Neuroprotective effects of erythromycin on ischemic injury following permanent focal cerebral ischemia in rats.

OBJECTIVE: This study aims to determine if erythromycin provides neuroprotective effects against ischemic injury following permanent focal cerebral ischemia. METHODS: Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO). Each animal received a single subcutaneous injection of erythromycin lactobionate (EM, 50 mg/kg) or vehicle immediately after ischemia. The infarct volume, edema index and neurological performance were evaluated at 24 and 72 h after MCAO. The cerebral blood flow (CBF) was measured with an MRI system at 30 min after MCAO. TUNEL staining and immunohistochemical analyses for oxidative stress (4-HNE, 8-OHdG) and inflammation (Iba-1, TNF-α) in the cortex were conducted at 24 and 72 h after MCAO. RESULTS: The CBF did not differ between the EM-treated and vehicle-treated groups. The EM treatment significantly reduced the infarct volume (p < 0.01) at 24 and 72 h after MCAO and significantly reduced the edema index (p < 0.01) at 24 h. The EM treatment significantly improved the neurological deficit scores (p < 0.05) at 24 and 72 h. EM also significantly suppressed the accumulation of 4-HNE (p < 0.01) and 8-OHdG (p < 0.01) and markedly reduced Iba-1 (p < 0.01) and TNF-α expression (p < 0.05) at both time points. The EM treatment significantly reduced TUNEL-positive cells (p < 0.01) at both time points. CONCLUSION: These findings suggest that EM can protect against the neuronal damage caused by cerebral ischemia by alleviating inflammation and reducing oxidant stress.

Relative risk values of age, acrolein, IL-6 and CRP as markers of periventricular hyperintensities: a cross-sectional study.

OBJECTIVE: Brain white matter hyperintensities can be divided into periventricular hyperintensity (PVH) and deep-and-subcortical white matter hyperintensity (DSWMH); the former contributes more to cognitive dysfunction and infarction risk. We conducted the present investigation to define the relationship between PVH and DSWMH. DESIGN: Cross-sectional study. SETTING: University hospital. PARTICIPANTS: We prospectively enrolled 228 healthy Japanese volunteers with relative risk values (RRVs) >0.5. PRIMARY OUTCOME MEASURES: We investigated whether it is possible to use the RRV to predict PVH and DSWMH. RESULTS: Among 228 volunteers, 103 (45.1%) and 157 (68.8%) exhibited PVH and DSWMH, respectively. Age, body mass index and PVH were significant independent determinants of RRV. A significant OR for PVH was noted in the highest RRV tertile compared with the lowest, after adjusting for potential confounding factors. A significant OR for high predicted PVH risk was found for RRV levels as well. CONCLUSIONS: Elevated RRV levels were significantly associated with increased predicted PVH, suggesting that measuring the plasma protein-conjugated acrolein, interleukin 6 and C reactive protein levels may be useful for identifying Japanese at high risk for PVH.

Acute vertebral artery origin occlusion leading to basilar artery thrombosis successfully treated by angioplasty with stenting and thrombectomy.

Few reports have described the successful treatment of stroke caused by acute vertebral artery (VA) origin occlusion by endovascular surgery. We describe the case of a 68-year-old man who experienced stroke due to left acute VA origin occlusion. Cerebral angiography showed that the left VA was occluded at its origin, the right VA had hypoplastic and origin stenosis, and the basilar artery was occluded by a thrombus. The VA origin occlusion was initially passed through with a 0.035-inch guide wire. An angioplasty was performed, and a coronary stent was appropriately placed. The VA origin was successfully recanalized. A balloon-assisted guiding catheter was navigated through the stent and a thrombectomy was performed using the Penumbra system. The patient's symptoms gradually improved postoperatively. Balloon-assisted catheter guidance through a vertebral artery stent permitted a successful thrombectomy using the Penumbra system and may be useful for treating stroke due to VA origin occlusion.

Asymmetric dimethylarginine is related to the predicted stroke risk in middle-aged Japanese men.

BACKGROUND: Asymmetric dimethylarginine (ADMA) has recently been investigated as a risk marker for cardio- and cerebrovascular diseases. However, whether ADMA levels are related to the risk of stroke in the Japanese general population remains unclear. METHODS: We examined 769 Japanese men (mean age, 47 ± 5 years) undergoing health examinations. Each subject's ADMA level and various vascular risk factors were assessed; the predicted 10-year stroke risk was calculated using the point-based prediction model from the Japan Public Health Center Study. RESULTS: In a multiple linear regression analysis, age, body mass index, estimated glomerular filtration rate, and current smoking status were significant independent determinants of ADMA levels. A significant odds ratio (OR) for high predicted stroke risk (10-year risk ≥ 5%)was noted in the highest quartile of ADMA levels (OR, 2.47; 95% CI, 1.002-6.07), compared with the lowest quartile, after adjusting for potential confounding factors. A significant OR for high predicted stroke risk was also found for each standard deviation increment in ADMA level (adjusted OR, 1.46; 95% CI, 1.10-1.92). CONCLUSION: Elevated ADMA levels were significantly associated with an increased predicted stroke risk, suggesting that measuring ADMA levels may be useful for identifying middle-aged Japanese men with a high risk of stroke.

Continuous oral administration of atorvastatin ameliorates brain damage after transient focal ischemia in rats.

AIMS: Pre-treatment with statins is known to ameliorate ischemic brain damage after experimental stroke, and is independent of cholesterol levels. We undertook pre- vs post-ischemic treatment with atorvastatin after focal cerebral ischemia in rats. MAIN METHODS: Male Sprague-Dawley rats underwent transient 90-min middle cerebral artery occlusion (MCAO). Atorvastatin (20mg/kg/day) or vehicle was administered orally. Rats were divided into vehicle-treated, atorvastatin pre-treatment, atorvastatin post-treatment, and atorvastatin continuous-treatment groups. In the pre-treatment, rats were given atorvastatin or vehicle for 7 days before MCAO. In the post-treatment, rats received atorvastatin or vehicle for 7 days after MCAO. Measurement of infarct volume, as well as neurological and immunohistochemical assessments, were done 24h and 7 days after reperfusion. KEY FINDINGS: Each atorvastatin-treated group demonstrated significant reductions in infarct and edema volumes compared with the vehicle-treated group 24h after reperfusion. Seven days after reperfusion, infarct volumes in the post-treatment group and continuous-treatment group (but not the pre-treatment group) were significantly smaller than in the vehicle-treated group. Only the continuous-treatment group had significantly improved neurological scores 7 days after reperfusion compared with the vehicle group. Post-treatment and continuous-treatment groups had significantly decreased lipid peroxidation, oxidative DNA damage, microglial activation, expression of tumor necrosis factor-alpha, and neuronal damage in the cortical ischemic boundary area after 7 days of reperfusion. SIGNIFICANCE: These results suggest that continuous oral administration (avoiding withdrawal) with statins after stroke may reduce the extent of post-ischemic brain damage and improve neurological outcome by inhibiting oxidative stress and inflammatory responses.

Effect of repeated allogeneic bone marrow mononuclear cell transplantation on brain injury following transient focal cerebral ischemia in rats.

AIMS: Transplantation of bone marrow mononuclear cells (BMMCs) exerts neuroprotection against cerebral ischemia. We examined the therapeutic timepoint of allogeneic BMMC transplantation in a rat model of focal cerebral ischemia, and determined the effects of repeated transplantation outside the therapeutic window. MAIN METHODS: Male Sprague-Dawley rats were subjected to 90 minute focal cerebral ischemia, followed by intravenous administration of 1 × 10(7) allogeneic BMMCs or vehicle at 0, 3 or 6 h after reperfusion or 2 × 10(7) BMMCs 6 h after reperfusion. Other rats administered 1 × 10(7) BMMCs at 6 h after reperfusion received additional BMMC transplantation or vehicle 9 h after reperfusion. Infarct volumes, neurological deficit scores and immunohistochemistry were evaluated 24 or 72 h after reperfusion. KEY FINDINGS: Infarct volumes at 24 h were significantly decreased in transplantation rats at 0 and 3 h, but not at 6 h, after reperfusion, compared to vehicle-treatment. Even high dose BMMC transplantation at 6h after reperfusion was ineffective. Repeated BMMC transplantation at 6 and 9h after reperfusion reduced infarct volumes and significantly improved neurological deficit scores at 24 and 72 h. Immunohistochemistry showed repeated BMMC transplantation reduced ionized calcium-binding adapter molecule 1, 4-hydroxy-2-nonenal and 8-hydroxydeoxyguanosine expression at 24 and 72 h after reperfusion. SIGNIFICANCE: Intravenous allogeneic BMMCs were neuroprotective following transient focal cerebral ischemia, and the therapeutic time window of BMMC transplantation was >3 h and <6 h after reperfusion in this model. Repeated transplantation at 6 and 9 h after reperfusion suppressed inflammation and oxidative stress in ischemic brains, resulting in improved neuroprotection.

Posterior reversible encephalopathy syndrome due to hypercalcemia associated with parathyroid hormone-related peptide: a case report and review of the literature.

We herein report the case of a 58-year-old man with advanced esophageal carcinoma who developed posterior reversible encephalopathy syndrome (PRES). He initially presented with a severe consciousness disturbance. A subsequent examination revealed hypercalcemia and an elevated serum parathyroid hormone-related peptide (PTHrP) level. Magnetic resonance imaging performed on admission and 24 days later showed reversible widespread white matter abnormalities, which confirmed a diagnosis of PRES. The patient's clinical and radiological manifestations improved upon normalization of the serum calcium level. To the best of our knowledge, this is the first report describing hypercalcemia-induced PRES occurring in association with elevated PTHrP.

Bilateral symmetrical pallidal lesions following severe anemia associated with gastrointestinal hemorrhage: report of two cases.

We herein report the cases of two patients with bilateral symmetrical pallidal lesions mimicking hypoxic encephalopathy following severe anemia associated with gastrointestinal hemorrhage despite a lack of carbon monoxide intoxication. Although severe anemia can theoretically result in anemic hypoxia, vulnerable pallidal lesions have rarely been described in anemic patients. Interestingly, both patients shared common conditions associated with atherosclerosis, including heavy smoking, hypertension, type 2 diabetes mellitus and a history of coronary artery bypass grafting for ischemic heart disease. Anemic hypoxia may cause pallidal involvement in atherosclerotic patients with multiple risk factors.

In vivo monitoring of arterially transplanted bone marrow mononuclear cells in a rat transient focal brain ischemia model using magnetic resonance imaging.

OBJECTIVES: Intra-arterial transplantation of bone marrow mononuclear cells (BMMCs) effectively improves neuronal function and limits the infarct size. We monitored the fate of BMMCs labeled with super paramagnetic iron oxide (SPIO) until 7 days after the transplantation using high-field magnetic resonance imaging (MRI). METHODS: Male Sprague-Dawley rats were subjected to 90-minute focal ischemia using the intraluminal suture technique followed by transplantation of 1 × 10(7) BMMCs or vehicle only via the ipsilateral carotid artery immediately after reperfusion. Autologous BMMCs were labeled with SPIO by electroporation prior to ischemia. MRI studies were performed at 1 hour, 24 hours, 3 days, and 7 days after reperfusion on each rat. The total infarct volume and the volume of negative dots were measured on T2-weighted images and T2*-weighted images, respectively. RESULTS: One hour after BMMC transplantation, we confirmed wide spread distribution of BMMCs in the ischemic hemisphere as a negative dot. The volume of negative dot normalized by hemispheric volume decreased rapidly and was seldom seen at the seventh day after transplantation. The infarct volume was significantly smaller in the transplanted group than the vehicle group at 24 hours and 7 days after reperfusion. DISCUSSION: The present study established In vivo monitoring of intra-arterial transplanted SPIO-labeled BMMCs immediately after reperfusion using MRI of a rat transient focal ischemia model. The accumulation of BMMCs in ischemic lesion at the acute stage of ischemia can be part of the conditions to limit the infarct size.

An unusual cerebral air embolism developing within the posterior circulation territory after a needle lung biopsy.

We herein report the case of a 75-year-old woman with a paradoxical cerebral air embolism (CAE). She developed a bilateral visual disturbance at the time of needle puncture during a computed tomography (CT)-guided percutaneous needle lung biopsy in the face down position. The air density within the descending aorta on chest CT suggested the presence of a cerebral air embolism. Brain MRI demonstrated increased signal intensity in the bilateral occipital lobes on diffusion-weighted images. Usually, CAE occurs predominantly in the right hemisphere for anatomical reasons. The face down position and the anatomical features of the right subclavian artery, which diverges backward from the brachiocephalic artery, might explain such a unique distribution of CAE in this patient.

A case of secondary focal segmental glomerulosclerosis associated with malignant hypertension.

Focal segmental glomerulosclerosis (FSGS) is associated with various clinicopathological conditions, including hypertension. We report here a case of secondary FSGS associated with malignant hypertension. A 33-year-old man with a 1-month history of visual impairment and headache visited the Department of Ophthalmology at our hospital and was found to have hypertensive retinopathy and severe hypertension (230/160 mmHg). He was referred to our department based on suspected renal dysfunction. His blood pressure on admission was 250/130 mmHg. Physical examination and laboratory tests revealed hypertensive cardiac dysfunction, focal brain edema, renal dysfunction (serum creatinine, Cr 7.07 mg/dl, blood urea nitrogen, BUN 49.9 mg/dl), massive proteinuria (10.7 g/day), and thrombotic microangiopathy. Funduscopy showed exudate, hemorrhage, and papilledema. The cause of secondary hypertension could not be identified. He was treated for primary malignant hypertension, but required hemodialysis 3 days after admission due to anuria. Treatment with antihypertensive agents resulted in the gradual recovery of renal function, although heavy proteinuria continued with nephrotic syndrome. Renal biopsy performed 1 month after admission showed features of malignant nephrosclerosis with secondary FSGS. Hemodialysis was discontinued following further improvement in renal function and the most recent laboratory tests showed proteinuria 1.8 g/day and persistent renal dysfunction (BUN 36.5 mg/dl, Cr 3.14 mg/dl). Malignant hypertension may cause various injuries, including glomerular endothelial and epithelial cell injuries in glomerular hypertension and hyperfiltration, increase of the renin-angiotensin-aldosterone system, and endothelial-epithelial interaction, resulting in the development of secondary FSGS and heavy proteinuria.

Proliferative glomerulonephritis with monoclonal immunoglobulin G3κ deposits in association with parvovirus B19 infection.

Proliferative glomerulonephritis with monoclonal immunoglobulin G deposits is a recently described disease entity, characterized by nonorganized electron-dense deposits in glomeruli and immunofluorescence findings indicating monoclonal immunoglobulin G deposits. The pathogenesis of many cases of proliferative glomerulonephritis with monoclonal immunoglobulin G deposits remains unknown. We herein report 2 patients with parvovirus B19 infection who developed acute nephritic syndrome with hypocomplementemia (patient 1) or persistent proteinuria and congestive heart failure (patient 2); however, neither patient had detectable levels of serum monoclonal immunoglobulin G. Renal biopsy in both patients showed diffuse endocapillary proliferative glomerulonephritis with monoclonal immunoglobulin G3κ deposits, and electron microscopy showed nonorganized electron-dense deposits mainly in the subendothelial and mesangial areas. Clinical symptoms, abnormal laboratory findings, and urinary abnormalities recovered spontaneously in both cases within 4 weeks. Our 2 cases may be the first reported patients with proliferative glomerulonephritis with monoclonal immunoglobulin G deposits possibly associated with parvovirus B19 infection. Virus infection-associated immune disorders could be implicated in the pathogenesis of proliferative glomerulonephritis with monoclonal immunoglobulin G deposits.

Differential effects of age on human striatal adenosine A1 and A(2A) receptors.

The aim of this study was to investigate the effect of age on the distribution of adenosine A1 receptors (A1Rs) and adenosine A(2A) receptors (A(2A)Rs) in the striatum of healthy subjects using PET imaging with 8-dicyclopropylmethyl-1-[¹¹C]methyl-3-propylxanthine ([¹¹C]MPDX) and [7-methyl-¹¹C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthine ([¹¹C]TMSX), respectively. We recruited 8 young (22.0 ± 1.7 years) and 10 elderly (65.4 ± 7.6 years) volunteers to undergo [¹¹C]MPDX PET scanning, and 11 young (22.7 ± 2.7 years) and six elderly (60.7 ± 8.5 years) volunteers to undergo [¹¹C]TMSX PET scanning. A dynamic series of decay-corrected PET scans was performed for 60 min following injection of [¹¹C]MPDX or [¹¹C]TMSX. We calculated the binding potential (BP(ND) ) of [¹¹C]MPDX and distribution volume ratio (DVR) of [¹¹C]TMSX in the striatum. The BP(ND) of [¹¹C]MPDX was significantly lower in elderly than in young subjects, both in the putamen and head of the caudate nucleus. The BP(ND) was negatively correlated with age in both the putamen and the head of the caudate nucleus. However, no difference was found between the DVR of [¹¹C]TMSX in the striata of young and elderly subjects, nor was there a correlation between age and the DVR of [¹¹C]TMSX. The effect of age on the distribution of A1Rs in the human striatum described herein is similar to previous reports of age-related decreases in dopamine D1 and D2 receptors. Unlike A1Rs, however, this study suggests that the distribution of A(2A) Rs does not change with age.

Proteomic analysis of bone marrow-adherent cells in rheumatoid arthritis and osteoarthritis.

AIM: To elucidate the pathophysiology of rheumatoid arthritis (RA) as well as osteoarthritis (OA), we analyzed protein profiles of bone marrow-derived adherent cells (BMACs) from patients with these diseases. METHODS: Proteins, extracted from BMACs from three RA and three OA patients, were comprehensively analyzed by 2-dimensional differential image gel electrophoresis (2D-DIGE). Then a part of the detected proteins, differently expressed between the two diseases, were identified by mass spectrometric analysis. RESULTS: 2D-DIGE analysis detected more than 1600 protein spots in both RA and OA BMACs. Out of these, expression of 340 spots was significantly altered between the diseases (more than 1.5-fold: RA > OA, 26 spots; OA > RA, 314 spots; P < 0.05). Eleven protein spots the intensity of which were significantly altered by more than 2.0-fold were identified, which included vimentin and annexin A5 as increased proteins in RA rather than in OA. As increased proteins in OA compared to RA, alpha chain of collagen VI, a membrane anchor for acetylcholine esterase, heat shock protein 27, caldesmon and cytoskeletal proteins, such as beta actin and alpha tubulin, were identified. CONCLUSIONS: We here report different protein profiles of BMACs between RA and OA for the first time. BMACs possessing differently expressed proteins may be involved in the pathophysiology of the two diseases.

A case of monoclonal immunoglobulin G1-lambda deposition associated with membranous feature in a patient with hepatitis C viral infection.

A 63-year-old man with hepatitis C virus infection was admitted to our hospital for nephrotic syndrome. Light microscopic analysis of a percutaneous renal biopsy showed thickening of the glomerular capillary walls and spike formation. Immunofluorescence revealed granular deposition of monoclonal immunoglobulin G1-lambda and C3 complement along the glomerular basement membrane. Urinary protein excretion decreased slightly after combined treatment with steroid and an immunosuppressive agent. Monoclonal immunoglobulin deposition disease with membranous feature is rare. Additional reports of such cases are needed to elucidate the mechanisms and optimal therapy for this rare entity.

Role of matrix metalloproteinase-2 in recovery after tubular damage in acute kidney injury in mice.

BACKGROUND/AIMS: Matrix metalloproteinases (MMPs) are zinc endopeptidases that degrade extracellular matrix and are involved in the pathogenesis of ischemic damage in acute kidney injury (AKI). In the present study, we analyzed the role of MMP-2 in the repair process in ischemic AKI. METHODS: AKI was induced in MMP-2 wild-type (MMP-2(+/+)) and MMP-2-deficient (MMP-2(-/-)) mice by 90-min renal artery clamping followed by reperfusion. Renal histology and the activity and distribution of MMP-2 were examined from day 1 to day 14. During the recovery from AKI, MMP-2(+/+) mice were also treated with MMP-2/MMP-9 inhibitor. RESULTS: In both MMP-2(+/+) and MMP-2(-/-) mice, AKI developed on day 1 after ischemia/reperfusion with widespread acute tubular injury, but subsequent epithelial cell proliferation was evident on days 3-7. During the repair process, active MMP-2 and MMP-9 increased in regenerating tubular epithelial cells in MMP-2(+/+) mice on days 7-14, and the tubular repair process was almost complete by day 14. On the other hand, in MMP-2(-/-) mice, less prominent proliferation of tubular epithelial cells was evident on days 3 and 7, and damaged tubules that were covered with elongated and immature regenerated epithelial cells were identified on days 7 and 14. Incomplete recovery of injured microvasculature was also noted with persistent macrophage infiltration. Similarly, treatment with MMP-2/MMP-9 inhibitor resulted in impaired recovery in MMP-2(+/+) mice. CONCLUSION: MMP-2 is involved in tubular repair after AKI. The use of the MMP-2/MMP-9 inhibitor was a disadvantage when it was administered during the repair stage of ischemic AKI. Treatment with MMP inhibitor for AKI needs to be modified to enhance recovery from AKI.

A case of (double) ANCA-negative granulomatosis with polyangiitis (Wegener's).

A 60-year-old man had experienced cough, bloody sputum, and a 38 °C fever for 1.5 months. He visited an outpatient clinic and received antibiotics and nonsteroidal anti-inflammatory drugs. However, because the symptoms continued, he visited our hospital. The past medical history included chronic sinusitis, hypertension, and diabetes mellitus. A chest x-ray film and computed tomography showed multiple pulmonary nodules with cavities. Macrohematuria had developed 3 days before admission, and renal function had deteriorated (creatinine, 2.45 mg/dL) in 2 weeks. He was admitted to our hospital because of rapidly progressive glomerulonephritis (RPGN) and multiple pulmonary nodules. On admission, the clinical diagnosis was suspected to be granulomatosis with polyangiitis (Wegener's) (GPA), although tests for proteinase-3 anti-neutrophil cytoplasmic antibody (PR3-ANCA) were negative. Antibiotics were administered for 5 days. After renal biopsy, methylprednisolone pulse therapy and cyclophosphamide pulse therapy were performed. The pathological diagnosis on the basis of the renal biopsy was glomerular and interstitial hemorrhage, possibly associated with vasculitis. After the treatment, the pulmonary symptoms, multiple pulmonary nodules, and severe inflammatory reactions in the peripheral blood were resolved. However, renal dysfunction progressed to end-stage renal disease 1 month after renal biopsy. Hemodialysis was started, and the steroid therapy was continued. During hemodialysis, a second renal biopsy was performed and led to a diagnosis of pauci-immune focal segmental crescentic glomerulonephritis. Renal function gradually recovered, and hemodialysis was discontinued. This case was (double) ANCA-negative GPA which presented prominent glomerular and interstitial hemorrhage, may be associated with small vessel vasculitis, but without active necrotizing and crescentic glomerular lesions, in the rapidly progressive glomerulonephritis.

Mild hypothermia enhanced the protective effect of protein therapy with transductive anti-death FNK protein using a rat focal transient cerebral ischemia model.

We previously reported that the protein transduction domain fused FNK (PTD-FNK) protein, which was derived from anti-apoptotic Bcl-xL protein and thereby gained higher anti-cell death activity, has a strong neuroprotective effect on rat focal brain ischemia models. The aim of this study was to investigate the effect of PTD-FNK protein and hypothermia combined therapy on cerebral infarction. Male SD rats were subjected to 120min middle cerebral artery occlusion (MCAO) with intraluminal thread. Rats were divided into 4 groups: 1) 37°C vehicle administration (37V); 2) 37°C PTD-FNK administration (37F); 3) 35°C vehicle administration (35V); and 4) 35°C PTD-FNK administration (35F). PTD-FNK protein was intravenously administered 60min after the induction of MCAO. Hypothermia (35°C) was applied during 120min MCAO. Rats were sacrificed 24h later; infarct volumes were measured, and Bax, Bcl-2, TUNEL and caspase-12 immunostaining was evaluated. There was significant infarct volume reduction in 37F, 35V, and 35F groups compared to 37V. There was also a significant difference between 37F and 35F. This suggests that hypothermia enhanced the effect of PTD-FNK. Similar results were found in neurological symptoms. Caspase-12 and TUNEL staining showed a significant difference between 37F and 35F; however, Bax and Bcl-2 staining failed to show a difference. In this study we showed an additive protective effect of hypothermia on PTD-FNK treatment, and immunohistological results showed that the protective mechanisms might involve the inhibition of apoptotic pathways through caspase-12, but not through Bcl-2.