High pressure induces superoxide production in isolated arteries viaprotein kinase C-dependent activation of NAD(P)H oxidase

Background - Oxidative stress seems to be present in all forms of hypertension. Thus, we tested the hypothesis that high intraluminal pressure (P-i) itself, by activating vascular oxidases, elicits increased superoxide (O-2(.-)) production interfering with flow-induced dilation. Methods and Results - Isolated, cannulated rat femoral arterial branches were exposed in vitro ( for 30 minutes) to normal P-i (80 mm Hg) or high P-i (160 mm Hg). High P-i significantly increased vascular O-2(.-) production ( as measured by lucigenin chemiluminescence and ethidium bromide fluorescence) and impaired endothelium-dependent dilations to flow; these effects could be reversed by superoxide dismutase. Administration of the NAD(P)H oxidase inhibitor diphenyleneiodonium, apocynin, the protein kinase C (PKC) inhibitor chelerythrine or staurosporin or the removal of extracellular Ca2+ during high P-i treatment prevented the increases in O-2(.-) production, whereas administration of losartan or captopril had no effect. High P-i resulted in significant increases in intracellular Ca2+ ([Ca2+](i)) in the vascular wall ( fura 2 fluorescence) and phosphorylation of PKCalpha ( Western blotting). The PKC activator phorbol myristate acetate significantly increased vascular O-2(.-) production, which was inhibited by superoxide dismutase, diphenyleneiodonium, chelerythrine, or removal of extracellular Ca2+. Both high P-i and phorbol myristate acetate increased the phosphorylation of the NAD( P) H oxidase subunit p47(phox). Conclusion - High P-i itself elicits arterial O-2(.-) production, most likely by PKC-dependent activation of NAD( P) H oxidase, thus providing a potential explanation for the presence of oxidative stress and endothelial dysfunction in various forms of hypertension and the vasculoprotective effect of antihypertensive agents of different mechanisms of action

O advento do tratamento psiquiátrico moderno: a terapia convulsiva de László Meduna

Convulsive therapy (COT) is a major European contribution to the psychiatric armamentarium and biological psychiatry. COT was introduced in psychiatry by László Meduna, a Hungarian neuropsychiatrist. All subsequent publications about the first patient treated with COT, Zoltán L (ZL), were based on Meduna's papers and autobiography. After 4 years of catatonic stupor, ZL received camphor-induced COT which resulted in full remission and discharge from the institution. The aim of this paper is to reconstruct ZL's case history from the original case notes-partly written by Meduna himself-which were recovered from the archives of the National Institute of Psychiatry and Neurology. The case notes show that ZL repeatedly received COT between 1934 and 1937, first with camphor and then with cardiazol induction. After the first course of COT the catatonic stupor was resolved and the psychotic symptoms subsided. However, the remission lasted for only a few months and was followed by a relapse. Despite repeated courses of COT, ZL never became symptom free again, was never discharged and died in the Institute in 1945. This historical case is discussed from both the diagnostic and therapeutic points of view, and an attempt is made to explain the possible reasons for the discrepancies found between Meduna's account and ZL's case notes.A terapia convulsiva (TC) constitui uma das principais contribuições européias ao tratamento psiquiátrico moderno e à psiquiatria biológica. A TC foi introduzida na psiquiatria em 1934 por László Meduna, neuropsiquiatra húngaro. As publicações subseqüentes sobre o primeiro paciente tratado com TC, Zoltán L (ZL), baseiam-se nos artigos e na autobiografia de Meduna. De acordo com essas referências, após quatro anos de estupor catatônico, ZL recebeu TC induzida por cânfora que resultou em plena remissão dos sintomas esquizofrênicos, culminando com alta da instituição. Este artigo reconstrói a história do caso de ZL a partir da recente recuperação de anotações - algumas escritas pelo próprio Meduna - dos Arquivos do Instituto Nacional de Psiquiatria e Neurologia (Hungria). Essas anotações mostram que ZL recebeu repetidas sessões de TC entre 1934 e 1937, primeiramente induzidas por cânfora e depois por cardiazol. A primeira série de TC resultou na suspensão do estupor catatônico e na remissão parcial da psicose. Entretanto, a remissão foi breve e, a despeito de repetidas sessões de TC, ZL nunca esteve inteiramente livre de sintomas, nunca teve alta hospitalar e veio a falecer no Instituto em 1945. Na discussão do caso de ZL, tentamos explicar as possíveis razões das discrepâncias entre o relato de Meduna e as notas originais do prontuário médico

Single Mild Traumatic Brain Injury Induces Persistent Disruption of the Blood-Brain Barrier, Neuroinflammation and Cognitive Decline in Hypertensive Rats

Traumatic brain injury (TBI) induces blood-brain barrier (BBB) disruption, which contributes to secondary injury of brain tissue and development of chronic cognitive decline. However, single mild (m)TBI, the most frequent form of brain trauma disrupts the BBB only transiently. We hypothesized, that co-morbid conditions exacerbate persistent BBB disruption after mTBI leading to long term cognitive dysfunction. Since hypertension is the most important cerebrovascular risk factor in populations prone to mild brain trauma, we induced mTBI in normotensive Wistar and spontaneously hypertensive rats (SHR) and we assessed BBB permeability, extravasation of blood-borne substances, neuroinflammation and cognitive function two weeks after trauma. We found that mTBI induced a significant BBB disruption two weeks after trauma in SHRs but not in normotensive Wistar rats, which was associated with a significant accumulation of fibrin and increased neuronal expression of inflammatory cytokines TNFα, IL-1β and IL-6 in the cortex and hippocampus. SHRs showed impaired learning and memory two weeks after mild TBI, whereas cognitive function of normotensive Wistar rats remained intact. Future studies should establish the mechanisms through which hypertension and mild TBI interact to promote persistent BBB disruption, neuroinflammation and cognitive decline to provide neuroprotection and improve cognitive function in patients with mTBI

Elhízó Magyarország. A túlsúly és az elhízás trendje és prevalenciája Magyarországon, 2015.

Bevezetés: A világszerte növekvő arányú elhízás Magyarországon is észlelhető, populációs előfordulásáról az első nagyszabású felmérés 1988-ban történt. Célkitűzés: A szerzők az eddigi legnagyobb esetszámú hazai elhízásprevalenciavizsgálataik eredményeit mutatják be, amelyet háziorvosok és foglalkozás-egészségügyi orvosok részvételével bonyolítottak le. Módszer: A 18 év fölötti magyar lakosság 0,55%-ának, 43 287 fő (17 901 férfi és 25 386 nő) regisztrált adatait elemezték, országosan reprezentatív megoszlásban. Összehasonlították a korábbi hazai vizsgálatokkal, elemezték a testtömegindex, haskörfogat, iskolázottság, hypertonia és/vagy diabetes jelenléte és az életkor közötti kapcsolatot. Eredmények: Összességében férfiaknál a túlsúly 40%, az elhízás 32%-ban van jelen, míg nőknél mindkét kategória közel 32%-ban. A 18–34 év közötti életkori csoportban a férfiak 32,7%-a túlsúlyos, míg 18,2%-uk elhízott, 35–59 év között 40,1% és 34,4%, 60 év fölött 43,5%, illetve 38,8%. Ugyanezen korosztályi adatok nőknél: 19,6 és 15,7%, 36,8 és 38,7%, 36,5 és 39,7%. A testtömegindex-eloszlásokat és a hasi elhízás (férfiaknál >102 cm, nőknél >88 cm) adatait évtizedes életkori csoportokban és településtípusok szerint is bemutatják. A legnagyobb arányú túlsúly a felsőfokú végzettségű férfiaknál, a legtöbb elhízott a legalacsonyabb végzettségű nőknél volt. A testtömegindex szerinti és hasi elhízás a falvakban volt a legnagyobb arányú, különösen nőknél. A metabolikus betegségek jelenléte erősen korrelált a testtömegindexszel, és inverz módon az urbanizáció mértékével. Következtetések: Az elmúlt évtizedekben a túlsúly és főleg az elhízás aránya jelentősen megnőtt, különösen látványosan férfiaknál, szembetűnően a fiatalabbaknál. Ez nemcsak orvosi, de komoly népegészségügyi és gazdasági problémát is jelent, kezelése össztársadalmi figyelmet, a jelenleginél nagyobb szakmapolitikai támogatást igényel. Orv. Hetil., 2016, 157(31), 1248–1255

Nicotinamide mononucleotide (NMN) supplementation rescues cerebromicrovascular endothelial function and neurovascular coupling responses and improves cognitive function in aged mice

Adjustment of cerebral blood flow (CBF) to neuronal activity via neurovascular coupling (NVC) has an essential role in maintenance of healthy cognitive function. In aging increased oxidative stress and cerebromicrovascular endothelial dysfunction impair NVC, contributing to cognitive decline. There is increasing evidence showing that a decrease in NAD+ availability with age plays a critical role in a range of age-related cellular impairments but its role in impaired NVC responses remains unexplored. The present study was designed to test the hypothesis that restoring NAD+ concentration may exert beneficial effects on NVC responses in aging. To test this hypothesis 24-month-old C57BL/6 mice were treated with nicotinamide mononucleotide (NMN), a key NAD+ intermediate, for 2 weeks. NVC was assessed by measuring CBF responses (laser Doppler flowmetry) evoked by contralateral whisker stimulation. We found that NVC responses were significantly impaired in aged mice. NMN supplementation rescued NVC responses by increasing endothelial NO-mediated vasodilation, which was associated with significantly improved spatial working memory and gait coordination. These findings are paralleled by the sirtuin-dependent protective effects of NMN on mitochondrial production of reactive oxygen species and mitochondrial bioenergetics in cultured cerebromicrovascular endothelial cells derived from aged animals. Thus, a decrease in NAD+ availability contributes to age-related cerebromicrovascular dysfunction, exacerbating cognitive decline. The cerebromicrovascular protective effects of NMN highlight the preventive and therapeutic potential of NAD+ intermediates as effective interventions in patients at risk for vascular cognitive impairment (VCI)

Nicotinamide mononucleotide (NMN) supplementation rescues cerebromicrovascular endothelial function and neurovascular coupling responses and improves cognitive function in aged mice

Adjustment of cerebral blood flow (CBF) to neuronal activity via neurovascular coupling (NVC) has an essential role in maintenance of healthy cognitive function. In aging increased oxidative stress and cerebromicrovascular endothelial dysfunction impair NVC, contributing to cognitive decline. There is increasing evidence showing that a decrease in NAD+ availability with age plays a critical role in a range of age-related cellular impairments but its role in impaired NVC responses remains unexplored. The present study was designed to test the hypothesis that restoring NAD+ concentration may exert beneficial effects on NVC responses in aging. To test this hypothesis 24-month-old C57BL/6 mice were treated with nicotinamide mononucleotide (NMN), a key NAD+ intermediate, for 2 weeks. NVC was assessed by measuring CBF responses (laser Doppler flowmetry) evoked by contralateral whisker stimulation. We found that NVC responses were significantly impaired in aged mice. NMN supplementation rescued NVC responses by increasing endothelial NO-mediated vasodilation, which was associated with significantly improved spatial working memory and gait coordination. These findings are paralleled by the sirtuin-dependent protective effects of NMN on mitochondrial production of reactive oxygen species and mitochondrial bioenergetics in cultured cerebromicrovascular endothelial cells derived from aged animals. Thus, a decrease in NAD+ availability contributes to age-related cerebromicrovascular dysfunction, exacerbating cognitive decline. The cerebromicrovascular protective effects of NMN highlight the preventive and therapeutic potential of NAD+ intermediates as effective interventions in patients at risk for vascular cognitive impairment (VCI)