Connecting the dots between SHP2 and glutamate receptors

SHP2 is an unusual protein phosphatase that functions as an activator for several signaling pathways, including the RAS pathway, while most other phosphatases suppress their downstream signaling cascades. The physiological and pathophysiological roles of SHP2 have been extensively studied in the field of cancer research. Mutations in the PTPN11 gene which encodes SHP2 are also highly associated with developmental disorders, such as Noonan syndrome (NS), and cognitive deficits including learning disabilities are common among NS patients. However, the molecular and cellular mechanism by which SHP2 is involved in cognitive functions is not well understood. Recent studies using SHP2 mutant mice or pharmacological inhibitors have shown that SHP2 plays critical role in learning and memory and synaptic plasticity. Here, we review the recent studies demonstrating that SHP2 is involved in synaptic plasticity, and learning and memory, by the regulation of the expression and/or function of glutamate receptors. We suggest that each cell type may have distinct paths connecting the dots between SHP2 and glutamate receptors, and these paths may also change with aging.

Connecting the dots between SHP2 and glutamate receptors

SHP2 is an unusual protein phosphatase that functions as an activator for several signaling pathways, including the RAS pathway, while most other phosphatases suppress their downstream signaling cascades. The physiological and pathophysiological roles of SHP2 have been extensively studied in the field of cancer research. Mutations in the PTPN11 gene which encodes SHP2 are also highly associated with developmental disorders, such as Noonan syndrome (NS), and cognitive deficits including learning disabilities are common among NS patients. However, the molecular and cellular mechanism by which SHP2 is involved in cognitive functions is not well understood. Recent studies using SHP2 mutant mice or pharmacological inhibitors have shown that SHP2 plays critical role in learning and memory and synaptic plasticity. Here, we review the recent studies demonstrating that SHP2 is involved in synaptic plasticity, and learning and memory, by the regulation of the expression and/or function of glutamate receptors. We suggest that each cell type may have distinct paths connecting the dots between SHP2 and glutamate receptors, and these paths may also change with aging.

Differentiating Carotid Terminus Occlusions into Two Distinct Populations Based on Willisian Collateral Status / 대한뇌졸중학회지

BACKGROUND AND PURPOSE: The outcomes of acute internal carotid artery (ICA) terminus occlusions are poor. We classified ICA terminus occlusions into 2 groups according to the occlusion pattern of the circle of Willis and hypothesized that clinical outcomes would significantly differ between them. METHODS: Consecutive patients with acute ICA terminus occlusions evaluated by baseline computed tomographic angiography were enrolled. We investigated the occlusion patterns in the circle of Willis, retrospectively classified patients into simple ICA terminus occlusion (STO; with good Willisian collaterals from neighboring cerebral circulation) and complex ICA terminus occlusion (CTO; with one or more of A2 anterior cerebral artery, fetal posterior cerebral artery occlusion, or hypoplastic/absent contralateral A1; or with poor collaterals from anterior communicating artery) groups, and compared their baseline characteristics and outcomes. RESULTS: The STO group (n=58) showed smaller infarct volumes at 72 hours than the CTO group (n=34) (median, 81 mL [interquartile range, 38-192] vs. 414 mL [193-540], P<0.001) and more favorable outcomes (3-month modified Rankin Scale 0-3, 44.8% vs. 8.8%, P<0.001; 3-month mortality, 24.1% vs. 67.6%, P<0.001). In multivariable analyses, STO remained an independent predictor for favorable outcomes (odds ratio 6.1, P=0.010). CONCLUSIONS: Favorable outcomes in STO group suggested that the outcomes of acute ICA terminus occlusions depend on Willisian collateral status. Documenting the subtypes on computed tomographic angiography would help predict patient outcome.

Primary stent retrieval for acute intracranial large artery occlusion due to atherosclerotic disease / 대한뇌졸중학회지

BACKGROUND AND PURPOSE: The goal of stent retriever-based thrombectomy is removal of embolic clots in patients with intracranial large artery occlusion. However, outcomes of stent retrieval may differ between acute arterial occlusions due to intracranial atherosclerotic disease (IAD) and those due to embolism. This case series describes the outcomes of stent retriever-based thrombectomy and rescue treatments in 9 patients with IAD-related occlusion. METHODS: Among patients who underwent endovascular treatment for acute intracranial large artery occlusion, those in whom stent retrieval was attempted as first-line treatment were included in this review. IAD was defined as significant fixed focal stenosis at the occlusion site, which was evident on final angiographic assessment or observed during endovascular treatment. RESULTS: Median number of stent retriever passes was 2 (range, 1-3), and temporary bypass was seen in all patients. Immediate partial recanalization (arterial occlusive lesion grade 2-3) was observed in 7 patients. Immediate modified thrombolysis in cerebral infarction grade 2b-3 was seen in 6 patients, but the lesions often required rescue treatment due to reocclusion or flow insufficiency. In terms of rescue treatments, angioplasty and intra-arterial tirofiban infusion seemed to be effective. CONCLUSIONS: Our findings suggest that stent retrieval can effectively remove thrombi from stenotic lesions and achieve partial recanalization despite the tendency toward reocclusion in most patients with IAD-related occlusion. Further research into the use of rescue treatments, such as tirofiban infusion and angioplasty, is warranted.

Primary stent retrieval for acute intracranial large artery occlusion due to atherosclerotic disease / 대한뇌졸중학회지

BACKGROUND AND PURPOSE: The goal of stent retriever-based thrombectomy is removal of embolic clots in patients with intracranial large artery occlusion. However, outcomes of stent retrieval may differ between acute arterial occlusions due to intracranial atherosclerotic disease (IAD) and those due to embolism. This case series describes the outcomes of stent retriever-based thrombectomy and rescue treatments in 9 patients with IAD-related occlusion. METHODS: Among patients who underwent endovascular treatment for acute intracranial large artery occlusion, those in whom stent retrieval was attempted as first-line treatment were included in this review. IAD was defined as significant fixed focal stenosis at the occlusion site, which was evident on final angiographic assessment or observed during endovascular treatment. RESULTS: Median number of stent retriever passes was 2 (range, 1-3), and temporary bypass was seen in all patients. Immediate partial recanalization (arterial occlusive lesion grade 2-3) was observed in 7 patients. Immediate modified thrombolysis in cerebral infarction grade 2b-3 was seen in 6 patients, but the lesions often required rescue treatment due to reocclusion or flow insufficiency. In terms of rescue treatments, angioplasty and intra-arterial tirofiban infusion seemed to be effective. CONCLUSIONS: Our findings suggest that stent retrieval can effectively remove thrombi from stenotic lesions and achieve partial recanalization despite the tendency toward reocclusion in most patients with IAD-related occlusion. Further research into the use of rescue treatments, such as tirofiban infusion and angioplasty, is warranted.

Cerebral Venous Thrombosis Treated with the Penumbra System(TM) and Various Neurointervention

A 33-year-old male was admitted with severe headache lasting 3 days. He did not have a focal neurologic deficit, but had a high intracranial pressure of 512 mmH2O. Cerebral angiography revealed venous sinus thrombosis that mainly involved the superior sagittal and right transverse sinuses. His headache remained severe after intravenous heparin infusion, and so interventional procedures were performed. Mechanical aspiration with the Penumbra system(TM) and other interventional procedures reopened the outflow of the superior sagittal sinus and effectively ameliorated this patient's headache.

A Case of Linezolid-Associated Lactic Acidosis / 대한내과학회지

Linezolid has been used for treatment of vancomycin-resistant Enterococcus faecium infection, nosocomial pneumonia caused by Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus or Streptococcus pneumoniae, and complicated and uncomplicated skin and skin structure infections. Lactic acidosis is an adverse effect associated with drugs, including metformin, the nucleoside reverse-transcriptase inhibitors and, rarely, linezolid. We report a case in which severe lactic acidosis developed as an adverse effect of linezolid in a 75-year-old woman who had been on linezolid for 30 days for treatment of a wound infection caused by methicillin-resistant coagulase-negative Staphylococcus. Discontinuation of linezolid and hemodialysis improved her lactic acidosis.

Quantitative Analysis of Developmental Process of Cranial Suture in Korean Infants

OBJECTIVE: The purpose of this study was to elucidate the anatomical development of physiologic suture closure processes in infants using three dimensional reconstructed computed tomography (CT). METHODS: A consecutive series of 243 infants under 12 months of age who underwent three dimensional CT were included in this study. Four major cranial sutures (sagittal, coronal, lambdoidal and metopic suture) were classified into four suture closure grades (grade 0=no closure along the whole length, grade 1=partial or intermittent closure, grade 2=complete closure with visible suture line, grade 3=complete fusion (ossification) without visible suture line), and measured for its closure degree (suture closure rates; defined as percentage of the length of closed suture line divided by the total length of suture line). RESULTS: Suture closure grade under 12 months of age comprised of grade 0 (n=195, 80.2%), grade 1 (n=24, 9.9%) and grade 2 (n=24, 9.9%) in sagittal sutures, whereas in metopic sutures they were grade 0 (n=61, 25.1%), grade 1 (n=167, 68.7%), grade 2 (n=6, 24%) and grade 3 (n=9, 3.7%). Mean suture closure rates under 12 months of age was 58.8% in metopic sutures, followed by coronal (right : 43.8%, left : 41.1%), lambdoidal (right : 27.2%, left : 25.6%) and sagittal sutures (15.6%), respectively. CONCLUSION: These quantitative descriptions of cranial suture closure may help understand the process involved in the cranial development of Korean infants.

A Case of Linezolid-Associated Lactic Acidosis / 대한내과학회지

Linezolid has been used for treatment of vancomycin-resistant Enterococcus faecium infection, nosocomial pneumonia caused by Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus or Streptococcus pneumoniae, and complicated and uncomplicated skin and skin structure infections. Lactic acidosis is an adverse effect associated with drugs, including metformin, the nucleoside reverse-transcriptase inhibitors and, rarely, linezolid. We report a case in which severe lactic acidosis developed as an adverse effect of linezolid in a 75-year-old woman who had been on linezolid for 30 days for treatment of a wound infection caused by methicillin-resistant coagulase-negative Staphylococcus. Discontinuation of linezolid and hemodialysis improved her lactic acidosis.

Utility of Acetazolamide-challenged CT Perfusion in Patients with High-grade Carotid Stenosis / 신경중재치료의학

OBJECTIVE: To correlate quantitative cerebrovascular reserve calculated by acetazolamide - challenged CT perfusion with clinical symptoms in hemodynamically compromised patients with high-grade (>70%) carotid stenosis, who did not have evidence of embolic stroke. MATERIALS AND METHODS: 37 patients diagnosed as unilateral severe carotid stenosis and 10 age-matched normal controls underwent acetazolamide - challenged CT perfusion. For quantitative measurement, asymmetric index of cerebral blood flow, cerebral blood volume, and mean transit time were determined before and after acetazolamide challenge. Reactivity index was also calculated from asymmetric index of cerebral blood flow before and after acetazolamide challenge. RESULTS: On visual analysis, all of 14 asymptomatic patients and 4 of 23 symptomatic patients showed bilateral symmetric cerebrovascular reserve on CT perfusion, and 19 symptomatic patients showed decreased cerebrovascular reserve ipsilateral to carotid stenosis. On quantitative analysis, the reactivity index was significantly different between the symptomatic and the asymptomatic groups (-24% vs -8% in external border zone) but the resting parameters were not. 11 patients with decreased cerebrovascular reserve who underwent carotid stenting showed improved clinical symptoms and quantitative cerebrovascular reserve on follow up CT perfusion. CONCLUSION: Compared with resting hemodynamic parameters, quantitative cerebrovascular reserve calculated by CT perfusion is most significantly correlated with clinical symptoms in hemodynamically compromised patients with high-grade carotid stenosis.

Effect of Curettage and DBM-CaSO4 Graft for the Treatment of Ischemic Necrosis of the Capital Femoral Epiphysis in Immature Pigs / 대한정형외과연구학회지

PURPOSE: The purpose of this study was to determine the effect of curettage and DBM complex graft as a new treatment modality for LCP disease using piglet capital femoral epiphysis ischemic necrosis model. MATERIALS AND METHODS: Five to six weeks old piglets were used for the experiment. Ischemic necrosis of the capital femoral epiphysis was surgically induced by cervical ligation on both sides. Three weeks following ischemic insult, the left hip joint was approached medially. About 15% of the necrotic capital femoral epiphysis was curetted through a window which was opened at medial cervical cortex, then, demineralized bone matrix complex was engrafted. The right femoral heads served as controls. Piglets were sacrificed three, six, nine, and twelve weeks following were harvested for histologic examination. RESULTS: In control group, photomicrographs of specimens showed central necrosis and fibrovascular invasion in capital femoral necrosis at three weeks after ischemic insult. Six, nine, and twelve weeks following ischemic insult, fibrovascular invasion advanced without noticeable new bone formation and collapse of femoral head progressed. At twelve weeks, definite coxa plana developed. In curettage and DBM complex graft group, there was evident new bone formation observed in the site of DBM complex graft. At three weeks, new bone formation along with fibrovascular invasion was observed around the engrafted DBM complex mainly in the cervical metaphyseal area. At six and nine weeks, new bone formation progressed into the engrafted DBM complex in the cervical metaphysis and around the engrafted DBM complex in the capital femoral epiphysis. At twelve weeks, new bone along with new cartilage formation was observed in the capital femoral epiphysis. CONCLUSION: In conclusion, curettage and DBM complex graft is thought to be an effective treatment modality that promote regeneration of ischemic necrosis of capital femoral epiphysis.

Treatment of Bunionette Deformity with S.E.R.I. (simple, effective, rapid, inexpensive) Operation / 대한족부족관절학회지

PURPOSE: The purpose of this study was to evaluate the clinical and radiological outcomes of the S.E.R.I. (simple, effective, rapid, inexpensive) operation for the bunionette deformity. MATERIALS AND METHODS: Between March 2005 and February 2009, 22 patients (26 feet) who had been treated for the bunionette deformity with minimally invasive osteotomy were reviewed retrospectively. Clinically, Visual Analogue Scale (VAS), American Orthopaedic Foot and Ankle Society (AOFAS) score, shoes selectivity, disappearance of callus and patient's satisfaction level by Coughlin scoring system were evaluated. Radiologically, the bunionette was classified as four types according to the Fallat classification. The 4-5th intermetatarsal angle (4-5th IMA), the 5th metatarsophalangeal angle (5th MPA) and the length of 5th metatarsal bone (5th MTL) were analyzed at preoperatively and at final follow up visit. RESULTS: VAS improved from 6.8+/-1.8 points to 2.2+/-1.8 points (p<0.05). AOFAS score improved from 54.0+/-14.2 points to 90.0+/-4.8 points (p<0.05). There was no change in shoes selectivity. 9 feet (34.6%) were satisfied with excellent results, 16 feet (61.5%) with good results and 1 foot (3.9%) with fair results. The average 4-5th IMA was corrected from 10.1+/-2.3degrees to 4.4+/-1.7degrees (p<0.05). The average 5th MPA was corrected from 11.5+/-8.6degrees to -0.1+/-4.1degrees (p<0.05). The average 5th MTL was changed from 66.1+/-4.3 millimeters to 64.1+/-4.4 millimeters (p=0.069). There was no malunion, nonunion or delayed union and other perioperative complications. CONCLUSION: S.E.R.I. operation is less invasive and easy technique. This procedure is recommendable for the treatment of the bunionette deformity.

Treatment of Bunionette Deformity with S.E.R.I. (simple, effective, rapid, inexpensive) Operation / 대한족부족관절학회지

PURPOSE: The purpose of this study was to evaluate the clinical and radiological outcomes of the S.E.R.I. (simple, effective, rapid, inexpensive) operation for the bunionette deformity. MATERIALS AND METHODS: Between March 2005 and February 2009, 22 patients (26 feet) who had been treated for the bunionette deformity with minimally invasive osteotomy were reviewed retrospectively. Clinically, Visual Analogue Scale (VAS), American Orthopaedic Foot and Ankle Society (AOFAS) score, shoes selectivity, disappearance of callus and patient's satisfaction level by Coughlin scoring system were evaluated. Radiologically, the bunionette was classified as four types according to the Fallat classification. The 4-5th intermetatarsal angle (4-5th IMA), the 5th metatarsophalangeal angle (5th MPA) and the length of 5th metatarsal bone (5th MTL) were analyzed at preoperatively and at final follow up visit. RESULTS: VAS improved from 6.8+/-1.8 points to 2.2+/-1.8 points (p<0.05). AOFAS score improved from 54.0+/-14.2 points to 90.0+/-4.8 points (p<0.05). There was no change in shoes selectivity. 9 feet (34.6%) were satisfied with excellent results, 16 feet (61.5%) with good results and 1 foot (3.9%) with fair results. The average 4-5th IMA was corrected from 10.1+/-2.3degrees to 4.4+/-1.7degrees (p<0.05). The average 5th MPA was corrected from 11.5+/-8.6degrees to -0.1+/-4.1degrees (p<0.05). The average 5th MTL was changed from 66.1+/-4.3 millimeters to 64.1+/-4.4 millimeters (p=0.069). There was no malunion, nonunion or delayed union and other perioperative complications. CONCLUSION: S.E.R.I. operation is less invasive and easy technique. This procedure is recommendable for the treatment of the bunionette deformity.

Delayed Spinal Epidural Hematoma after En Block Spondylectomy for Vertebral Ewing's Sarcoma

We report here on a case of a 23-year-old male who received en block spondylectomy for a vertebral Ewing's sarcoma at our hospital. Nine days after surgery, he presented with severe back pain and motor weakness of the lower extremities. Based on the physical examination and the computed tomography scan, he was diagnosed with acute cauda equina syndrome that was caused by compression from an epidural hematoma. His neurological functions recovered after emergency evacuation of the hematoma. This case showed that extensive surgery for a malignant vertebral tumor has a potential risk of delayed epidural hematoma and acute cauda equina syndrome and this should be treated with emergency evacuation.

Indications and Prognostic Factors of Groin Flap for Reconstruction of the Extremities

There are several advantages for groin flap, but its small and unpredictable vessels of pedicle have made it to lose its initial popularity. Although it would be ideal flap when it is focused on its useful advantages such as relative larger size, low donor site morbidity and possible bone graft, there have been few studies for prognostic factors for successful groin flap. Authors intended to determine prognostic factors which are relative with success of free groin flap. From January 1985 to December 2007, 107 patients who underwent groin flap for reconstruction of extremities were selected consecutively. Univariate and multivariate analysis were performed to determine prognostic factors which were related with success of groin flap. Eighty of 107 (74.8%) flaps survived. There was significant difference in success rate according to the recipient site. Nineteen of 20 cases (95%) survived in upper extremities, but 61 of 87 cases (70.1%) survived in lower extremities, which was statistically significant (p=0.022). Univariate analysis showed that mean diameter of donor veins was significantly larger in success group (p=0.021). Groin flap is recommended for reconstruction of upper extremities than lower extremities. It is thought to be critical that surgeons try to match vessel diameters between donor and recipient site.

Acetazolamide-Challenged Brain CT Perfusion before and after Carotid Stenting / 신경중재치료의학

PURPOSE: To test hypothesis that pre-stenting measurement of reactivity index by using acetazolamide-challenged CT perfusion could identify patients at risk for hyperperfusion after carotid stenting. MATERIALS AND METHODS: For 24 regions of interest in 12 patients with symptomatic unilateral high-grade carotid stenosis, asymmetric indexes for cerebral blood volume, cerebral blood flow, and mean transit time and reactivity index were calculated from resting and acetazolamide-challenged CT perfusion before and 1 day after carotid stenting. We subsequently compared pre-stenting asymmetric indexes and reactivity index with percent increase of cerebral blood flow 1 day after carotid stenting. RESULTS: Percent increase of cerebral blood flow on the first post-stenting day was not significantly different between visually decreased and normal cerebrovascular reserve groups. There was no significant correlation between pre-stenting asymmetric indexs of resting CT perfusion parameters and percent increase of cerebral blood flow 1 day after carotid stenting. On the other hand, pre-stenting reduction of reactivity index showed fair correlation with 1 day cerebral blood flow increase. However, hyperperfusion or hyperperfusion syndrome was not observed in any patient with reduced reactivity index. CONCLUSION: Pre-stenting measurements of resting CT perfusion parameters and reactivity index could not predict hyperperfusion after carotid stenting. However, pre-stenting reduction of reactivity index seems to fairly correlate with immediate post-stenting cerebral blood flow increase. Further studies with larger population should be performed to validate this preliminary result.

Treatment of Vertebrobasilar Artery Dissection / 신경중재치료의학

Intracranial vertebrobasilar artery (VBA) dissection can be classified into three major clinical types: subarachnoid hemorrhage, headache, and nonhemorrhagic ischemic symptoms. And it has been more frequently identified since the introduction of advanced diagnostic imaging modalites including MR angiography and multidetector CT angiography. Aggressive treatment has been considered due to their tendency for early rebleeding and a fatal natural course. We describe approproiate neurointerventional options, based on he patterns of angiographic features and location of dissection.

A "Benign" Sphenoid Ridge Meningioma Manifesting as a Subarachnoid Hemorrhage Associated with Tumor Invasion into the Middle Cerebral Artery

Meningioma rarely manifests as a subarachnoid hemorrhage (SAH), and invasion directly into a major intracranial artery is extremely rare. To the best of our knowledge, meningioma presenting with an SAH associated with major intracranial arterial invasion has never been reported. We present a case of sphenoid ridge meningotheliomatous meningioma manifesting as an SAH without pathologically atypical or malignant features, due to direct tumor invasion into the middle cerebral artery.

The Usefulness of MDCT Angiography in the Diagnosis of Vertebrobasilar Artery Dissection

PURPOSE: To evaluate the usefulness of MDCT angiography in the diagnosis of vertebrobasilar artery dissection. MATERIALS AND METHODS: Between July 2003 and December 2005, 39 patients who underwent MDCT angiography and digital subtraction angiography with a history of suspicious vertebrobasilar artery dissection were selected. A blind interpretation of images was made by two observers, retrospectively. A diagnosis of dissection in MDCT angiography was made according to the following criteria: presence of an intimal flap, aneurysmal dilatation, abrupt or tapered luminal narrowing, alternatively dilated and narrowed lumen. The sensitivity and specificity of MDCT angiography in depicting vertebrobasilar artery dissection were determined. RESULTS: 43 vertebrobasilar artery dissections were diagnosed by MDCT angiography in 39 patients. The interobserver agreement was good (kappa =0.92). A diagnosis was made by the presence of an intimal flap (n=16, 36%), abrupt or tapered luminal narrowing (n=16, 36%), aneurysmal dilatation (n=13, 30%), alternatively dilated and narrow lumen (n=14, 32%). The sensitivities and specificities of MDCT angiography were 91%, 88% as determined by the first radiologist, and were 89%, 87% as determined by a second radiologist, respectively. CONCLUSION: MDCT angiography is a useful method for the diagnosis of vertebrobasilar artery dissection.

Stent Assisted Coil Embolization of Unruptured Aneurysm Associated with Basilar Artery Fenestration: A Case Report / 신경중재치료의학

We report a case of unruptured aneurysm associated with basilar fenestration treated with coil-assisted coil embolization. A 46-year-old man had suffered from intermittent, progressive occipital headache for 2 months. Magnetic resonance (MR) angiography showed a large aneurysm at the proximal basilar artery. Both three-dimensional CT angiography and angiography demonstrated a saccular, 20x15-mm aneurysm arising at the proximal end of associated fenestration at the basilar artery. The aneurysm was successfully occluded with stent-assisted coil embolization. The patient was discharged home after 1 week and received 75 mg clopidogrel once daily for 4 weeks and 100 mg aspirin once daily for life.