Muscle velocity recovery cycles in myopathy.

OBJECTIVE: To understand the pathophysiology of myopathies by using muscle velocity recovery cycles (MVRC) and frequency ramp (RAMP) methodologies. METHODS: 42 patients with quantitative electromyography (qEMG) and biopsy or genetic verified myopathy and 42 healthy controls were examined with qEMG, MVRC and RAMP, all recorded from the anterior tibial muscle. RESULTS: There were significant differences in the motor unit potential (MUP) duration, the early and late supernormalities of the MVRC and the RAMP latencies in myopathy patients compared to controls (p < 0.05 apart from muscle relatively refractory period (MRRP)). When dividing into subgroups, the above-mentioned changes in MVRC and RAMP parameters were increased for the patients with non-inflammatory myopathy, while there were no significant changes in the group of patients with inflammatory myopathy. CONCLUSIONS: The MVRC and RAMP parameters can discriminate between healthy controls and myopathy patients, more significantly for non-inflammatory myopathy. MVRC differences with normal MRRP in myopathy differs from other conditions with membrane depolarisation. SIGNIFICANCE: MVCR and RAMP may have a potential in understanding disease pathophysiology in myopathies. The pathogenesis in non-inflammatory myopathy does not seem to be caused by a depolarisation of the resting membrane potential but rather by the change in sodium channels of the muscle membrane.

Bystander cardiopulmonary resuscitation and survival in patients with out-of-hospital cardiac arrest of non-cardiac origin.

BACKGROUND: Knowledge about the effect of bystander cardiopulmonary resuscitation (CPR) in out-of-hospital cardiac arrest (OHCA) of non-cardiac origin is lacking. We aimed to investigate the association between bystander CPR and survival in OHCA of presumed non-cardiac origin. METHODS: From the Danish Cardiac Arrest Registry and through linkage with national Danish healthcare registries we identified all patients with OHCA of presumed non-cardiac origin in Denmark (2001-2014). These were categorized further into OHCA of medical and non-medical cause. We analyzed temporal trends in bystander CPR and 30-day survival during the study period. Multiple logistic regression was used to examine the association between bystander CPR and 30-day survival and reported as standardized 30-day survival chances with versus without bystander CPR standardized to the prehospital OHCA-factors and patient characteristics of all patients in the study population. RESULTS: We identified 10,761 OHCAs of presumed non-cardiac origin. Bystander CPR was associated with a significantly higher 30-day survival chance of 3.4% (95% confidence interval [CI]: 2.9-3.9) versus 1.8% (95% CI: 1.4-2.2) without bystander CPR. A similar association was found in subgroups of both medical and non-medical OHCA. During the study period, the overall bystander CPR rates increased from 13.6% (95% CI: 11.2-16.5) to 62.7% (95% CI: 60.2-65.2). 30-day survival increased overall from 1.3% (95% CI: 0.7-2.6) to 4.0% (95% CI: 3.1-5.2). CONCLUSION: Bystander CPR was associated with a higher chance of 30-day survival among OHCA of presumed non-cardiac origin regardless of the underlying cause (medical/non-medical). Rates of bystander CPR and 30-day survival improved during the study period.

Cardiac Abnormalities in Adult Patients With Polymyositis or Dermatomyositis as Assessed by Noninvasive Modalities.

OBJECTIVE: Cardiac events are a major cause of death in patients with idiopathic inflammatory myopathies. The study objective was in a controlled setting to describe cardiac abnormalities by noninvasive methods in a cohort of patients with polymyositis (PM) or dermatomyositis (DM) and to identify predictors for cardiac dysfunction. METHODS: In a cross-sectional study, 76 patients with PM/DM and 48 matched healthy controls (HCs) were assessed by serum levels of cardiac troponin I, electrocardiography, Holter monitoring, echocardiography with tissue Doppler imaging, and quantitative cardiac (99m) Tc-pyrophosphate ((99m) Tc-PYP) scintigraphy. RESULTS: Compared to HCs, patients with PM/DM more frequently had left ventricular diastolic dysfunction (LVDD) (12% versus 0%; P = 0.02) and longer QRS and QT intervals (P = 0.007 and P < 0.0001, respectively). In multivariate analysis, factors associated with LVDD were age (P = 0.001), disease duration (P = 0.004), presence of myositis-specific or -associated autoantibodies (P = 0.05), and high cardiac (99m) Tc-PYP uptake (P = 0.006). In multivariate analysis of the pooled data for patients and HCs, a diagnosis of PM/DM (P < 0.0001) was associated with LVDD. CONCLUSION: Patients with PM or DM had an increased prevalence of cardiac abnormalities compared to HCs. LVDD was a common occurrence in PM/DM patients and correlated to disease duration. In addition, the association of LVDD with myositis-specific or -associated autoantibodies and high cardiac (99m) Tc-PYP uptake supports the notion of underlying autoimmunity and myocardial inflammation in patients with PM/DM.

Nephrogenic systemic fibrosis is found only among gadolinium-exposed patients with renal insufficiency: a case-control study from Denmark.

BACKGROUND: Nephrogenic systemic fibrosis (NSF) is a systemic fibrosing disease associated with exposure to gadolinium-based contrast agents (GBCA) in patients with renal insufficiency. OBJECTIVES: To report the prevalence of NSF in a well-defined cohort of patients with renal insufficiency exposed to GBCA, to investigate if GBCA-unexposed controls showed signs of NSF and to evaluate selected risk factors among NSF cases and GBCA-exposed controls. METHODS: A study among GBCA-exposed patients with renal insufficiency (n=565) was conducted to identify cases of NSF. The NSF cases found were age and sex matched and clinically compared with GBCA-exposed and unexposed patients with renal insufficiency in a case-control study. RESULTS: We identified 17 NSF cases. No signs of NSF were observed among the controls. The prevalence of NSF was 4·7%, highest among patients with chronic kidney disease (CKD) stage 5 exposed to GBCA and undergoing haemodialysis or peritoneal dialysis. Three NSF cases were identified among patients with CKD stage 3 and 4. Three patients developed NSF after macrocyclic GBCA exposure. NSF cases had a tendency to have higher serum phosphate concentrations than GBCA-exposed controls. CONCLUSIONS: Our study supports the view that GBCA is a major risk factor for NSF. Importantly, we found that patients with CKD stage 3 and 4 can be at risk of NSF. NSF may also be triggered by macrocyclic GBCA. Further, we observed a trend for higher phosphate levels in NSF cases compared with controls. The important findings drawn from this case-control study indicate that NSF is not an overlooked condition among patients with renal insufficiency not exposed to GBCA.

Percutaneous endoscopic gastrostomy in patients with systemic sclerosis.

Gastrointestinal (GI) problems are common in patients with systemic sclerosis (SSc) and some develop pronounced underweight despite dietary intervention. Two patients with SSc were referred to our department because of severe GI symptoms and critical underweight. They had lost 24 and 23 kg, respectively, and their body mass index (BMI) was only 15 and 17 kg/m(2), respectively. After careful GI evaluation, both were treated with percutaneous endoscopic gastrostomy (PEG). Eight months later one patient had gained 13 kg (BMI 19 kg/m(2)) and after 5 months follow-up the other had gained 9 kg (BMI 20 kg/m(2)). Weight was no longer critically low and quality of life improved in both. In conclusion, PEG is an option in selected patients with severe malnutrition due to SSc. However, we advocate that thorough GI evaluation is performed in advance.

Learning effect of isokinetic measurements in healthy subjects, and reliability and comparability of Biodex and Lido dynamometers.

The aim of this study was to examine the learning effect during a set of isokinetic measurements, to evaluate the reliability of the Biodex System 3 PRO dynamometer, and to compare the Biodex System 3 PRO and the Lido Active dynamometers on both extension and flexion over the elbow and the knee at 60 degrees s(-1). Thirteen (nine women, four men) healthy participants were measured five times using the Biodex and once using the Lido dynamometer. The intervals between the first four tests were 20 min, and 1 week between tests 4 and 5. Between Biodex and Lido measurements there was a 20 min time interval. When comparing the first five measurements (Biodex), no systematic effect over time and an excellent reliability were found with respect to elbow and knee flexion and extension. No difference in muscle strength (Nm) between the Biodex and Lido was observed for knee flexion (P = 0.59), knee extension (P = 0.18) and elbow extension (P = 0.63). However, elbow flexion showed a 14.8% (95% CI: 11.2-18.4%; P = 0.0001) higher peak torque on Biodex. In conclusion, no learning effect was observed and the Biodex proved to be a highly reliable isokinetic dynamometer. A difference was observed when comparing Biodex and Lido on elbow flexion, but the difference did not outrange the expected variation found with a typical isokinetic measurement, which is why both sets of equipment seem applicable in clinical practice.

Expression of hypoxia-inducible factor 1alpha in tumours of patients with glioblastoma.

Angiogenesis is a prominent feature of glioblastomas but the mechanisms involved in the control of this process are poorly understood. We have investigated the potential role of a recently described transcription factor, hypoxia-inducible factor 1 (HIF-1), which initiates the transcription of a number of hypoxia-inducible genes, including those encoding vascular endothelial growth factor and its receptors. HIF-1 protein expression was assessed by immunocytochemistry, using a monoclonal antibody to the alpha subunit (HIF-1alpha). HIF-1 mRNA expression was assessed by reverse transcriptase-polymerase chain reaction (RT-PCR) and the ribonuclease protection assay (RPA). Strong nuclear expression of HIF-1alpha protein was seen in the majority of glioblastomas and anaplastic astrocytomas, particularly surrounding areas of necrosis in glioblastomas. In the majority of these tumours upregulation of HIF-1alpha mRNA was also demonstrated, with a significant increase in glioblastomas compared to lower grade tumours. No correlation was found between the presence of HIF-1alpha protein and immunohistochemical expression of p53 protein. These findings are in keeping with an important role of HIF-1alpha in the vascularization of glioblastomas and suggest that upregulation is at least partly at a transcriptional level.

Synthesis of 5-azacastanospermine, a conformationally restricted azafagomine analogue.

The 5-aza-6-deoxy analogue of castanospermine (+/-)-5a and its 1-epimer (+/-)-5b was synthesized. The synthesis started from the known compound 5-benzyloxy-7-hydroxyhepta-1,3-diene, which was protected and subjected to Diels-Alder reaction with 4-phenyl-1,2,4-triazoline-3,5-dione to give two epimeric adducts. One of these was transformed through epoxidation, acetolysis, a series of side-chain transformations that converted it into a terminally protected aldehyde, deprotection, and hydrogenolysis/reductive amination into 5a. By a similar set of reactions the other adduct epimer was converted into 5b. The castanospermine analogue 5a was a weaker inhibitor of almond beta-glucosidase and rice alpha-glucosidase than castanospermine (2) or 1-azafagomine (4), but was considerably more potent than its epimer 5b. This suggests that these enzymes have a strong preference for binding substrates or azasugars with the 6-OH in an axial conformation.

Aldose reductase expression is induced by hyperglycemia in diabetic nephropathy.

BACKGROUND: Despite good metabolic control, many patients with type 1 diabetes still develop nephropathy, implicating a role for genetic factors. Recent studies examining the regulatory region of the aldose reductase (ALR2) gene, the rate-limiting enzyme of the polyol pathway, support its role as a candidate gene for nephropathy. Here we report the quantitation of ALR2, together with sorbitol dehydrogenase mRNA in the peripheral blood mononuclear cells (PBMCs) of type 1 diabetic patients with (N = 29) and without nephropathy (N = 11) following stimulation with high levels of D-glucose. METHODS: PBMCs from patients and normal controls were cultured for five days with phytohemagglutinin in either normoglycemia (11 mmol/L D-glucose) or supplemented with 10 mmol/L D-glucose (moderate hyperglyemia) or 20 mmol/L D-glucose (hyperglycemia). The RNA was extracted and analyzed by ribonuclease protection assay. RESULTS: ALR2 mRNA levels were significantly elevated with increasing D-glucose concentration (normal to hyperglycemic) in those patients with nephropathy (P < 0.0001). In marked contrast, in those without nephropathy and in the normal healthy controls, there was no change in mRNA expression. Furthermore, those patients with nephropathy and the Z-2/X susceptibility genotype had the greatest increase in ALR2 mRNA compared with those with low-risk genotypes (P < 0.007). CONCLUSION: These results show that patients with nephropathy exhibit marked disturbances in the expression of the enzyme components of the polyol pathway. Ultimately this leads to tissue damage and ischemia.

Soluble intercellular adhesion molecule-1 (sICAM-1) and soluble interleukin-2 receptors (sIL-2R) in scleroderma skin.

In order to investigate whether soluble intercellular adhesion molecule-1 (sICAM-1) and soluble interleukin-2 receptors (sIL-2R) were present in scleroderma skin, and to compare their levels to concentrations measured in plasma and clinical parameters, we examined suction blister fluid and plasma from 13 patients with systemic sclerosis and 11 healthy volunteers. Suction blisters and biopsies were from the transition zone between normal skin and scleroderma, and uninvolved abdominal skin. The levels of sICAM-1 and sIL-2R were significantly increased in both plasma and suction blister fluid from systemic sclerosis patients compared with healthy volunteers. ICAM-1 was localized to vessels and perivascular mononuclear infiltrates by immunohistochemical methods. IL-2R was expressed by CD3-positive cells. The elevated levels of sICAM-1 and sIL-2R in suction blister fluid point towards activation of endothelial cells and T cells in both the transition zone and uninvolved skin of systemic sclerosis patients.

The steroid-sparing effect of long-term plasmapheresis in pemphigus: an update.

Glucocorticoids and immunosuppressive agents can induce remission in most pemphigus patients, but mortality remains at 5 to 15% as a result of side effects. We reviewed the adjunctive effect of long-term plasmapheresis in 8 pemphigus patients. Four cases had been resistant to conventional therapy. One or 2 large-volume plasmapheresis treatments were given monthly over 5 to 141 months. All patients, were in clinical remission within 2 months. Relapses seldom occurred: the patients stayed in remission 90% (40-94) (median, ranges) of the period. In all cases the daily dose of glucocorticoid was reduced. The prednisone level could be decreased from 38 (15-80) mg/day to 7.5 (2.5-35) mg/day (p = 0.002). The overall level of other immunosuppressive agents remained unchanged, except in 1 patient for whom cyclosporine was introduced. This indicates that long-term plasmapheresis could have a steroid-sparing effect and clinical efficacy in pemphigus.

[Occupational systemic sclerosis in men]. / Arbejdsbetinget systemisk sklerodermi hos maend.

An analysis of the history of 28 men suffering from systemic sclerosis, diagnosed at our department during the last 25 years, showed that 21 (75%) had been subject to exposures previously suggested to be of importance in occupational scleroderma. The exposures were revealed by patient files, reports to health authorities, interviews and/or answers to questionnaires. Organic solvents being the most frequent exposure. This was found in thirteen of the patients (46%). A significant difference was found between scleroderma patients and control patients not suffering from connective tissue diseases in relation to total number of subjects exposed to one or several of the agents in question.

Increased levels of type I and III collagen and hyaluronan in scleroderma skin.

The aminoterminal propeptide of type III procollagen (PIIINP) and the carboxyterminal propeptide of type I procollagen (PICP) and hyaluronan (HA) were measured in plasma and suction blister fluid from 13 systemic sclerosis patients and 11 healthy volunteers. Suction blisters and skin biopsies were from the transition zone between normal skin and scleroderma, and uninvolved abdominal skin of patients. The median value of suction blister PIIINP from the transition zone was 38% higher than suction blister PIIINP from uninvolved skin. PIIINP was localized to the dermis by immunohistochemical techniques. PICP and HA levels in blisters from the transition zone were 87% and 53%, respectively, above the levels measured in uninvolved skin. Furthermore, PICP and HA blister levels from the transition zone were 67% and 63%, respectively, higher than the levels measured in healthy volunteers. In plasma from scleroderma patients levels of PIIINP and HA were 38% and 127% higher, respectively, than in plasma of healthy volunteers. The plasma PICP level was not significantly higher in scleroderma patients. Finally, PICP, PIIINP and HA levels were several times higher in suction blister fluid than in plasma. The data indicate that a fibrogenetic process takes place in the transition zone of scleroderma. The method may be used to monitor the progression of scleroderma skin lesions in vivo.

Redox regulation of apoptosis in interleukin-3-dependent haemopoietic cells: absence of alteration in both mitochondrial membrane potential (delta psi(m)) and free radical production during apoptosis induced by IL3 withdrawal.

Apoptosis in haemopoietic cells has been linked to the production of free radicals and reduction in mitochondrial transmembrane potential, delta psi(m). We have found that apoptosis in murine IL3-dependent haemopoietic cells induced by IL3 withdrawal lowers a principal source of anti-oxidant (reduced glutathione) but does not increase free radicals nor affect delta psi(m). Increased free radicals are, however, produced during IL3 signalling. Artificially increasing intracellular free radicals by depleting internal glutathione mimics IL3 signalling in that cells maintain shape and are transiently stimulated into S-phase in the absence of IL3. Conversely, depletion of free radicals by anti-oxidants accelerates apoptosis both in the presence and absence of IL3. Our studies suggest that redox conditions rather than free radicals or mitochondrial membrane potential per se may play a significant role in maintaining cell and replicative integrity, and in determining apoptosis in haemopoietic cells.

The use of serologic markers for collagen synthesis and degradation in systemic sclerosis.

BACKGROUND: Systemic sclerosis is characterized by excessive accumulation of collagen in all involved organs. Serum markers of collagen synthesis and degradation, the aminoterminal propeptide of type III procollagen (PIIINP), the carboxyterminal propeptide of type I procollagen (PICP), and the crosslinked telopeptide of type I collagen (ICTP), can be measured. OBJECTIVE: Our purpose was to investigate these markers in different subgroups of untreated patients with systemic sclerosis and in patients before and after various types of therapy. PIIINP and PICP were also investigated in blister fluid from involved and uninvolved skin. METHODS: Sera from 97 patients and suction blister fluid from 13 patients were radioimmunoassayed. RESULTS: The highest levels of PIIINP and PICP were found in blister fluid from involved skin. Patients with systemic sclerosis had higher serum levels of PIIINP than control subjects. The highest levels were found in patients with diffuse cutaneous systemic (type III) sclerosis; increased serum PIIINP was also characteristic of type II limited cutaneous systemic sclerosis. Most patients with limited cutaneous type I systemic sclerosis had normal levels. Serum PICP was within normal limits in all three types of systemic sclerosis. Variations in ICTP type I collagen degradation in general followed PICP. Immunosuppressive drugs significantly reduced PIIINP, whereas no significant decrease was found after photopheresis. PICP and ICTP also diminished after treatment with D-penicillamine and cyclophosphamide given together with prednisone. CONCLUSION: PIIINP can be recommended for monitoring collagen synthesis in systemic sclerosis. Our data support the use of immunosuppressive therapy for this disease.

The steroid-sparing effect of long-term plasmapheresis in pemphigus.

Glucocorticoids and immunosuppressive agents can induce remission in most patients with pemphigus, but mortality remains at 5 to 15% due to complications from these drugs. We reviewed the adjunctive effect of long-term plasmapheresis in 8 patients with pemphigus. Four cases had been resistant to conventional therapy. One or two large-volume plasmapheresis treatments were given monthly for 5 to 73 months. All patients were in clinical remission within 2 months after the addition of plasmapheresis. Relapses of pemphigus seldom occurred, and the patients stayed in remission 90% (40-100%) (median and ranges) of the plasmapheresis period. In all cases the daily dose of glucocorticoid was reduced. The prednisone level could be decreased significantly from 38 (15-80) mg/day to 10 (5-35) mg/day (p = 0.008). The overall level of other immunosuppressive agents remained unchanged, except in one patient where cyclosporine was introduced. This first report of long-term plasmapheresis demonstrates clinical efficacy in pemphigus and a considerable steroid-sparing effect.

Skin scoring in systemic sclerosis: a modification--relations to subtypes and the aminoterminal propeptide of type III procollagen (PIIINP).

Forty-one patients with systemic sclerosis were investigated with a new and simple skin score method measuring the degree of thickening and pliability in seven regions together with area involvement in each region. The highest values were, as expected, found in diffuse cutaneous systemic sclerosis (type III SS) and the lowest in limited cutaneous systemic sclerosis (type I SS) with no lesions extending above wrists and ancles. A positive correlation was found to the aminoterminal propeptide of type III procollagen, a serological marker for synthesis of type III collagen. The skin score is considered simpler than previous methods and is recommended for more general use.

The high-affinity folate receptor of normal and malignant human colonic mucosa.

The hypothesis that folate depletion is a risk factor for development of colonic neoplasia prompted us to study the presence of a putative folate receptor in human colon mucosa. Binding of 3H-folate to normal and malignant mucosa studied by equilibrium dialysis was of high-affinity type (K = 10(10) L/mol) and displayed apparent positive cooperativity. Radioligand dissociation was slow at pH 7.4, but rapid at pH 3.5. As compared to methotrexate, 5-formyltetrahydrofolate was a potent inhibitor of binding. Gel filtration revealed a 25 kDa and a 100 kDa peak of folate-binding activity. Immunoreactivity studies were performed with rabbit antibodies against human 25 kDa milk folate-binding protein. Immunoblotting showed a single band at 65 kDa, and tissue sections exhibited immunostaining of mucosal areas. The present folate receptor with characteristics similar to those of other high-affinity folate-binding proteins may serve as a regulator of intracellular folate concentration in colon mucosa.