Non-Invasive PET Imaging of EGFR Degradation Induced by a Heat Shock Protein 90 Inhibitor

Purpose The aim of this study is to non-invasively monitor the epidermal growth factor receptor (EGFR) response to a Hsp90 inhibitor–17-AAG treatment in a PC-3 prostate cancer model. Procedures Nude mice bearing PC-3 tumor were injected intraperitoneally with 17-AAG and then imaged with micro positron emission tomography (microPET) using ⁶⁴Cu-DOTA–cetuximab. Biodistribution studies, immunofluorescence staining, and Western blot were performed to validate the microPET results. Results PC-3 cells are sensitive to 17-AAG treatment in a dose-dependent manner. Quantitative microPET showed that ⁶⁴Cu-DOTA–cetuximab has prominent tumor activity accumulation in untreated tumors (14.6 ± 2.6%ID/g) but significantly lower uptake in 17-AAG-treated tumors (8.9 ± 1.6% ID/g) at 24 h post-injection. Both immunofluorescence staining and Western blot confirmed the significantly lower EGFR expression level in the tumor tissue upon 17-AAG treatment. Conclusions The early response to anti-Hsp90 therapy was successfully monitored by quantitative PET using ⁶⁴Cu-DOTA–cetuximab, which indicates that this approach may be valuable in monitoring the therapeutic response to Hsp90 inhibitor 17-AAG in EGFR-positive cancer patients.     

Implantation of olfactory ensheathing cells promotes neuroplasticity in murine models of stroke

Murine olfactory ensheathing cells (OECs) promote central nervous system axonal regeneration in models of spinal cord injury. We investigated whether OECs could induce a neuroplastic effect to improve the neurological dysfunction caused by hypoxic/ischemic stress. In this study, human OECs/olfactory nerve fibroblasts (hOECs/ONFs) specifically secreted trophic factors including stromal cell-derived factor-1alpha (SDF-1alpha). Rats with intracerebral hOEC/ONF implantation showed more improvement on behavioral measures of neurological deficit following stroke than control rats. [18F]fluoro-2-deoxyglucose PET (FDG-PET) showed increased glucose metabolic activity in the hOEC/ONF-treated group compared with controls. In mice, transplanted hOECs/ONFs and endogenous homing stem cells including intrinsic neural progenitor cells and bone marrow stem cells colocalized with specific neural and vascular markers, indicating stem cell fusion. Both hOECs/ONFs and endogenous homing stem cells enhanced neuroplasticity in the rat and mouse ischemic brain. Upregulation of SDF-1alpha and CXCR4 in hOECs/ONFs promoted neurite outgrowth of cocultured primary cortical neurons under oxygen glucose deprivation conditions and in stroke animals through upregulation of cellular prion protein (PrP C) expression. Therefore, the upregulation of SDF-1alpha and the enhancement of CXCR4 and PrP C interaction induced by hOEC/ONF implantation mediated neuroplastic signals in response to hypoxia and ischemia.     

Hospitalized osteoporotic vertebral fracture increases the risk of stroke: A population‐based cohort study

The association between osteoporosis and cardiovascular diseases has been demonstrated. Higher cardiovascular risk has also been correlated with vertebral fractures. However, the association between osteoporotic vertebral fracture and the possibly higher risk of stroke remains uncertain. This study aimed to evaluate the incidence, risk, and type of stroke in patients with osteoporotic vertebral fracture. Patients with osteoporotic vertebral fracture were identified (n = 380) and 10 age‐ and sex‐matched controls per case (comparison group, n = 3795) were chosen from a nationwide representative cohort of 999,997 people from 1998 to 2005. Both groups were followed‐up for stroke events for 3 years, matched by propensity scores with adjustments for covariates such as comorbidities (ie, hypertension, diabetes, arrhythmia, or coronary heart diseases) and exposure to medications (ie, aspirin, lipid lowering drug, or nitrates), and assessed by Kaplan‐Meier and Cox regression analyses. The incidence rate of stroke in the osteoporotic vertebral fracture group (37.5 per 1000 person‐years; 95% confidence interval [CI], 27.5–51.2) was significantly higher than in the comparison group (14.0 per 1000 person‐years; 95% CI, 12.0–16.4, p < 0.001). Stroke was more likely to occur in the osteoporotic vertebral fracture patients than in the normal controls (crude hazard ratio [HR] 2.68, 95% CI 1.89–3.79, p < 0.001; adjusted HR 2.71, 95% CI 1.90–3.86, p < 0.001). In conclusion, patients with osteoporotic vertebral fracture have a higher risk of stroke (ie, both ischemic and hemorrhagic) and require stroke prevention strategies. © 2013 American Society for Bone and Mineral Research.     

Antibacterial activity and PK/PD of ceftriaxone against penicillin-resistant <Emphasis Type="Italic">Streptococcus pneumoniae</Emphasis> and β-lactamase-negative ampicillin-resistant <Emphasis Type="Italic">Haemophilus influenzae</Emphasis> isolates from patients with community-acquired pneumonia

The suitability of ceftriaxone for penicillin-resistant Streptococcus pneumoniae (PRSP) and ampicillin-resistant Haemophilus influenzae (especially β-lactamase-negative ampicillin-resistant (BLNAR) H. influenzae) and the relationship between in vitro antimicrobial activities and pharmacokinetic parameters were evaluated. The values for percentage of time above the MIC (%T>MIC) for ceftriaxone, cefotiam, flomoxef, sulbactam/cefoperazone, sulbactam/ampicillin, and meropenem, using 400 S. pneumoniae isolates and 430 H. influenzae isolates from patients with community-acquired pneumonia (CAP) from more than 100 geographically diverse medical centers during January to July of 2005, were calculated by measuring the MIC for each isolate and by using patameters of pharmacokinetics. A broth microdilution method was used to determine the MIC, using the guidelines of the Clinical and Laboratory Standards Institute (CLSI). Meropenem showed the lowest MIC against penicillin-susceptible S. pneumoniae, followed by sulbactam/cefoperazone and ceftriaxone. Ceftriaxone had the best activity against penicillin-resistant S. pneumoniae and β-lactamase-negative and β-lactamase–producing ampicillin-resistant H. influenzae. Ceftriaxone was unique, showing a long elimination half-life and low MIC values where its serum level duration time was above the MIC for longer than other cephalosporins. Accordingly, the %T>MIC of ceftriaxone for a once-daily administration greatly exceeded the efficacy levels of those for the other antibacterial agents tested. Ceftriaxone has an excellent balance between in vitro antimicrobial activities and pharmacokinetic profiles; and therefore remains effective as a therapeutic agent against PRSP and BLNAR H. influenzae in CAP.     

Myofascial dysfunction associated with chronic pelvic floor pain: Management strategies

Myofascial pain as a cause of chronic pelvic pain with or without pelvic organ pathology is well-documented in the literature. Causes of this pain are multifactorial, including specific pelvic organ pathologies, neuromuscular disorders, and psychologic causes. Management of this myofascial component of chronic pelvic pain involves a multidisciplinary approach including physicians, physical therapists, neurologists, and psychiatrists. Treatment strategies, including behavioral management, medications, physical therapy, trigger point injections, neuromodulation, botulinum toxin injection, and other lesser known treatment modalities, are discussed in detail in this article.     

Eating Habits and Dietary Status in Young Children with Autism

While clinical lore appears to accept that young children with autism have limited or narrow diets and unusual food aversions in comparison to same age peers, the empirical basis for this is missing. The goals of this preliminary study were to examine the eating habits and nutritional intake of a young cohort of well characterized children with autism compared to young children with no evidence of autism or other autism spectrum disorders. Parents reported on 19 young children with autism and 15 similar aged children with typical development using a number of informant instruments. Results indicated that children with autism had more mealtime behavioral differences, but these did not translate to significant differences in nutritional status compared to typically developing children. However, there was much variability within both groups. Results are discussed in relationship to what has been previously found in older children with autism spectrum disorders.     

XT-2000i全自动血液分析仪检测网织红细胞的评价与应用

目的评价Sysmex XT-2000i测定网织红细胞(Ret)的性能。方法用XT-2000i检测Ret,并与参考方法检测结果进行比较。结果XT-2000i检测Ret的精密度高(高、中、低值标本的批内和批间Cv%<5%),在1.58×109/L~273×109/L范围内线性良好(r=0.9952),互染率低(0.15%),与人工法相关性较好(r=0.9648),具有良好的敏感性,结论XT-2000i检测Ret具有快速、简便、准确、稳定、精密度高等特点。     

MOB-1 and TNF-alpha interact to induce microvascular lung injury

We have recently identified the alpha-chemokine mob-1 as a highly inducible gene in several rat models of microvascular lung injury, whose expression was suppressed by inhibition of tumor necrosis TNF-alpha (TNF-alpha). This work provides further insight into the relationship between mob-1 and TNF-alpha in the development of lung injury assessed by pulmonary edema and leukosequestration. First, pulmonary mob-1 and TNF-alpha were upregulated in animals subjected to lung injury produced by the intratracheal administration of recombinant TNF-alpha and recombinant mob-1, respectively. Second, mob-1 inhibition by intratracheal anti-mob-1 antibody attenuated lung injury induced by recombinant TNF-alpha. Third, pretreatment with anti-TNF-alpha monoclonal antibody administered intratracheally abrogated recombinant mob-1-induced microvascular lung injury. In vitro, mob-1 and TNF-alpha increased each other's production in RAW 264.7 cells and mob-1 or TNF-alpha inhibition prevented endotoxin-induced upregulation of TNF-alpha or mob-1, respectively, from these cells. Together, these data suggest that mob-1 and TNF-alpha interact to promote lung inflammation.     

Efficacy,safety, and tolerability of valsartan/hydrochlorothiazide in Asian patients with essential hypertension

Introduction  

Previous studies have demonstrated that hypertensive patients need concomitant therapy with one or more drugs from different classes of antihypertensive agents to achieve their blood pressure control targets. We performed the first multinational observational study of valsartan/hydrochlorothiazide (HCTZ) single pill combination in Asia to determine the efficacy, safety, and tolerability in hypertensive patients. The objective of this multinational, multicenter, 24-week follow-up observational study is to evaluate the efficacy, safety, and tolerability of valsartan/hydrochlorothiazide single pill combination in the treatment of essential hypertension in the Asia-Pacific region.     

Management of 350 aneurysmal subarachnoid hemorrhages in 22 Italian neurosurgical centers

OBJECTIVE: To collect information on clinical practice and current management strategies in 22 Italian neurosurgical hospitals for patients with aneurysmal subarachnoid hemorrhage. DESIGN AND SETTING: Observational 6-month study for prospective data collection. PATIENTS: 350 cases of aneurysmal subarachnoid hemorrhage. MEASUREMENTS AND RESULTS: Each center enrolled from 4-36 patients. Neurological deterioration (24%) was more frequent in patients with higher Fisher classification, and with pretreatment rebleeding and it was associated with an unfavorable outcome (46%, 36/78, vs. 33%, 83/251). Aneurysms were mainly secured by clipping (55%, 191/350). An endovascular approach was utilized in 35% (121/350). The more frequent medical complications were fever, recorded in one-half of cases, pneumonia (18%), sodium disturbances (hyponatremia 22%, hypernatremia 17%), cardiopulmonary events as neurogenic pulmonary edema (4%) and myocardial ischemia (5%). Intracranial hypertension was experienced in one-third of the patients, followed by hydrocephalus (29%) and vasospasm (30%). Cerebral ischemia was found in an about one-quarter of the cohort. To identify the independent predictors of outcome we developed a model in which the dichotomized Glasgow Outcome Scale was tested as function of extracranial and intracranial complications. Only high intracranial pressure and deterioration in neurological status were independent factors related to unfavorable outcome. CONCLUSIONS: Our data confirm that in every step of care there is extreme heterogeneity among centers. These patients are complex, with comorbidities, immediate risk of rebleeding, and delayed risk of intracranial and medical complications. Following SAH early treatment and careful intensive care management requires the careful coordination of the various clinical specialties.