Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Monocular pattern-shift visual evoked potentials were obtained in (i) 33 patients with unilateral non-hemorrhagic hemispheric infarction (age 50-79 years; 23 males, 10 females), (ii) 21 age- and sex-matched patient controls (control group or CGI) with no remote or recent stroke, normal neurological examination and similar incidence of diabetes mellitus, hypertension and heart disease, and (iii) 21 age- and sex-matched healthy elderly community volunteers (CGII). Subjects with history of glaucoma, cataracts, other media opacities or symptomatic retinal lesions were not considered or included in any of the 3 study groups. In addition, all subjects in each of the 3 groups had a normal ocular and fundoscopic examination. The mean interocular P100 latency difference in the stroke group was significantly greater than that in CGI or II (P less than 0.01). The mean interocular P100 amplitude ratio (small P100/large P100) in the stroke subjects was significantly different from that of CGI or II (P less than 0.02). The mean P100 latency on ocular stimulation ipsilateral to the side of infarction was significantly longer than that of either left or right ocular stimulation in CGI or II (P less than 0.01). The mean P100 latency on ocular stimulation contralateral to the side of infarction was similarly but less significantly longer than that on left or right ocular stimulation in CGI or II (P less than 0.05). Evidence of anterior visual pathway dysfunction was thus elicited in the stroke population using the technique.
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PMID:Monocular pattern-shift visual evoked potentials in hemispheric strokes. 620 51

Evaluation of therapeutic efficacy in neurologic rehabilitation is methodologically limited by the well established polypragmasia and the lack of untreated controls. Controversial discussion is generated by the following topics: superiority of specific therapy versus spontaneous recovery, higher efficacy of in-patient-setting versus out-patient-setting and the value of neurorehabilitation treatment in latency of more than 1 year after the event. To develop a practicable method for the evaluation of efficacy, we surveyed retrospectively 30 patients after stroke in a sequential study design on 4 scheduled visits: first admission to in-patient rehabilitation, discharge to out-patient treatment, admission and discharge of second in-patient rehabilitation. Impairment, disability and handicap were documented by NIH-Stroke Scale, Barthel-Index, CGI, WWK-Pflegeskala N and Risk-Profile. A descriptive data-analysis implies a therapeutic gain of stroke rehabilitation in-patient setting which is apparently superior to out-patient treatment. A measurable therapeutic effect was evident even more than one year after the stroke.
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PMID:[Validating rehabilitation after stroke]. 785 4

Depression is a common but often unrecognized complication after cerebrovascular stroke. Tricyclic antidepressants (TCA) have been found to be effective in poststroke depression, but side effects such as orthostatic hypotension, arrhythmia limit their wider use. In this pilot study the effects of treatment with the specific serotonin reuptake inhibitor (SSRI) fluoxetine (20 mg) in 10 severely depressed patients (HAM-D score between 27 and 35) after cerebrovascular stroke were investigated. Four patients dropped out of the study prematurely because of worsening of their condition (n = 4) and one patient discontinued the study because of transfer to a nursing home. After 3 weeks of fluoxetine treatment there was a significant amelioration in all the measured scores (HAM-D, Beck, CGI and Barthel: P < 0.05). At the end of the study one patient with recurrent cerebrovascular lesions still had an HAM-D score of 25, but the other four patients had HAM-D scores between 6 and 11. The physical rehabilitation scores measured with the Barthel Index showed negative correlations with the HAM-D, Beck and CGI scores for most items; this has to be interpreted with caution considering the number of patients involved in this investigation. The authors suggest that future double blind trials are warranted to test the efficacy of fluoxetin therapy for poststroke depression. Methodological problems in connection with pharmacological trials in these severely ill patients are discussed.
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PMID:[Therapy of post-stroke depression with fluoxetine. A pilot project]. 867 90

We are studying a Turkish family with autosomal-dominant hypertension and brachydactyly; affected persons die of stroke before 50 years of age. With interphase fluorescence in situ hybridization, we found a chromosome 12p deletion, reinsertion, and inversion in affected persons. This finding suggested that the hypertension could be caused by one or more of 3 genes, the ATP-dependent potassium channel Kir6.1, its regulator the sulfonyl urea receptor SUR2, and the phosphodiesterase PDE3A. We further studied 6 affected and 4 nonaffected persons. Buttocks biopsies were done, small vessels were tested on a myograph, and mRNA was extracted. We performed forearm blood flow studies with intrabrachial artery diazoxide, isoproterenol, and milrinone infusions. Systemic pharmacological testing was done with intravenous diazoxide, nitroprusside, and isoproterenol. PDE3A mRNA was high in vessels from 3 affected subjects, but not high in 3 others. The vessels responded similarly to forskolin, with or without glibenclamide, and to cromakalim. However, there was a suggestion that the dilatation after milrinone might be exaggerated. The forearm infusion studies showed no differences in the responses to diazoxide, isoproterenol, or milrinone. Systemically, affected persons showed a greater blood pressure response to diazoxide and nitroprusside, and a greater heart rate response to isoproterenol than nonaffected persons. The results shed doubt on Kir6.1 and SUR2. The differences in PDE3A expression and responses may be the result of hypertension rather than the cause. Although our 3 candidate genes are no longer likely, the rearrangement we describe greatly enhances the perspectives of this project.
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PMID:Autosomal-dominant hypertension with type E brachydactyly is caused by rearrangement on the short arm of chromosome 12. 1470 63

Ibudilast is widely used in Japan to treat ischemic stroke and bronchial asthma. Its mode of action is through the inhibition of cyclic nucleotide phosphodiesterases (PDEs). Growing evidence suggests this compound has utility in a range of neurological conditions linked to its ability to elevate cellular cyclic nucleotide concentrations, however limited data exists on Ibudilast's action on individual PDE families. We therefore used an extensive panel of human PDE enzymes to define the PDE inhibitory profile of this compound. Ibudilast preferentially inhibits PDE3A, PDE4, PDE10 and PDE11 with lesser inhibition of a number of other families. The significance of these findings is discussed in relation to Ibudilast's observed effects on certain disease states.
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PMID:The inhibitory profile of Ibudilast against the human phosphodiesterase enzyme family. 1667 36

Cardiovascular disease is the most common cause of death worldwide, and hypertension is the major risk factor. Mendelian hypertension elucidates mechanisms of blood pressure regulation. Here we report six missense mutations in PDE3A (encoding phosphodiesterase 3A) in six unrelated families with mendelian hypertension and brachydactyly type E (HTNB). The syndrome features brachydactyly type E (BDE), severe salt-independent but age-dependent hypertension, an increased fibroblast growth rate, neurovascular contact at the rostral-ventrolateral medulla, altered baroreflex blood pressure regulation and death from stroke before age 50 years when untreated. In vitro analyses of mesenchymal stem cell-derived vascular smooth muscle cells (VSMCs) and chondrocytes provided insights into molecular pathogenesis. The mutations increased protein kinase A-mediated PDE3A phosphorylation and resulted in gain of function, with increased cAMP-hydrolytic activity and enhanced cell proliferation. Levels of phosphorylated VASP were diminished, and PTHrP levels were dysregulated. We suggest that the identified PDE3A mutations cause the syndrome. VSMC-expressed PDE3A deserves scrutiny as a therapeutic target for the treatment of hypertension.
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PMID:PDE3A mutations cause autosomal dominant hypertension with brachydactyly. 2596 42

Autosomal-dominant hypertension with brachydactyly is a salt-independent Mendelian syndrome caused by activating mutations in the gene encoding phosphodiesterase 3A. These mutations increase the protein kinase A-mediated phosphorylation of phosphodiesterase 3A resulting in enhanced cAMP-hydrolytic affinity and accelerated cell proliferation. The phosphorylated vasodilator-stimulated phosphoprotein is diminished, and parathyroid hormone-related peptide is dysregulated, potentially accounting for all phenotypic features. Untreated patients die prematurely of stroke; however, hypertension-induced target-organ damage is otherwise hardly apparent. We conducted clinical studies of vascular function, cardiac functional imaging, platelet function in affected and nonaffected persons, and cell-based assays. Large-vessel and cardiac functions indeed seem to be preserved. The platelet studies showed normal platelet function. Cell-based studies demonstrated that available phosphodiesterase 3A inhibitors suppress the mutant isoforms. However, increasing cGMP to indirectly inhibit the enzyme seemed to have particular use. Our results shed more light on phosphodiesterase 3A activation and could be relevant to the treatment of severe hypertension in the general population.
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PMID:Clinical effects of phosphodiesterase 3A mutations in inherited hypertension with brachydactyly. 2628 42

Autosomal-dominant hypertension and brachydactyly syndrome (HTNB; Bilginturan syndrome) is known to cause stroke before age 50 when untreated. We report a novel PDE3A gene mutation in a mother and daughter affected with dominant brachydactyly of the hands and feet, a short stature, and hypertension. The hypertension was medically responsive to anti-hypertensive treatment. The 3-bp deletion in the PDE3A gene presented de novo in the mother. Here, we expand the list of PDE3A mutations identified in Bilginturan syndrome and emphasize the importance of standardized genetic testing of HTNB patients to improve diagnostics at an early age. We recommend extended phenotyping in patients with brachydactyly, a short stature or hypertension in clinical practice.
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PMID:PDE3A gene screening improves diagnostics for patients with Bilginturan syndrome (hypertension and brachydactyly syndrome). 3020 82

Endothelial dysfunction is a key element in cerebral small vessel disease (CSVD), which may cause stroke and cognitive decline. Cyclic nucleotide signaling modulates endothelial function. The cyclic adenosine monophosphate-degrading enzyme phosphodiesterase 3 (PDE3) is an important treatment target which may be modulated by microRNAs (miRNAs) important for regulating gene expression. We aimed to identify PDE3-targeting miRNAs to highlight potential therapeutic targets for endothelial dysfunction and CSVD. PDE3-targeting miRNAs were identified by in silico analysis (TargetScan, miRWalk, miRanda, and RNA22). The identified miRNAs were ranked on the basis of TargetScan context scores and their expression (log2 read counts) in a human brain endothelial cell line (hCMEC/D3) described recently. miRNAs were subjected to co-expression meta-analysis (CoMeTa) to create miRNA clusters. The pathways targeted by the miRNAs were assigned functional annotations via the KEGG pathway and COOL. hCMEC/D3 cells were transfected with miRNA mimics miR-27a-3p and miR-222-3p, and the effect on PDE3A protein expression was analyzed by Western blotting. Only PDE3A is expressed in hCMEC/D3 cells. The in silico prediction identified 67 PDE3A-related miRNAs, of which 49 were expressed in hCMEC/D3 cells. Further analysis of the top two miRNA clusters (miR-221/miR-222 and miR-27a/miR-27b/miR-128) indicated a potential link to pathways relevant to cerebral and vascular integrity and repair. hCMEC/D3 cells transfected with miR-27a-3p and miR-222-3p mimics had reduced relative expression of PDE3A protein. PDE3A-related miRNAs miR-221/miR-222 and miR-27a/miR-27b/miR-128 are potentially linked to pathways essential for immune regulation as well as cerebral and vascular integrity/function. Furthermore, relative PDE3A protein expression was reduced by miR27a-3p and miR-222-3p.
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PMID:miRNA-27a-3p and miRNA-222-3p as Novel Modulators of Phosphodiesterase 3a (PDE3A) in Cerebral Microvascular Endothelial Cells. 3060 56

Hypertension and brachydactyly syndrome (HTNB; MIM 112410) is a rare, recently described, autosomal dominant syndromic disease characterized by the triad of brachydactyly type E (BDE), short stature, and hypertension. HTNB is caused by a heterozygous mutation in the PDE3A (MIM 123805) gene on chromosome 12p12; this gene encodes a member of the cGMP-inhibited cyclic nucleotide phosphodiesterase family. PED3A plays a role in many signal transduction pathways, including those involved in vascular smooth muscle proliferation and contraction, cardiac contractility, platelet aggregation, and hormone secretion. Here, we present a new case of HTNB in a 42-year-old patient who experienced recurrent ischemic strokes in various vascular territories; these strokes were caused by intracranial multiarterial dissection, and were experienced for 2 weeks. She was found to harbor a de novo heterozygous in-frame deletion, c.1333_1335del p.(Thr445del), in exon 4 of the PDE3A gene. Our finding is expected to contribute to the elucidation of the pathophysiology of stroke in HTNB patients. We further review all clinical and molecular genetic features of this rare disease described in the literature to date.
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PMID:PDE3A variant associated with hypertension and brachydactyly syndrome in a patient with ischemic stroke caused by spontaneous intracranial artery dissection: A review of the clinical and molecular genetic features. 3158 36


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