A novel mesial temporal stereotactic coordinate system.

OBJECTIVE Stereotactic laser ablation and neurostimulator placement represent an evolution in staged surgical intervention for epilepsy. As this practice evolves, optimal targeting will require standardized outcome measures that compare electrode lead or laser source with postprocedural changes in seizure frequency. The authors propose and present a novel stereotactic coordinate system based on mesial temporal anatomical landmarks to facilitate the planning and delineation of outcomes based on extent of ablation or region of stimulation within mesial temporal structures. METHODS The body of the hippocampus contains a natural axis, approximated by the interface of cornu ammonis area 4 and the dentate gyrus. The uncal recess of the lateral ventricle acts as a landmark to characterize the anterior-posterior extent of this axis. Several volumetric rotations are quantified for alignment with the mesial temporal coordinate system. First, the brain volume is rotated to align with standard anterior commissure-posterior commissure (AC-PC) space. Then, it is rotated through the axial and sagittal angles that the hippocampal axis makes with the AC-PC line. RESULTS Using this coordinate system, customized MATLAB software was developed to allow for intuitive standardization of targeting and interpretation. The angle between the AC-PC line and the hippocampal axis was found to be approximately 20°-30° when viewed sagittally and approximately 5°-10° when viewed axially. Implanted electrodes can then be identified from CT in this space, and laser tip position and burn geometry can be calculated based on the intraoperative and postoperative MRI. CONCLUSIONS With the advent of stereotactic surgery for mesial temporal targets, a mesial temporal stereotactic system is introduced that may facilitate operative planning, improve surgical outcomes, and standardize outcome assessment.

Purification and Characterization of Progenitor and Mature Human Astrocytes Reveals Transcriptional and Functional Differences with Mouse.

The functional and molecular similarities and distinctions between human and murine astrocytes are poorly understood. Here, we report the development of an immunopanning method to acutely purify astrocytes from fetal, juvenile, and adult human brains and to maintain these cells in serum-free cultures. We found that human astrocytes have abilities similar to those of murine astrocytes in promoting neuronal survival, inducing functional synapse formation, and engulfing synaptosomes. In contrast to existing observations in mice, we found that mature human astrocytes respond robustly to glutamate. Next, we performed RNA sequencing of healthy human astrocytes along with astrocytes from epileptic and tumor foci and compared these to human neurons, oligodendrocytes, microglia, and endothelial cells (available at http://www.brainrnaseq.org). With these profiles, we identified novel human-specific astrocyte genes and discovered a transcriptome-wide transformation between astrocyte precursor cells and mature post-mitotic astrocytes. These data represent some of the first cell-type-specific molecular profiles of the healthy and diseased human brain.

Development of Volunteer International Craniofacial Surgery Missions: The Komedyplast Protocol.

Volunteer surgical missions to provide cleft care to patients in developing countries has been done successfully for a number of years. Similar missions that provide craniofacial surgery introduce a dramatic step up in complexity. While articles have addressed protocols for the safe delivery of cleft care around the world, little has been written on volunteer craniofacial surgical missions. Komedyplast was established in March 2001 as a 501c(3) nonprofit organization to provide craniofacial surgical care to underserved populations and educate local surgeons in craniofacial principles. During 9 annual missions, the organization has provided surgical care to more than 150 patients with various complex, congenital, craniofacial conditions. The article addresses important safeguards that have been implemented to maximize safety and minimize risk.

Incidental atherosclerotic renal artery stenosis diagnosed at cardiac catheterization: no difference in kidney function with or without stenting.

BACKGROUND: The long-term kidney function of patients with atherosclerotic renal artery stenosis (ARAS) diagnosed incidentally at the time of cardiac catheterization is not well described despite the increasingly common practice of assessing these vessels at the time of cardiac investigation. METHODS: This is a retrospective analysis of a cohort identified prospectively at the time of non-emergent coronary angiography. Those with >or=50% ARAS were managed medically and underwent stenting if recommended by their nephrologist and/or cardiologist. Longitudinal regression analysis was used to compare the annualized change in estimated glomerular filtration rate (GFR) in stented and unstented patients. Cox regression analysis was used to determine the predictors of a decline in GFR by >or=25%. RESULTS: Of 140 patients, 67 (48%) were stented, mostly for preservation of kidney function (70.1%) and/or resistant hypertension (53.7%). Median follow-up time was 943 days. Stented patients were younger, had higher systolic blood pressure and more severe ARAS. The adjusted rate of change in GFR was -1.49 (95% CI -2.33 to -0.65) ml/min/1.73 m(2)/year in the unstented group, and -1.48 (95% CI -2.34 to -0.62) ml/min/1.73 m(2)/year in the stented group (p = 0.99). A decline of GFR >or=25% occurred in 42 (30%) patients; no patient required dialysis. Only the presence of cereberovascular disease was associated with this outcome (hazard ratio 2.52, 95% CI 1.56-5.41). CONCLUSION: We were unable to demonstrate a benefit or harm of renal artery stenting for ARAS, thus further increasing the uncertainty of the significance of these lesions and how they are best managed.

Multiplicity of cerebrospinal fluid functions: New challenges in health and disease.

UNLABELLED: This review integrates eight aspects of cerebrospinal fluid (CSF) circulatory dynamics: formation rate, pressure, flow, volume, turnover rate, composition, recycling and reabsorption. Novel ways to modulate CSF formation emanate from recent analyses of choroid plexus transcription factors (E2F5), ion transporters (NaHCO3 cotransport), transport enzymes (isoforms of carbonic anhydrase), aquaporin 1 regulation, and plasticity of receptors for fluid-regulating neuropeptides. A greater appreciation of CSF pressure (CSFP) is being generated by fresh insights on peptidergic regulatory servomechanisms, the role of dysfunctional ependyma and circumventricular organs in causing congenital hydrocephalus, and the clinical use of algorithms to delineate CSFP waveforms for diagnostic and prognostic utility. Increasing attention focuses on CSF flow: how it impacts cerebral metabolism and hemodynamics, neural stem cell progression in the subventricular zone, and catabolite/peptide clearance from the CNS. The pathophysiological significance of changes in CSF volume is assessed from the respective viewpoints of hemodynamics (choroid plexus blood flow and pulsatility), hydrodynamics (choroidal hypo- and hypersecretion) and neuroendocrine factors (i.e., coordinated regulation by atrial natriuretic peptide, arginine vasopressin and basic fibroblast growth factor). In aging, normal pressure hydrocephalus and Alzheimer's disease, the expanding CSF space reduces the CSF turnover rate, thus compromising the CSF sink action to clear harmful metabolites (e.g., amyloid) from the CNS. Dwindling CSF dynamics greatly harms the interstitial environment of neurons. Accordingly the altered CSF composition in neurodegenerative diseases and senescence, because of adverse effects on neural processes and cognition, needs more effective clinical management. CSF recycling between subarachnoid space, brain and ventricles promotes interstitial fluid (ISF) convection with both trophic and excretory benefits. Finally, CSF reabsorption via multiple pathways (olfactory and spinal arachnoidal bulk flow) is likely complemented by fluid clearance across capillary walls (aquaporin 4) and arachnoid villi when CSFP and fluid retention are markedly elevated. A model is presented that links CSF and ISF homeostasis to coordinated fluxes of water and solutes at both the blood-CSF and blood-brain transport interfaces. OUTLINE: 1 Overview2 CSF formation2.1 Transcription factors2.2 Ion transporters2.3 Enzymes that modulate transport2.4 Aquaporins or water channels2.5 Receptors for neuropeptides3 CSF pressure3.1 Servomechanism regulatory hypothesis3.2 Ontogeny of CSF pressure generation3.3 Congenital hydrocephalus and periventricular regions3.4 Brain response to elevated CSF pressure3.5 Advances in measuring CSF waveforms4 CSF flow4.1 CSF flow and brain metabolism4.2 Flow effects on fetal germinal matrix4.3 Decreasing CSF flow in aging CNS4.4 Refinement of non-invasive flow measurements5 CSF volume5.1 Hemodynamic factors5.2 Hydrodynamic factors5.3 Neuroendocrine factors6 CSF turnover rate6.1 Adverse effect of ventriculomegaly6.2 Attenuated CSF sink action7 CSF composition7.1 Kidney-like action of CP-CSF system7.2 Altered CSF biochemistry in aging and disease7.3 Importance of clearance transport7.4 Therapeutic manipulation of composition8 CSF recycling in relation to ISF dynamics8.1 CSF exchange with brain interstitium8.2 Components of ISF movement in brain8.3 Compromised ISF/CSF dynamics and amyloid retention9 CSF reabsorption9.1 Arachnoidal outflow resistance9.2 Arachnoid villi vs. olfactory drainage routes9.3 Fluid reabsorption along spinal nerves9.4 Reabsorption across capillary aquaporin channels10 Developing translationally effective models for restoring CSF balance11 Conclusion.

Gender differences in the renal response to renin-angiotensin system blockade.

Evidence suggests that gender differences exist in renin-angiotensin system (RAS) function. It was hypothesized that women may differ also in their response to RAS blockade. The renal and peripheral hemodynamic responses to incremental dosages of an angiotensin receptor blocker and the degree of angiotensin II (AngII) insensitivity achieved during 8 wk were examined in men and women. Participants were 30 young healthy men (n = 15; mean age 27 +/- 2) and women (n = 15; mean age 28 +/- 2) who were on a controlled sodium and protein diet for 1 wk before each study. The humoral, renal, and systemic response to incremental dosages of irbesartan (75 mg for 4 wk, then 150 mg for 4 wk) was assessed, as was the pressor response to AngII (3 ng/kg per min), at 2-wk intervals. AngII type 1 receptor expression in skin biopsies was assessed at baseline and after 8 wk by a real-time PCR protocol. Men and women both exhibited significant declines in BP. Women achieved significantly reduced AngII sensitivity compared with men at lower dosages, showing no pressor response at 4 wk of 75 mg/d irbesartan, whereas men continued to exhibit a pressor response at 4 wk of 150 mg/d. Receptor expression at baseline did not differ between men and women but by 8 wk was significantly decreased in women and unchanged in men. Our findings indicate that men may require larger dosages of angiotensin receptor blocker than do women and that the BP response cannot be used as a surrogate marker for adequate RAS blockade of the renal microvasculature.

RAGE, LRP-1, and amyloid-beta protein in Alzheimer's disease.

The receptor for advanced glycation end products (RAGE) is thought to be a primary transporter of beta-amyloid across the blood-brain barrier (BBB) into the brain from the systemic circulation, while the low-density lipoprotein receptor-related protein (LRP)-1 mediates transport of beta-amyloid out of the brain. To determine whether there are Alzheimer's disease (AD)-related changes in these BBB-associated beta-amyloid receptors, we studied RAGE, LRP-1, and beta-amyloid in human elderly control and AD hippocampi. In control hippocampi, there was robust RAGE immunoreactivity in neurons, whereas microvascular staining was barely detectable. LRP-1 staining, in contrast, was clearly evident within microvessels but only weakly stained neurons. In AD cases, neuronal RAGE immunoreactivity was significantly decreased. An unexpected finding was the strongly positive microvascular RAGE immunoreactivity. No evidence for colocalization of RAGE and beta-amyloid was seen within either microvessels or senile plaques. A reversed pattern was evident for LRP-1 in AD. There was very strong staining for LRP-1 in neurons, with minimal microvascular staining. Unlike RAGE, colocalization of LRP-1 and beta-amyloid was clearly present within senile plaques but not microvessels. Western blot analysis revealed a much higher concentration of RAGE protein in AD hippocampi as compared with controls. Concentration of LRP-1 was increased in AD hippocampi, likely secondary to its colocalization with senile plaques. These data confirm that AD is associated with changes in the relative distribution of RAGE and LRP-1 receptors in human hippocampus. They also suggest that the proportion of amyloid within the brains of AD patients that is derived from the systemic circulation may be significant.

The choroid plexus-cerebrospinal fluid system: from development to aging.

The function of the cerebrospinal fluid (CSF) and the tissue that secretes it, the choroid plexus (CP), has traditionally been thought of as both providing physical protection to the brain through buoyancy and facilitating the removal of brain metabolites through the bulk drainage of CSF. More recent studies suggest, however, that the CP-CSF system plays a much more active role in the development, homeostasis, and repair of the central nervous system (CNS). The highly specialized choroidal tissue synthesizes trophic and angiogenic factors, chemorepellents, and carrier proteins, and is strategically positioned within the ventricular cavities to supply the CNS with these biologically active substances. Through polarized transport systems and receptor-mediated transcytosis across the choroidal epithelium, the CP, a part of the blood-CSF barrier (BCSFB), controls the entry of nutrients, such as amino acids and nucleosides, and peptide hormones, such as leptin and prolactin, from the periphery into the brain. The CP also plays an important role in the clearance of toxins and drugs. During CNS development, CP-derived growth factors, such as members of the transforming growth factor-beta superfamily and retinoic acid, play an important role in controlling the patterning of neuronal differentiation in various brain regions. In the adult CNS, the CP appears to be critically involved in neuronal repair processes and the restoration of the brain microenvironment after traumatic and ischemic brain injury. Furthermore, recent studies suggest that the CP acts as a nursery for neuronal and astrocytic progenitor cells. The advancement of our knowledge of the neuroprotective capabilities of the CP may therefore facilitate the development of novel therapies for ischemic stroke and traumatic brain injury. In the later stages of life, the CP-CSF axis shows a decline in all aspects of its function, including CSF secretion and protein synthesis, which may in themselves increase the risk for development of late-life diseases, such as normal pressure hydrocephalus and Alzheimer's disease. The understanding of the mechanisms that underlie the dysfunction of the CP-CSF system in the elderly may help discover the treatments needed to reverse the negative effects of aging that lead to global CNS failure.

Enhanced prospects for drug delivery and brain targeting by the choroid plexus-CSF route.

The choroid plexus (CP), i.e., the blood-cerebrospinal fluid barrier (BCSFB) interface, is an epithelial boundary exploitable for drug delivery to brain. Agents transported from blood to lateral ventricles are convected by CSF volume transmission (bulk flow) to many periventricular targets. These include the caudate, hippocampus, specialized circumventricular organs, hypothalamus, and the downstream pia-glia and arachnoid membranes. The CSF circulatory system normally provides micronutrients, neurotrophins, hormones, neuropeptides, and growth factors extensively to neuronal networks. Therefore, drugs directed to CSF can modulate a variety of endocrine, immunologic, and behavioral phenomema; and can help to restore brain interstitial and cellular homeostasis disrupted by disease and trauma. This review integrates information from animal models that demonstrates marked physiologic effects of substances introduced into the ventricular system. It also recapitulates how pharmacologic agents administered into the CSF system prevent disease or enhance the brain's ability to recover from chemical and physical insults. In regard to drug distribution in the CNS, the BCSFB interaction with the blood-brain barrier is discussed. With a view toward translational CSF pharmacotherapy, there are several promising innovations in progress: bone marrow cell infusions, CP encapsulation and transplants, neural stem cell augmentation, phage display of peptide ligands for CP epithelium, CSF gene transfer, regulation of leukocyte and cytokine trafficking at the BCSFB, and the purification of neurotoxic CSF in degenerative states. The progressively increasing pharmacological significance of the CP-CSF nexus is analyzed in light of treating AIDS, multiple sclerosis, stroke, hydrocephalus, and Alzheimer's disease.

Increased expression of vasopressin v1a receptors after traumatic brain injury.

Experimental evidence obtained in various animal models of brain injury indicates that vasopressin promotes the formation of cerebral edema. However, the molecular and cellular mechanisms underlying this vasopressin action are not fully understood. In the present study, we analyzed the temporal changes in expression of vasopressin V1a receptors after traumatic brain injury (TBI) in rats. In the intact brain, the V1a receptor was expressed in neurons located in all layers of the frontoparietal cortex. The V1a receptor-immunoreactive product was predominantly localized to neuronal nuclei and had both a diffused and punctate staining pattern. The V1a receptors were also expressed in astrocytes, especially in layer 1 of the frontoparietal cortex. In these cells, two distinctive patterns of immunopositive staining for V1a receptors were observed: a diffused cytosolic staining of cell bodies and processes and a clearly punctate staining pattern that was predominantly localized to the astrocytic cell bodies. The real-time reverse-transcriptase polymerase chain reaction analysis of changes in mRNA for the V1a receptor demonstrated that after TBI, there is an early (4 h post-TBI) increase in the number of transcripts in the ipsilateral frontoparietal cortex, when compared to the contralateral hemisphere or the sham-injured rats. This increase in the message was followed by the up-regulation of expression of the V1a receptors at the protein level. This was most evident in cortical astrocytes in the areas surrounding the lesion. The number of the V1a receptor-immunopositive astrocytes in the traumatized parenchyma gradually increased, starting at 8 h and peaking at 4-6 days after TBI. Furthermore, a redistribution of V1a receptors from the astrocytic cell bodies to the astrocytic processes was observed. In addition to astrocytes, an increased expression of V1a receptors was found in the endothelium of both blood microvessels and the large-diameter blood vessels in the frontoparietal cortex ipsilateral to injury. This increase in the V1a receptor expression was apparent between 2 and 4 days after TBI. As early as 1-2 h following the impact, there was also a striking increase in the number of the V1a receptor-immunopositive beaded axonal processes, with greatly enlarged varicosities, that were localized to various areas of the injured parenchyma. It is suggested that the increased expression of V1a receptors plays an important role in the vasopressin-mediated formation of edema in the injured brain.

The profile of cardiac patients with renal artery stenosis.

OBJECTIVES: We examined the prevalence and severity of renal artery stenosis (RAS) in patients undergoing cardiac catheterization who were deemed at risk for RAS based on clinical or laboratory criteria for study entry, but who had not previously been suspected of having RAS. BACKGROUND: The diagnosis of atherosclerotic RAS remains problematic because its clinical manifestations are nonspecific. METHODS: Consecutive patients undergoing non-emergent cardiac catheterization at a single institution during a 12-month period were evaluated using standardized clinical, laboratory, and angiographic criteria. Patients exhibiting at least one of four predefined selection criteria (severe hypertension, unexplained renal dysfunction, acute pulmonary edema with hypertension, or severe atherosclerosis) were prospectively registered and underwent coincident diagnostic renal angiography. RESULTS: Renal angiography was performed in 851 patients and was diagnostic in 837. Angiographically evident renal atherosclerosis was present in 39% of the population, with RAS > or =50% in 120 (14.3%) and severe stenosis (> or =70%) in 61 (7.3%). Severe stenosis was present in 48 (7%) patients with severe atherosclerosis, 38 (16%) with renal dysfunction, 25 (9%) with hypertension, and 2 (22%) with acute pulmonary edema with hypertension. The prevalence was higher in those exhibiting multiple selection criteria. In a multivariate model, severe RAS was associated with age, female gender, reduced creatinine clearance, increased systolic blood pressure, and peripheral or carotid artery disease. CONCLUSIONS: In a population at risk of, but not previously suspected of having RAS, severe RAS is associated with simple and readily determined clinical and laboratory patient characteristics. These data facilitate focused application of diagnostic renal angiography.

Interactions between gender and the angiotensin type 1 receptor gene polymorphism.

BACKGROUND: The cardiovascular effects of angiotensin II are mediated by the angiotensin II type 1 receptor (AGT1R); one polymorphism of the AGT1R gene, A1166-->C, has been associated with hypertension. The hemodynamic response to angiotensin II is blunted in women compared to men, but interactions between gender, blood pressure, and AGT1R gene polymorphisms are unclear. METHODS: A total of 81 young healthy normotensive individuals maintained regulated sodium and protein intake prior to study. They were divided into four groups based on gender and A1166-->C genotype (AA versus AC/CC); serial supine blood pressures were obtained. A subset of 52 individuals received graded infusions of angiotensin II. Inulin and paraaminohippurate clearance techniques were used to measure renal hemodynamic function at baseline and in response to the infusions. RESULTS: Men with the AC/CC genotype exhibited higher blood pressures than men with the AA genotype; however, this relationship was not found among women. Analysis of covariance revealed a significant interaction between gender and AGT1R genotype in the determination of blood pressure. Glomerular filtration rate (GFR) declined variably in the study subjects following infusion of angiotensin II, and a statistical model incorporating gender and genotype best predicted the fall in GFR. There was a trend for females of the AA genotype to have a greater fall in GFR in response to angiotensin II infusion, than any of the other groups. CONCLUSION: In young healthy subjects, there is an important interaction between gender, the AGT1R A1166-->C gene polymorphism, and blood pressure. In addition, the renal hemodynamic response to angiotensin II infusion is a function of both gender and the AGT1R genotype.

Pediatric intracranial aneurysm: a diagnostic dilemma solved with contrast-enhanced MR imaging.

Childhood intracranial aneurysms are exceedingly uncommon. Diagnosis of intracranial aneurysms in infancy may be difficult because of their infrequency and confusing clinical presentation. Findings with routine radiographic methods may be misleading and difficult to interpret. We present a case of the rupture of an anterior communicating artery aneurysm in a 7-month-old child. The rupture had eluded diagnosis until contrast-enhanced MR imaging was performed.

Vertebrobasilar thrombosis in children: report of two cases and recommendations for treatment.

Two consecutive cases of children with vertebrobasilar thrombosis (VBT) were treated with high-dose intra-arterial urokinase within 4 h of presenting to the emergency room, after full evaluation by CT scan, MRI and MR angiography. Complete resolution of neurologic symptoms was achieved in both cases. Based on our limited pediatric experience, previous treatment of VBT at our institution and a review of the relevant literature, the authors suggest that VBT be specifically ruled out at initial diagnosis, and if present, full consideration be given to immediate treatment with intra-arterial thrombolytic therapy. This may lead to a significant reduction in the morbidity and mortality associated with VBT in children. A large prospective multi-institution study is needed to further evaluate the efficacy of this approach to childhood stroke.

Variation in the renin angiotensin system throughout the normal menstrual cycle.

It has been demonstrated elsewhere that circulating renin angiotensin system (RAS) components peak when plasma estrogen levels are highest, during the luteal phase of the normal menstrual cycle. This phenomenon has been attributed to "activation" of the RAS. The end-organ vasoconstrictive response to this phenomenon has not been well established. In two related experiments, the RAS was studied in healthy, premenopausal women during predefined phases of the normal menstrual cycle. In the first experiment, the circulating components of the RAS and the systemic hemodynamic response to incremental lower body negative pressure (LBNP) during the follicular and luteal phases of the menstrual cycle were examined. Response variables included mean arterial pressure (MAP), renin, plasma renin activity (PRA), angiotensin II (AngII), and aldosterone. Baseline levels of renin, PRA, and aldosterone were significantly higher in the luteal phase. In response to LBNP, there were significant increases in all variables in both phases; however, the humoral response to this stimulus was significantly augmented in the luteal phase compared with the follicular phase. Despite these elevations in circulating components of the RAS during the luteal phase, subjects were unable to maintain MAP in response to LBNP, exhibiting a dramatic depressor response that did not occur during the follicular phase. In the second experiment, renal and peripheral hemodynamic function at baseline, and in response to AngII blockade with losartan, were examined in women during these high and low estrogen phases of the menstrual cycle. The renal and peripheral hemodynamic responses were similar in the luteal phase and the follicular phase. These results demonstrate that, despite an increase in circulating RAS components during the luteal phase of the menstrual cycle, the system is blunted rather than "activated," at least at a tissue level. Further studies are needed to clarify this mechanism.