A systematic review and meta‐analysis of clinical variables used in Huntington disease research

Treatment effect in Huntington disease (HD) clinical trials has relied on primary outcome measures such as total motor score or functional rating scales. However, these measures have limited sensitivity, particularly in pre‐ to early stages of the disease. We performed a systematic review of HD clinical studies to identify endpoints that correlate with disease severity. Using standard HD keywords and terms, we identified 749 published studies from 1993 to 2011 based on the availability of demographic, biochemical, and clinical measures. The average and variability of each measure was abstracted and stratified according to pre‐far, pre‐close, early, mild, moderate, and severe HD stages. A fixed‐effect meta‐analysis on selected variables was conducted at various disease stages. A total of 1,801 different clinical variables and treatment outcomes were identified. Unified Huntington Disease Rating Scale (UHDRS) Motor, UHDRS Independence, and Trail B showed a trend toward separation between HD stages. Other measures, such as UHDRS Apathy, Verbal Fluency, and Symbol Digit, could only distinguish between pre‐ and early stages of disease and later stages, whereas other measures showed little correlation with increasing HD stages. Using cross‐sectional data from published HD clinical trials, we have identified potential endpoints that could be used to track HD disease progression and treatment effect. Longitudinal studies, such as TRACK‐HD, are critical for assessing the value of potential markers of disease progression for use in future HD therapeutic trials. A list of variables, references used in this meta‐analysis, and database is available at http://www.cmmt.ubc.ca/research/investigators/leavitt/publications . © 2013 International Parkinson and Movement Disorder Society     

Bacteriomimetic poly-γ-glutamic acid surface coating for hemocompatibility and safety of nanomaterials

Poly-γ-glutamic acid (PGA), a major component of the bacterial capsule, is known to confer hydrophilicity to bacterial surfaces and protect bacteria from interactions with blood cells. We tested whether applying a bacteriomimetic surface coating of PGA modulates interactions of nanomaterials with blood cells or affects their safety and photothermal antitumor efficacy. Amphiphilic PGA (APGA), prepared by grafting phenylalanine residues to PGA, was used to anchor PGA to reduced graphene oxide (rGO) nanosheets, a model of hydrophobic nanomaterials. Surface coating of rGO with bacterial capsule-like APGA yielded APGA-tethered rGO nanosheets (ArGO). ArGO nanosheets remained stable in serum over 4?weeks, whereas rGO in plain form precipitated in serum within 5?minutes. Moreover, ArGO did not interact with blood cells, whereas rGO in plain form or as a physical mixture with PGA formed aggregates with blood cells. Mice administered ArGO at a dose of 50?mg/kg showed 100% survival and no hepatic or renal toxicity. No mice survived exposure at the same dose of rGO or a PGA/rGO mixture. Following intravenous administration, ArGO showed a greater distribution to tumors and prolonged tumor retention compared with other nanosheet formulations. Irradiation with near-infrared light completely ablated tumors in mice treated with ArGO. Our results indicate that a bacteriomimetic surface modification of nanomaterials with bacterial capsule-like APGA improves the stability in blood, biocompatibility, tumor distribution, and photothermal antitumor efficacy of rGO. Although APGA was used here to coat the surfaces of rGO, it could be applicable to coat surfaces of other hydrophobic nanomaterials.     

Flagellin Modulates the Function of Invariant NKT Cells From Patients With Asthma via Dendritic Cells

PurposeInvariant natural killer T (iNKT) cells play a critical role in the pathogenesis of asthma. We previously reported the association between circulating Th2-like iNKT cells and lung function in asthma patients and the suppressive effect of Toll-like receptor 5 ligand flagellin B (FlaB) on asthmatic in a mouse model. Thus, we investigated whether FlaB modulates the function of circulating iNKT cells in asthmatic patients.MethodsPeripheral blood mononuclear cells (PBMCs) were treated with FlaB, and the secreted and intracellular cytokines of iNKT cells were evaluated by using ELISA and flow cytometry, respectively, following stimulation with α-galactosylceramide. Foxp3⁺ iNKT cells were also measured. To determine the effect of FlaB-treated dendritic cells (DCs) on iNKT cells, we co-cultured CD14⁺ monocyte-derived DCs and T cells from patients with house dust mite-sensitive asthma and analyzed intracellular cytokines in iNKT cells.ResultsA reduction of IL-4 and IL-17 production by iNKT cells in PBMCs after FlaB treatment was alleviated following blocking of IL-10 signaling. A decrease in the frequencies of IL-4⁺ and IL-17⁺ iNKT cells by FlaB-treated DCs was reversed after blocking of IL-10 signaling. Simultaneously, an increase in Foxp3⁺ iNKT cells induced by FlaB treatment disappeared after blocking of IL-10.ConclusionsFlaB may inhibit Th2- and Th17-like iNKT cells and induce Foxp3⁺ iNKT cells by DCs via an IL-10-dependent mechanism in asthmatic patients. In patients with a specific asthma phenotype associated with iNKT cells, FlaB may be an effective immunomodulator for iNKT cell-targeted immunotherapy.     

Accuracy of a high prostate-specific antigen level for prostate cancer diagnosis upon initial biopsy in Korean men

PURPOSE: This study aimed to evaluate the cancer detection rate in a Korean population with prostate-specific antigen (PSA) levels greater than or equal to 20.0 ng/mL. MATERIALS AND METHODS: A total of 174 men 50 to 79 years old (median 69) included in the study. The median prostate volume of the patients was 44.8 mL (range 14.1 to 210.0) and their serum PSA ranged from 20.0 to 9725.0 ng/mL (median 44.8). RESULTS: Of 174 men 141 (81.0%) were diagnosed with prostate cancer on initial biopsy. In the total number of patients, the positive predictive value (PPV) was 62.9% for PSA 20 to 29.9, 72.7% for PSA 30 to 39.9 and 100% for PSA 40 to 49.9 ng/mL. In patients with an abnormal digital rectal examination (DRE), the values for these PSA ranges increased to 89.5%, 91.7% and 100%, respectively. The PPV was 81.0% for PSA cutoff of 20, 89.2% for a cutoff of 30, 95.4% for a cutoff of 40, and 94.7% for a cutoff of 50 ng/mL. In conjunction with an abnormal DRE, the values for these PSA cutoffs increased to 95.9%, 98.1%, 100%, and 100%, respectively. CONCLUSION: Our data suggest the ability to predict the presence of prostate cancer reliably on initial biopsy when PSA threshold is greater than or equal to 50 ng/mL. This PSA threshold may be lowered to 40 ng/mL in the presence of an abnormal DRE. In Korean men with high PSA, the detection rate of prostate cancer on biopsy appears to be comparable to that for American men.     

What are the Causative Factors for a Slow,Progressive Enlargement of a Chronic Subdural Hematoma?

PURPOSE: To test the hypothesis that chronic subdural hematoma (CSDH) enlarges by the causative factors, this study has performed. MATERIALS AND METHODS: In 10 patients with CSDH, coagulation factors in venous blood taken at the time of surgery and hematomic contents aspirated from the CSDH were studied, using both laboratory assays and microscopy. RESULTS: When compared to the range of normal plasma, the hematoma fluids demonstrated a marked reduction in factor II, V, VII, VIII, and X, moderate reduction of factors IX and XI, and slight reduction of factor XII. Activated protein C and antithrombin III levels were decreased. The FDP (Fibrinogen Degradation Product) levels in chronic subdural hematoma were extremely high. The endothelial cells of the macrocapillaries (also called 'sinusoid') showed numerous gap junctions between adjacent endothelial cells and a thinness or absence of the basement membrane, suggesting that the macrocapillaries are very fragile and susceptible to bleeding. CONCLUSION: Excessive coagulation in the hematoma, predominantly via the extrinsic clotting pathway, local hyperfibrinolysis, transmitted pulsations, and characteristics of the macrocapillaries play an important role in the leakage of blood and the enlargement of CSDH.     

Disruption of Dhcr7 and Insig1/2 in cholesterol metabolism causes defects in bone formation and homeostasis through primary cilium formation

Human linkage studies suggest that craniofacial deformities result from either genetic mutations related to cholesterol metabolism or high-cholesterol maternal diets. However, little is known about the precise roles of intracellular cholesterol metabolism in the development of craniofacial bones, the majority of which are formed through intramembranous ossification. Here, we show that an altered cholesterol metabolic status results in abnormal osteogenesis through dysregulation of primary cilium formation during bone formation. We found that cholesterol metabolic aberrations, induced through disruption of either Dhcr7(which encodes an enzyme involved in cholesterol synthesis) or Insig1 and Insig2(which provide a negative feedback mechanism for cholesterol biosynthesis), result in osteoblast differentiation abnormalities. Notably, the primary cilia responsible for sensing extracellular cues were altered in number and length through dysregulated ciliary vesicle fusion in Dhcr7 and Insig1/2 mutant osteoblasts. As a consequence, WNT/β-catenin and hedgehog signaling activities were altered through dysregulated primary cilium formation.Strikingly, the normalization of defective cholesterol metabolism by simvastatin, a drug used in the treatment of cholesterol metabolic aberrations, rescued the abnormalities in both ciliogenesis and osteogenesis in vitro and in vivo. Thus, our results indicate that proper intracellular cholesterol status is crucial for primary cilium formation during skull formation and homeostasis.     

Twist technique for removal of spinal extradural arachnoid cyst: technical note

Study design

We document a spinal extradual arachnoid cyst treated by twist technique. The cyst is tightly adherent to the neural tissue or the dura, and the communication stalk is little or short.

Objective

To demonstrate the effectiveness of twist technique of closure of the communication stalk for the removal of spinal extradural arachnoid cyst.

Summary of background data

The standard treatment for a spinal extradural arachnoid cyst is complete excision of the cyst, followed by obliteration of the communication stalk and repair of the dural defect. To our knowledge, twist technique of the communication stalk for removal of spinal extradural arachnoid cyst has not been reported.

Methods

A 44-year-old woman presented with a 10-year history of pain and dysesthesia, initially in the posterior neck region and extending gradually to the distal portion of the right upper extremity. Pain and dysesthesia were exaggerated when she was lying down and relieved when standing or walking. She was diagnosed with an extradural arachnid cyst ranging from spinal regions T1 to T3 using MRI. Computerized tomography myelography revealed a mass located posterior to the spinal cord. Pooling of contrast medium was observed in the lesion indicating communication with the subarachnoid space. Laminectomy of the T1–T3 region was performed, preserving the spinous processes and the facet joints. A short communication stalk was found at the proximal root sleeve of right T3. This stalk was closed using twist technique.

Results

The patient experienced marked reduction of pain and dysesthesia after surgery, and the headache and blurred vision completely disappeared. Five days after the operation, she was discharged home in good condition. Postoperative 1 year later, the patient had completely recovered and resumed her normal life.

Conclusions

Twist technique can be seen safe and effective as another surgical option for spinal extradural arachnoid cysts containing a short stalk and dense fibrous adhesion with the dura mater.