Influence of Resistance Training on Neuromuscular Function and Physical Capacity in ALS Patients.

OBJECTIVES: The present study aimed to explore the effect of resistance training in patients with amyotrophic lateral sclerosis (ALS), a disease characterized by progressive motor neuron loss and muscle weakness. MATERIALS AND METHODS: Following a 12-week "lead-in" control period, a population of ALS patients from Funen, Denmark, completed a 12-week resistance training program consisting of 2-3 sessions/week. Neuromuscular function (strength and power) and voluntary muscle activation (superimposed twitch technique) were evaluated before and after both control and training periods. Physical capacity tests (chair rise and timed up and go), the revised ALS functional rating scale (ALSFRS-R) scores, and muscle cross sectional area (histology) were also assessed. RESULTS: Of twelve ALS patients assessed for eligibility, six were included and five completed the study. Training did not significantly affect the ALSFRS-R score, and loss of neuromuscular function (strength and power) increased following the training period. However, an improved functionality (chair rise) and an increase in greatly hypertrophied type II fibres combined with an increase in atrophied fibres following the training period compared to the control period were observed. CONCLUSION: In this small study, the present form of resistance training was unable to attenuate progressive loss of neuromuscular function in ALS, despite some changes in physical capacity and morphology.

Muscular response to the first three months of deflazacort treatment in boys with Duchenne muscular dystrophy.

OBJECTIVE: Duchenne muscular dystrophy (DMD) patients are often treated with glucocorticoids; yet their precise molecular action remains unknown. METHODS: We investigated muscle biopsies from nine boys with DMD (aged: 7,6±2,8 yrs.) collected before and after three months of deflazacort treatment and compared them to eight healthy boys (aged: 5,3±2,4 yrs.). mRNA transcripts involved in activation of satellite cells, myogenesis, regeneration, adipogenesis, muscle growth and tissue inflammation were assessed. Serum creatine kinase (CK) levels and muscle protein expression by immunohistochemistry of selected targets were also analysed. RESULTS: Transcript levels for ADIPOQ, CD68, CDH15, FGF2, IGF1R, MYF5, MYF6, MYH8, MYOD, PAX7, and TNFα were significantly different in untreated patients vs. normal muscle (p⟨0.05). Linear tests for trend indicated that the expression levels of treated patients were approaching normal values (p⟨0.05) following treatment (towards an increase; CDH15, C-MET, DLK1, FGF2, IGF1R, MYF5, MYF6, MYOD, PAX7; towards a decrease: CD68, MYH8, TNFα). Treatment reduced CK levels (p⟨0.05), but we observed no effect on muscle protein expression. CONCLUSIONS: This study provides insight into the molecular actions of glucocorticoids in DMD at the mRNA level, and we show that multiple regulatory pathways are influenced. This information can be important in the development of new treatments.

High number of kinome-mutations in non-small cell lung cancer is associated with reduced immune response and poor relapse-free survival.

Lung cancer is the leading cause of cancer related death, and the past years' improved insight into underlying molecular events has significantly improved outcome for specific subsets of patients. In particular, several new therapies that target protein kinases have been implemented, and many more are becoming available. We have investigated lung cancer specimens for somatic mutations in a targeted panel of 612 human genes, the majority being protein kinases. The somatic mutation profiles were correlated to profiles of immune cell infiltration as well as relapse-free survival. Targeted deep sequencing was performed on 117 tumour/normal pairs using the SureSelect Human Kinome kit (Agilent Technologies), with capture probes targeting 3.2 Mb of the human genome, including exons and untranslated regions of all known kinases, kinase receptors and selected cancer-related genes (612 genes in total). CD8 staining was determined using Ventana Benchmark. Survival analyses were performed using SPSS. The number of mutations per sample ranged from 0 to 50 (within the 612 genes tested), with a median of nine. The prognosis was worse for patients with more than the median number of mutations. A significant correlation was found between mutations in one of selected DNA-repair genes and the total number of mutations in that tumour (p < 0.001). There was a significant inverse correlation between the number of infiltrating stromal CD8+ lymphocytes and the presence of EGFR mutations.

Skeletal Muscle Remodelling as a Function of Disease Progression in Amyotrophic Lateral Sclerosis.

Muscle weakness is considered the pivotal sign of amyotrophic lateral sclerosis (ALS). Knowledge about the skeletal muscle degeneration/regeneration process and the myogenic potential is limited in ALS patients. Therefore, we investigate these processes in a time course perspective by analysing skeletal muscle biopsies from ALS patients collected before and after a 12-week period of normal daily activities and compare these with healthy age-matched control tissue. We do this by evaluating mRNA and protein (immunohistochemical) markers of regeneration, neurodegeneration, myogenesis, cell cycle regulation, and inflammation. Our results show morphological changes indicative of active denervation and reinnervation and an increase in small atrophic fibres. We demonstrate differences between ALS and controls in pathways controlling skeletal muscle homeostasis, cytoskeletal and regenerative markers, neurodegenerative factors, myogenic factors, cell cycle determinants, and inflammatory markers. Our results on Pax7 and MyoD protein expression suggest that proliferation and differentiation of skeletal muscle stem cells are affected in ALS patients, and the myogenic processes cannot overcome the denervation-induced wasting.

The usefulness of detecting thyroglobulin in fine-needle aspirates from patients with neck lesions using a sensitive thyroglobulin assay.

The aim of this study was to assess the diagnostic utility of thyroglobulin (Tg) in fine needle aspirates (Tg-FNAB) of nonthyroidal neck masses using a sensitive in-house method for detecting Tg in washout specimens. A total of 256 samples from 145 patients were evaluated for Tg in washout specimen from FNAB and compared to corresponding cytological smear and histology of 46 surgical specimens. Tg was measured by a sensitive in-house time-resolved immunofluorometric assay. The sensitivity for Tg-FNAB alone or in combination with cytological findings was found to be 100% in both the follow-up group and before primary surgery. In the follow-up group the specificity of Tg-FNAB was 100%. Fifty-nine of 60 follow-up specimens with malignant cytology were Tg-FNAB positive (n = 195). Histological examination of one lymph node with malignant cytology and negative Tg-FNAB showed metastasis from carcinoma of the salivary gland. Tg-FNAB was positive in 25 specimens with suspicious or cystic cytology. Tg-FNAB values were high (median 4557 microg/l, range 122-37200 microg/l) in washout specimen from cystic metastasis from which cytology did not confirm malignancy. Of the 20 lymph nodes with histology confirming metastasis from differentiated thyroid carcinoma (DTC), the Tg-FNAB was positive in 19 and intermediate in one. However, before primary surgery, two Tg-FNABs were false positive compared to the histology of the lymph nodes. TgAb in serum did not interfere with FNAB-Tg measurements. Tg-FNAB measurement is accurate with high sensitivity (100%) and of great importance in detecting cystic metastasis when cytology is not conclusive. Even metastases to small neck lymph nodes may be detected by using sensitive Tg-assay. Serum thyroglobulin antibodies appear to have ignorable effect on the clinical performance of Tg-FNAB.

Response to changing plasma concentrations of isosorbide-bound NO2 during acute and sustained treatment with isosorbide dinitrate in patients with coronary artery disease.

BACKGROUND: The mechanisms behind development of tolerance to nitrate effects during sustained, asymmetric isosorbide dinitrate (ISDN) therapy are not fully understood. HYPOTHESIS: The study was undertaken to investigate the changes of the relationships between left ventricular (LV) function and plasma concentrations of ISDN and its vasoactive metabolites (2- and 5-ISMO) during acute and sustained, asymmetric ISDN therapy. METHODS: Left ventricular function and plasma concentrations of ISDN, 2- and 5-isosorbide mononitrates (P-ISDN, P-2- and 5-ISMO) were measured at rest and at supine exercise before and for 4 h after peroral 30 mg ISDN in 15 patients with coronary artery disease, all with initial exercise pulmonary artery wedge pressure (PAWP) > 25 mmHg. Seven patients were untreated (acute group), while eight received 30 mg ISDN b.i.d. for 2 weeks before the invasive study. P-ISDN and the concentration of available isosorbide-bound nitrate (NO2) in plasma (P-ISDN.2 + P-2-ISMO + P-5-ISMO) (P-NO2) were used as measures of the nitric oxide (NO) offer to the tissues. RESULTS: Throughout the study, after administration of medication, all plasma concentrations, in particular P-ISDN, were higher in the chronic than in the acute group. Peak P-ISDN was reached after 15 min in the chronic group and after 25 min in the acute group, while P-2- and 5-ISMO reached maximum only after 40 min in both groups. At rest, the full effect on PAWP was observed after 10 min in both groups, but at markedly higher levels of P-ISDN and P-NO2 in the chronic group. Afterward, no further changes in PAWP were observed. During exercise, 1 h after medication, PAWP and stroke index to PAWP ratio (SI/PAWP) were normal in both groups. Thereafter, at slowly declining P-NO2, PAWP rose and SI/PAWP declined toward the initial level in the chronic group, but remained unchanged in the acute group, in spite of higher P-NO2 and greater NO release in the former. CONCLUSIONS: Patients receiving sustained, asymmetric 30 mg ISDN b.i.d. dosing had the same immediate beneficial effects on LV function during exercise after a morning dose as did untreated patients. However, in spite of higher P-NO2 and higher rate of NO release during sustained treatment, the effects deteriorated gradually 2 to 3 h after medication. The changes in metabolism and/or distribution of isosorbide-bound NO2 may possibly be part of the tolerance induced by long-term treatment, even with asymmetric dosing.

Effects of isosorbide dinitrate on electrocardiography, hemodynamics, and ventilation in patients with exercise-induced elevation of pulmonary artery wedge pressure.

BACKGROUND: The mechanisms underlying exertional hyperpnea in patients with coronary artery disease and transient left ventricular dysfunction are still not fully understood. HYPOTHESIS: The study was undertaken to investigate whether the ventilatory response to exercise reflects the effects of acute medical treatment of exercise-induced left ventricular dysfunction, and to evaluate mechanisms relevant to excessive exertional ventilation. METHODS: In 11 male patients, aged 65.2 +/- 6.0 years, all with pulmonary artery wedge pressure (PAWP) > 25 mmHg and ST depression > 2 mm during moderate supine exercise, ventilation (V), oxygen uptake (VO2), hemodynamics, electrocardiogram (ECG), and arterial and mixed venous blood gases were examined during supine rest and exercise, before and at hourly intervals after peroral intake of 30 mg isosorbide dinitrate (ISDN). Six similar patients were examined with the same protocol without ISDN administration and comprised a control group. RESULTS: Before administration of ISDN, exercise PAWP was 35.3 +/- 5.9 mmHg, ECG showed 2.77 +/- 1.06 mm ST depression, and V/VO2 was 31.8 +/- 4.8 l/l. One h after ISDN administration, exercise mean PAWP was 11.0 +/- 2.5 mmHg (p < 0.001), ST depression 0.59 +/- 0.8 mm (p < 0.001), whereas V/VO2 was unchanged, 30.1 +/- 5.3 l/l. Two h later, PAWP remained reduced and there were only minor ST depressions, while V/VO2 remained high. Exercise cardiac index (CI) and mixed venous oxygen tension (PvO2), initially 4.7 +/- 0.67 l/min/m2 and 3.54 +/- 0.35 kPa, respectively, remained at the same low level throughout the study. In the six nontreated patients, there were no significant changes in ST depression, exercise PAWP, or exertional ventilation. CONCLUSION: Isosorbide dinitrate treatment markedly improved exercise-induced left heart dysfunction, whereas excessive ventilatory response was unaffected, even after 3 h. Thus, measurements of the exercise hyperpnea did not properly reflect effective reduction of myocardial ischemia.

Relationship between exercise hyperpnea, hemodynamics, and blood gases before and during glyceryl trinitrate infusion in patients with exercise-induced elevation of pulmonary artery wedge pressure.

BACKGROUND: The mechanisms underlying the excessive ventilatory response to exercise in patients with cardiac failure are still not fully understood. HYPOTHESIS: This study was undertaken to investigate the mechanisms behind exercise hyperpnea in patients with exercise-induced left ventricular dysfunction. METHODS: In 18 patients, aged 57-82 years, all with atherosclerotic lumbar aorta aneurysm and pulmonary artery wedge pressure (PAWP) > 25 mmHg during supine exercise, ventilation (V), central hemodynamics, and arterial and venous blood gases were examined during supine rest and exercise, before and during infusion of glyceryl trinitrate (GTN). RESULTS: Before GTN, exercise PAWP was 32.2 +/- 6.1 mmHg and V/V O2 was 33.8 +/- 7.7 l/l (130% of predicted). With GTN, exercise PAWP was markedly reduced to 15.3 +/- 3.8 mmHg (p < 0.001), whereas V/V O2 was only marginally reduced to 32.3 +/- 3.0 l/l (124% of predicted) (p < 0.05). Exercise physiologic dead space (VD/VT) declined from 0.31 +/- 0.16 to 0.26 +/- 0.17 (p < 0.05), while PaCO2 was reduced from 5.20 +/- 0.31 to 5.10 +/- 0.24 kPa (p < 0.05). PvO2 and cardiac output (CO), however, were unchanged below normal. CONCLUSION: The data show that exercise-induced hyperpnea was not substantially reduced by rapid normalization of PAWP and could not be related to preservation of normal PaCO2 in the presence of high VD/VT. The persistence of exercise hyperpnea and reduced PvO2 after GTN is consistent with augmented ventilatory stimuli from hypoxia-induced metabolic abnormalities in the skeletal muscles, or/and persistently reduced CO, due to changes in the integrated superior command of ventilation and circulation.

Hemodynamic time course of acute and chronic isosorbide dinitrate treatment at rest and during exercise in patients with stable ischemic heart disease.

HYPOTHESIS: The study was undertaken to establish differences between venous and arterial isosorbide dinitrate (ISDN) effects during acute and chronic treatment, hemodynamics at rest, and during supine exercise. METHODS: These effects were assessed invasively in 16 patients with stable ischemic heart disease before and at hourly intervals for 4 h after administration of peroral 30 mg ISDN. Eight patients were previously untreated (acute group), and eight were treated with 30 mg ISDN asymmetrically b.i.d. for two weeks (chronic group). RESULTS: Prior to ISDN administration, right atrial, mean pulmonary artery, pulmonary artery wedge, and mean arterial pressure (RAP, MPAP, PAWP, and MAP) rose from normal resting to pathologic values during exercise. One h after ISDN administration, all exercise pressures were normalized (p < 0.001). During the following 3 h, exercise RAP rose similarly in both groups (p < 0.01), while MPAP rose particularly in the chronic group (p < 0.001). Exercise PAWP and MAP, however, remained low in the acute group, but increased markedly in the chronic group (p < 0.01), particularly from the third to the fourth hour after ISDN. CONCLUSION: The daily, asymmetric administration of 30 mg ISDN b.i.d. maintained beneficial, anti-ischemic effects for 2 to 3 h after a morning dose of the drug, but thereafter attenuation of the effects occurred in the arteries but not in the veins.

Early hemodynamic effects at rest with acute and chronic isosorbide dinitrate treatment in patients with ischemic heart disease.

Asymmetric dosage regimens are used to circumvent development of nitrate tolerance and are believed to restore totally the hemodynamic responsiveness to an acute dosage of nitrates. This study assessed invasively the hemodynamics during supine rest before and for 50 min after peroral 30 mg isosorbide dinitrate (ISDN) in 16 patients with stable ischemic heart disease; 8 previously untreated patients (NT group) and 8 patients treated asymmetrically b.i.d. with 30 mg ISDN for 14 days prior to the invasive investigation (T group). Before initiation of treatment, both groups had identical mean arterial pressure (MAP) and heart rate (HR). On the day of invasive investigation, before intake of ISDN, MAP was higher in the T group but unchanged in the NT group. After the intake of ISDN, right atrial pressure (RAP), mean pulmonary arterial pressure, and pulmonary arterial wedge pressure declined markedly within 10 to 15 min in both groups, while MAP showed a more protracted decline, reaching a new level only after 25 to 30 min. In the NT group, HR accelerated markedly and remained elevated throughout the observation period, whereas in the T group HR showed no significant alteration after ISDN intake. At the end of the observation period, the cardiac index (CI) was definitely reduced in the NT group, but remained unchanged in the T group, while the systemic vascular resistance index was unchanged in the former and was clearly reduced in the latter. It is concluded that the fall in MAP in the NT group was solely due to a fall in CI, and that the decline in RAP and venous return in the NT group induced neurohumoral reflexes leading to a rise in HR and prevention of arterial dilation, whereas in the T group, already influenced by chronic treatment, such acute counterregulatory responses were markedly attenuated or absent.

Influence of glyceryl trinitrate on venous and arterial effects of chronic, asymmetric isosorbide dinitrate treatment in patients with ischemic heart disease.

Asymmetric dosage regimes have been introduced to circumvent development of nitrate tolerance. This study assessed invasively the hemodynamics during supine rest and exercise before and after 4 weeks treatment with 30 mg isosorbide dinitrate (ISDN) or placebo asymmetrically b.i.d. in 14 randomized patients with stable ischemic heart disease in a double-blinded study. An intravenous infusion of glyceryl trinitrate (GTN) was used to assess possible nitrate tolerance. During the initial, medication-free exercise all patients had increased pulmonary arterial wedge pressure (PAWP) 31.4 +/- 5.56 mmHg (mean +/- SD), showing impaired left ventricular function, while mean arterial pressures (MAP) rose from 112 +/- 16.3 mmHg at rest to 141 +/- 15.9 mmHg during exercise. After 4 weeks ISDN treatment, mean exercise PAWP and MAP, 3 h after morning dose, were reduced to 22.4 +/- 7.09 mmHg and 127 +/- 18.2 mmHg, respectively. Before the ISDN treatment, GTN reduced exercise PAWP to 13.9 +/- 5.27 mmHg and MAP to 119 +/- 11.2 mmHg, whereas after 4 weeks ISDN treatment, the addition of GTN did not reduce exercise PAWP and MAP to the same low levels. Thus, the applied ISDN regimen improved the hemodynamics, but induced a definite, partial nitrate tolerance.

Total androgen suppression: experience from the Scandinavian Prostatic Cancer Group Study No. 2.

A total of 294 patients with metastatic prostatic cancer were randomized prospectively in a Scandinavian multicenter study to either bilateral orchiectomy+placebo or orchiectomy+cyproterone acetate (CPA). The study was double blind. Patients with histologically verified prostatic cancer, with diagnosed skeletal metastases on X-ray or bone scintigrams and histological grade 1 and 2 were included: T0-4NXM1G1-2. 273 evaluable patients were followed either to progression, death or for a period of 3 years. 195 of these patients showed disease progression during the 3-year treatment period, 29 had stable disease and 49 patients experienced disease remission. The Kaplan-Meier analyses showed that time to progression as well as time to death for patients treated with castration+placebo are identical to that for patients treated with castration+PCA. Total androgen blockade with this antiandrogen was not superior to the standard orchiectomy treatment.