BMK1 is activated in glomeruli of diabetic rats and in mesangial cells by high glucose conditions

BACKGROUND: High glucose causes renal cell injury through various signal transduction pathways, including mitogen-activated protein (MAP) kinases cascades. Big MAP kinase 1 (BMK1), also known as extracellular signal-regulated kinase 5 (ERK5), is a recently identified MAP kinase family member and was reported to be sensitive to osmotic and oxidative stress. However, the role of BMK1 in diabetic nephropathy has not been elucidated yet. METHODS: We investigated whether BMK1 is activated in the glomeruli of Otsuka Long Evans Tokushima Fatty (OLETF) rats, a model of type 2 diabetes mellitus in comparison with the control Long Evans Tokushima Otsuka (LETO) rats. We also examined the effect of high glucose on BMK1 activity in cultured rat mesangial cells. RESULTS: BMK1 and ERK1/2 but not p38 were activated in the glomeruli of OLETF rats, which showed diabetic nephropathy at 52 weeks of age. High glucose, in addition to a high concentration of raffinose, caused rapid and significant activation of BMK1 in rat mesangial cells. MAP kinase/ERK kinase (MEK) inhibitors, U0126 and PD98059, both inhibited BMK1 activation by high glucose in a concentration-dependent manner. Protein kinase C (PKC) inhibition by GF109203X and PKC down-regulation with long-time phorbol myristate acetate (PMA) treatment both inhibited BMK1 and Src kinase activation. Src kinase inhibitors, herbimycin A and PP2, also inhibited high glucose-induced BMK1 activation. PKC inhibitors, Src inhibitors and MEK inhibitors, all inhibited cell proliferation by high glucose. Finally, transfection of dominant-negative MEK5, which is an upstream regulator of BMK1, abolished the BMK1-mediated rat mesangial cell proliferation stimulated by high glucose. CONCLUSION: In the present study, we demonstrated that high glucose activates BMK1 both in vivo and in vitro. It was suggested that high glucose induces PKC- and c-Src-dependent BMK1 activation. It could not be denied that BMK1 activation is induced through an osmotic stress-sensitive mechanism. BMK1-mediated mesangial cell growth may be involved in the pathogenesis of diabetic nephropathy.     

Long-term clinical and neurologic recovery in the hand after surgery for severe cubital tunnel syndrome

PURPOSE: Functional outcomes of cubital tunnel surgery may decline as the severity of preoperative ulnar neuropathy increases. When functional recovery will be adequate, or whether tendon transfers should be required, may be unclear. We investigated the extent of functional recovery, the duration of the recovery process, and the necessity of restoring intrinsic muscle function in patients with severe cubital tunnel syndrome after surgery. METHODS: We retrospectively studied outcomes after cubital tunnel release in 15 patients with marked intrinsic muscle atrophy, claw-hand deformity, immeasurable (electrically silent) sensory and motor nerve conduction velocities, and Semmes-Weinstein test (SWT) results ranging from purple (3.84-4.31) to red (4.56-6.65). We evaluated subjective (numbness and activities of daily living [ADL] disturbances), objective (manual muscle testing [MMT] of index-finger abduction, and SWT), and neurophysiologic (nerve conduction velocity) outcomes. Overall functional outcome was evaluated by Akahori's criteria. RESULTS: At a median follow-up evaluation of 4.5 years all outcomes had improved. Numbness was gone in 5 patients and greatly reduced in 9 patients; 6 patients reported slight difficulties in ADLs; and 9 patients had no difficulties. Motor nerve conduction velocity was measurable (mean, 35.3 m/s) in all 15 patients and sensory nerve conduction velocity was measurable (mean, 43.4 m/s) in 12. Recoveries in nerve conduction velocities persisted beyond 2 years. The SWT results were blue (3.22-3.61) in 6 patients, purple (3.84-4.31) in 8 patients, and red (4.56-6.65) in 1 patient. MMT of index finger abduction was grade 4 or 5 in 11 of 15 patients. Half the patients over 70 years old, however, were grade 3 or less. Akahori's criteria were excellent in 3 patients, good in 6 patients, and fair in 6 patients. CONCLUSIONS: Patients with severe intrinsic muscle atrophy and absent motor and sensory nerve conduction velocities can expect satisfactory long-term functional results after surgery. Function continues to improve beyond 2 years. Restoring index finger abduction is not always necessary for ADLs, although recovery requires several years and is poorer in the elderly.     

Microsurgical excision of a retro-odontoid disc hernia via a far-lateral approach: successful treatment of a rare cause of myelopathy: case report

OBJECTIVE AND IMPORTANCE: Among mass lesions causing myelopathy at the craniovertebral junction, retro-odontoid intervertebral disc hernias are very rare, with only four such cases reported in the literature. CLINICAL PRESENTATION: A 77-year-old woman with this rare condition complained of motor and sensory disturbances in her extremities. Magnetic resonance imaging scans demonstrated an extradural mass lesion at the craniovertebral junction, compressing the lower medulla oblongata and the upper cervical cord posteriorly. INTERVENTION: The lesion, which was partly mucinous cartilaginous and partly fatty and fibrous, was meticulously removed via a left far-lateral approach. The lesion was not neoplastic but was determined to be composed of fibrocartilaginous tissue, consistent with disc material. Postoperatively, the patient's sensory disturbances and motor weakness improved, and magnetic resonance imaging scans demonstrated marked shrinkage of the lesion. CONCLUSION: Sagittal, T1-weighted, magnetic resonance imaging scans demonstrated a low-intensity band between the odontoid process and the body of the axis, which suggested a persistent cartilaginous band. Although upward migration of a herniated disc from the lower cervical spine and degeneration of retro-odontoid ligaments might be possible causes, a persistent cartilaginous band extending between the odontoid process and the body of the axis was considered to be the more likely origin of the retro-odontoid intervertebral disc hernia. Because the far-lateral surgical approach does not require retraction of the cervical cord and provides safe access to the lesion at the craniovertebral junction, it is a suitable surgical method for this condition.     

Molecular Mechanisms of the Inhibitory Effects of Propofol and Thiamylal on Sarcolemmal Adenosine Triphosphate-sensitive Potassium Channels

Background: Both propofol and thiamylal inhibit adenosine triphosphate-sensitive potassium (KATP) channels. In the current study, the authors investigated the effects of these anesthetics on the activity of recombinant sarcolemmal KATP channels encoded by inwardly rectifying potassium channel (Kir6.1 or Kir6.2) genes and sulfonylurea receptor (SUR1, SUR2A, or SUR2B) genes.

Methods: The authors used inside-out patch clamp configurations to investigate the effects of propofol and thiamylal on the activity of recombinant KATP channels using COS-7 cells transfected with various types of KATP channel subunits.

Results: Propofol inhibited the activities of the SUR1/Kir6.2 (EC50 = 77 [mu]m), SUR2A/Kir6.2 (EC50 = 72 [mu]m), and SUR2B/Kir6.2 (EC50 = 71 [mu]m) channels but had no significant effects on the SUR2B/Kir6.1 channels. Propofol inhibited the truncated isoform of Kir6.2 (Kir6.2[DELTA]C36) channels (EC50 = 78 [mu]m) that can form functional KATP channels in the absence of SUR molecules. Furthermore, the authors identified two distinct mutations R31E (arginine residue at position 31 to glutamic acid) and K185Q (lysine residue at position 185 to glutamine) of the Kir6.2[DELTA]C36 channel that significantly reduce the inhibition of propofol. In contrast, thiamylal inhibited the SUR1/Kir6.2 (EC50 = 541 [mu]m), SUR2A/Kir6.2 (EC50 = 248 [mu]m), SUR2B/Kir6.2 (EC50 = 183 [mu]m), SUR2B/Kir6.1 (EC50 = 170 [mu]m), and Kir6.2[DELTA]C36 channels (EC50 = 719 [mu]m). None of the mutants significantly affects the sensitivity of thiamylal.     

Value of diffusion-weighted MR imaging in acute cervical cord injury as a predictor of outcome

Introduction We analyzed the findings of diffusion-weighted (DW) imaging using the single-shot fast spin-echo sequence in acute cervical cord injury and evaluated the usefulness of this method for predicting the prognosis.Methods Our patient group comprised 14 patients examined 2 h to 3 days after injury. First, we visually evaluated the DW imaging findings in all patients. Apparent diffusion coefficient (ADC) maps were also assessed in 13 patients. Second, we assessed follow-up magnetic resonance (MR) examinations obtained in six patients whose DW images showed hyperintensity. Third, we reviewed the functional outcome at discharge.Results The lesions showed hyperintensity in ten patients, and no abnormal signal was noted in the remaining four patients. The ADC maps showed restricted diffusion in all patients with hyperintensity on DW imaging except in one patient for whom the ADC map was unavailable. Repeated MR examinations obtained in six of the ten patients showed either myelomalacia or exacerbation. Seven of the ten patients (70%) required assistance and the other three were independent. Among the four patients without hyperintensity on DW imaging, three (75%) were independent and only one required assistance.Conclusion DW imaging in acute cervical cord injury often reveals restricted diffusion. This finding may predict an unfavorable functional prognosis.     

Diffusion-tensor fiber tractography: intraindividual comparison of 3.0-T and 1.5-T MR imaging

PURPOSE: To prospectively evaluate the depiction of brain fiber tracts at 3.0- versus 1.5-T diffusion-tensor (DT) fiber tractography performed with parallel imaging. MATERIALS AND METHODS: Institutional review board approval was obtained, and each subject provided written informed consent. Subjects were 30 healthy volunteers (15 men, 15 women; mean age, 28 years; age range, 21-46 years). Single-shot spin-echo echo-planar magnetic resonance (MR) sequences with parallel imaging were applied. Four fiber tracts were reconstructed: corticospinal tract (CST), superior longitudinal fasciculus (SLF), corpus callosum (CC), and fornix. Two neuroradiologists compared 3.0- and 1.5-T tractography in terms of fiber tract depiction by using five depiction scores (scores 0-4) and numbers of reconstructed tract fibers and in terms of lateral asymmetry in the CST by using numbers of reconstructed fibers. The Wilcoxon signed rank test was applied for statistical analysis. RESULTS: Visual scores for both CST hemispheres (P < .001), the right SLF (P = .005), the CC (P = .01), and the right fornix (P = .04) were higher at 3.0-T DT tractography. Larger numbers of CST (right, P = .008; left, P < .001), SLF (right, P = .001; left, P = .02), and fornix (bilaterally, P = .02) tract fibers were depicted at 3.0 T. The asymmetry index for the CST was lower (P < .001) at 3.0 T. Visual scores for the left SLF and the left fornix and numbers of CC tract fibers were not significantly different. CONCLUSION: Depiction of most fiber tracts was improved at 3.0-T DT tractography compared with depiction at 1.5-T tractography.     

Simple visualization of the corticospinal pathway using tractography: one-ROI and two-ROI methods

Diffusion tensor imaging (DTI), a magnetic resonance (MR) technique to analyze diffusion anisotropy of the brain, is able to demonstrate subtle white matter anatomy. Tractography is expected to be a unique, non-invasive tool to provide more pertinent insights into brain structure and orientation not accessible by conventional MRI. In this report, preliminary experiences of visualization of the corticospinal tract using tractography are described. DTI of the brain was performed in 5 normal volunteers using single-shot echo-planar imaging, then tractography was generated by our original software. We determined that the two-region-of-interest (ROI) method is superior to the one-ROI method.     

MR imaging of ischemic penumbra

Cerebral ischemic stroke is one of the most fatal diseases despite current advances in medical science. Recent demonstration of efficacy using intravenous and intra-arterial thrombolysis demands therapeutic intervention tailored to the physiologic state of the individual tissue and stratification of patients according to the potential risks for therapies. In such an era, the role of the neuroimaging becomes increasingly important to evaluate the extent and location of tissues at risk of infarction (ischemic penumbra), to distinguish it from unsalvageable infarcted tissues or doomed hemorrhagic parenchyma. In this review, we present briefly the current role and limitation of computed tomography and conventional magnetic resonance imaging (MRI). We also present the possible applications of advanced MR techniques, such as diffusion and perfusion imaging, concentrating on the delineation or detection of ischemic penumbra.     

Correlation between cardiac norepinephrine overflow during exercise and cardiac 123I-MIBG uptake in patients with chronic heart failure.

Cardiac (123)I-metaiodobenzylguanidine ((123)I-MIBG) uptake is reduced in chronic heart failure, and its reduction is reported to relate to the decrease in exercise capacity. Reduced (123)I-MIBG uptake may predict an inadequately reduced adrenergic drive to the heart during cardiac sympathetic stimulation, including exercise. However, there is little information about the relationship between cardiac (123)I-MIBG uptake at rest and norepinephrine (NE) release during exercise in relation to the exercise capacity in the failing heart. The aim of this study was to examine whether cardiac (123)I-MIBG uptake at rest can predict cardiac sympathetic activity during exercise in patients with chronic heart failure. We determined how cardiac (123)I-MIBG uptake at rest relates to NE overflow from the heart during symptom-limited graded exercise in such patients. METHODS: Twelve patients (mean +/- SD, 52 +/- 12 y) with chronic stable heart failure performed symptom-limited graded exercise tests under catheterizations with a 4-min stage using a supine bicycle ergometer within 2 wk after (123)I-MIBG imaging. NE concentrations in the arterial and coronary sinus blood (NE(A) and NE(CS), respectively) were measured at each exercise stage, and NE overflow was approximated by the difference between NE(CS) and NE(A) (NE(CS-A)). RESULTS: The left ventricular ejection fraction at rest was 47% +/- 16% and peak oxygen uptake was 17.7 +/- 5.1 mL/kg/min. The heart-to-mediastinum uptake ratio of the delayed (123)I-MIBG image (1.00 - 1.72; mean +/- SD, 1.30 +/- 0.19) correlated with NE(CS-A) at peak exercise (r = 0.80, P < 0.01) and peak heart rate (r = 0.73, P < 0.01) but not with peak oxygen uptake. CONCLUSION: Cardiac (123)I-MIBG uptake of the delayed image can predict the degree of the increase in adrenergic drive to the heart during sympathetic stimuli induced by exercise in patients with chronic heart failure.     

Reduction of coronary flow reserve in areas with and without ischemia on stress perfusion imaging in patients with coronary artery disease: A study using oxygen 15-labeled water PET

BACKGROUND: Myocardial perfusion single photon emission computed tomography (SPECT) occasionally fails to detect coronary stenosis in patients with coronary artery disease (CAD). We evaluated coronary flow reserve (CFR) using oxygen 15-labeled water in areas with and without ischemia on technetium 99m tetrofosmin stress perfusion SPECT in patients with angiographically documented CAD. METHODS AND RESULTS: Twenty-seven patients with CAD and eleven age-matched normal subjects were studied. Baseline myocardial blood flow (MBF) and MBF during hyperemia induced by intravenous adenosine triphosphate infusion (0.16 mg. kg(-1). min(-1)) were determined with the use of O-15-labeled water positron emission tomography, and the CFR was calculated. Tc-99m tetrofosmin stress/rest SPECT was performed for comparison. On the basis of the results of coronary angiography and SPECT, coronary segments were divided into 3 types: segments with coronary stenosis and a perfusion abnormality on stress SPECT imaging (group A, n = 16), segments with coronary stenosis without a perfusion abnormality (group B, n = 42), and remote segments with no coronary stenosis or perfusion abnormality (group C, n = 18). Baseline MBF values were similar among the 3 groups. CFR in group A was lower (1.82 +/- 0.54) than in group B (2.22 +/- 0.87, P <.05), in group C (2.92 +/- 1.21, P <.01), and in normal segments (3.86 +/- 1.24, P <.001). CFR in group B was lower than in group C (P <.02) and in normal segments (P <.001). CFR in group C was lower than in normal segments (P <.02). CONCLUSIONS: Areas with a perfusion abnormality on stress SPECT had reduced CFR. In the areas without a perfusion abnormality and with coronary stenosis, lowering of CFR was intermediate between the areas with a perfusion abnormality and remote segments. Moreover, CFR was slightly, but significantly, lower in remote segments in patients with CAD compared with normal segments.