[Treatment goals in patients with post-stroke upper limb spasticity following injection of botulinum toxin A : Results of the German-Austrian subgroup of the ULIS-II study]. / Therapieziele bei Patienten mit Armspastik nach Schlaganfall nach Injektion mit Botulinumtoxin A : Ergebnisse der deutsch-österreichischen Subgruppe der ULIS-II-Studie.

BACKGROUND: The ULIS-II was an international cohort study (NCT01020500) evaluating current treatment of upper limb spasticity in post-stroke adult patients with botulinum toxin A (BoNT-A) in real-life practice. OBJECTIVE: Post hoc analysis to compare current management of post-stroke adult patients regarding goal setting and attainment with BoNT-A in Germany (D) and Austria (A) with the full cohort of ULIS-II. MATERIAL AND METHODS: The ULIS-II was a global, open-label, prospective, multicenter observational study with 2 visits conducted in 84 centers worldwide. A total of 468 patients aged ≥18 years with post-stroke upper limb spasticity were included. The primary outcome measure was the responder rate defined as achievement of a goal attainment scale (GAS) score of 0, 1 or 2 after 1 cycle of BoNT-A. RESULTS: A total of 57 patients from D/A were included in the efficacy analysis. The number of patients in D/A and the full cohort achieving the primary (78.9% vs. 79.6%) and secondary treatment goal (76.8% vs. 75.6%), respectively, was comparable. Deviating from the full cohort, the most common primary treatment goal in D/A was related to impairment (33.3%). Compared to baseline there was a marked reduction in concomitant therapies at the follow-up visit after 3-5 months in the D/A group: patients receiving oral anti-spastic medication 61.4% vs. 40.4%, positioning 50.9% vs. 36.8% and splinting 43.9% vs. 31.6%. Injection control techniques were less frequently used in the D/A group compared to the global study cohort (electrical stimulation: 26.3% vs. 45.8% and electromyography: 12.3% vs. 29.2%). No adverse events were documented in the D/A cohort. CONCLUSION: A single injection of BoNT-A in adult patients with post-stroke spasticity of the arm led to a high response rate of approximately 80% in both cohorts. The BoNT-A injections in post-stroke adult patients contributed to an improvement in the daily life of patients and their carers beyond simple reduction of muscle tone or spasticity.

Early botulinum toxin treatment for spastic pes equinovarus--a randomized double-blind placebo-controlled study.

BACKGROUND AND PURPOSE: Spastic pes equinovarus is a frequent pathological posture of the lower extremity. Botulinum toxin (BoNT/A) has been successfully applied to treat lower limb spasticity. However, the best time to initiate treatment remains unclear. A beneficial effect of an early treatment has been suggested in previous studies. METHODS: A single-centre double-blind randomized placebo-controlled trial was performed to investigate the efficacy of BoNT/A to reduce muscle hypertonicity at the ankle. Fifty-two patients with unilateral or bilateral spastic pes equinovarus with a modified Ashworth score (mAS) of at least 1+ after stroke, traumatic brain injury or hypoxic encephalopathy were allocated to receive either BoNT/A or placebo treatment. A second, open injection was optional at week 12. Patients received unilateral or bilateral injections with 230 or 460 U onabotulinumtoxinA, respectively. The course of the mAS was explored during the open study phase. RESULTS: Patients who had received BoNT/A treatment had lower mAS compared with placebo at week 12 (P < 0.01). During the open label phase, patients from the placebo group showed further deterioration of muscle tone despite starting from a similar baseline and receiving BoNT treatment. Spastic feet that had received BoNT/A in the first cycle had comparatively lower mAS scores over all follow-up data and at week 24 (P < 0.01). CONCLUSIONS: The study demonstrates a reduction of muscular hypertonicity in spastic pes equines with BoNT/A treatment given during the first 3 months after the lesion. Exploratory analyses of the course of muscular hypertonicity during the open phase favour earlier to later treatment.

Botulinum toxin B increases mouth opening in patients with spastic trismus.

BACKGROUND: Severe generalized spastic movement disorders of various aetiologies often involve the jaw muscles and lead to a spastic trismus with masseter muscle hypertonia. We report a placebo-controlled randomized study on patients with spastic trismus. METHODS: Eleven patients with masseter hypertonia because of stroke, hypoxic encephalopathy or traumatic brain injury were allocated to either botulinum toxin serotype B (BoNT/B) injections into the masseter muscles or placebo treatment. The dental gap, the amount of saliva, salivation scales, and a clinical goal attainment were evaluated. RESULTS: Three weeks after injection the BoNT/B group showed a significantly increased mouth opening compared with placebo treatment (P < 0.05). In addition to the muscle paralysing effect, a goal attainment scale demonstrated a clinical benefit for the BoNT/B group (P < 0.01). CONCLUSIONS: Botulinum toxin serotype B injections into the masseter muscles effectively reduce hypertonia and provide for better mouth opening, thereby contributing to a positive and desired clinical goal.

Mechanisms of apoptosis after ischemia and reperfusion: role of the renin-angiotensin system.

BACKGROUND: Apoptosis plays a key role in the pathogenesis of cardiac diseases. We examined the influence of the renin-angiotensin system (RAS) on different regulators of apoptosis using an isolated hemoperfused working porcine heart model of acute ischemia (2 h), followed by reperfusion (4 h). METHODS AND RESULTS: 23 porcine hearts were randomized to 5 groups: hemoperfused non-infarcted hearts (C), infarcted hearts (MI: R. circumflexus), infarcted hearts treated with quinaprilat (Q), infarcted hearts treated with angiotensin-I (Ang I), and infarcted hearts treated with angiotensin-I and quinaprilat (QA). Fas, Bax, bcl-2 and p53 proteins were increased in MI hearts and further elevated by Ang I. Quinaprilat reduced Bax and p53. Bcl-2 was elevated in Q and reduced in QA. An early upregulation of caspase-3 gene and protein expression was detected in MI and Ang I hearts compared to C. Q reduced caspase-3 gene expression, but had no effect on caspase-3 and Fas protein. CONCLUSIONS: These data suggest that the RAS plays a pivotal role in cardiac apoptosis which is the early and predominant form of death in myocardial infarction. Ischemia/reperfusion induces programmed cell death via extrinsic and intrinsic pathways. Early treatment with quinaprilat attenuated cardiomyocyte apoptosis.

Induction of three-dimensional assembly and increase in apoptosis of human endothelial cells by simulated microgravity: impact of vascular endothelial growth factor.

Endothelial cells play a crucial role in the pathogenesis of many diseases and are highly sensitive to low gravity conditions. Using a three-dimensional random positioning machine (clinostat) we investigated effects of simulated weightlessness on the human EA.hy926 cell line (4, 12, 24, 48 and 72 h) and addressed the impact of exposure to VEGF (10 ng/ml). Simulated microgravity resulted in an increase in extracellular matrix proteins (ECMP) and altered cytoskeletal components such as microtubules (alpha-tubulin) and intermediate filaments (cytokeratin). Within the initial 4 h, both simulated microgravity and VEGF, alone, enhanced the expression of ECMP (collagen type I, fibronectin, osteopontin, laminin) and flk-1 protein. Synergistic effects between microgravity and VEGF were not seen. After 12 h, microgravity further enhanced all proteins mentioned above. Moreover, clinorotated endothelial cells showed morphological and biochemical signs of apoptosis after 4 h, which were further increased after 72 h. VEGF significantly attenuated apoptosis as demonstrated by DAPI staining, TUNEL flow cytometry and electron microscopy. Caspase-3, Bax, Fas, and 85-kDa apoptosis-related cleavage fragments were clearly reduced by VEGF. After 72 h, most surviving endothelial cells had assembled to three-dimensional tubular structures. Simulated weightlessness induced apoptosis and increased the amount of ECMP. VEGF develops a cell-protective influence on endothelial cells exposed to simulated microgravity.

Effects of angiotensin II subtype 1 receptor blockade on cardiac fibrosis and sarcoplasmic reticulum Ca2+ handling in hypertensive transgenic rats overexpressing the Ren2 gene.

OBJECTIVE: We evaluated the effects of angiotensin II subtype 1 (AT1) receptor antagonism on cardiac fibrosis and sarcoplasmic (SR) Ca2+ handling in a transgenic rat model of renin-dependent left ventricular (LV) hypertrophy (LVH). METHODS: Hypertensive transgenic rats overexpressing the Ren2 gene (TGR(mRen2)27) were treated between 10 and 30 weeks of age with the angiotensin II subtype 1 (AT1) receptor antagonist, eprosartan, in an antihypertensive (Ren2-E60, 60 mg/kg per day) and a non-antihypertensive (Ren2-E6, 6 mg/kg per day) dose applied intraperitoneally via osmotic-mini-pumps. They were compared to age-matched Ren2 and Sprague-Dawley (SD) control rats receiving 0.9% NaCl as vehicle via osmotic mini-pumps (Ren2-Vehicle, SD-Vehicle, respectively). RESULTS: Systolic blood pressure (SBP), LV weight, LV end-diastolic pressure (LVEDP), and cardiac fibrosis were elevated in Ren2-Vehicle, while diastolic function (-dP/dt(max)) and sarcoplasmic reticulum (SR) Ca2+ uptake were decreased in Ren2-Vehicle compared to SD-Vehicle (P < 0.05, respectively). SBP was not altered in Ren2-E6, but reduced to normotensive levels in Ren2-E60 compared to Ren2-Vehicle and SD-Vehicle (P < 0.0001). In both Ren2-E6 and Ren2-E60, LV weights were reduced and LVEDP and -dP/dt(max)normalized compared to Ren2-Vehicle (P < 0.05). SR Ca2+ uptake was normalized in both Ren2-E6 and Ren2-E60. Cardiac fibrosis did not change in Ren2-E6, but perivascular LV fibrosis and hydroxyprolin content were reduced in Ren2-E60 compared to Ren2-Vehicle (P < 0.05, respectively). CONCLUSIONS: Normalization of LV SR Ca2+ uptake is an important mechanism by which AT1 receptor antagonism improves LV diastolic dysfunction independent from a reduction of SBP and cardiac fibrosis in the TGR (mRen2)27 model.

Renal endothelin ET(A)/ET(B) receptor imbalance differentiates salt-sensitive from salt-resistant spontaneous hypertension.

It is unclear why a subgroup of patients with essential hypertension develop salt-sensitive hypertension with progression of target organ damage over time. We evaluated the role of the renal endothelin (ET) system in the stroke-prone spontaneously hypertensive rat (SHRSP) model of salt-sensitive spontaneous hypertension (SS-SH) compared with the spontaneously hypertensive rat (SHR) model of salt-resistant spontaneous hypertension (SR-SH). Both strains were studied after either sham-operation on a normal diet (Sham) or after unilateral nephrectomy and high NaCl loading (NX-NaCl) with 4% NaCl in diet for 6 weeks (n=10, respectively). Systolic blood pressure (SBP) increased only in SHRSP-NX-NaCl compared with SHRSP-Sham (250+/-6 versus 172+/-5 mm Hg, P:<0.0001). SBP remained unchanged in SHR-NX-NaCl compared with SHR-Sham. In SHRSP-NX-NaCl animals, urinary albumin and ET-1 excretion, renal ET-1 mRNA expression, glomerulosclerosis index, and tubulointerstitial damage index were elevated compared with SHRSP-Sham (P:<0.05, respectively), whereas no significant changes were found in SHR after NX-NaCl. Urinary sodium excretion (U(Na(+))) was significantly reduced by 38% in SHRSP-NX-NaCl compared with SHR-NX-NaCl (P:<0.005, respectively). SHR animals showed a similar increase in both renal ET(A) and ET(B) receptor densities after NX-NaCl (2.2-fold, P:<0.05). In contrast, SHRSP-NX-NaCl developed a significantly more pronounced increase in ET(A) compared with ET(B) binding (4.7-fold versus 2.4-fold, P:<0.05, compared with SHRSP-Sham, respectively), resulting in a significant 2.1-fold increase in ET(A)/ET(B) receptor ratio only in the SHRSP-NX-NaCl (P:<0.05). Thus, activation of the renal ET system together with an increased ET(A)/ET(B) receptor ratio may contribute to the development and progression of SS-SH.