Increased pro‐inflammatory cytokine levels and proliferation of activated microglia have been found in Parkinson's disease (PD) patients and animal models of PD, suggesting that targeting of the ...microglial inflammatory response may result in neuroprotection in PD. Microglial proliferation is regulated by many factors, but colony stimulating factor‐1 receptor (CSF1R) has emerged as a primary factor. Using data mining techniques on existing microarray data, we found that mRNA expression of the CSF1R ligand, CSF‐1, is increased in the brain of PD patients compared to controls. In two different neurotoxic mouse models of PD, acute MPTP and sub‐chronic LPS treatment, mRNA and protein levels of CSF1R and CSF‐1 were significantly increased. Treatment with the CSF1R inhibitor GW2580 significantly attenuated MPTP‐induced CSF1R activation and Iba1‐positive cell proliferation, without a reduction of the basal Iba1‐positive population in the substantia nigra. GW2580 treatment also significantly decreased mRNA levels of pro‐inflammatory factors, without alteration of anti‐inflammatory mediators, and significantly attenuated the MPTP‐induced loss of dopamine neurons and motor behavioral deficits. Importantly, these effects were observed in the absence of overt microglial depletion, suggesting that targeting CSF1R signaling may be a viable neuroprotective strategy in PD that disrupts pro‐inflammatory signaling, but maintains the beneficial effects of microglia.
Neuroinflammation is one of the hallmarks of neurodegenerative diseases, such as Parkinson's disease (PD). Activation of glial cells, including microglia and astrocytes, is a characteristic of the ...inflammatory response. Glycoprotein non-metastatic melanoma protein B (GPNMB) is a transmembrane glycoprotein that releases a soluble signaling peptide when cleaved by ADAM10 or other extracellular proteases. GPNMB has demonstrated a neuroprotective role in animal models of ALS and ischemia. However, the mechanism of this protection has not been well established. CD44 is a receptor expressed on astrocytes that can bind GPNMB, and CD44 activation has been demonstrated to reduce NFκB activation and subsequent inflammatory responses in macrophages. GPNMB signaling has not been investigated in models of PD or specifically in astrocytes. More recently, genetic studies have linked polymorphisms in GPNMB with risk for PD. Therefore, it is important to understand the role this signaling protein plays in PD.
We used data mining techniques to evaluate mRNA expression of GPNMB and its receptor CD44 in the substantia nigra of PD and control brains. Immunofluorescence and qPCR techniques were used to assess GPNMB and CD44 levels in mice treated with MPTP. In vitro experiments utilized the immortalized mouse astrocyte cell line IMA2.1 and purified primary mouse astrocytes. The effects of recombinant GPNMB on cytokine-induced astrocyte activation was determined by qPCR, immunofluorescence, and measurement of nitric oxide and reactive oxygen production.
Increased GPNMB and CD44 expression was observed in the substantia nigra of human PD brains and in GFAP-positive astrocytes in an animal model of PD. GPNMB treatment attenuated cytokine-induced levels of inducible nitric oxide synthase, nitric oxide, reactive oxygen species, and the inflammatory cytokine IL-6 in an astrocyte cell line and primary mouse astrocytes. Using primary mouse astrocytes from CD44 knockout mice, we found that the anti-inflammatory effects of GPNMB are CD44-mediated.
These results demonstrate that GPNMB may exert its neuroprotective effect through reducing astrocyte-mediated neuroinflammation in a CD44-dependent manner, providing novel mechanistic insight into the neuroprotective properties of GPNMB.
The androgen receptor (AR) is a key regulator of prostate growth and the principal drug target for the treatment of prostate cancer. Previous studies have mapped AR targets and identified some ...candidates which may contribute to cancer progression, but did not characterize AR biology in an integrated manner. In this study, we took an interdisciplinary approach, integrating detailed genomic studies with metabolomic profiling and identify an anabolic transcriptional network involving AR as the core regulator. Restricting flux through anabolic pathways is an attractive approach to deprive tumours of the building blocks needed to sustain tumour growth. Therefore, we searched for targets of the AR that may contribute to these anabolic processes and could be amenable to therapeutic intervention by virtue of differential expression in prostate tumours. This highlighted calcium/calmodulin‐dependent protein kinase kinase 2, which we show is overexpressed in prostate cancer and regulates cancer cell growth via its unexpected role as a hormone‐dependent modulator of anabolic metabolism. In conclusion, it is possible to progress from transcriptional studies to a promising therapeutic target by taking an unbiased interdisciplinary approach.
Using a combination of genomic and metabolomic profiling strategies, the CAMKK2 kinase is identified as a critical downstream target of the androgen receptor. CAMKK2 regulates anabolic flux, and represents an attractive therapeutic target for prostate cancer treatments.
Nonsteroidal antiinflammatory drugs (NSAIDs) have become an important adjunctive tool for surgeons performing routine and complicated cataract surgery. These medications have been found to reduce ...pain, prevent intraoperative miosis, modulate postoperative inflammation, and reduce the incidence of cystoid macular edema (CME). Whether used alone, synergistically with steroids, or for specific high-risk eyes prone to the development of CME, the effectiveness of these medications is compelling. This review describes the potential preoperative, intraoperative, and postoperative uses of NSAIDs, including the potency, indications and treatment paradigms and adverse effects and contraindications. A thorough understanding of these issues will help surgeons maximize the therapeutic benefits of these agents and improve surgical outcomes. Financial Disclosure Proprietary or commercial disclosures are listed after the references.
We present the B-fields mapped in IRDC G34.43+0.24 using 850 m polarized dust emission observed with the POL-2 instrument at the James Clerk Maxwell telescope. We examine the magnetic field ...geometries and strengths in the northern, central, and southern regions of the filament. The overall field geometry is ordered and aligned closely perpendicular to the filament's main axis, particularly in regions containing the central clumps MM1 and MM2, whereas MM3 in the north has field orientations aligned with its major axis. The overall field orientations are uniform at large (POL-2 at 14″ and SHARP at 10″) to small scales (TADPOL at 2 5 and SMA at 1 5) in the MM1 and MM2 regions. SHARP/CSO observations in MM3 at 350 m from Tang et al. show a similar trend as seen in our POL-2 observations. TADPOL observations demonstrate a well-defined field geometry in MM1/MM2 consistent with MHD simulations of accreting filaments. We obtained a plane-of-sky magnetic field strength of 470 190 G, 100 40 G, and 60 34 G in the central, northern, and southern regions of G34, respectively, using the updated Davis-Chandrasekhar-Fermi relation. The estimated value of field strength, combined with column density and velocity dispersion values available in the literature, suggests G34 to be marginally critical with criticality parameter λ values 0.8 0.4, 1.1 0.8, and 0.9 0.5 in the central, northern, and southern regions, respectively. The turbulent motions in G34 are sub-Alfvénic with Alfvénic Mach numbers of 0.34 0.13, 0.53 0.30, and 0.49 0.26 in the three regions. The observed aligned B-fields in G34.43+0.24 are consistent with theoretical models suggesting that B-fields play an important role in guiding the contraction of the cloud driven by gravity.
Posterior spinal fusions (PSF) for adolescent idiopathic scoliosis (AIS) have higher blood loss than other pediatric orthopedic surgeries. There is a paucity of literature estimating the hidden blood ...loss (HBL) in patients with AIS undergoing PSF. The purpose of this study was to compare intraoperative and postoperative estimated blood loss (EBL) in patients undergoing PSF for AIS to determine HBL.
With contemporary blood loss prevention strategies, HBL will be higher than intraoperative EBL.
Over a 3-year period, 67 patients with preoperative and postoperative hemoglobin (Hgb) measurements undergoing PSF for AIS were evaluated. Intraoperative EBL was estimated using a volumetric method and recorded by a perfusionist managing a cell saver machine. Total perioperative EBL was estimated using the validated formula: EBL=weight (kg)×age sex factor×(preoperative Hgb – postoperative Hgb)/preoperative Hgb. HBL was calculated as the total perioperative EBL minus the intraoperative EBL.
Calculated total EBL was higher than intraoperative EBL (771±256mL vs. 110±115mL, p<0.001). Mean HBL after wound closure was 660±400mL. Patients 14 years or greater (p=0.03), with a BMI≥25kg/m2(p=0.02) and with surgical times over 3.5hours (p=0.05) had increased HBL. Multivariate analysis determined BMI≥25kg/m2 (OR 9.91; CI, 1.01–104.26; p=0.05) was associated with increased HBL. Allogenic blood transfusion was rare (4%) and associated with increased HBL (897±112mL vs. 540±402mL, p=0.05).
For patients undergoing PSF for AIS there is more HBL after wound closure than intraoperative blood loss. This HBL is higher in older patients who undergo longer operations and have a BMI≥25kg/m2.
IV; retrospective cohort study.
Guided growth affects the physis in children to produce a desired effect. Several devices achieve alteration of growth, including staples, plates, and screws. Complications can include device ...failures, failure to modulate growth as expected, and unintended physeal arrest. We present the results of a unique technique designed to minimize these complications. This was a retrospective review of guided growth at the knee at a single institution utilizing cannulated screws with epiphyseal-entry points. Each case was reviewed to determine the presence of complications related to guided growth, including implant breakage, implant pull-out or pull-through, iatrogenic physeal arrest, failure to modulate growth, and the incidence of revision surgeries. There were 89 patients who had 146 epiphyseal-entry guided growth procedures with a total of 221 4.5 mm cannulated screws. There were no iatrogenic physeal arrests. Five (2.26%) screws in 4 (4.49%) patients had either a broken screw or screw pull-out/pull-through requiring revision procedures. Three patients had osteotomies after skeletal maturity. Four had revision-guided growth for other reasons: 2 due to a lack of timely follow-up, 1 for iatrogenic genu varum without implant failure, and 1 due to recurrent deformity after implant removal. Revision procedures were unanticipated in 6 (6.74%) patients. This study describes a technique for placing cannulated screws at the knee with epiphyseal starting points. Our rate of complications and number of revision surgeries compare favorably with those noted for other techniques. Guided growth using epiphyseal-entry cannulated screws is a safe, effective option for most patients.
Atlantoaxial Rotatory Subluxation in Children Neal, Kevin M; Mohamed, Ahmed S
Journal of the American Academy of Orthopaedic Surgeons,
2015-June, Letnik:
23, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Atlantoaxial rotatory subluxation is a rare condition in which patients present with the acute onset of torticollis. Atlantoaxial rotatory subluxation represents a spectrum of disease from muscle ...spasm to a fixed mechanical block to reduction of the atlantoaxial complex. If left untreated, some cases may resolve spontaneously; however, other cases may result in the development of secondary changes in the bony anatomy of the atlantoaxial joint, leading to persistent deformity. Diagnosis of the condition is largely clinical but can be aided by various imaging modalities, including radiographs, dynamic CT scanning, three-dimensional CT reconstructions, or MRI. Consideration should always be given to infection or other inflammatory disease as an underlying, precipitating cause. Treatments include observation, the use a cervical collar and analgesics, halter or skeletal traction, and posterior fusion of C1-C2. The most important factor for success of conservative treatment is the time from the onset of symptoms to recognition and the initiation of treatment.
Human life span is a phenotype that integrates many aspects of health and environment into a single ultimate quantity: the elapsed time between birth and death. Though it is widely believed that long ...life runs in families for genetic reasons, estimates of life span "heritability" are consistently low (∼15-30%). Here, we used pedigree data from
public trees, including hundreds of millions of historical persons, to estimate the heritability of human longevity. Although "nominal heritability" estimates based on correlations among genetic relatives agreed with prior literature, the majority of that correlation was also captured by correlations among nongenetic (in-law) relatives, suggestive of highly assortative mating around life span-influencing factors (genetic and/or environmental). We used structural equation modeling to account for assortative mating, and concluded that the true heritability of human longevity for birth cohorts across the 1800s and early 1900s was well below 10%, and that it has been generally overestimated due to the effect of assortative mating.
PDF
