaze positions in horizontal and vertical planes. Results: In dysthyroid ophthalmopathy, the muscle volume of the six external eye muscles was significantly larger than in controls, except for the IO. The IR and MR showed the largest increase in muscle volume. The correlation between muscle thickness and different degrees of eye deflections was linear for all four rectus muscles both in patients and controls, and no significant differences in the slopes of the regression lines were found. The volume of OFT was significantly larger in patients than in controls, and the change in volume was larger than that of muscle volume. Conclusions: MRI technique makes it possible to observe and evaluate quantitatively the volume of all six extraocular muscles and the orbital fatty tissue in dysthyroid ophthalmopathy. It also makes it possible to evaluate changes in morphology during eye muscle contraction.

It is important but sometimes difficult to establish a diagnosis of toxoplasma encephalitis (TE) in an HIV-positive immunodeficient patient. The most promising non-invasive method is polymerase chain reaction (PCR) for Toxoplasma gondii in cerebrospinal fluid (CSF). In a retrospective study PCR was used to analyse CSF for the presence of T. gondii DNA in 5 HIV-infected patients with a clinical suspicion of TE (group 1), 8 patients with other HIV-associated symptoms (group 2) and 7 other patients with neurological disorders (group 3). PCR was positive in 2/4 patients with a final diagnosis of TE and negative in all remaining patients in all 3 groups. The 2 patients with positive PCR had a fulminant course and experienced treatment failure. The albumin index was elevated in 4/5 patients in group 1, of whom 3/4 had a final diagnosis of TE, with suspected TE in 1. This small study confirms earlier data indicating that the PCR test has a low sensitivity but a high specificity.

Objectives: The issue to be resolved was whether peripheral leg blood flow in patients with chronic heart failure (CHF) is reduced by low local flow capacity or as a function of the amount of muscle mass activated during exercise. Methods and results: In ten CHF patients (ejection fraction 26 (9)%), and 12 healthy controls central and peripheral circulatory responses were assessed during dynamic one- and two-legged knee extensor work. The patients reached a peak perfusion of 234 (16) ml 100 g−1 min−1 in the one-legged mode, which was similar to the controls (244 (11) ml 100 g−1 min−1). At peak two-legged work muscle perfusion was reduced in the patients by 24% ( P

Summary. The knee extensor and the whole-body exercise capacities were measured in 11 chronic heart failure (CHF) patients and 11 healthy age- and sex-matched controls, and were related to ejection fraction and to biochemical and histochemical markers of the musculature. The CHF patients had a 39% lower maximal oxygen uptake measured on an ergometer cycle than the healthy controls (1.54±0.57 vs. 2.51±0.70 1 min-1, P < 0.001). The low exercise capacity was markedly related to the ejection fraction (r =0.77, P < 0.001)TThe maximal strength of m. quadriceps femoris was 15% lower in the CHF patients than in the controls (P < 0.05). The cross-sectional area (CSA) of m. quadriceps femoris explained 55% (r =0.74, P < 0.001) of the difference in strength between both groups. The endurance capacity of m. quadriceps femoris was 30% lower in CHF patients than in controls, partly as a result of the 25% lower capillary density (P < 0.05) and the 27% lower aerobic enzyme capacity (P < 0.05), as estimated by the citrate synthase activity, in the CHF patients. The citrate synthase activity correlated with the maximal oxygen uptake (r =0.61, P < 0.05). Moreover, the ejection fraction, together with the CSA of m. quadriceps femoris, explained 75% (r =0.86, P < 0.01) of the difference in maximal oxygen uptake between CHF patients and controls. These results demonstrate that CHF patients have both a lower local and a lower whole-body work capacity than healthy controls. This is a function of a smaller leg muscle mass and a lower capillary density and mitochondrial enzyme capacity in the CHF patients; however, a lowered pump capacity of the heart is the factor which limits the exercise capacity the most.

Eight healthy and regularly physically active men, 44-69 years old, performed one- and two-legged dynamic knee extension exercise at increasing work intensities, including one leading to exhaustion. Leg blood flow increased linearly in relation to work rate, reaching a peak value of 5.1 +/- 0.4 l min-1. With a mean weight of quadriceps femoris of 2.2 +/- 0.1 kg, a peak perfusion of 2.3 +/- 0.1 l kg-1 min-1 was attained. The maximal leg oxygen uptake was 0.72 +/- 0.07 l min-1 (0.33 +/- 0.03 l kg-1 min-1). At submaximal work the elevation in limb oxygen uptake accounted for between 70 and 100% of the rise in pulmonary oxygen uptake. Comparing two- with one-legged knee extension the cardiac output was 1.5 l min-1 higher at each work level, reaching 13.7 +/- 0.7 and 12.3 +/- 1.0, respectively at exhaustion, leaving 3.5 and 7.2 l min-1 of blood flow to the remaining body (cardiac output--leg blood flow). The mean arterial pressure was 119 +/- 5 mmHg at rest and increased to 155 mmHg for both test modes at the maximal work rate. The femoral arterial and venous plasma concentrations of lactate, ammonia and noradrenaline were significantly higher for two-legged as compared with one-legged exercise at the maximal load performed. However, the rate of release per leg, for both lactate and ammonia, did not differ between the two test conditions. It is concluded that physically active middle-aged men, with a well-retained muscle mass, can maintain a high skeletal muscle perfusion, similar to that of young males. However, the blood flow is achieved with a higher mean arterial pressure and an elevated sympathetic activity, as reflected by noradrenaline in plasma and spillover from the exercising limb.

Hyperprolactinemia is associated with decreased bone mineral density, which may be caused by the hypogonadism and hypoestrogenicity noticed in patients with hyperprolactinemia. Since calcitonin inhibits the bone resorption, and insulin-like growth factor I (IGF-I) has important anabolic effects on the skeleton, lack of one or both peptides may contribute to the development of osteopenia. We therefore measured the plasma calcitonin and IGF-I levels in nine women with hyperprolactinemia caused by a prolactin-producing pituitary tumor. The calcium-stimulated C-cell reactivity was studied by measuring calcitonin in plasma during a calcium clamp before and after normalization of serum prolactin during treatment with bromocriptine. Basal CT levels were measurable but lower than in healthy controls. Basal IGF-I levels and calcium-stimulated plasma calcitonin were normal in the hyperprolactinemic state and similar to the calcitonin and IGF-I levels during bromocriptine treatment. The serum prolactin levels decreased (p

Observations of the gallium spectrum emitted from a pulsed hollow cathode and a sliding spark in the region 400-6000 A have been used for an extended and revised analysis of doubly ionized gallium, Ga III. The wavelength accuracy has been substantially improved as compared to previous observations. The ns, nd, nf and ng series of the 3d10nl system have been extended, and the ionization energy has been determined to 247 820 ± 2 cm-1. The previous level values for 3d9 4s2 have been discarded, and the correct positions have been established from several combinations. New levels of 3d9 4s4p have been found, making 3d9 (2D)4s4p(1P) complete.

The gallium spectrum emitted from a hollow cathode has been recorded in the region 500-9800 A. 142 lines have been classified as transitions in Ga II. Energy levels have been derived from the observations, and perturbations within the n = 4 configuration complex are discussed. Besides the previously known mixing between 4s4d and 4p2, it has been found that the structure of 4s4f is strongly affected by interaction with 4p4d. The ionization limit has been determined to 165 465.8 cm-1.

We measured the lumbar bone mineral of 19 cadavers (10 women, 9 men) by dual photon absorptiometry (DPA) and quantitative computed tomography (QCT). In addition, we determined the ultimate load and stress of each vertebra, and finally ash content and volumetric ash density of the vertebral body. We found that single energy QCT was inferior to DPA and dual energy QCT in the prediction of the ultimate load or stress of vertebrae (P less than 0.001). The ultimate stress was best predicted by using the dual energy QCT results (r = 0.71; SEE = 36.3 N/cm2) whereas the ultimate vertebral load was best predicted by using the DPA (BMC) results (r = 0.80; SEE = 740 N). If the QCT finding was multiplied with the surface area of the vertebral body it could be used to predict the ultimate load with good accuracy (r = 0.74; SEE = 841 N). All the above correlations were higher in women than in men. The frequency of vertebral compression fractures in the material was well correlated with the bone mineral findings. A nonlinear (third degree) relationship between mineral content and mechanical characteristics is proposed but within the area of measurement used in clinical practice a linear (first degree) equation is preferred.

Thirty-three patients treated with a Krogius tenoplasty for recurrent dislocation of the patella have been followed for an average of 3 years; the knees were classified according to Runow. In 14 of 34 operated knees dislocations had recurred. Most of the recurrences were found in patients with generalized joint laxity, whereas only one of nine knees with only a high Insall index had redislocated. Patients with generalized joint laxity should not be treated with the Krogius tenoplasty as the sole procedure.