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Collagenofibrotic glomerulopathy is considered as a form of glomerulopathy in which organized collagen type III progressively deposits. We report a case of this disease with widespread expression of collagen type V. A 65-year-old woman was admitted to our hospital for further evaluation of nephrotic-range proteinuria. The patient had had anemia and hypertension for 9 years, and proteinuria for 3 years. A renal biopsy specimen showed a remarkable mesangial expansion with Congo red-negative and periodic acid-Schiff-positive deposits. At the ultrastructural level, two forms of bundling fibers were found in the mesangium and subendothelial side of the glomerular basement membranes (GBM). The GBM itself appeared normal. Immunohistochemical investigation showed that the glomerular lesions were strongly reactive with both anti-collagen type-III and -V antibodies. Immunoelectron microscopy demonstrated collagen type V in both forms of bundling fibers. Despite therapy, her renal function declined. The clinical course and renal pathology of this case were in accordance with collagenofibrotic glomerulopathy except for the widespread expression of collagen type V. Collagen type V is a fibrillar collagen capable of forming banding fibrils. This report poses the question whether collagen type V accumulates only in this particular case or whether it is a normal component in collagenofibrotic glomerulopathy.

Summary Background Present angiotensin-converting-enzyme inhibitor treatment fails to prevent progression of non-diabetic renal disease. We aimed to assess the efficacy and safety of combined treatment of angiotensin-converting-enzyme inhibitor and angiotensin-II receptor blocker, and monotherapy of each drug at its maximumdose, in patients with non-diabetic renal disease. Methods 336 patients with non-diabetic renal disease were enrolled from one renal outpatient department in Japan. After screening and an 18-week run-in period, 263 patients were randomly assigned angiotensin-II receptor blocker (losartan, 100 mg daily), angiotensin-converting-enzyme inhibitor (trandolapril, 3 mg daily), or a combination of both drugs at equivalent doses. Survival analysis was done to compare the effects of each regimen on the combined primary endpoint of time to doubling of serum creatinine concentration or end-stage renal disease. Analysis was by intention to treat. Findings Seven patients discontinued or were otherwise lost to follow-up. Ten (11%) of 85 patients on combination treatment reached the combined primary endpoint compared with 20 (23%) of 85 on trandolapril alone (hazard ratio 0·38, 95% CI 0·18–0·63, p=0·018) and 20 (23%) of 86 on losartan alone (0·40, 0·17–0·69, p=0·016). Covariates affecting renal survival were combination treatment (hazard ratio 0·38, 95% CI 0·18–0·63, p=0·011), age (1·30, 1·03–2·29, p=0·009), baseline renal function (1·80, 1·02–2·99, p=0·021), change in daily urinary protein excretion rate (0·58, 0·24–0·88, p=0·022), use of diuretics (0·80, 0·30–0·94, p=0·043), and antiproteinuric response to trandolapril (0·81, 0·21–0·91, p=0·039). Frequency of side-effects with combination treatment was the same as with trandolapril alone. Interpretation Combination treatment safely retards progression of non-diabetic renal disease compared with monotherapy. However, since some patients reached the combined primary endpoint on combined treatment, further strategies for complete management of progressive nondiabetic renal disease need to be researched.

Pulmonary involvement in cryoglobulinemia usually is mild. We present a rare case of severe lung involvement in mixed cryoglobulinemia. A 73-year-old woman with cryoglobulinemic glomerulonephritis was admitted. Dyspnea appeared suddenly two days later. She received the diagnosis of acute lung injury according to the concept proposed by the American-European Consensus Conference. Management required corticosteroid pulse therapy and plasma exchange. This case is the first description of successful early and long-term management of severe lung involvement observed in cryoglobulinemia. Although she has been free of chest symptoms for seven months, further follow-up may be necessary to assess the potential danger of relapse.

We report the effect of pallidal stimulation for the patients with Parkinson's disease (PD) and the changes of neurotransmitters in the cerebrospinal fluid (CSF) during stimulation. Chronic pallidal stimulation was performed on 23 patients. Fourteen patients (60%) had an improvement in the H&Y scale and 16 patients (70%) showed more than 10% of improvement rate in the Unified Parkinson's Disease Rating Scale (UPDRS) score. Both showed statistic significance. The treatment was effective for tremor and rigidity, on the other hand, less effective for gait disturbance and bradykinesia. There were no serious complications or adverse effects. The concentration of Gamma-aminobutyric acid (GABA) in the CSF significantly increased during stimulation. In a few cases, an increase in the level of dopamine (DA), homovanillic acid (HVA) and noradrenaline (NA) was also seen. We conclude that pallidal stimulation has great effects in patients with PD, especially those who have tremor and/or rigidity as a chief symptom. The mechanism of the treatment would involve an activation of the GABAergic system in the globus pallidus.

Objectives Radiation-induced aneurysm is a rare complication for head and neck tumors. Only seven cases of an aneurysm after stereotactic radiosurgery and/or stereotactic radiotherapy (SRT) have been described. We report two patients with a ruptured internal carotid artery (ICA) aneurysm presenting with catastrophic epistaxis after repeated SRT for an anterior skull base tumor. Results Two male patients received repeated SRT in various combinations following surgery for an anterior skull base tumor. They presented with significant epistaxis due to rupture of the aneurysm of the ICA 6 and 77 months after the final SRT, respectively. The aneurysms were located within the radiation field. Preoperative angiography had revealed no aneurysms. Thus the aneurysms in these cases were most likely induced by the repeated SRT. Conclusions This is a proven report of aneurysm formation following repeated SRT without conventional radiotherapy. SRT may be very effective to control malignant skull base tumors. However, the possible development of radiation-induced aneurysm of the ICA should be considered in the case of repeated SRT. The surviving patients who have received SRT should undergo sequential follow-up for possible vascular involvement.

Temozolomide (TMZ), a DNA methylating agent, is widely used in the adjuvant treatment of malignant gliomas. O6-methylguanine-DNA methyltranferase (MGMT), a DNA repair enzyme, is frequently discussed as the main factor that limits the efficacy of TMZ. Zoledronic acid (ZOL), which is clinically applied to treat cancer-induced bone diseases, appears to possess direct anti-tumor activity through apoptosis induction by inhibiting mevalonate pathway and prenylation of intracellular small G proteins. In this study, we evaluated whether ZOL can be effectively used as an adjuvant to TMZ in human malignant glioma cells that express MGMT. Malignant glioma cell lines, in which the expression of MGMT was detected, did not exhibit growth inhibition by TMZ even at a longer exposure. However, combination experiment of TMZ plus ZOL revealed that a supra-additive effect resulted in a significant decrease in cell growth. In combined TMZ/ZOL treatment, an increased apoptotic rate was apparent and significant activation of caspase-3 and cleavage of poly-(ADP-ribose) polymerase were observed compared with each single drug exposure. There were decreased amounts of Ras-GTP, MAPK and Akt phosphorylation and MGMT expression in the ZOL-treated cells. Subcutanous xenograft models showed significant decrease of tumor growth with combined TMZ/ZOL treatment. These results suggest that ZOL efficaciously inhibits activity of Ras in malignant glioma cells and potentiates TMZ-mediated cytotoxicity, inducing growth inhibition and apoptosis of malignant glioma cells that express MGMT and resistant to TMZ. Based on this work, combination of TMZ with ZOL might be a potential therapy in malignant gliomas that receive less therapeutic effects of TMZ due to cell resistance.

Object. There is growing evidence to indicate that tissue transplantation can potentially be a restorative neurosurgical treatment for patients with Parkinson disease (PD). In this study the authors investigated the clinical effect of unilateral intrastriatal grafting of autologous sympathetic neurons in patients with PD. Methods. Four patients with PD who had been observed for 1 year after graft placement of autologous sympathetic neurons were selected for an analysis of the effect of that procedure. Sympathetic ganglion tissue was endoscopically excised from the thoracic sympathetic trunk and grafted into the unilateral caudate head and putamen of the PD patients. No changes were made in the patients' preoperative regimens of antiparkinsonian medications, and clinical evaluations were made principally according to those established by the Core Assessment Program for Intracerebral Transplantation Committee. Whereas the sympathetic neuron grafts failed to affect clinical scores reflecting the patients' motor performance, which was evaluated during either the “on” or “off” phases, the grafts significantly increased the duration of the levodopa-induced on period with consequent reduction in the percentage of time spent in the off phase. This beneficial effect may be explained by the results of the present in vitro experiment, which show that human sympathetic neurons have the ability to convert exogenous levodopa to dopamine and to store this synthesized dopamine. Conclusions. Sympathetic neuron autografts were found to improve performance status in patients with PD by reducing the time spent in the off phase. This clearly indicates that sympathetic ganglion tissue, the use of which involves few ethical issues, can be an efficacious donor source in cell transplantation therapy for PD. Further studies are needed to determine whether the grafts may provide long-lasting clinical benefits.

A 69-year-old right-handed man who exhibited unilateral spatial neglect in association with a chronic subdural haematoma, presented with mild left arm and leg weakness first noted 4 weeks prior to admission. Neurologic examination on admission revealed a mild left hemiparesis, including the face. Neuropsychologic examination revealed left unilateral spatial neglect, but no language disturbance. Minimal support was necessary to maintain activities of daily living. Computed tomography revealed a large right temporoparietal, extraaxial hypodense fluid collection containing scattered hypodense foci. The haematoma was evacuated via a right parietal burr hole. Following surgery, the patient dramatically improved neurologically and neuropsychologically, as well as in independent performance of daily activities. It is suggested that the improvement in ADL provides a behavioural correlate of improvement in the latter, represented a behavioural correlate of improved cerebral function, and that either direct compression by the chronic subdural haematoma or an interhemispheric pressure difference had caused unilateral spatial neglect. Such neglect is an unusual consequence of chronic subdural haematoma.

Recent in vitro studies have described the toxicity of levodopa ( l -DOPA) to dopamine (DA) neurons. We investigated whether metabolic inhibition with rotenone, an inhibitor of complex I of the mitochondrial respiratory chain, may enhance the toxicity of l -DOPA toward DA neurons in mesencephalic cultures. The uptakes of DA and GABA were determined to evaluate the functional and morphological integrity of DA and non-DA neurons, respectively. Pretreatment with rotenone significantly augmented the toxic effect of l -DOPA on DA neurons. Interestingly, prior metabolic inhibition with rotenone rendered DA cells susceptible to a dose (5 μM) of l -DOPA that otherwise exhibited no toxic effect. DA uptake was more intensely attenuated than GABA uptake after the combined exposure to rotenone and l -DOPA. This was confirmed by cell survival estimation showing that tyrosine hydroxylase-positive DA cells are more vulnerable to the sequential exposure to the drugs than total cells. The selective toxic effect of l -DOPA on rotenone-pretreated DA neurons was significantly blocked by antioxidants, but not antagonists of NMDA or non-NMDA glutamate receptors. This indicates that oxidative stress play a central role in mediating the selective damage of DA cells in the present experimental paradigm. Our results raise the possibility that long-term l -DOPA treatment could accelerate the progression of degeneration of DA neurons in patients with Parkinson's disease where potential energy failure due to mitochondrial defects has been demonstrated to take place.

Hemodynamic insults--high wall shear stress (WSS) combined with high positive WSS gradient (WSSG)--have been proposed to link to cerebral aneurysm initiation. We report 4 cases of aneurysms with proximal stenosis, including 1 de novo aneurysm, that might be associated with hemodynamic insults caused by the proximal stenosis.In 4 clinical cases, the diameter stenosis was 37% to 49% (mean, 42%) located 2.7 to 4.7 mm (mean, 3.7 mm) from the apex. We performed computational fluid dynamics simulations for 2 cases: a ruptured basilar terminus aneurysm with proximal stenosis (which had an angiogram taken 15 years previously that showed no aneurysm and no stenosis) and a cavernous carotid artery aneurysm with proximal stenosis. In both cases, the stenosis caused unphysiologically high WSS (7 Pa) at the apex, nearly doubling the WSS and WSSG values. To investigate the relationship between stenosis and distal hemodynamic elevation, we created a series of T-shaped vascular models by varying the degree and location of stenosis. We found that stenosis40% by diameter located within 10 mm from the apex caused unphysiologically high WSS and WSSG. All 4 clinical cases satisfied these conditions.Proximal stenosis could produce high WSS and high positive WSSG at the apex, thus potentially inducing de novo aneurysm formation.BT, basilar terminusCFD, computational fluid dynamicsICA, internal carotid arteryWSS, wall shear stressWSS, wall shear stress gradient.

Results of Gamma Knife radiosurgery (GKS) were retrospectively evaluated in 16 patients with histologically confirmed atypical and anaplastic intracranial meningiomas.There were nine men and seven women (mean age 61.0 years). Atypical meningiomas were diagnosed in nine cases and anaplastic meningiomas in seven. In nine patients there was malignant transformation of a tumor that had initially proved to be benign. In total, 21 radiosurgical procedures were performed. The mean tumor volume at the time of GKS was 7.1 cm3. The mean marginal and maximum irradiation doses were 18.8 and 37.0 Gy, respectively. The mean length of follow-up after treatment was 37.1 months.Of 21 radiosurgical procedures, 6 (29 %) led to stabilization of tumor growth during the mean follow-up of 40.5 months. It was significantly associated with small lesion volume (P = 0.02), and greater marginal (P = 0.04) and maximum (P = 0.02) irradiation doses. Seven patients underwent eight surgical resections of a progressing tumor during the mean period of 26.1 months after irradiation. Five patients (31 %) died because of tumor progression within the average time period of 16.8 months after GKS. Overall, at the time of the last follow-up just two patients (13 %) had no evidence of tumor regrowth, and only three patients (19 %) maintained good activities of daily living during 12, 59, and 69 months, respectively, after radiosurgery.GKS has limited efficacy in cases of non-benign meningioma. Better tumor control rates can be attained for small neoplasms treated with greater marginal and maximum irradiation doses.

Background: Different embolic protection devices in carotid artery stenting(CAS) have been developed to prevent procedural cerebral embolization. Proximal flow reverse protection has theoretically advantages from the view point of prevention of distal embolism, compared with distal protection. On the other hand, there is a disadvantage that this system is complexity. Purpose: we evaluated the safety and efficacy of proximal reverse flow protection for CAS in patients with high-grade stenosis. Methods: Distal protection has mainly been used as protection device in our institute. In case that there was high possibility of distal embolism, proximal reverse flow protection has been used. These cases treated with proximal flow reverse protection were included in this study. A total of 75 patients(71 men, mean age 71.9 years) with a high grade stenosis≧80% were treated between September 2003 and March 2012. 72% (n=54) of the patients were symptomatic.The primary endpoint was death and stroke rate at 30 days. The outcome was also compared to data from 386 patients with a high-grade stenosis who were treated under only distal protection device in the same period. Results: The procedure was technically successful in all cases. In 2 cases out of proximal reverse flow protection group, intracerebral hemorrhage was occurred. However, there was no ischemic complication. In distal protection group, the incidence of complication occurred in 11 cases (7 ischemic, 4 otheres). The stroke/death rate at 30 days was 2.6% (n=2) in proximal reverse flow protection group compared to 2.8% (n=11) in the distal protection group. There was no significant difference. However, the incidence of ischemic complication in the proximal reverse flow protection group tended to be lower than that of distal protection group. Conclusion: In selected patients with large atherosclerotic plaques, the clinical results of CAS with proximal reverse flow protection is safe and feasible. Especially, the incidence of ischemic stroke was lower than that of distal protection.

We assessed the effects of addition of the lazaroid U-83836E to a preservation medium on the survival of rat dopamine neurons stored before culturing or intracerebral transplantation. Embryonic ventral mesencephalic tissue was preserved at 4 degrees C for 8 days with or without the addition of 0.3 mu M of U-83836E to a chemically defined "hibernation" medium. Freshly dissected mesencephalic tissue was used in control groups. For culture experiments, the mesencephalic tissue was dissociated and grown in serum-containing medium. Following 24-48 h in vitro, the number of dopamine neurons in cultures derived from tissue hibernated without the lazaroid was 40% of fresh control, compared with 67% of control in cultures prepared from tissue stored in the presence of U-83836E. When mesencephalic tissue was transplanted to the dopamine-depleted striatum of hemiparkinsonian rats following 8 days storage at 4 degrees C in a medium without U-83836E, the mean number of surviving dopamine neurons in the grafts was significantly reduced to 40% of control. In contrast, grafts of tissue which had been hibernated in U-83836E-containing medium contained as many dopamine neurons as transplants of freshly dissected tissue. High yields of surviving grafted dopamine neurons were correlated to a significantly faster onset of functional recovery of amphetamine-induced motor asymmetry. We conclude that the storage period for rat mesencephalic tissue can be prolonged up to 8 days when using lazaroid-supplemented hibernation medium. As lazaroids have undergone clinical safety testing, the application of lazaroids for tissue storage in clinical transplantation trials can be envisaged.

We have examined the effects of either brain-derived neurotrophic factor (BDNF), the BB-isoform of platelet-derived growth factor (PDGF-BB), or a combination of these growth factors on the survival and the morphological development of embryonic striatal neurons grown under serum-free culture conditions. Striatal neurons were identified using immunocytochemistry for "dopamine- and adenosine 3':5'-monophosphate-regulated phosphoprotein with a molecular weight of 32 kilodalton" (DARPP-32). BDNF and PDGF-BB promoted the survival of DARPP-32-positive neurons, with the magnitude of their effects being comparable. A combination of these growth factors exerted no significant additive effects on cell survival. BDNF stimulated morphological differentiation of DARPP-32-containing neurons by increasing the length of neurites, the number of branching points on the neurites, and the soma area. By contrast, PDGF-BB increased the neurite length and the cell body area, but not the number of branching points. BDNF also protected striatal neurons from excitotoxicity induced by N-methyl-D-aspartate, whereas PDGF-BB had no effect under the same treatment conditions as those for BDNF. Thus, BDNF is trophic for striatal DARPP-32-containing neurons in vitro by enhancing the survival, morphological differentiation and resistance to excitotoxicity, and its mechanisms of action are probably different from those of PDGF-BB.

This video demonstrates surgical techniques of the occipital transtentorial approach to a pineal region tumor without using a fixed brain retractor, which may cause functional impairment or even tissue injury to the occipital visual cortex. There are several ways to facilitate retractorless surgery through this approach. A lateral-semiprone positioning of the patient can induce gravity retraction. The brain is relaxed by draining CSF fluid through lumbar drainage or lateral ventricular tap in the case of obstructive hydrocephalus. Dynamic retraction with handheld instruments after extensive dissection of the deep venous system, including basal veins, can provide a sufficient working space.The video can be found here: https://youtu.be/kQvEHiNcRow.

Leksell GammaPlan (LGP) software was initially designed for Gamma Knife radiosurgery, but it can be suc­cessfully applied to planning of the open neurosurgical procedures as well. We present our initial experience of delineating the cranial nerves in the vicinity of skull base tumors, combined visualization of the implanted subdural electrodes and cortical anatomy to facilitate brain mapping, and fusion of structural magnetic resonance imaging and diffusion tensor imaging performed with the use of LGP before removal of intracranial neoplasms. Such preoperative information facilitated choosing the optimal approach and general surgical strategy, and corresponded well to the intraoperative findings. Therefore, LGP may be helpful for planning open neurosurgical procedures in cases of both extraaxial and intraaxial intracranial tumors.

Objective: Results of Gamma Knife radiosurgery (GKS) were retrospectively evaluated in 16 patients with histologically confirmed atypical and anaplastic intracranial meningiomas.

In rodent models of Parkinson disease in which transplants of dissociated rodent and human embryonic mesencephalic tissue, rich in dopamine neurons, have been studied, only 5-20% of the dopamine neurons survive the implantation procedure. We have investigated the effects of inhibiting free radical generation with two lazaroids, U-74389G and U-83836E, on the survival of embryonic rat dopamine neurons. U-74389G is a 21-aminosteroid, and U-83836E combines the piperazinyl pyrimidine portion of 21-aminosteroids with the antioxidant ring of alpha-tocopherol. In an initial study, we found that the lazaroids markedly prolonged the period after tissue dissociation that an embryonic mesencephalic cell suspension exhibits high cell viability in vitro, as assessed by using a dye exclusion method. In a second series of experiments, addition of lazaroids to dissociated mesencephalic graft tissue increased the yield of surviving rat dopamine neurons 2.6-fold after implantation in the dopamine-denervated rat striatum. The improved survival correlated with an earlier onset of graft-induced functional effects in the amphetamine-induced rotation test. Thus, inhibition of free radical generation can significantly increase the yield of grafted embryonic dopamine neurons. Addition of lazaroids to the graft preparation is a relatively simple modification of the transplantation protocol and could readily be applied in a clinical setting. Moreover, since iron-dependent lipid peroxidation has been suggested to play a role in the death of nigral dopamine neurons in Parkinson disease and lazaroids are particularly potent inhibitors of such processes, the findings may have implications for the pathogenesis of this disease.

We have studied the effect of selectively dissecting the lateral (LGE) and medial (MGE) ganglionic eminences of the striatal primordium on the yield of DARPP-32-immunoreactive striatal neurones in serum-free cultures maintained for 2 or 5 days. The LGE cultures yielded an approximately four-fold higher number of DARPP-32-positive neurones compared with the MGE cultures, without an accompanying difference in total cell numbers. In both types of culture, there was a 70% reduction in DARPP-32 positive neurones from 2 to 5 days in vitro. In conclusion, the LGE is a rich source of striatal precursors and the present culture system provides a good model for the study of factors that may prevent striatal neuronal death.

The effects of pretreatment with interleukin-1 (IL-1) on neurite growth and cell survival of rat superior cervical ganglion (SCG) explants were examined. Neonate rat SCG explants were cultured with serum-containing growth media. Pretreatment with IL-1 beta (30 U/ml) for 3 hours stimulated neurite outgrowth of the SCG explant, which was inhibited by the addition of anti-nerve growth factor (NGF) antibody to the growth medium. Adult rat autologous SCG with the same pretreatment and non-treated ganglia were transplanted into the lateral ventricle. Histological evaluation of the grafts 2 weeks after transplantation revealed that the pretreated SCG cells survived better. Pretreatment with IL-1 may achieve the NGF-mediated neurotrophic effect in sympathetic ganglionic neurons resulting in enhanced graft survival.

Leptin, the product of the ob gene, plays important roles in the regulation of food intake and body weight through its receptor in the hypothalamus. To identify novel transcripts induced by leptin, we performed cDNA subtraction based on selective suppression of the polymerase chain reaction by using mRNA prepared from the forebrain of leptin-injected ob/ob mice. One of the genes isolated was a mouse homolog of human negative regulatory element-binding protein (NREBP). Its expression was markedly increased by leptin in the growth hormone secretagogue-receptor (GHS-R)-positive neurons of the arcuate nucleus and ventromedial hypothalamic nucleus. The promoter region of GHS-R contains one NREBP binding sequence, suggesting that NREBP regulates GHS-R transcription. Luciferase reporter assays showed that NREBP repressed GHS-R promoter activity in a hypothalamic neuronal cell line, GT1-7, and its repressive activity was abolished by the replacement of negative regulatory element in GHS-R promoter. Overexpression of NREBP reduced the protein expression of endogenous GHS-R without affecting the expression of ob-Rb in GT1-7 cells. To determine the functional importance of NREBP in the hypothalamus, we assessed the effects of NREBP on ghrelin action. Although phosphorylation of AMP-activated protein kinase α (AMPKα) was induced by ghrelin in GT1-7 cells, NREBP repressed ghrelin-induced AMPKα phosphorylation. These results suggest that leptin-induced NREBP is an important regulator of GHS-R expression in the hypothalamus and provides a novel molecular link between leptin and ghrelin signaling.

Pituitary adenomas with extensive suprasellar extension are a therapeutic challenge. The efficacy and safety of the endoscopic endonasal approach for non-functioning giant pituitary adenoma was evaluated retrospectively. A total of 43 consecutive patients with pituitary adenomas with a suprasellar extension of >20 mm underwent tumor resection with a purely endoscopic endonasal approach, and their surgical outcomes were analyzed. At surgery, irrespective of the size and shape of the adenoma, every effort was made to perform intracapsular resection under direct visual control using an angled-lens endoscope. Gross total removal was achieved in 20 out of 43 patients. Postoperatively, 42 patients showed varying improvement of both visual field defects and impaired visual acuity. In two patients who presented with gait disturbance and cognitive dysfunction due to obstructive hydrocephalus, these symptoms were completely resolved. There were no serious operative complications. The results indicate that intracapsular resection via the endoscopic approach can be a safe and effective treatment for giant pituitary adenomas.

The possible involvement of atrial natriuretic peptide (ANP) in cerebral cortical microcirculation was investigated in rats by means of laser-Doppler flowmetry and immunohistochemistry. In the laser-Doppler study, local cerebral blood flow (LCBF) changes after the administration of 10(-6) to 10(-8) mol/LANP solution or vehicle (saline solution) as an intracortical injection for 5 minutes were continuously monitored throughout the 30 minutes of the study and were expressed as percentages of preinjection values represented as 0%. The administration of 10(-6) to 10(-8) mol/LANP caused a significant decrease in LCBF; the onset of LCBF responses occurred within a few minutes after the start of the injection and the decrease in LCBF reached the maximum level within 7 to 10 minutes after the completion of the administration, after which LCBF gradually recovered. In the immunohistochemical study, no specific ANP immunoreactivity was found associated with the intraparenchymal blood vessels; however, ANP-immunoreactive neurons were observed primarily in the hypothalamus and septum, in which high concentrations of ANP-containing neurons have been identified. The data from the laser-Doppler study suggest that central ANP may produce a vasoconstriction of the intraparenchymal blood vessels, regardless of whether through direct action on these vessels or through the mediation by some system in the central nervous system. Because there is no evidence for ANP-containing nerves around these vessels, the role of central ANP in the cerebral circulation must await identification of the source of perivascular ANP.

An unusual case of posttraumatic porencephaly preceded by neither overt cerebral contusion nor hemorrhage is reported. The cerebral cortex just above the porencephalic cyst was found intra-operatively to be partially herniated into a fracture line, while the cortex elsewhere was completely intact. The porencephalic cyst communicated with the lateral ventricle. Apparently, brain herniation and the cyst-ventricle communication can be causative factors in the occurrence and growth of posttraumatic porencephaly.

Whereas fibrous dysplasia is a well-known, developmental skeletal disorder with a benign clinical course, fibrous dysplasia of the clivus is extremely rare and has seldom been reported. Differentiating this benign entity from more aggressive diseases involving the clivus is important for the proper management of lesions in this area. We here report a case of fibrous dysplasia of the clivus and discuss its radiographic features. The patient was 55-year-old male who had suffered from headache for months. Physical and neurological examinations found no abnormalities. The computed tomographic (CT) scan and magnetic resonance imaging (MRI) showed an abnormal mass lesion in the lower of the third clivus. On CT scan, the mass lesion exhibited a ground-glass appearance. The lesion was detected as hypointense and a mixture of hyperintense and isointense areas on T1-weighted and T2-weighted MRI, respectively. Heterogenous enhancement was noted after infusion of GD-DTPA. The patient underwent a transsphenoidal resection of the mass and the histopathologic diagnosis was fibrous dysplasia.

Background The Kidney Disease Outcomes Quality Initiative (K/DOQI) Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease recommend 1.25 mmol/l Ca dialysate for both hemodialysis and peritoneal dialysis, while 1.5 mmol/l Ca dialysate has been used in our dialysis center. Methods Therefore, we switched the dialysate calcium concentration from 1.5 - 1.25 mmol/l and observed the effects on serum calcium (S-Ca), phosphorus (S-P), 1-84 parathyroid hormone (whole PTH, w-PTH), bone-specific alkaline phosphatase (BAP), and tartrate-resistant acid phosphatase isoform 5b (TRACP-5b) for 6 months in 58 hemodialysis patients. Prescription of active vitamin D (VD) metabolites and Ca carbonate was increased in response to the changes in laboratory data. Results Decrease of S-Ca was evident at 2 weeks and S-Ca remained low for 6 months. Transient elevation of S-P, which might be caused by stimulated bone resorption, was observed after the switch. In patients with low PTH (w-PTH less than 90 pg/ml before the switch), continuous increase of w-PTH, BAP, and TRACP-5b was observed. This appeared to be a favorable response because the risk ofadynamic bone disease was high in this group of patients. On the other hand, acute elevation of the 3 parameters was well-controlled in patients with moderate and high PTH (w-PTH from 90 - 180 pg/ml, w-PTH more than 180 pg/ml, respectively) by increased dosage of active VD. Conclusion These results demonstrate that 1.25 mmol/l Ca dialysate improved mineral metabolism by lowering S-Ca and releasing oversuppression of PTH. Our data also suggest that appropriate use of active VD could prevent acute rise of PTH.

Grafting of catecholamine-producing cells can be a possible therapeutic strategy for attenuating motor symptoms in Parkinson's disease (PD). The potential of autologous sympathetic neurons has been investigated as a donor for cell therapy of PD. The clinical trials of autotransplantation of sympathetic ganglion cells in PD have revealed that the grafts increase the duration of L-DOPA (L-dihydroxy phenyl alanine)-induced beneficial effects, and that the graft-mediated effect is detectable during a follow-up period of at least 1 year postgrafting. In an in vitro analysis of the ability of human sympathetic neurons to release catecholamines, although DA was not detectable under basal conditions, DA levels were significantly increased upon exposure to exogenous L-DOPA. Furthermore, animal experiments with xenografting of human sympathetic ganglionic neurons in the DA-denervated striatum of rats demonstrated that a significant increase in striatal DA levels is noted after systemic L-DOPA treatment, and that the DA levels remain high for longer periods of time in the grafted rats than in control animals with sham surgery. The L-DOPA-induced rise of striatal DA levels was significantly attenuated when given reserpine pretreatment. This suggests that DA derived from exogenously administered L-DOPA is subjected to, at least in part, vesicular storage in grafted sympathetic neurons. Histological examinations indeed showed that the grafts express aromatic-L-amino acid decarboxylase and vesicular monoamine transporter-2, both of which are important molecules for the synthesis and the storage of DA, respectively. Taken together, grafted sympathetic neurons can provide a site for both the conversion of exogenous L-DOPA to DA and the storage of the synthesized DA in the DA-denervated striatum. This might be an explanation for a mechanism by which sympathetic neuron autografts can increase the duration of L-DOPA effects in PD patients. This review article summarizes the clinical effect of transplantation of autologous sympathetic neurons in PD and discusses the underlying mechanism for the effect based on experimental evidence previously obtained.

A 23-year-old man presented with the right upper monoparesis. The right little finger paresis was apparent at first, and ring finger two weeks later, and middle, index, thumb were simultaneously four weeks later. Then the monoparesis gradually progressed to the proximal upper limb. Magnetic resonance imaging showed a small lesion at the knob of the left precentral gyrus. The lesion was low-intensity on T1-, and high-intensity on T2-weighted images, and clearly detected on high-intensity on FLAIR images, but showed no enhancement by gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA). Angiography and thallium scintigraphy showed no remarkable findings. Proton MR spectroscopy demonstrated lower N-acetylaspartate (NAA) and higher choline (Cho) level compared to the contralateral cortico-subcortical area. Diffusion weighted images demonstrated low apparent diffusion coefficient (ADC) value and high intensity on b = 1,000. To clarify the diagnosis of the lesion, we performed open biopsy by using the neuronavigation system to detect the lesion accurately and minimize the biopsy. Histological examination revealed an high grade astrocytoma with high MlIB-1 index over 30%. The progressive symptoms were due to highly infiltrative and proliferative nature of the tumor arising in the focal hand area of the primary motor cortex, according to the homunculus. We discuss herein the neuroimagings of the case that was considered to be in the initial stage of a malignant tumor.

A 30-year-old man was hospitalized with dysarthria and weakness of his right arm and leg. Three months previously, he had noticed numbness and weakness of his right shoulder, which spread to involve his left leg but which improved after 8 months. On admission, neurological examination revealed limb kinetic apraxia and constructive apraxia of the right hand, motor aphasia, dysarthria, and spastic quadriplegia. Sensory examination revealed hyperalgesia and dysesthesia in the right arm and left leg. Deep tendon reflexes were hyperactive in all four extremities. And he had bilateral Babinski signs. Laboratory examination revealed pH 7.38, PCO2 46.1 Torr, PO2 93.4 Torr, BE 1.7, and blood lactate, 9.0 mg/dl (normal 5-20 mg/dl). Cerebrospinal fluid lactate level was 20.0 mg/dl. pyruvate 1.34 mg/dl. and protein 83 mg/dl. Blood lactate and pyruvate values were markedly elevated after aerobic exercise. T2WI brain MRI showed scattered high signal lesions in the left precentral and postcentral gyrus, right paracentral lobes, both superior frontal gyri, and right superior temporal gyrus. Right biceps brachi biopsy showed almost complete cytochrome c oxidase (COX) deficiency. There were no ragged-red fibers. There was marked decrease of COX activity: 2.7 nmol/min/mg-mitochondrial protein (normal range: 33.0 +/- 16.1, n = 7) in the biopsied muscle. Open brain biopsy (after permission from the patient and his family) revealed gliosis and perivascular infiltration of lymphocytes and macrophages without vascular proliferation. There was no mitochondrial DNA mutations, deletion or duplication, including tRNA-Leu 3243, 8993, 3271, 9176, 3291, and tRNA-Lys 8344, 8356, and 8363. From these findings, a diagnosis of COX deficiency presenting as MELAS-like episodes was done. His mother also showed abnormality on aerobic exercise test, but she had no episode of stroke or neurological dysfunction. Six months later, his aphasia and apraxia of the right hand had resolved, and at discharge he was able to ambulate with a cane. Ten months later, he returned to his work. There has been no recurrence of neurologic symptoms over the next 3 years and 10 months. This patient appears to represent a rare case of adult onset COX deficiency presenting as MELAS-like episodes.

The renin-angiotensin-aldosterone system has an important role in the progression of both diabetic and nondiabetic nephropathy. Angiotensin-converting enzyme inhibitors and angiotensin-II receptor blocker can effectively retard or halt this progression. However, their renoprotective effect is not enough, because approximately 20% of patients have a progressive course to endstage renal disease. There is now clear evidence that combination therapy of two agents is more antiproteinuric and, likely renoprotective, than each agent alone. However, several critical issues should be addressed before recommending it as standard treatment in chronic renal disease.

To the Editor: We have demonstrated [1, 2] the remarkable regional difference in the incidence of endstage renal disease (ESRD) within Japan, which has an ethnically homogenous population, suggesting the presence of factors other than genetics, which may contribute to the difference. Renoprotective actions of statins, recently proposed [3], were estimated by correlating two maps of ESRD incidence and the amount of expenses prescribed on statins in Japan. Annually, the Japanese Society for Dialysis Therapy reports the numbers of patients entering maintenance dialysis in each prefecture of Japan [4]. We used the findings for 1996 to 2000 to correlate the regional ESRD distribution with regional differences in annual amounts paid for antihypertensive drugs and statins during the same 5 years (Crecon Research & Consulting, Inc., Tokyo, Japan) (Table 1). Multiple regression analysis identified converting enzyme inhibitor (F = 34.3) and statins (F = 7.1) as independently negative factors arresting the progression of nephropathies, while total antihypertensives as positive factors (F = 17.8). Renal protective actions of statins, in addition to converting enzyme inhibitors, those of which we already reported [2], were revealed by analyzing ESRD map. Our epidemiologic approaches for Japan as a whole seemed useful to estimate the renoprotective actions of certain agents that have not been clarified by large-scale clinical trials.

We have investigated the potential of autologous sympathetic neurons as a donor for cell therapy of Parkinson's disease (PD). Our recent study demonstrated that sympathetic neuron autografts increase the duration of levodopa-induced "on" periods with consequent reduction in the percent time spent in "off" phase. We also found that human sympathetic neurons grown in culture have the ability to convert exogenous levodopa to dopamine and to store the synthesized dopamine. This may explain the clinically observed prolongation in the duration of levodopa effects. To further analyze the mechanism for the graft-mediated effect, the present study investigated the metabolic function of human sympathetic ganglionic neurons xenografted into the dopamine (DA)-denervated striatum of rats by monitoring striatal levels of DA and its primary metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), after systemic administration of levodopa. We also explored whether the graft-mediated effect above may last in four PD patients who had been given the grafts and followed for 12-36 months postgrafting. Clinical evaluations showed that an increase in the duration of levodopa-induced "on" phase is detected during a follow-up period of 12-36 months postgrafting in all the four patients tested. Accordingly, the percent time spent in "off" phase exhibited a 30-40% reduction as compared to the pregrafting values. The animal experiment showed that a significant increase in striatal DA levels is noted after systemic levodopa treatment, and that the DA levels remain high for longer periods of time in the grafted rats than in control animals. When given reserpine pretreatment, the levodopa-induced rise of striatal DA levels was significantly attenuated with concomitant increase in DOPAC levels. Histological examinations demonstrated that the grafts contain some tyrosine hydroxylase (TH)-positive cells. These cells were also found to express aromatic-l-amino acid decarboxylase (AADC) and vesicular monoamine transporter-2 (VMAT), both of which are important molecules for the synthesis and the storage of DA, respectively. These results indicate that grafted sympathetic neurons can provide a site for both the conversion of exogenous levodopa to DA and the storage of the synthesized DA in the DA-denervated striatum, explaining a mechanism by which sympathetic neuron autografts can increase the duration of levodopa-induced "on" phase in PD patients.

The first trial of restoring brain functions with cell grafting was performed in 1979 using a rat model of Parkinson's disease. Fetal nigral tissue was demonstrated to survive grafted tissue and to repair motor dysfunction in the model rat. The encouraging results indicate that cell transplantation may be useful to restore brain functions in neurodegenerative disorders in which a certain type of neuronal populations is specifically damaged. This review article discussed the possibility of cell transplantation therapy in several neurodegenerative disorders, such as Parkinson's disease, Huntington's disease and Alzheimer's disease.

Mesencephalic precursor cells may one day provide dopaminergic neurons for the treatment of Parkinson's disease. However, the generation of dopaminergic neurons from mesencephalic precursors has been difficult to follow, partly because an appropriate means for recognizing mesencephalic ventricular zone precursors has not been available. To visualize and isolate mesencephalic precursor cells from a mixed population, we used transgenic mice and rats carryinggreen fluorescent protein(GFP) cDNA under the control of thenestinenhancer.nestin-driven GFP was detected in the mesencephalic ventricular zone, and it colocalized with specific markers for neural precursor cells. In addition, data from flow-cytometry indicated that Prominin/CD133, a cell-surface marker for ventricular zone cells, was expressed specifically in these GFP-positive (GFP+) cells. After sorting by fluorescence-activated cell sorting, the GFP+cells proliferatedin vitroand expressed precursor cell markers but not neuronal markers. Using clonogenic sphere formation assays, we showed that this sorted population was enriched in multipotent precursor cells that could differentiate into both neurons and glia. Importantly, many neurons generated fromnestin-GFP-sorted mesencephalic precursors developed a dopaminergic phenotypein vitro. Finally,nestin-GFP+cells were transplanted into the striatum of a rat model of Parkinson's disease. Bromodeoxyuridine–tyrosine hydroxylase double-labeling revealed that the transplanted cells generated new dopaminergic neurons within the host striatum. The implanted cells were able to restore dopaminergic function in the host striatum, as assessed by a behavioral measure: recovery from amphetamine-induced rotation. Together, these findings indicate that precursor cells harvested from the embryonic ventral mesencephalon can generate dopaminergic neurons able to restore function to the chemically denervated adult striatum.

We have recently found that human amniotic epithelial (HAE) cells synthesize catecholamines including dopamine (DA). The present study was designed to explore the possibility of HAE cells to serve as a donor for transplantation therapy of Parkinson's disease (PD). Thus, we investigated their ability to produce DA in vitro and the survival and function of HAE cells grafted into a rat model of PD. RT-PCR and Western blotting revealed that HAE cells express tyrosine hydroxylase (TH) mRNA and protein, respectively. TH-immunohistochemistry on cultured HAE cells demonstrated that around 10% of the total cells are immunopositive for this protein. The production of DA by HAE cells was increased with time in the presence of L-tyrosine and BH(4), and was abolished with a specific TH inhibitor, alpha-methyl-rho-tyrosine. Dissociated HAE cells transduced with the Escherichia coli LacZ marker gene (beta-gal) were implanted into the previously DA-depleted striatum of immunosuppressed rats. Two weeks postgrafting HAE grafts were demonstrated to survive without overgrowth, as evidenced by the presence of beta-gal-positive cells and TH-immunoreactive cells within the grafts. The grafts also provided partial amelioration of apomorphine-induced rotational asymmetry. The results clearly indicate that HAE cells capable of producing DA can survive and function in the brain of a rat model of PD. Although DA replacement therapy of PD could possibly be achieved with implantation of HAE cells, further studies are needed to develop strategies to enhance the ability of HAE cells to produce DA as well as the graft survival.

Object. The P19 embryonal carcinoma—derived cell line consists of undifferentiated multipotential cells, which irreversibly differentiate into mature neurons after exposure to retinoic acid (RA). In the present study, the authors genetically engineered P19 cells to produce glial cell line—derived neurotrophic factor (GDNF), and grafted the cells in a rat model that had been rendered parkinsonian.Methods. Undifferentiated P19 cells were grown in vitro and transduced with GDNF complementary DNA. The level of GDNF released from the transduced cells was measured using an enzyme-linked immunosorbent assay, and its neurotrophic activities were assessed by testing the effects on rat embryonic dopamine (DA) neurons in culture. After having been exposed to RA for 48 hours and allowed to differentiate into postmitotic neurons, the GDNF gene—transduced cells were implanted into the midbrain of immunosuppressed rats. A unilateral nigrostriatal lesion was then induced by intrastriatal infusions of 6-hydroxydopamine. Immunohistochemical analyses performed 4 weeks postgrafting revealed that the GDNF-producing cells expressed several neuronal markers without evidence of overgrowth. The grafts expressed GDNF protein and prevented the death of nigral DA neurons. Furthermore, the GDNF-producing cells implanted 4 weeks after nigrostriatal lesions restored the expression of tyrosine hydroxylase in injured DA neurons and induced their dendritic sprouting.Conclusions. The results indicate that the P19 cell line transduced with the GDNF gene can stably secrete functional levels of GDNF, even after being converted to postmitotic neurons. Because it is has been established that GDNF exerts trophic effects on DA neurons, the means currently used to deliver GDNF into the brain could be a viable strategy to prevent the death of nigral DA neurons in cases of Parkinson's disease.

Accumulating evidence indicates that grafts of embryonic neurons achieve the anatomical and functional reconstruction of damaged neuronal circuitry. The restorative capacity of grafted embryonic neural tissue is most illustrated by studies with striatal tissue transplantation in animals with striatal lesions. Striatal neurons implanted into the lesioned striatum receive some of the major striatal afferents such as the nigrostriatal dopaminergic inputs and the gluatmatergic afferents from the neocortex and thalamus. The grafted neurons also send efferents to the primary striatal targets, including the globus pallidus (GP, the rodent homologue of the external segment of the globus pallidus) and the entopeduncular nucleus (EP, the rodent homologue of the internal segment of the globus pallidus). These anatomical connections provide the reversal of the lesion-induced alterations in neuronal activities of primary and secondary striatal targets. Furthermore, intrastriatal striatal grafts improve motor and cognitive deficits seen in animals with striatal lesions. Since the grafts affect motor and cognitive behaviors that are critically dependent on the integrity of neuronal circuits of the basal ganglia, the graft-mediated recovery in these behavioral deficits is most likely attributable to the functional reconstruction of the damaged neuronal circuits. The fact that the extent of the behavioral recovery is positively correlated to the amount of grafted neurons surviving in the striatum encourages this view. Based on the animal studies, embryonic striatal tissue grafting could be a viable strategy to alleviate motor and cognitive disorders seen in patients with Huntington’s disease where massive degeneration of striatal neurons occurs.