LRP1 in GABAergic neurons is a key link between obesity and memory function.

OBJECTIVE: Low-density lipoprotein receptor-related protein-1 (LRP1) regulates energy homeostasis, blood-brain barrier integrity, and metabolic signaling in the brain. Deficiency of LRP1 in inhibitory gamma-aminobutyric acid (GABA)ergic neurons causes severe obesity in mice. However, the impact of LRP1 in inhibitory neurons on memory function and cognition in the context of obesity is poorly understood. METHODS: Mice lacking LRP1 in GABAergic neurons (Vgat-Cre; LRP1loxP/loxP) underwent behavioral tests for locomotor activity and motor coordination, short/long-term and spatial memory, and fear learning/memory. This study evaluated the relationships between behavior and metabolic risk factors and followed the mice at 16 and 32 weeks of age. RESULTS: Deletion of LRP1 in GABAergic neurons caused a significant impairment in memory function in 32-week-old mice. In the spatial Y-maze test, Vgat-Cre; LRP1loxP/loxP mice exhibited decreased travel distance and duration in the novel arm compared with controls (LRP1loxP/loxP mice). In addition, GABAergic neuron-specific LRP1-deficient mice showed a diminished capacity for performing learning and memory tasks during the water T-maze test. Moreover, reduced freezing time was observed in these mice during the contextual and cued fear conditioning tests. These effects were accompanied by increased neuronal necrosis and satellitosis in the hippocampus. Importantly, the distance and duration in the novel arm, as well as the performance of the reversal water T-maze test, negatively correlated with metabolic risk parameters, including body weight, serum leptin, insulin, and apolipoprotein J. However, in 16-week-old Vgat-Cre; LRP1loxP/loxP mice, there were no differences in the behavioral tests or correlations between metabolic parameters and cognition. CONCLUSIONS: Our findings demonstrate that LRP1 from GABAergic neurons is important in regulating normal learning and memory. Metabolically, obesity caused by GABAergic LRP1 deletion negatively regulates memory and cognitive function in an age-dependent manner. Thus, LRP1 in GABAergic neurons may play a crucial role in maintaining normal excitatory/inhibitory balance, impacting memory function, and reinforcing the potential importance of LRP1 in neural system integrity.

Prosthetics, Medicine, and Disability in Modern America: The Case of the A. A. Marks Artificial Limb Company.

Through the case of the A. A. Marks Artificial Limb Company, this article explores how the technology and business of prosthetics grew in America up to the First World War. In 1853, Amasa A. Marks established the artificial limb company A. A. Marks in New York. By the time of the First World War, the company had become the largest supplier of artificial limbs in the United States and had gained international recognition, exporting its products all over the world. Focusing on the company's growth before the war, this paper analyzes how American artificial limb makers positioned themselves between art and medicine and between surgeons and disabled customers at a time when their occupation had yet to be established as a specialized profession. From the mid-nineteenth century when the artificial limb business burgeoned to the First World War, American society went through various social and cultural changes that influenced the prosthetics industry and the perception of disability. During the Civil War, numerous soldiers were injured but survived because advancements in amputation techniques enabled surgeons to save more lives despite limb loss. The growing number of maimed veterans required more mechanical and public support for their rehabilitation. As a reconstruction project of the nation and a way to address the sense of damaged masculinity felt by injured war veterans, both Union and Confederate states approved support for providing them with artificial limbs at public expense. In postbellum America, as well as deformity and amputation, industrialization created a need for artificial limbs as the brutality of advanced weapons and unfortunate accidents involving machines and railroads increased the number of amputees. Thus during the late nineteenth century and early twentieth century, recognition of maimed bodies in public places went through a legislative and cultural transformation. The growth of artificial limb manufacturer A. A. Marks was in tune with such technological, medical, and sociocultural changes. Along with technological innovations and patents to protect these innovations, Amasa Marks devised various marketing methods and strategies through which the company secured customers and finally expanded the prosthetics market. As its customers increased, the company accumulated quantitative and qualitative data from patients' responses and interviews, and its own observations. In the late nineteenth century, George E. Marks, Amasa Marks's son and a representative of the company, analyzed customers' experiences of disability, gathering information on patterns of disability and mortality rates. Based on the company's rich experience with a large number of patient cases, George Marks advanced criticisms of surgical methods and provided second opinions on amputation surgeries. In doing so, he attempted to promote the limb maker's position from mere artisan to specialist, redefining the relationship between medicine and prosthetics and between surgeon and prosthetist. He also conveyed patients' complaints and needs to the medical men in the process, and distributed the company's findings and knowledge to surgeons and the general public by publishing treatises, articles, and manuals. Consequently, the company influenced an important epistemological turn in which the prosthetic perspective was considered prior to amputation surgery, not just as an inevitable follow-up.

Recent progress in development and applications of second near-infrared (NIR-II) nanoprobes.

Optical probes for near-infrared (NIR) light have clear advantages over UV/VIS-based optical probes, such as their low levels of interfering auto-fluorescence and high tissue penetration. The second NIR (NIR-II) window (1000-1350 nm) offers better light penetration, lower background signal, higher safety limit, and higher maximum permitted exposure than the first NIR (NIR-I) window (650-950 nm). Therefore, NIR-II laser-based photoacoustic (PA) and fluorescence (FL) imaging can offer higher sensitivity and penetration depth than was previously available, and deeper lesions can be treated in vivo by photothermal therapy (PTT) and photodynamic therapy (PDT) with an NIR-II laser than with an NIR-I laser. Advances in creation of novel nanomaterials have increased options for improving light-induced bioimaging and treatment. Nanotechnology can provide advantages such as good disease targeting ability and relatively long circulation times to supplement the advantages of optical technologies. In this review, we present recent progress in development and applications of NIR-II light-based nanoplatforms for FL, PA, image-guided surgery, PDT, and PTT. We also discuss recent advances in smart NIR-II nanoprobes that can respond to stimuli in the tumor microenvironment and inflamed sites. Finally, we consider the challenges involved in using NIR-II nanomedicine for effective diagnosis and treatment.

FDA Approval: Belinostat for the Treatment of Patients with Relapsed or Refractory Peripheral T-cell Lymphoma.

On July 3, 2014, the FDA granted accelerated approval for belinostat (Beleodaq; Spectrum Pharmaceuticals, Inc.), a histone deacetylase inhibitor, for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). A single-arm, open-label, multicenter, international trial in the indicated patient population was submitted in support of the application. Belinostat was administered intravenously at a dose of 1000 mg/m(2) over 30 minutes once daily on days 1 to 5 of a 21-day cycle. The primary efficacy endpoint was overall response rate (ORR) based on central radiology readings by an independent review committee. The ORR was 25.8% [95% confidence interval (CI), 18.3-34.6] in 120 patients that had confirmed diagnoses of PTCL by the Central Pathology Review Group. The complete and partial response rates were 10.8% (95% CI, 5.9-17.8) and 15.0% (95% CI, 9.1-22.7), respectively. The median duration of response, the key secondary efficacy endpoint, was 8.4 months (95% CI, 4.5-29.4). The most common adverse reactions (>25%) were nausea, fatigue, pyrexia, anemia, and vomiting. Grade 3/4 toxicities (≥5.0%) included anemia, thrombocytopenia, dyspnea, neutropenia, fatigue, and pneumonia. Belinostat is the third drug to receive accelerated approval for the treatment of relapsed or refractory PTCL.

Early cognitive function tests predict early progression in glioblastoma.

BACKGROUND: Early progression of glioblastoma prevents patients from completing the standard chemoradiation protocol. Given that cognitive function is associated with prognosis in glioblastoma, we investigated the usefulness of preoperative cognitive function tests for predicting the early progression of glioblastoma. METHODS: Consecutive patients who underwent glioma surgery were preoperatively evaluated with cognitive function tests including the Mini Mental State Examination, digit span tests, the Controlled Oral Word Association Test, the Trail Making Tests (TMT, parts A, B, and C), and the Stroop test. Glioblastomas were treated with a standard protocol using radiation and temozolomide, and 6-month progression-free survival (PFS-6) was analyzed retrospectively. RESULTS: Among 126 patients who underwent glioma surgery, 55 patients were diagnosed with glioblastoma, and 50 patients were eligible for the PFS-6 analysis. Thirty-four patients (68%) achieved PFS-6. No significant differences were observed in demographics or tumor characteristics between patients without progression (PFS-6) or patients with progression (no-PFS-6). In the cognitive function tests, the PFS-6 patients exhibited better performance in TMT-A and TMT-B. In a multivariate logistic regression, TMT-B was the only independent predictor for PFS-6, whereas age, years of education, gross total or near total resection, concomitant chemoradiation, and TMT-A were not predictors. Patients with good TMT-B performance exhibited better early prognosis in the Kaplan-Meier survival analysis and had better recursive partitioning analysis classes. CONCLUSIONS: Our results indicated that preoperative TMTs can be useful for rapid evaluation of early prognosis in patients with glioblastoma.

Cystatin C, a novel indicator of renal function, reflects severity of cerebral microbleeds.

BACKGROUND: Chronic renal insufficiency, diagnosed using creatinine based estimated glomerular filtration rate (GFR) or microalbumiuria, has been associated with the presence of cerebral microbleeds (CMBs). Cystatin C has been shown to be a more sensitive renal indicator than conventional renal markers. Under the assumption that similar pathologic mechanisms of the small vessel exist in the brain and kidney, we hypothesized that the levels of cystatin C may delineate the relationship between CMBs and renal insufficiency by detecting subclinical kidney dysfunction, which may be underestimated by other indicators, and thus reflect the severity of CMBs more accurately. METHODS: Data was prospectively collected for 683 patients with ischemic stroke. The severity of CMBs was categorized by the number of lesions. Patients were divided into quartiles of cystatin C, estimated GFR and microalbumin/creatinine ratios. Ordinal logistic regression analysis was used to examine the association of each renal indicator with CMBs. RESULTS: In models including both quartiles of cystatin C and estimated GFR, only cystatin C quartiles were significant (the highest vs. the lowest, adjusted OR, 1.88; 95% CI 1.05-3.38; p = 0.03) in contrast to estimated GFR (the highest vs. the lowest, adjusted OR, 1.28; 95% CI 0.38-4.36; p = 0.70). A model including both quartiles of cystatin C and microalbumin/creatinine ratio also showed that only cystatin C quartiles was associated with CMBs (the highest vs. the lowest, adjusted OR, 2.06; 95% CI 1.07-3.94; p = 0.03). These associations were also observed in the logistic models using log transformed-cystatin C, albumin/creatinine ratio and estimated GFR as continuous variables. Cystatin C was a significant indicator of deep or infratenorial CMBs, but not strictly lobar CMBs. In addition, cystatin C showed the greatest significance in c-statistics for the presence of CMBs (AUC = 0.73 ± 0.03; 95% CI 0.66-0.76; p = 0.02). CONCLUSION: Cystatin C may be the most sensitive indicator of CMB severity among the renal disease markers.

U.S. Food and drug administration approval: obinutuzumab in combination with chlorambucil for the treatment of previously untreated chronic lymphocytic leukemia.

On November 1, 2013, the U.S. Food and Drug Administration (FDA) approved obinutuzumab (GAZYVA; Genentech, Inc.), a CD20-directed cytolytic antibody, for use in combination with chlorambucil for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL). In stage 1 of the trial supporting approval, patients with previously untreated CD20-positive CLL were randomly allocated (2:2:1) to obinutuzumab + chlorambucil (GClb, n = 238), rituximab + chlorambucil (RClb, n = 233), or chlorambucil alone (Clb, n = 118). The primary endpoint was progression-free survival (PFS), and secondary endpoints included overall response rate (ORR). Only the comparison of GClb to Clb was relevant to this approval and is described herein. A clinically meaningful and statistically significant improvement in PFS with medians of 23.0 and 11.1 months was observed in the GClb and Clb arms, respectively (HR, 0.16; 95% CI, 0.11-0.24; P < 0.0001, log-rank test). The ORRs were 75.9% and 32.1% in the GClb and Clb arms, respectively, and the complete response rates were 27.8% and 0.9% in the GClb and Clb arms, respectively. The most common adverse reactions (≥10%) reported in the GClb arm were infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, and musculoskeletal disorders. Obinutuzumab was the first Breakthrough Therapy-designated drug to receive FDA approval.

Hypertension correlates with lenticulostriate arteries visualized by 7T magnetic resonance angiography.

Hypertension, a major risk factor for stroke, is associated with altered arterial anatomy and function; however, the limited resolution of current imaging techniques has restricted the in vivo study of microvascular changes in the brain. In this report, we quantitatively examined the lenticulostriate arteries in hypertensive patients using ultrahigh-field 7T MRI. We compared the number of stems and branches, curvature, and tortuosity of the lenticulostriate arteries by 3D time-of-flight magnetic resonance angiography among 20 hypertensive patients (mean age: 46.6+/-9.1 years) and 20 age-matched healthy subjects (mean age: 47.7+/-8.1 years). The average numbers of stems and branches in hypertensive patients were significantly less than those of healthy subjects (P<0.002). However, this difference was abolished in older volunteers (>45 years old), whereas the difference between young hypertensive patients (< or = 45 years old) and age-matched healthy controls was augmented by 55% for stems and 91% for branches (P=0.001). In comparison, there were no differences in the average curvature and tortuosity of the lenticulostriate arteries and no significant difference when corrected for smoking (P=0.064). In conclusion, our results showed that there was a substantial difference in the lenticulostriate arteries of hypertensive patients compared with healthy individuals when observed in vivo by ultrahigh-resolution 7T magnetic resonance angiography, and the difference was considerable in young subjects.

High tidal volume ventilation induces NOS2 and impairs cAMP- dependent air space fluid clearance.

Tidal volume reduction during mechanical ventilation reduces mortality in patients with acute lung injury and the acute respiratory distress syndrome. To determine the mechanisms underlying the protective effect of low tidal volume ventilation, we studied the time course and reversibility of ventilator-induced changes in permeability and distal air space edema fluid clearance in a rat model of ventilator-induced lung injury. Anesthetized rats were ventilated with a high tidal volume (30 ml/kg) or with a high tidal volume followed by ventilation with a low tidal volume of 6 ml/kg. Endothelial and epithelial protein permeability were significantly increased after high tidal volume ventilation but returned to baseline levels when tidal volume was reduced. The basal distal air space fluid clearance (AFC) rate decreased by 43% (P < 0.05) after 1 h of high tidal volume but returned to the preventilation rate 2 h after tidal volume was reduced. Not all of the effects of high tidal volume ventilation were reversible. The cAMP-dependent AFC rate after 1 h of 30 ml/kg ventilation was significantly reduced and was not restored when tidal volume was reduced. High tidal volume ventilation also increased lung inducible nitric oxide synthase (NOS2) expression and air space total nitrite at 3 h. Inhibition of NOS2 activity preserved cAMP-dependent AFC. Because air space edema fluid inactivates surfactant and reduces ventilated lung volume, the reduction of cAMP-dependent AFC by reactive nitrogen species may be an important mechanism of clinical ventilator-associated lung injury.