Mild traumatic brain injury-induced persistent blood-brain barrier disruption is prevented by cyclosporine A treatment in hypertension.

Introduction: Mild traumatic brain injury (mTBI) and hypertension synergize to induce persistent disruption of the blood-brain barrier (BBB), neuroinflammation and cognitive decline. However, the underlying mechanisms are not known. Cerebral production of Cyclophilin A (CyPA) is induced in hypertension and after TBI, and it was demonstrated to activate the nuclear factor-κB (NF-kB)- matrix-metalloproteinase-9 (MMP-9) pathway in cerebral vessels leading to BBB disruption. Methods: To test the role of CyPA in mTBI- and hypertension-induced BBB disruption we induced mTBI in normotensive and spontaneously hypertensive rats (SHR), then the animals were treated with cyclosporine A (a specific inhibitor of CyPA production) or vehicle for 7 days. We assessed BBB permeability and integrity, cerebral expression and activity of the CyPA-NF-kB-MMP-9 pathway, extravasation of fibrin and neuroinflammation. Results: We found that mild TBI induced BBB disruption and upregulation of the CyPA-NF-kB-MMP-9 pathway in hypertension, which were prevented by blocking CyPA. Cyclosporine treatment and preservation of BBB function prevented accumulation of blood-derived fibrin in the brain parenchyma of hypertensive rats after mTBI and reversed increased neuroinflammation. Discussion: We propose that mTBI and hypertension interact to promote BBB disruption via the CyPA-NF-kB-MMP-9 pathway, and inhibition of cyclophilin production after mTBI may exert neuroprotection and improve cognitive function in hypertensive patients.

The Effect of Mild Traumatic Brain Injury on Cerebral Microbleeds in Aging.

A traumatic brain injury (TBI) induces the formation of cerebral microbleeds (CMBs), which are associated with cognitive impairments, psychiatric disorders, and gait dysfunctions in patients. Elderly people frequently suffer TBIs, especially mild brain trauma (mTBI). Interestingly, aging is also an independent risk factor for the development of CMBs. However, how TBI and aging may interact to promote the development of CMBs is not well established. In order to test the hypothesis that an mTBI exacerbates the development of CMBs in the elderly, we compared the number and cerebral distribution of CMBs and assessed them by analysing susceptibility weighted (SW) MRI in young (25 ± 10 years old, n = 18) and elder (72 ± 7 years old, n = 17) patients after an mTBI and in age-matched healthy subjects (young: 25 ± 6 years old, n = 20; aged: 68 ± 5 years old, n = 23). We found significantly more CMBs in elder patients after an mTBI compared with young patients; however, we did not observe a significant difference in the number of cerebral microhemorrhages between aged and aged patients with mTBI. The majority of CMBs were found supratentorially (lobar and basal ganglion). The lobar distribution of supratentorial CMBs showed that aging enhances the formation of parietal and occipital CMBs after mTBIs. This suggests that aging and mTBIs do not synergize in the induction of the development of CMBs, and that the different distribution of mTBI-induced CMBs in aged patients may lead to specific age-related clinical characteristics of mTBIs.

Molecular Pathomechanisms of Impaired Flow-Induced Constriction of Cerebral Arteries Following Traumatic Brain Injury: A Potential Impact on Cerebral Autoregulation.

(1) Background: Traumatic brain injury (TBI) frequently occurs worldwide, resulting in high morbidity and mortality. Here, we hypothesized that TBI impairs an autoregulatory mechanism, namely the flow-induced constriction of isolated rat middle cerebral arteries (MCAs). (2) Methods: TBI was induced in anaesthetized rats by weight drop model, and then MCAs were isolated and transferred into a pressure-flow chamber. The internal diameter was measured by a video-microscopy. (3) Results: In MCAs from intact rats, increases in flow and pressure + flow elicited constrictions (-26 ± 1.9 µm and -52 ± 2.8 µm, p < 0.05), which were significantly reduced after TBI or in the presence of thromboxane-prostanoid (TP receptor) antagonist SQ 29,548. Flow-induced constrictions were significantly reduced by HET0016, inhibitor of cytochrome P450 4A (CYP450 4A). Arachidonic acid, (AA, 10-7 M), and CYP-450 4A metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) elicited constrictions of intact MCA (-26 ± 2.3% and -31 ± 3.6%), which were significantly reduced after TBI (to 11 ± 1.3% and -16 ±2.5%). The TP receptor agonist U46619 (10-7 M) elicited substantial constrictions of MCA from intact rats (-21 ± 3.3%), which were also significantly reduced, after TBI (to -16 ± 2.4%). (4) Conclusions: Flow-induced constrictor response of MCA is impaired by traumatic brain injury, likely due to the reduced ability of cytochrome P450 4A to convert arachidonic acid to constrictor prostaglandins and the mitigated sensitivity of thromboxane-prostanoid receptors.

Effect of Growth Hormone on Neuropsychological Outcomes and Quality of Life of Patients with Traumatic Brain Injury: A Systematic Review.

One of the most devastating chronic consequences of traumatic brain injury (TBI) is cognitive impairment. One of the possible underlying causes is growth hormone deficiency (GHD) caused by TBI-induced hypopituitarism. Currently, TBI patients are not routinely screened for pituitary function, and there are no standard therapies when GHD is diagnosed. Further, the possible positive effects of GH replacement on cognitive function and quality of life after TBI are not well established. We aimed to assess the current knowledge regarding the effect of GH therapy on cognitive function and quality of life after TBI. We performed a literature search in PubMed, Embase, and Central® databases from inception to October 2019. We extracted data on each term of severity (mild-moderate-severe) of TBI with and without GHD, time since injury, parameters of growth hormone treatment (dosing, length), and cognitive outcomes in terms of verbal and non-verbal memory, and executive, emotional, and motor functions, and performed a meta-analysis on the results of a digit span test assessing working memory. We identified 12 studies (containing two randomized controlled trials) with 264 mild-to-moderate-to-severe TBI patients (Glasgow Coma Score [GCS] varied between 6 and 15) with (n = 255) or without (n = 9) GHD who received GH therapy. GH was administered subcutaneously in gradually increasing doses, monitoring serum insulin-like growth factor-I (IGF-I) level. After TBI, regardless of GCS, 6-12 months of GH therapy, started in the chronic phase post-TBI, induced a moderate improvement in processing speed and memory capacities, decreased the severity of depression, and led to a marked improvement in quality of life. Limitations include the relatively low number of patients involved and the divergent neuropsychological tests used. These results indicate the need for further multi-centric controlled studies to substantiate the use of GH replacement therapy as a potential tool to alleviate TBI-related cognitive impairment and improve quality of life.

Traumatic brain injury-induced cerebral microbleeds in the elderly.

Traumatic brain injury (TBI) was shown to lead to the development of cerebral microbleeds (CMBs), which are associated with long term cognitive decline and gait disturbances in patients. The elderly is one of the most vulnerable parts of the population to suffer TBI. Importantly, ageing is known to exacerbate microvascular fragility and to promote the formation of CMBs. In this overview, the effect of ageing is discussed on the development and characteristics of TBI-related CMBs, with special emphasis on CMBs associated with mild TBI. Four cases of TBI-related CMBs are described to illustrate the concept that ageing exacerbates the deleterious microvascular effects of TBI and that similar brain trauma may induce more CMBs in old patients than in young ones. Recommendations are made for future prospective studies to establish the mechanistic effects of ageing on the formation of CMBs after TBI, and to determine long-term consequences of CMBs on clinically relevant outcome measures including cognitive performance, gait and balance function.

Prostaglandin E2, a postulated mediator of neurovascular coupling, at low concentrations dilates whereas at higher concentrations constricts human cerebral parenchymal arterioles.

There is considerable controversy regarding the vasoactive action of prostaglandin E2 (PGE2). On the one hand, indirect evidence implicates that astrocytic release of PGE2 contributes to neurovascular coupling responses mediating functional hyperemia in the brain. On the other hand, overproduction of PGE2 was also reported to contribute to cerebral vasospasm associated with subarachnoid hemorrhage. The present study was conducted to resolve this controversy by determining the direct vasoactive effects of PGE2 in resistance-sized human cerebral parenchymal arterioles. To achieve this goal PGE2-induced isotonic vasomotor responses were assessed in parenchymal arterioles isolated from fronto-temporo-parietal cortical tissues surgically removed from patients and expression of PGE2 receptors were examined. In functionally intact parenchymal arterioles lower concentrations of PGE2 (from 10-8 to 10-6 mol/l) caused significant, endothelium-independent vasorelaxation, which was inhibited by the EP4 receptor blocker BGC201531. In contrast, higher concentrations of PGE2 evoked significant EP1-dependent vasoconstriction, which could not be reversed by the EP4 receptor agonist CAY10598. We also confirmed previous observations that PGE2 primarily evokes constriction in intracerebral arterioles isolated from R. norvegicus. Importantly, vascular mRNA and protein expression of vasodilator EP4 receptors was significantly higher than that of vasoconstrictor EP1 receptors in human cerebral arterioles. PGE2 at low concentrations dilates whereas at higher concentrations constricts human cerebral parenchymal arterioles. This bimodal vasomotor response is consistent with both the proposed vasodilator role of PGE2 during functional hyperemia and its putative role in cerebral vasospasm associated with subarachnoid hemorrhage in human patients.

Hypertension Exacerbates Cerebrovascular Oxidative Stress Induced by Mild Traumatic Brain Injury: Protective Effects of the Mitochondria-Targeted Antioxidative Peptide SS-31.

Traumatic brain injury (TBI) induces cerebrovascular oxidative stress, which is associated with neurovascular uncoupling, autoregulatory dysfunction, and persisting cognitive decline in both pre-clinical models and patients. However, single mild TBI (mTBI), the most frequent form of brain trauma, increases cerebral generation of reactive oxygen species (ROS) only transiently. We hypothesized that comorbid conditions might exacerbate long-term ROS generation in cerebral arteries after mTBI. Because hypertension is the most important cerebrovascular risk factor in populations prone to mild brain trauma, we induced mTBI in normotensive and spontaneously hypertensive rats (SHR) and assessed changes in cytoplasmic and mitochondrial superoxide (O2-) production by confocal microscopy in isolated middle cerebral arteries (MCA) 2 weeks after mTBI using dihydroethidine (DHE) and the mitochondria-targeted redox-sensitive fluorescent indicator dye MitoSox. We found that mTBI induced a significant increase in long-term cytoplasmic and mitochondrial O2- production in MCAs of SHRs and increased expression of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit Nox4, which were reversed to the normal level by treating the animals with the cell-permeable, mitochondria-targeted antioxidant peptide SS-31 (5.7 mg kg-1 day-1, i.p.). Persistent mTBI-induced oxidative stress in MCAs of SHRs was significantly decreased by inhibiting vascular NADPH oxidase (apocyinin). We propose that hypertension- and mTBI-induced cerebrovascular oxidative stress likely lead to persistent dysregulation of cerebral blood flow (CBF) and cognitive dysfunction, which might be reversed by SS-31 treatment.

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-1ß 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.

Traumatic Brain Injury Impairs Myogenic Constriction of Cerebral Arteries: Role of Mitochondria-Derived H2O2 and TRPV4-Dependent Activation of BKca Channels.

Traumatic brain injury (TBI) impairs autoregulation of cerebral blood flow, which contributes to the development of secondary brain injury, increasing mortality of patients. Impairment of pressure-induced myogenic constriction of cerebral arteries plays a critical role in autoregulatory dysfunction; however, the underlying cellular and molecular mechanisms are not well understood. To determine the role of mitochondria-derived H2O2 and large-conductance calcium-activated potassium channels (BKCa) in myogenic autoregulatory dysfunction, middle cerebral arteries (MCAs) were isolated from rats with severe weight drop-impact acceleration brain injury. We found that 24 h post-TBI MCAs exhibited impaired myogenic constriction, which was restored by treatment with a mitochondria-targeted antioxidant (mitoTEMPO), by scavenging of H2O2 (polyethylene glycol [PEG]-catalase) and by blocking both BKCa channels (paxilline) and transient receptor potential cation channel subfamily V member 4 (TRPV4) channels (HC 067047). Further, exogenous administration of H2O2 elicited significant dilation of MCAs, which was inhibited by blocking either BKCa or TRPV4 channels. Vasodilation induced by the TRPV4 agonist GSK1016790A was inhibited by paxilline. In cultured vascular smooth muscle cells H2O2 activated BKCa currents, which were inhibited by blockade of TRPV4 channels. Collectively, our results suggest that after TBI, excessive mitochondria-derived H2O2 activates BKCa channels via a TRPV4-dependent pathway in the vascular smooth muscle cells, which impairs pressure-induced constriction of cerebral arteries. Future studies should elucidate the therapeutic potential of pharmacological targeting of this pathway in TBI, to restore autoregulatory function in order to prevent secondary brain damage and decrease mortality.

Hypertension-Induced Enhanced Myogenic Constriction of Cerebral Arteries Is Preserved after Traumatic Brain Injury.

Traumatic brain injury (TBI) was shown to impair pressure-induced myogenic response of cerebral arteries, which is associated with vascular and neural dysfunction and increased mortality of TBI patients. Hypertension was shown to enhance myogenic tone of cerebral arteries via increased vascular production of 20-hydroxyeicosatrienoic acid (HETE). This adaptive mechanism protects brain tissue from pressure/volume overload; however, it can also lead to increased susceptibility to cerebral ischemia. Although both effects may potentiate the detrimental vascular consequences of TBI, it is not known how hypertension modulates the effect of TBI on myogenic responses of cerebral vessels. We hypothesized that in hypertensive rats, the enhanced myogenic cerebrovascular response is preserved after TBI. Therefore, we investigated the myogenic responses of isolated middle cerebral arteries (MCA) of normotensive and spontaneously hypertensive rats (SHR) after severe impact acceleration diffuse brain injury. TBI diminished myogenic constriction of MCAs isolated from normotensive rats, whereas the 20-HETE-mediated enhanced myogenic response of MCAs isolated from SHRs was not affected by TBI. These results suggest that the optimal cerebral perfusion pressure values and vascular signaling pathways can be different and, therefore, should be targeted differently in normotensive and hypertensive patients following TBI.

Traumatic brain injury-induced autoregulatory dysfunction and spreading depression-related neurovascular uncoupling: Pathomechanisms, perspectives, and therapeutic implications.

Traumatic brain injury (TBI) is a major health problem worldwide. In addition to its high mortality (35-40%), survivors are left with cognitive, behavioral, and communicative disabilities. While little can be done to reverse initial primary brain damage caused by trauma, the secondary injury of cerebral tissue due to cerebromicrovascular alterations and dysregulation of cerebral blood flow (CBF) is potentially preventable. This review focuses on functional, cellular, and molecular changes of autoregulatory function of CBF (with special focus on cerebrovascular myogenic response) that occur in cerebral circulation after TBI and explores the links between autoregulatory dysfunction, impaired myogenic response, microvascular impairment, and the development of secondary brain damage. We further provide a synthesized translational view of molecular and cellular mechanisms involved in cortical spreading depolarization-related neurovascular dysfunction, which could be targeted for the prevention or amelioration of TBI-induced secondary brain damage.

[Patient satisfaction with care in gastrooesophageal reflux disease]. / A gastrooesophagealis refluxban szenvedo betegek elégedettségének felmérése.

INTRODUCTION: Besides medical treatment, adequate communication and personal relationships between physicians and patients are the most important determinants of patient satisfaction. AIM: To explore doctor-patient relationships, and factors that may determine patient satisfaction with care. METHOD: Patients with gastroesophageal reflux (n = 80) were divided into subgroups treated by family doctors or by gastroenterologists. Patients were asked to fill in a questionnaire about communication and patient satisfaction. RESULTS: Significantly more patients visited family doctors than gastroenterologists with health problems (80%; 20%, p < 0.001). Patients were significantly more satisfied with the information they received about the process of care provided by family doctors (95%) compared to that they obtained from gastroenterologists (65%; p = 0.002). Significantly more patients in family practices indicated that their doctors spent enough time with them compared to subspecialists (96.7%; 80% p = 0.032). CONCLUSIONS: Patients develop a closer personal relationship and more appropriate communication with family doctors compared to specialists, which can be an important component of successful treatment.