ABSTRACT
Vessels of female rats constrict less and relax more to adrenergic stimulation than vessels of males. Although we have reported that these sex-specific differences rely on endothelial ß-adrenoceptors, the role of sex hormones in ß-adrenoceptor expression and related vessel tone regulation is unknown. We investigated the role of estrogen, progesterone and testosterone on ß-adrenoceptor expression and adrenergic vessel tone regulation, along with sex-specific differences in human mammary arteries. The sex-specific differences in vasoconstriction and vasorelaxation in rat vessels were eliminated after ovariectomy in females. Ovariectomy increased vessel vasoconstriction to norepinephrine more than twofold. Vasorelaxations by isoprenaline and a ß3-agonist were reduced after ovariectomy. Estrogen, but not progesterone substitution, restored sex-specific differences in vasoconstriction and vasorelaxation. Vascular mRNA levels of ß1- and ß3- but not ß2-adrenoreceptors were higher in vessels of females compared with males. Ovariectomy reduced these differences by decreasing ß1- and ß3- but not ß2-adrenoreceptor expression in females. Consistently, estrogen substitution restored ß1- and ß3-adrenoreceptor expression. Orchiectomy or testosterone treatment affected neither vasoconstriction and vasorelaxation nor ß-adrenoceptor expression in vessels of male rats. In human mammary arteries, sex-specific differences in vasoconstriction and vasorelaxation were reduced after removal of endothelium or treatment with l-NMMA. Vessels of women showed higher levels of ß1- and ß3-adrenoceptors than in men. In conclusion, the sex-specific differences in vasoconstriction and vasorelaxation are common for rat and human vessels. In rats, these differences are estrogen but not testosterone or progesterone dependent. Estrogen determines these differences via regulation of vascular endothelial ß1- and ß3-adrenoreceptor expression. NEW & NOTEWORTHY This study proposes a mechanistic concept regulating sex-specific differences in adrenergic vasoconstriction and vasorelaxation. Estrogen increases vascular ß1- and ß3-adrenoceptor expression in female rats. This and our previous studies demonstrate that these receptors are located primarily on endothelium and when activated by norepinephrine act via nitric oxide (NO). Therefore, ß-adrenergic stimulation leads to a more pronounced vasorelaxation in females. Coactivation of endothelial ß1- and ß3-adrenoreceptors leads to higher NO release in vessels of females, ultimately blunting vasoconstriction triggered by activation of smooth muscle α-adrenoceptors.
Subject(s)
Endothelium, Vascular/drug effects , Estradiol/administration & dosage , Estrogen Replacement Therapy , Mammary Arteries/drug effects , Receptors, Adrenergic, beta/metabolism , Vasoconstriction/drug effects , Vasodilation/drug effects , Vasomotor System/drug effects , Animals , Endothelium, Vascular/metabolism , Female , Humans , Male , Mammary Arteries/metabolism , Middle Aged , Orchiectomy , Ovariectomy , Progesterone/administration & dosage , Rats, Wistar , Receptors, Adrenergic, beta/genetics , Receptors, Adrenergic, beta-1/metabolism , Receptors, Adrenergic, beta-3/metabolism , Sex Factors , Signal Transduction , Testosterone Propionate/administration & dosage , Vasomotor System/metabolismABSTRACT
To close a gap between inpatient and outpatient care, the Hamburg Parkinson day-clinic (HPDC) has been developed as a new and comprehensive, individual, interdisciplinary type of treatment for patients with complex Parkinsonian syndromes (PS). First, we describe the HPDC concept, in which a multi-professional medical team of PD specialists provide a time- and personnel-wise intensive care and focuses on the patients' individual deficits and resources. Second, we present short-term outcome results of the first 184 PS patients enrolled during 16 months including objective clinical motor and non-motor scores taken before and after participation in the HPDC, as well as the patients' subjective evaluation of the HPDC. Out of the 184 patients with PS (aged 39-88 years with Hoehn and Yahr scores between 1.0 and 4.5), 169 were diagnosed to have Parkinson disease (PD). HPDC treatment led to improvement of all applied motor (UPDRS III, AIMS) and non-motor (BDI-II, MoCA, PDNMS, PDSS-2, King's PD Pain Scale, QUIP, PDQ-39) scores (p < 0.05) indicating benefits for akinesia, tremor, dyskinesia, cognition, sleep, pain, impulse control disorders and quality of life. Patients evaluated HPDC care positively with values from 1.39 to 2.79 ("very good" to "satisfying") with an overall grade of 1.69 ("good") on a 6-point Likert scale (1-6: best to worst). Patients with advanced PS benefit from the HPDC concept which is considered to close a gap between inpatient and outpatient care.
Subject(s)
Ambulatory Care/methods , Day Care, Medical/organization & administration , Outpatient Clinics, Hospital/organization & administration , Parkinson Disease/therapy , Adult , Aged , Aged, 80 and over , Combined Modality Therapy , Female , Germany , Humans , Interdisciplinary Communication , Male , Middle Aged , Parkinson Disease/nursing , Parkinson Disease/rehabilitation , Patient Care Team , Patient Reported Outcome Measures , Precision Medicine , Recovery of Function , Severity of Illness IndexABSTRACT
Evidence of sex-specific differences in renin-angiotensin-system (RAS) and arterial pressure has been shown in many mammals, including spontaneously hypertensive rats (SHRs). Although SHRs have been used extensively as a leading experimental model of hypertension, the effects of sex-specific differences in RAS on aortic function and related cardiac remodeling during aging and hypertension have not been documented in detail. We examined structural and functional changes in aorta and heart of female and male SHRs at the ages of 5, 14, 29, and 36 wk. SHRs of both sexes were hypertensive from 14 wk. Aortic endothelial dysfunction and fibrosis, left ventricular (LV) hypertrophy, and cardiac fibrosis were evident at the age of 29 wk in male SHRs but first appeared only at the age of 36 wk in female SHRs. There was a pronounced delay of matrix metalloproteinase-2 activity in the aorta and heart of female SHRs, which was associated with preservation of 40% more elastin and less extensive cardiac fibrosis than in males. At 5, 29, and 36 wk of age, female SHRs showed higher levels of aortic and myocardial AT2R and MasR mRNA and decreased ANG II-mediated aortic constriction. Although female SHRs had increased relaxation to AT2R stimulation at 5 and 29 wk compared with males, this difference disappeared at 36 wk of age. This study documents sex-specific differences in the temporal progression of aortic dysfunction and LV hypertrophy in SHRs, which are independent of arterial pressure and are apparently mediated by higher AT2R expression in the heart and aorta of female SHRs.
Subject(s)
Aging , Aortic Diseases/pathology , Aortic Diseases/physiopathology , Hypertension/pathology , Hypertension/physiopathology , Ventricular Remodeling , Animals , Aortic Diseases/etiology , Disease Progression , Female , Hypertension/complications , Male , Rats , Rats, Inbred SHR , Rats, Inbred WKY , Sex CharacteristicsABSTRACT
INTRODUCTION: Pallidal deep brain stimulation (DBS) has been shown to be effective in cervical dystonia (CD) with an improvement of about 50-60% in the Toronto Western Spasmodic Torticollis Rating (TWSTR) Scale. However, predictive factors for the efficacy of DBS in CD are missing with the anatomical location of the electrodes being one of the most important potential predictive factors. METHODS: In the present blinded observational study we correlated the anatomical localisation of DBS contacts with the relative clinical improvement (CI %) in the TWSTR as achieved by DBS at different pallidal contacts in 20 patients with CD. Localisations of DBS contacts were derived from postoperative MRI-data following anatomical normalisation into the standard Montreal Neurological Institute stereotactic space. The CIs following 76 bilateral test stimulations of 24â h were mapped to stereotactic coordinates of the corresponding bilateral 152 active contacts and were allocated to low CI (<30%; n=74), intermediate CI (≥30%; <60%; n=52) or high CI (≥60%; n=26). RESULTS: Euclidean distances between contacts and the centroid differed between the three clusters (p<0.001) indicating different anatomical variances between clusters. The Euclidean distances between contacts and the centroid of the cluster with high CIs correlated with the individual level of CIs (r=-0.61; p<0.0001). This relationship was best fitted with an exponential regression curve (r(2)=0.41). DISCUSSION: Our data show that the clinical effect of pallidal DBS on CD displays an exponential decay over anatomical distance from an optimised target localisation within a subregion of the internal pallidum. The results will allow a comparison of future DBS studies with postoperative MRI by verifying optimised (for instance pallidal) targeting in DBS-treated patients.
Subject(s)
Deep Brain Stimulation/methods , Globus Pallidus , Torticollis/therapy , Adult , Aged , Deep Brain Stimulation/instrumentation , Electrodes , Female , Globus Pallidus/anatomy & histology , Globus Pallidus/physiopathology , Humans , Magnetic Resonance Imaging/methods , Male , Middle Aged , Neuroimaging/methods , Torticollis/surgery , Treatment OutcomeABSTRACT
Chronic activation of angiotensin II (ANGII) and matrix metalloproteinase-2 (MMP-2) during hypertension contributes to increased aortic stiffness. We studied signalling mechanisms employed by ANGII in the regulation of latent (pro-) and active forms of MMP-2 in rat aortic endothelial and smooth muscle cells, along with isolated rat aorta. Using western blotting, we demonstrate that ANGII (1 µmol/L) significantly (P < 0.01) increases pro-MMP-2 protein expression after 8 h not only in endothelial and smooth muscle cells, but also in isolated rat aorta. We demonstrate that ANGII acts via AT1 receptor-activated cell-specific pathways. In endothelial cells, the JNK1/c-jun pathway is activated, whereas in smooth muscle cells, the JAK2/STAT3 pathway. Activation of JAK2/STAT3 pathway in response to ANGII was EGF receptor-dependent. Results obtained in cell culture are in agreement with the results obtained in isolated aorta. However, active MMP-2 was not found under cell culture conditions, whereas in isolated aorta, active MMP-2 was significantly (P < 0.05) increased after stimulation with ANGII, as detected by gelatine zymography. This increase of MMP-2 activity was not inhibited by blocking the pathways we identified to control pro-MMP-2 protein expression, but was abolished in the absence of endothelium. Our findings demonstrate that ANGII regulates pro-MMP-2 protein expression via cell-specific pathways in rat aorta. The endothelium may play an essential role in the activation of pro-MMP-2. These results may lead to new strategies for inhibiting MMP-2 expression and activity in distinct cell types of the aortic wall.
Subject(s)
Endothelial Cells/enzymology , Enzyme Precursors/metabolism , Gelatinases/metabolism , Matrix Metalloproteinase 2/metabolism , Muscle, Smooth, Vascular/enzymology , Myocytes, Smooth Muscle/enzymology , Angiotensin II/pharmacology , Angiotensin II Type 1 Receptor Blockers/pharmacology , Animals , Aorta/drug effects , Aorta/enzymology , Cells, Cultured , Dose-Response Relationship, Drug , Endothelial Cells/drug effects , Enzyme Activation , ErbB Receptors/metabolism , Janus Kinase 2/metabolism , Male , Mitogen-Activated Protein Kinase 8/metabolism , Muscle, Smooth, Vascular/drug effects , Myocytes, Smooth Muscle/drug effects , Proto-Oncogene Proteins c-jun/metabolism , Rats, Inbred WKY , Receptor, Angiotensin, Type 1/metabolism , STAT3 Transcription Factor/metabolism , Signal Transduction , Time Factors , Up-RegulationABSTRACT
OBJECTIVE: Blood vessels are an important tissue for allogenic vessel replacement surgery, which is needed for example following infection of artificial grafts. For tissue banking, European legislation requires evidence of tissue sterility with assays performed over 1 week. Currently, used cold storage solutions do not protect vascular function longer than 2 days. This does not allow completion of microbiological testing. This discrepancy has almost completely stopped vessel banking in Europe. METHODS: We compared the recently developed storage solution TiProtec (Dr F Köhler Chemie, Bensheim, Germany) with traditionally used histidine-tryptophan-ketoglutarate (HTK) solution, 0.9% NaCl, and phosphate-buffered saline (physiological saline solution [PSS]) solution for extended cold (4°C) storage up to 25 days. Isolated rings of human internal mammary artery were studied with respect to several parameters of vessel function, including vessel tone development, endothelium-dependent and endothelium-independent relaxation, and tissue reductive capacity. RESULTS: Vessels stored in NaCl or PSS for ≥10 hours failed to develop tone after rewarming. Mammary arteries stored in HTK for 4 hours at 4°C initially showed a well-preserved vessel function with respect to vessel tone development, as well as endothelial and smooth muscle dilatative function. However, following 4 days of cold storage, vessel tone development and dilatative responses were significantly impaired. In contrast, arteries stored in TiProtec showed full preservation of vessel tone as well as endothelial and smooth muscle function after 4 days of cold storage. Even after 10 days of cold storage, endothelium-dependent relaxation was approximately 50% of control, and smooth muscle function was fully preserved. Over 2 weeks, tissue reductive capacity was significantly better maintained after cold storage in TiProtec compared with vessels stored in NaCl. CONCLUSIONS: In contrast to traditional HTK, NaCl, or PSS storage, TiProtec solution offers an excellent potential for prolonged cold storage of human arteries, which may close the existing gap between legal requirements for tissue banking and current cold preservation methods.
Subject(s)
Cold Temperature , Mammary Arteries/transplantation , Organ Preservation Solutions , Tissue Preservation/methods , Aged , Apoptosis , Dose-Response Relationship, Drug , Female , Humans , Male , Mammary Arteries/drug effects , Mammary Arteries/metabolism , Middle Aged , Mitochondria/metabolism , Oxidation-Reduction , Poly(ADP-ribose) Polymerases/metabolism , Time Factors , Vasoconstriction , Vasoconstrictor Agents/pharmacology , Vasodilation/drug effects , Vasodilator Agents/pharmacologyABSTRACT
Alternative splicing and the expression of intron-containing mRNAs is one hallmark of HIV gene expression. To facilitate the otherwise hampered nuclear export of non-fully processed mRNAs, HIV encodes the Rev protein, which recognizes its intronic response element and fuels the HIV RNAs into the CRM-1-dependent nuclear protein export pathway. Both alternative splicing and Rev-dependency are regulated by the primary HIV RNA sequence. Here, we show that these processes are extremely sensitive to sequence alterations in the 5'coding region of the HIV genomic RNA. Increasing the GC content by insertion of either GFP or silent mutations activates a cryptic splice donor site in gag, entirely deregulates the viral splicing pattern, and lowers infectivity. Interestingly, an adaptation of the inserted GFP sequence toward an HIV-like nucleotide bias reversed these phenotypes completely. Of note, the adaptation yielded completely different primary sequences although encoding the same amino acids. Thus, the phenotypes solely depend on the nucleotide composition of the two GFP versions. This is a strong indication of an HIV-specific mRNP code in the 5' gag region wherein the primary RNA sequence bias creates motifs for RNA-binding proteins and controls the fate of the HIV-RNA in terms of viral gene expression and infectivity.
Subject(s)
HIV-1/genetics , RNA Splicing , Virus Replication/genetics , gag Gene Products, Human Immunodeficiency Virus/genetics , Alternative Splicing , HEK293 Cells , HIV Infections/virology , HIV-1/pathogenicity , Humans , RNA Splice Sites , RNA, Messenger , RNA, Viral/geneticsABSTRACT
BACKGROUND: Cold storage of arteries for reconstructive and bypass surgery may result in injury of endothelial cells which may promote low perfusion and graft vasculopathy. METHODS: A recently developed N-acetyl histidine-buffered, potassium-chloride enriched, and amino acid-fortified vascular storage solution augmented with iron chelators deferoxamine (100 micromol/L) and LK 614 (20 micromol/L) was studied in the rat superior mesenteric artery and aorta with respect to: (1) potassium-induced vessel tone, (2) endothelium-dependent and -independent relaxation, and (3) endothelial nitric oxide synthase (eNOS) protein expression over 4-days cold storage (4 degrees C).This solution was compared with traditional storage solutions, histidine-tryptophan-ketoglutarate (HTK) and physiological saline solution (PSS). RESULTS: Vessels stored for 4 days in the new solution were significantly better protected than those stored in traditional HTK or PSS. The protective effects comprised: (1) vessel tone development after stimulation with potassium-chloride solution, (2) endothelium-dependent and -independent vessel relaxation, and (3) eNOS expression. With iron chelators (deferoxamine 100 microM, LK 614 20 microM) present in the storage solution, endothelium-dependent relaxations (eNOS-dependent and K(Ca)-channel-dependent) were fully maintained after 96 hours of cold storage. Endothelial cell structure was significantly better maintained after 96 hours in the new solution than in HTK or PSS solutions. Already, 2 hours of cold storage in HTK resulted in a significant loss of structurally intact endothelium. The structural changes correlated significantly with the diminished vessel relaxation capacity. Furthermore, tissue reductive capacity was only preserved after 96 hours storage if the new solution was used. CONCLUSION: The new storage solution is superior to traditional HTK and PSS cold storage with respect to: (1) preservation of vessel structure and function; (2) the presence of iron chelators significantly improved protection of endothelial function; and (3) the new solution permits cold vessel storage for a minimum of 4 days with full maintenance of endothelial function and its coupling to smooth muscle.
Subject(s)
Aorta , Cold Temperature , Mesenteric Artery, Superior , Organ Preservation Solutions/pharmacology , Organ Preservation/methods , Amino Acids/pharmacology , Analysis of Variance , Animals , Bayes Theorem , Chi-Square Distribution , Deferoxamine/pharmacology , Histidine/pharmacology , Ketoglutaric Acids/pharmacology , Nitric Oxide Synthase/pharmacology , Potassium Chloride/pharmacology , Rats , Sodium Chloride/pharmacology , Tryptophan/pharmacology , Vasodilation/drug effectsABSTRACT
The present data are related to the research article entitled "Whey peptide isoleucine-tryptophan inhibits expression and activity of matrix metalloproteinase-2 in rat aorta" [1]. Here we present data on removal of endothelium from aorta, endothelium dependent aortic relaxation and inhibition of expression of pro-MMP2 by di-peptide isoleucine-tryptophan (IW). Experiments were performed in rat aortic endothelial cells (EC) and smooth muscle cells (SMC) in vitro, along with isolated rat aorta ex vivo. The cells and isolated aorta were stimulated with angiotensin II (ANGII) or angiotensin I (ANGI). ACE activity was inhibited by treatment with either IW or captopril (CA). Losartan was used as a blocker of angiotensin type-1 receptor. IW inhibited MMP2 protein expression induced with ANGI in a dose-dependent manner. IW was effective both in ECs and SMCs, as well as in isolated aorta. Similarly, captopril (CA) inhibited ANGI-induced MMP2 protein expression in both in vitro and ex vivo. Neither IW nor CA inhibited ANGII-induced MMP2 protein expression in contrast to losartan. The data also displays that removal of endothelium in isolated rat aorta abolished the endothelium-dependent relaxation induced with acetylcholine. However, SMC-dependent relaxation induced with sodium nitroprusside remained intact. Finally, the data provides histological evidence of selective removal of endothelial cells from aorta.
ABSTRACT
Aortic stiffness is an independent risk factor for development of cardiovascular diseases. Activation of renin-angiotensin-aldosterone system (RAAS) including angiotensin converting enzyme (ACE) activity leads to overproduction of angiotensin II (ANGII) from its precursor angiotensin I (ANGI). ANGII leads to overexpression and activation of matrix metalloproteinase-2 (MMP2), which is critically associated with pathophysiology of aortic stiffness. We previously reported that the whey peptide Isoleucine-Tryptophan (IW) acts as a potent ACE inhibitor. Herein, we critically elucidate the mechanism of action by which IW causes inhibition of expression and activity of MMP2 in aortic tissue. Effects of IW on expression and activity of MMP2 were assessed on endothelial and smooth muscle cells (ECs and SMCs) in vitro and ex vivo (isolated rat aorta). As controls we used the pharmaceutical ACE inhibitor - captopril and the ANGII type 1 receptor blocker - losartan. In vitro, both ANGII and ANGI stimulation significantly (P<0.01) increased expression of MMP2 assessed with western blot. Similarly, to captopril IW significantly (P<0.05) inhibited ANGI, but not ANGII mediated increase in expression of MMP2, while losartan also blocked effects of ANGII. Signaling pathways regulating MMP2 expression in ECs and SMCs were similarly inhibited after treatment with IW or captopril. In ECs IW significantly (P<0.05) inhibited JNK pathway, whereas in SMCs JAK2/STAT3 pathway, assessed with western blot. In vitro findings were fully consistent with results in isolated rat aorta ex vivo. Moreover, IW not only inhibited the MMP2 expression, but also its activation assessed with gelatin zymography. Our findings demonstrate that IW effectively inhibits expression and activation of MMP2 in rat aorta by decreasing local conversion of ANGI to ANGII. Thus, similar to pharmaceutical ACE inhibitor captopril the dipeptide IW may effectively inhibit ACE activity and prevent the age and hypertension associated rise of aortic stiffness.
Subject(s)
Dipeptides/chemistry , Hypertension/drug therapy , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase Inhibitors/chemistry , Whey Proteins/chemistry , Angiotensin II/metabolism , Angiotensin-Converting Enzyme Inhibitors/chemistry , Angiotensin-Converting Enzyme Inhibitors/isolation & purification , Angiotensin-Converting Enzyme Inhibitors/metabolism , Animals , Dipeptides/administration & dosage , Dipeptides/isolation & purification , Disease Models, Animal , Gene Expression Regulation, Enzymologic/drug effects , Humans , Hypertension/metabolism , Losartan/administration & dosage , Matrix Metalloproteinase Inhibitors/administration & dosage , Matrix Metalloproteinase Inhibitors/isolation & purification , Rats , Renin-Angiotensin System/drug effects , Vascular Stiffness/drug effects , Whey Proteins/administration & dosage , Whey Proteins/isolation & purificationABSTRACT
AIMS: Aortic stiffness is an independent risk factor for progression of cardiovascular diseases. Degradation of elastic fibres in aorta due to angiotensin II (ANGII)-stimulated overactivation of latent membrane type 1 matrix metalloproteinase (MT1MMP) and matrix metalloproteinase-2 (MMP2) is regarded to represent an important cause of aortic stiffness. Therefore, clarification of the causal mechanisms triggering the overactivation of these MMPs is of utmost importance. This study addresses the endothelium as a novel key activator of latent pro-MT1MMP and pro-MMP2 in rat aorta. METHODS AND RESULTS: Using a co-culture model of rat aortic endothelial cells (ECs) and smooth muscle cells (SMCs), we found that ANGII stimulation resulted in activation of latent pro-MT1MMP and pro-MMP2 in SMCs exclusively when co-cultured with ECs (assessed with western blot and gelatin zymography, respectively). EC-specific AT1 receptor stimulation triggered endothelin-1 release and paracrine action on SMCs. Endothelin-1 increased expression and activity of pro-protein convertase furin in SMCs via endothelin receptor type A (assessed with qPCR and furin activity assay, respectively). Consequently, furin acted in two ways. First, it increased the activation of latent pro-MT1MMP and, second, it activated pro-αvß3 integrin. Both pathways led to overactivation of latent pro-MMP2. In vitro findings in the co-culture model were fully consistent with the ex vivo findings obtained in isolated rat aorta. CONCLUSIONS: We propose that the endothelium under ANGII stimulation acts as a novel and key activator of latent pro-MT1MMP and pro-MMP2 in SMCs of rat aorta. Therefore, endothelium may critically contribute to pathophysiology of aortic stiffness.
Subject(s)
Aorta/metabolism , Endothelial Cells/metabolism , Endothelin-1/metabolism , Matrix Metalloproteinase 14/metabolism , Matrix Metalloproteinase 2/metabolism , Muscle, Smooth, Vascular/metabolism , Animals , Cells, Cultured , Coculture Techniques , Endothelium/metabolism , Myocytes, Smooth Muscle/metabolism , RatsABSTRACT
BACKGROUND AND PURPOSE: We investigated whether transient ischemic attacks (TIAs) before stroke can induce tolerance by raising the threshold of tissue vulnerability in the human brain. METHODS: Sixty-five patients with first-ever ischemic territorial stroke received diffusion- and perfusion-weighted MRI within 12 hours of symptom onset. Epidemiological and clinical data, lesion volumes in T2, apparent diffusion coefficient (ADC) maps and perfusion maps, and cerebral blood flow and cerebral blood volume values were compared between patients with and without a prodromal TIA. RESULTS: Despite similar size and severity of the perfusion deficit, initial diffusion lesions tended to be smaller and final infarct volumes were significantly reduced (final T2: 9.1 [interquartile range, 19.7] versus 36.5 [91.2] mL; P=0.014) in patients with a history of TIA (n=16). This was associated with milder clinical deficits. CONCLUSIONS: The beneficial effect of TIAs on lesion size in ADC and T2 suggests the existence of endogenous neuroprotection in the human brain.
Subject(s)
Brain Ischemia/diagnosis , Brain/blood supply , Ischemic Attack, Transient/diagnosis , Ischemic Preconditioning/statistics & numerical data , Stroke/diagnosis , Blood Flow Velocity , Brain/pathology , Brain Ischemia/epidemiology , Cerebrovascular Circulation , Comorbidity/trends , Diffusion Magnetic Resonance Imaging , Disease Progression , Disease Susceptibility/epidemiology , Female , Germany/epidemiology , Hospitals, University/statistics & numerical data , Humans , Ischemic Attack, Transient/epidemiology , Ischemic Preconditioning/trends , Magnetic Resonance Angiography , Male , Middle Aged , Retrospective Studies , Risk Factors , Stroke/epidemiologyABSTRACT
BACKGROUND AND PURPOSE: Using perfusion- and diffusion-weighted MR imaging in acute ischemic stroke of the middle cerebral artery (MCA), previous studies have shown a typical pathophysiologic pattern that is characterized by a perfusion deficit larger than the diffusion lesion (mismatch), with the final lesion usually comprising the initial diffusion lesion (core) plus parts of the initial mismatch area. Little is known about underlying pathophysiology in small ischemic stroke. In this study, we used perfusion- and diffusion-weighted MR imaging to investigate the underlying pathophysiology of small subcortical ischemia. METHODS: Six consecutive patients (age range, 42-76 years) with small subcortical ischemia were examined by using a 1.5-T MR system 2-5, 22-55, and 144-392 hours after the onset of symptoms. T2-weighted, diffusion-weighted imaging at b=0 s/mm2 and b=1000 s/mm2, and bolus-track perfusion-weighted imaging were performed. Lesion sizes were determined on the basis of T2-weighted findings as well as those of apparent diffusion coefficient (ADC) maps and CBF. RESULTS: In every patient, the initial CBF lesion was smaller than the initial ADC lesion. Both the CBF lesion and the ADC lesion increased in size from first to second examination. In all instances, however, the CBF lesion remained smaller than the ADC lesion. The CBF lesion observed during the acute phase and the one seen on the following days were both smaller than the final T2 lesion. CONCLUSION: Our data suggest that in contrast to previous findings in MCA ischemia in small subcortical infarcts tissue damage may spread beyond the area of the initial perfusion disturbance. In light of the small number of patients, further studies will have to address the relevance of this observation.
Subject(s)
Brain Ischemia/diagnosis , Cerebral Infarction/diagnosis , Diffusion Magnetic Resonance Imaging , Magnetic Resonance Angiography , Adult , Aged , Brain Ischemia/pathology , Brain Ischemia/physiopathology , Cerebral Infarction/pathology , Cerebral Infarction/physiopathology , Cerebrovascular Circulation/physiology , Female , Germany , Humans , Male , Middle Aged , Prospective StudiesABSTRACT
In 2009, a study group of three Saxon hospitals set up a Saxon register with the aim of including all patients with bisphosphonate (BP) medication. In addition, specific concepts for surgical approach were developed. The target is to define relevant treatment and prevention strategies of bisphosphonate-related osteonecrosis of the jaws (BRONJ) based on high patient population statistics. Since July 2009, all patients with oral or intravenous BP medication have been registered in the 3 Saxon hospitals. Data was systematically acquired in detailed forms. Totally, 258 patients (â: 83, â: 175) were registered by October 2010. 100 patients out of this already had BRONJ which preferably affected the mandible (70%) and was mostly associated with intravenous medication. In 54 cases, treatment was carried out by surgery according to the strategy developed. The criterion for success was absence of symptoms at least for 3 months after surgery. The following stage-dependent success rates were obtained: stage I (13 patients) - 84.6%, stage II (22 patients) - 95.5%, stage III (14 patients) - 85.7%, stage IV (5 patients) - 80%. Under preventive aspects, teeth were extracted after a predefined scheme in 68 of all patients registered as being asymptomatic. No BRONJ was observed in 98.5%; the criterion also being absence of symptoms for a minimum period of 3 months after surgery. Surgical treatment is the treatment of choice in cases of BRONJ. Tooth extractions are rather unproblematic in asymptomatic patients if the predefined scheme is followed.
Subject(s)
Bisphosphonate-Associated Osteonecrosis of the Jaw/surgery , Bone Density Conservation Agents/adverse effects , Diphosphonates/adverse effects , Tooth Extraction , Administration, Oral , Bisphosphonate-Associated Osteonecrosis of the Jaw/prevention & control , Bone Density Conservation Agents/administration & dosage , Diphosphonates/administration & dosage , Female , Humans , Injections, Intravenous , Male , Prospective Studies , Treatment OutcomeABSTRACT
External and internal features of the male postabdomen of Tetraphalerus bruchi were examined with a broad spectrum of morphological techniques and are described in detail. The conditions found in males of Tetraphalerus are compared to those in other archostematan beetles and members of other coleopteran suborders. The far-reaching reduction of the sternite I, structural modifications of sternite II, the retracted condition of the terminal segments, and ventromedially fused apodemes arising from the anterior margin of tergite IX are likely autapomorphies of Coleoptera. The male postabdomen of Tetraphalerus is less derived than in most other groups of Coleoptera. The sclerotized elements are symmetrical. In contrast to earlier statements on the archostematan male genital apparatus a distinctly developed, sclerotized basal piece is present. The aedeagus is trilobed and all elements of the copulatory apparatus are distinct. The muscular equipment is simple and moderately developed. All muscles (except the transverse muscles 61 and 62) occur pairwise and symmetrically. The distinct increase of the number of postabdominal muscles in representatives of the higher lineages of Coleoptera is likely linked with a torsion of the copulatory apparatus, which also results in asymmetries of the sclerotised parts. The testes of Tetraphalerus are long, multi-coiled tubes like in other archostematans, Myxophaga (Torridincola) and Adephaga. The presence of a deep notch on the parameres is a synapomorphy of Tetraphalerus and Omma. Curved parameres, a shortened distal portion, and a distinctly shortened penis are potential synapomorphies of Omma rutherfordi and Omma mastersi. The large size of the sclerotized part of the phallobase ('basal piece') and the division of the sclerotization of sternum IX are potential ground-plan autapomorphies of Archostemata, with secondary modification of the latter feature in Cupedidae. The reduced condition of the sclerotization of sternum VIII is an apomorphic condition which has likely evolved independently in Tetraphalerus and Paracupes. Further anatomical investigation of the male genital apparatus of Coleoptera and holometabolous insects in general is required for a reliable morphological and phylogenetic interpretation. Concerning the presence or absence of particular sclerotizations (e.g., 'basal piece' of phallobase) histological section series and Confocal Laser Scanning Microscopy can add more precise information to what can be observed using permanent preparations of macerated specimens.
Subject(s)
Coleoptera/ultrastructure , Abdomen/anatomy & histology , Animals , Coleoptera/anatomy & histology , Coleoptera/classification , Genitalia, Male/anatomy & histology , Genitalia, Male/ultrastructure , Male , PhylogenyABSTRACT
For longitudinal studies in patients suffering from cerebrovascular diseases the poor reproducibility of perfusion measurements via dynamic susceptibility-weighted contrast-enhanced MRI (DSC-MRI) is a relevant concern. We evaluate a novel algorithm capable of overcoming limitations in DSC-MRI caused by partial volume and saturation issues in the arterial input function (AIF) by a blood flow stimulation-study. In 21 subjects, perfusion parameters before and after administration of blood flow stimulating L-arginine were calculated utilizing a block-circulant singular value decomposition (cSVD). A total of two different raters and three different rater conditions were employed to select AIFs: Besides 1) an AIF selection by an experienced rater, a beginner rater applied a steady state-oriented strategy, returning; 2) raw; and 3) corrected AIFs. Highly significant changes in regional cerebral blood flow (rCBF) by 9.0% (P < 0.01) could only be found when the AIF correction was performed. To further test for improved reproducibility, in a subgroup of seven subjects the baseline measurement was repeated 6 weeks after the first examination. In this group as well, using the correction algorithm decreased the SD of the difference between the two baseline measurements by 42%.
Subject(s)
Cerebrovascular Circulation/physiology , Magnetic Resonance Imaging/methods , Algorithms , Arginine/pharmacology , Humans , Image Enhancement , Perfusion , Reproducibility of ResultsSubject(s)
Brain/blood supply , Brain/physiology , Cerebrovascular Circulation/physiology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Leukoaraiosis/drug therapy , Translational Research, Biomedical , Aged , Brain/drug effects , Cerebrovascular Circulation/drug effects , Female , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Leukoaraiosis/physiopathology , Male , Middle Aged , Translational Research, Biomedical/methodsABSTRACT
In the human, visually evoked potentials (VEP) and cerebral oxygenation changes, as measured by near-infrared spectroscopy (NIRS), are assessed to elucidate the relation between electrophysiological and vascular responses to a checkerboard stimulus reversing at 3 Hz. Habituation of either response is analysed on two time scales. Within the 1-min stimulation period we find a decrease in P100N135-component amplitude, closely coupled to a decrease in the amplitude of the oxygenation parameters (concentration changes in oxygenated and deoxygenated haemoglobin, [oxy-Hb] and [deoxy-Hb]). The N75P100-component amplitude exhibits a different behaviour along the 1-min stimulation period. An initial increase is overridden by an overall decrease, the latter not reaching statistical significance. The analysis across the 13 successive stimulation blocks separated by resting periods of equal duration yields a trend for an decrease in the VEP-components' amplitude, not reflected in the vascular response. When calculating a ratio between the amplitude of the P100N135-component and the concentration changes in the haemoglobins a "coupling index" of a 0.2 microM decrease in [deoxy-Hb] and an increase of 0.6 microM in [oxy-Hb] is found per 1 microV increase in VEP-component amplitude. The ratio is the same irrespective of its assessment from the difference stimulation/ rest or from the habituation effect, i.e., the difference between the amplitudes at the beginning and towards the end of the stimulation period. Although supporting the notion that the coupling between neuronal activation and the vascular response exhibits linear aspects, our findings cannot be taken as a proof of such a linearity across all brain regions and activation types. On the contrary, tentatively calculating a coupling index for the data assessed in the visual system, we intend to stress the necessity to assess both neuronal and vascular response to allow for a comparison between different systems and conditions in whom neurovascular coupling is expected to be altered (Miller et al, 2001; Mechelli et al, 2001).