Aging Impairs Cerebrovascular Reactivity at Preserved Resting Cerebral Arteriolar Tone and Vascular Density in the Laboratory Rat.

The age-related (mal)adaptive modifications of the cerebral microvascular system have been implicated in cognitive impairment and worse outcomes after ischemic stroke. The magnitude of the hyperemic response to spreading depolarization (SD), a recognized principle of ischemic lesion development has also been found to be reduced by aging. Here, we set out to investigate whether the SD-coupled reactivity of the pial arterioles is subject to aging, and whether concomitant vascular rarefaction may contribute to the age-related insufficiency of the cerebral blood flow (CBF) response. CBF was assessed with laser-speckle contrast analysis (LASCA), and the tone adjustment of pial arterioles was followed with intrinsic optical signal (IOS) imaging at green light illumination through a closed cranial window created over the parietal cortex of isoflurane-anesthetized young (2 months old) and old (18 months old) male Sprague-Dawley rats. Global forebrain ischemia and later reperfusion were induced by the bilateral occlusion and later release of both common carotid arteries. SDs were elicited repeatedly with topical 1M KCl. Pial vascular density was measured in green IOS images of the brain surface, while the density and resting diameter of the cortical penetrating vasculature was estimated with micro-computed tomography of paraformaldehyde-fixed cortical samples. Whilst pial arteriolar dilation in response to SD or ischemia induction were found reduced in the old rat brain, the density and resting diameter of pial cortical vessels, and the degree of SD-related oligemia emerged as variables unaffected by age in our experiments. Spatial flow distribution analysis identified an age-related shift to a greater representation of higher flow ranges in the reperfused cortex. According to our data, impairment of functional arteriolar dilation, at preserved vascular density and resting vascular tone, may be implicated in the age-related deficit of the CBF response to SD, and possibly in the reduced efficacy of neurovascular coupling in the aging brain. SD has been recognized as a potent pathophysiological contributor to ischemic lesion expansion, in part because of the insufficiency of the associated CBF response. Therefore, the age-related impairment of cerebral vasoreactivity as shown here is suggested to contribute to the age-related acceleration of ischemic lesion development.

Age or ischemia uncouples the blood flow response, tissue acidosis, and direct current potential signature of spreading depolarization in the rat brain.

Spreading depolarization (SD) events contribute to lesion maturation in the acutely injured human brain. Neurodegeneration related to SD is thought to be caused by the insufficiency of the cerebral blood flow (CBF) response; yet the mediators of the CBF response, or their deficiency in the aged or ischemic cerebral cortex, remain the target of intensive research. Here, we postulated that tissue pH effectively modulates the magnitude of hyperemia in response to SD, the coupling of which is prone to be dysfunctional in the aged or ischemic cerebral cortex. To test this hypothesis, we conducted systematic correlation analysis between the direct current (DC) potential signature of SD, SD-associated tissue acidosis, and hyperemic element of the CBF response in the isoflurane-anesthetized, young or old, and intact or ischemic rat cerebral cortex. The data demonstrate that the amplitude of the SD-related DC potential shift, tissue acidosis, and hyperemia are tightly coupled in the young intact cortex; ischemia and old age uncouples the amplitude of hyperemia from the amplitude of the DC potential shift and acidosis; the duration of the DC potential shift, hyperemia and acidosis positively correlate under ischemia alone; and old age disproportionally elongates the duration of acidosis with respect to the DC potential shift and hyperemia under ischemia. The coincidence of the variables supports the view that local CBF regulation with SD must have an effective metabolic component, which becomes dysfunctional with age or under ischemia. Finally, the known age-related acceleration of ischemic neurodegeneration may be promoted by exaggerated tissue acidosis.NEW & NOTEWORTHY The hyperemic element of the cerebral blood flow response to spreading depolarization is effectively modulated by tissue pH in the young intact rat cerebral cortex. This coupling becomes dysfunctional with age or under ischemia, and tissue acidosis lasts disproportionally longer in the aged cortex, making the tissue increasingly more vulnerable.

Systemic administration of l-kynurenine sulfate induces cerebral hypoperfusion transients in adult C57Bl/6 mice.

The kynurenine pathway is a cascade of enzymatic steps generating biologically active compounds. l-kynurenine (l-KYN) is a central metabolite of tryptophan degradation. In the mammalian brain, l-KYN is partly converted to kynurenic acid (KYNA), which exerts multiple effects on neurotransmission. Recently, l-KYN or one of its derivatives were attributed a direct role in the regulation of the systemic circulation. l-KYN dilates arterial blood vessels during sepsis in rats, while it increases cerebral blood flow (CBF) in awake rabbits. Therefore, we hypothesized that acute elevation of systemic l-KYN concentration may exert potential effects on mean arterial blood pressure (MABP) and on resting CBF in the mouse brain. C57Bl/6 male mice were anesthetized with isoflurane, and MABP was monitored in the femoral artery, while CBF was assessed through the intact parietal bone with the aid of laser speckle contrast imaging. l-KYN sulfate (l-KYNs) (300mg/kg, i.p.) or vehicle was administered intraperitoneally. Subsequently, MABP and CBF were continuously monitored for 2.5h. In the control group, MABP and CBF were stable (69±4mmHg and 100±5%, respectively) throughout the entire data acquisition period. In the l-KYNs-treated group, MABP was similar to that, of control group (73±6mmHg), while hypoperfusion transients of 22±6%, lasting 7±3min occurred in the cerebral cortex over the first 60-120min following drug administration. In conclusion, the systemic high-dose of l-KYNs treatment destabilizes resting CBF by inducing a number of transient hypoperfusion events. This observation indicates the careful consideration of the dose of l-KYN administration by interpreting the effect of kynurenergic manipulation on brain function. By planning clinical trials basing on kynurenergic manipulation possible vascular side effects should also be considered.

Spreading depolarization remarkably exacerbates ischemia-induced tissue acidosis in the young and aged rat brain.

Spreading depolarizations (SDs) occur spontaneously in the cerebral cortex of subarachnoid hemorrhage, stroke or traumatic brain injury patients. Accumulating evidence prove that SDs exacerbate focal ischemic injury by converting zones of the viable but non-functional ischemic penumbra to the core region beyond rescue. Yet the SD-related mechanisms to mediate neurodegeneration remain poorly understood. Here we show in the cerebral cortex of isoflurane-anesthetized, young and old laboratory rats, that SDs propagating under ischemic penumbra-like conditions decrease intra and- extracellular tissue pH transiently to levels, which have been recognized to cause tissue damage. Further, tissue pH after the passage of each spontaneous SD event remains acidic for over 10 minutes. Finally, the recovery from SD-related tissue acidosis is hampered further by age. We propose that accumulating acid load is an effective mechanism for SD to cause delayed cell death in the ischemic nervous tissue, particularly in the aged brain.

Contribution of prostanoid signaling to the evolution of spreading depolarization and the associated cerebral blood flow response.

The significance of prostanoid signaling in neurovascular coupling during somatosensory stimulation is increasingly more appreciated, yet its involvement in mediating the cerebral blood flow (CBF) response to spreading depolarization (SD) has remained inconclusive. Selective cyclooxygenase (COX) enzyme inhibitors (NS-398, SC-560) or an antagonist (L161,982) of the EP4 type prostaglandin E2 receptor were applied topically to a cranial window over the parietal cortex of isoflurane-anesthetized Sprague-Dawley rats (n = 60). Global forebrain ischemia was induced by occlusion of both common carotid arteries in half of the animals. SDs were triggered by the topical application of 1M KCl. SD occurrence was confirmed by the acquisition of DC potential, and CBF variations were recorded by laser-Doppler flowmetry. EP4 receptor antagonism significantly decreased peak hyperemia and augmented post-SD oligemia in the intact but not in the ischemic cortex. COX-1 inhibition and EP4 receptor blockade markedly delayed repolarization after SD in the ischemic but not in the intact brain. COX-2 inhibition achieved no significant effect on any of the end points taken. The data suggest, that activation of EP4 receptors initiates vasodilation in response to SD in the intact brain, and - together with COX-1 derived prostanoids - shortens SD duration in the acute phase of ischemia.

[Use of whole-body diffusion-weighted magnetic resonance imaging for the diagnosis of and therapeutic response in multiple myeloma]. / Teljes test diffúziós mágneses rezonanciavizsgálat a myeloma multiplex diagnosztikájában és terápiájának követésében.

INTRODUCTION: Multiple myeloma is an incurable neoplastic disorder of B cells characterized by diffuse bone marrow infiltration, circumscribed bone lesions, and soft-tissue spreading. The role of novel functional imaging techniques in multiple myeloma includes initial staging of the disease, detection and characterization of complications, and evaluation of the response to treatment. AIM: The authors present their 2 and a half-year experience with diffusion-weighted magnetic resonance imaging in staging and follow up of patients with multiple myeloma. METHOD: Conventional T1 weighted, T2 weighted fat suppressed and 2 b-values diffusion-weighted sequences were performed from skull base to symphysis in 27 patients suspected to have multiple myeloma. Apparent diffusion coefficient calculation was carried out in 3 cases. The final diagnosis of multiple myeloma was verified by bone-marrow biopsy. RESULTS: In 13 cases magnetic resonance imaging revealed the suspected disease. In one patient magnetic resonance imaging failed to detect the disease because of metallic artifacts. In 6 cases diffusion-weighted sequences showed additional information about bone-marrow infiltration. CONCLUSIONS: Diffusion-weighted magnetic resonance imaging with conventional sequences is a useful and promising functional imaging modality in the early diagnosis of myeloma multiple.

[Pancreatic metastases. Report of four cases and literature review]. / Pancreasmetasztázisok. Négy eset és irodalmi áttekintés.

The authors present the history of 4 patients with pancreatic metastases revealed by CT and MR during the last 2 years. In 2 patients pancreatic metastases developed more than 10 years after the primary renal neoplasm was diagnosed. In the other two patients (one with non small cell lung cancer and one with non-Hodgkin disease) pancreatic metastases developed shortly after the diagnosis of the primary malignancy. According to literature data metastases in the pancreas are rare. The authors conclude that the symptoms and imaging features of pancreatic metastases are variable and, therefore, non-invasive imaging diagnosis is difficult. To resolve this problem a thorough scrutiny of the medical history of the patients and functional imaging methods may be helpful.

Hormonal and biochemical parameters correlated with bone densitometric markers in prepubertal Hungarian children.

BACKGROUND: The conditions that define bone development in prepuberty profoundly influence bone health later in life. We aimed to reveal important determinants of bone mass in Tanner stage I. METHODS: We studied 84 healthy children (43 girls and 41 boys) aged 7 to 11 years. Serum estradiol (E2), 25-hydroxyvitamin D3-vitamin [25(OH)D3], intact parathyroid hormone (PTHi), osteocalcin (OC) and ß-crosslaps (CTXs) were longitudinally analyzed (Roche Diagnostics System). Total and spine bone mineral content (tBMC and LBMC) and density (tBMD and LBMD) were assessed, and total fat body mass index (FBMi) was calculated (DXA Lunar Prodigy). RESULTS: The serum PTHi, OC and LBMD values were significantly higher in girls than in boys. The mean 25(OH)D3 level was lower but not significantly in girls compared to boys. Significant negative correlation was found between PTHi and 25(OH)D3 levels (r=-0.28; p=0.011) when tested in all subjects, but no correlation was detected when the gender groups were separately tested. There was a trend for higher E2 levels in girls. Significant positive correlation (r=0.32; p=0.042) was detected between FBMi and E2 concentration in girls only. A significant negative correlation was found between E2 and 25(OH)D3 levels (r=-0.37, p<0.05) in girls with elevated (>3.6pmol/l) PTHi and with suboptimal (<75nmol/l) 25(OH)D3 levels. Furthermore, positive correlations were noted between E2 and CTXs and OC (r=0.54, p<0.01 and r=0.39, p<0.03) and a marginally significant positive correlation (r=0.33; p=0.06) was detected between OC and PTHi levels in girls. However, we detected no correlations when these markers were analyzed in boys. There was a significant correlation between E2 and all BMC and LBMD values in both genders. The tBMD, LBMD and tBMC values showed weak, but significant negative associations with 25OHD3 levels (ß=-0.44 to -0.55; p<0.001) in girls only. All BMD and BMC values were positively predicted by OC levels, but not by CTXs, in both genders. Among the biochemical markers, E2 was the only factor correlating with all dependent variables (BMCs and BMDs) in both genders. Among all parameters analyzed, FBMi (ß=0.64) showed the strongest influence on tBMC characteristically in girls only. CONCLUSIONS: Our results support that 1.) E2 levels play a key role in defining bone turnover and bone mass in both genders already in prepuberty; 2.) high PTHi levels in childhood should be evaluated with caution, because the normal range for serum PTHi in different Tanner stage groups is not well established; and 3.) the negative correlation between 25(OH)D and E2 and the positive correlation between PTHi and OC suggest that estrogens regulate PTHi indirectly and cause lower circulating 25(OH)D3 levels. We propose that the decreased levels of 25(OH)D3 reflect not the real vitamin supply, but may rather be the result of E2 regulation. Therefore, the actual serum 25OHD levels may underestimate the availability of factors supporting bone formation.

[Diffusion-weighted MR imaging; the significance of ADC and perfusion values in the differential diagnosis of pancreatic adenocarcinoma and mass forming pancreatitis]. / A diffúziós MR-vizsgálat, az ADC- és a perfúziós érték jelentosége a pancreasadenocarcinoma és a körülírt gyulladás differenciáldiagnosztikájában.

UNLABELLED: Despite the increasing diagnostic accuracy of cross sectional imaging modalities, the correct differentiation between pancreatic adenocarcinoma and mass forming pancreatitis has remained a challenge. AIM: Based on their 2 and ½ -year experience, the aim of the authors was to assess the clinical utility of diffusion-weighted magnetic resonance imaging in the diagnosis and discernment of pancreatic adenocarcinoma and mass forming pancreatitis. METHODS: 3 b-values diffusion-weighted magnetic resonance examinations were performed in 19 patients suffering from adenocarcinoma and in 8 patients with pancreatitis. 12 healthy patients were examined as reference. Apparent diffusion coefficient and perfusion values were calculated. Malignancy was verified by pathology in all cases. An inflammatory disease was diagnosed on the basis of previous medical history, changes in laboratory values, follow-up computer tomographic examinations and improvement in the patients' condition. RESULTS: Comparison of the apparent diffusion coefficient and perfusion values revealed significant differences between healthy pancreatic tissues and those affected by inflammation or tumor. The highest apparent diffusion coefficient and perfusion values were detected in the normal pancreas. Mass forming pancreatitis had diminished the apparent diffusion coefficient and perfusion values, whereas these values were the lowest in tumorous tissues. CONCLUSION: In agreement with literature data, the authors conclude that diffusion-weighted magnetic resonance imaging is a promising differential-diagnostic imaging tool in the distinction of circumscribed pancreatic lesions.

[Investigation of adolescents' bone metabolism in the western part of Transdanubia]. / Serdülôk csontanyagcsere-markereinek vizsgálata a nyugat-dunántúli régióban.

UNLABELLED: Childhood reference range based on the age is not available in Hungary, therefore the diagnosis and therapy of bone metabolic diseases of childhood are subject to difficulties. The aim of this work is to provide information about the adolescents' results of bone mineral density and bone biomarkers. SUBJECTS AND METHODS: Measurements were performed in 169 healthy adolescents (98 girls, 71 boys, age: 17.0+/-1.2 years). Bone mineral content (BMC) and bone mineral density (BMD) of the lumbar spine were measured using Double X-ray Absorptiometry (DXA, LUNAR, GE Health Care, USA) and Z-score values were analyzed using different reference population. In the serum, bone biomarkers osteocalcin (OC) and beta-crosslaps (beta-Cl) were measured by a fully automated, electrochemiluminescence immunoassay method (Elecsys-2010, Roche). Data were analyzed according to gender and the Tanner stage and grade system. Associations between body mass index (BMI), calcium intake, consumption of soft drinks and coke, and physical exercise were investigated. RESULTS: BMC values for both age groups were significantly elevated in boys of the Tanner stage V. (15-16 years: 62.9+/-14.3 g; 17-19 years: 69.8+/-9.3g) than in girls (58.1+/-10.4; 61.6+/-8.5 g) (p<0.001). BMD values were higher in girls, than in boys (1.17+/-0.12 g/cm 2 vs. 1.13+/-0.11 g/cm 2) (p<0.05). OC and beta-Cl levels showed negative correlation with age in both gender (p<0.01), while OC and beta-Cl levels were higher in boys, than in girls (p<0.001). Elevation of BMC and BMD values were associated with increase of BMI in both gender (p<0.05), but the biomarkers in thin girls were higher, than in overweight girls (p<0.05). Authors obtained excellent correlations between the BMD-Z-score values compared to the German standard and to their own population (girls: r=0.97, boys: 0.88), but the absolute values significantly differed from one another. 80% of adolescents are on a diet with insufficient calcium intake, while 38% of them do not play sport regularly. Excessive intake of soft drinks was determined in 60% of adolescents. In the case of insufficient calcium intake (4.7%, 6/127), low bone mass was measured using the Z-score of the German reference values. Among children with adequate calcium intake, BMD assessed by DXA was normal. CONCLUSION: These data help to determine normal reference values among healthy high school students. Further studies are needed in wider range of young population for the establishment of Hungarian reference values of bone markers.

[The importance of multidetector computed tomography in the vascular imaging]. / A több detektorsoros komputertomográfia jelentosége a vascularis képalkotásban.

UNLABELLED: The introduction of multidetector CT and special post processing software has made an excellent image quality of vascular structures possible. AIM AND METHODS: The authors present the method and technique of CT angiography, added their own experience acquired on 700 patients in the last 3 years. Beside other vascular imaging methods the importance of CT angiography and its usefulness is demonstrated. CONCLUSIONS: CT angiography is a fast, non-invasive method, and either in itself or combined with other ones it is suitable for a definitive diagnosis.

[A rare localisation of ectopic pregnancy--a case of hepatic pregnancy]. / Ritka lokalizációjú méhen kívüli terhesség--májterhesség esete.

Ectopic pregnancy is a major gynecologic emergency, and remains a life-threatening syndrome. Hepatic pregnancy is an exceptionally rare form of ectopic pregnancy. The authors present a case of a 28 year old woman, who was admitted to hospital with epigastric pain. Diagnostic investigations showed a rare, 16-week-old ectopic pregnancy in the liver. The authors emphasise the importance of early diagnosis and management of ectopic pregnancy in order to reduce maternal mortality.

[The role of computed tomography perfusion in the diagnosis of brain ischaemic stroke]. / A perfúziós komputertomográfiai vizsgálatok szerepe az ischaemiás stroke diagnosztizálásában.

UNLABELLED: In recent years, the broad introduction of fast multidetector computed tomography (CT) systems and the availability of commercial software for perfusion analysis have made cerebral perfusion imaging with CT a practical technique for the clinical environment. AIM AND METHODS: This article reviews the use of CT for imaging cerebral perfusion, highlighting its advantages, disadvantages and limitations, and draws comparisons between perfusion CT and magnetic resonance imaging. The authors performed 96 perfusion CT examinations in the last one and a half years. Future technical developments in multi-slice CT systems may diminish the current limitations of limited spatial coverage and radiation burden. Yet CT is often not perceived as a technique for imaging cerebral perfusion. CONCLUSIONS: The technique is widely available at low cost, accurate and easy to perform. Perfusion CT is particularly applicable to those clinical circumstances where patients already undergo CT for other reasons, including stroke.