Focused ultrasound delivery of a selective TrkA agonist rescues cholinergic function in a mouse model of Alzheimer's disease.

The degeneration of cholinergic neurons is a prominent feature of Alzheimer's disease (AD). In animal models of injury and aging, nerve growth factor (NGF) enhances cholinergic cell survival and function, contributing to improved memory. In the presence of AD pathology, however, NGF-related therapeutics have yet to fulfill their regenerative potential. We propose that stimulating the TrkA receptor, without p75NTR activation, is key for therapeutic efficacy. Supporting this hypothesis, the selective TrkA agonist D3 rescued neurotrophin signaling in TgCRND8 mice, whereas NGF, interacting with both TrkA and p75NTR, did not. D3, delivered intravenously and noninvasively to the basal forebrain using MRI-guided focused ultrasound (MRIgFUS)-mediated blood-brain barrier (BBB) permeability activated TrkA-related signaling cascades and enhanced cholinergic neurotransmission. Recent clinical trials support the safety and feasibility of MRIgFUS BBB modulation in AD patients. Neuroprotective agents targeting TrkA, combined with MRIgFUS BBB modulation, represent a promising strategy to counter neurodegeneration in AD.

Risk Factors Associated with In-Hospital Mortality for Patients with Acute Abdomen After Cardiac Surgery.

OBJECTIVES: Management of acute abdomen (AA) differs due to the heterogeneity of underlying pathophysiology. Complications of AA and its overall outcome after cardiac surgery are known to be associated with poor results. The aim of this retrospective analysis was to evaluate risk factors for AA in patients undergoing cardiac surgery. METHODS: Between December 2011 and December 2014, a total of 131 patients with AA after cardiac surgery were identified and retrospectively analyzed using our institutional database. Statistical analysis of risk factors concerning in-hospital mortality of mentioned patient cohort was performed using IBM SPSS Statistics. RESULTS: Overall in-hospital mortality was 54.2% (71/131). Analyzing in-hospital non-survivors (NS) versus in-hospital survivors (S) peripheral artery disease (28.2% vs. 11.7%; p = 0.03), the need for assist device therapy (33.8% vs. 16.7%; p = 0.03) and the requirement of hemodialysis (67.6% vs. 23.3%; p < 0.01) were significantly higher in NS. Furthermore, lactic acid values at onset of symptoms were shown to be significantly higher in NS (5.7 ± 5.7 mmol/L vs. 2.8 ± 2.9 mmol/L; p < 0.01). Assured diagnosis of mesenterial ischemia was strongly associated with worse outcome (odds ratio 10.800, 95% confidence interval 2.003-58.224; p = 0.006). CONCLUSION: In conclusion, in critically ill patients after performed cardiac surgery peripheral vascular disease, need for supportive hemodynamic assist device systems and occurrence of renal failure are risk factors associated with worsen outcome. Additionally, rise of lactic acid could potentially be associated with onset of intestinal malperfusion and should be taken into account in therapeutic decisions preventing fatal mesenterial ischemia.

[Clinical results of the aspheric intraocular lens FY-60AD (Hoya) with particular respect to decentration and tilt]. / Klinische Ergebnisse unter besonderer Berücksichtigung von Dezentrierung und Verkippung der asphärischen Intraokularlinse FY-60AD.

BACKGROUND: Aspheric intraocular lenses (IOLs) aim to improve visual function and particularly contrast vision by neutralizing spherical aberration. One drawback of such IOLs is the enhanced sensitivity to decentration and tilt, which can deteriorate image quality. METHODS: A total of 30 patients who received bilateral phacoemulsification before implantation of the aspheric lens FY-60AD (Hoya) were included in a prospective study. In 25 of the patients (50 eyes) the following parameters could be assessed 3 months after surgery: visual acuity, refraction, contrast sensitivity, pupil size, wavefront errors and decentration and tilt using a newly developed device. RESULTS: The functional results were very satisfying and comparable to results gained with other aspheric IOLs. The mean refraction was sph + 0.1 D (±0.7 D) and cyl 0.6 D (±0.8 D). The spherical equivalent was −0.2 D (±0.6 D). Wavefront measurements revealed a good compensation of the corneal spherical aberration but vertical and horizontal coma also showed opposing values in the cornea and IOL. The assessment of the lens position using the Purkinje meter demonstrated uncritical amounts of decentration and tilt. The mean amount of decentration was 0.2 mm±0.2 mm in the horizontal and vertical directions. The mean amount of tilt was 4.0±2.1° in horizontal and 3.0±2.5° in vertical directions. CONCLUSIONS: In a normal dioptric power range the aspheric IOL FY-60AD compensates the corneal spherical aberration very well with only minimal decentration. The slight tilt is symmetrical in both eyes and corresponds to the position of the crystalline lens in young eyes. This may contribute to our findings of compensated corneal coma.

Performance evaluation of a computer-aided detection algorithm for solid pulmonary nodules in low-dose and standard-dose MDCT chest examinations and its influence on radiologists.

The aim of the study was to evaluate the performance of a computer-aided detection (CAD) algorithm in low-dose and full-dose multidetector-row CT (MDCT) of the thorax and its impact on radiologists' performance. Chest CT examinations of 77 patients were evaluated retrospectively for pulmonary nodules. All patients had undergone a 16-slice MDCT chest examination with a standard acquisition protocol. Artificial image noise was added to the raw data to simulate image acquisition at 10 mAs(eff.) The data were transferred to dedicated lung analysis software (LungCare) with a prototype CAD algorithm (LungCAD). CAD was applied to both dose settings. Images were read by a radiologist and a first-year resident with and without the software at both dose settings. All images were reviewed in consensus by the two radiologists to set the reference standard. Sensitivity results with respect to the reference standard were compared. No statistically significant differences in the detection rate for all pulmonary nodules could be found between low-dose and full-dose settings for the CAD software alone (p = 0.0065). Both radiologists displayed a statistically significant increase in sensitivity with the use of CAD (p<0.0001). In conclusion, CAD is beneficial in both low-dose and standard-dose settings. This may be beneficial in reducing false-negative diagnosis in lung cancer screening, standard chest examinations and the search for metastases.

Attachment of the soluble complement regulator factor H to cell and tissue surfaces: relevance for pathology.

Complement is a central element of innate immunity and this vital defense system initiates and coordinates immediate immune reactions which attack and eliminate microbes, foreign particles and altered self cells. Newly generated activation products are extremely toxic and consequently, activation is highly restricted in terms of time and space. The initial activation of the alternative complement pathway occurs continuously and the early phase acts indiscriminatoryl and forms on any surface. However, the system discriminates between self and foreign, and therefore allows activation on foreign surfaces e.g. microbes, and restricts activation on host cells. Consequently, self cells and tissues are protected from the harmful activation products. This protection is mediated by specific regulators or inhibitors, which exist in the fluid phase and/or in membrane-bound forms. Here we review a novel mechanism, i.e. the attachment of the soluble complement regulator factor H to the surface of self cells. This attachment, which is demonstrated experimentally by means of immunofluorescense microscopy and by flow cytometry, increases the inhibitory potential at the cell surface and mediates protection by reducing the local formation of toxic inflammatory products. This attachment is highly relevant and has pathophysiological consequences in several human diseases, including Factor H-associated hemolytic uremic syndrome (FH-HUS), membrano-proliferative glomerulonephritis type II, recurrent microbial infections and chronic inflammation, e.g. rheumatoid arthritis and immune evasion of tumor cells. Defects of this safeguard activity have been recently understood in patients with FH-HUS. Point mutations in the Factor H gene occurring in the C-terminus of the protein result in impaired cell binding capacity of Factor H and, consequently, during an inflammatory insult endothelial cells are not properly protected and are damaged.

Cholesterol efflux from macrophages mediated by high-density lipoprotein subfractions, which differ principally in apolipoprotein A-I and apolipoprotein A-II ratios.

High-density lipoprotein (HDL) was fractionated by preparative isoelectric focussing into six distinct subpopulations. The major difference between the subfractions was in the molar ratio of apolipoprotein A-I to apolipoprotein A-II, ranging from 2.1 to 0.5. The least acidic particles had little apolipoprotein A-II, were larger and contained the most lipid. The efflux capacity of the HDL subfractions was tested with mouse peritoneal macrophages and a mouse macrophage cell line (P388D1), either fed with acetylated low-density lipoprotein or free cholesterol. All the HDL subfractions were equally able to efflux cholesterol. The efflux was concentration dependant and linear for the first 6 h. The HDL subfractions bound with high affinity (Kd = 6.7-7.9 micrograms/ml) at 4 degrees C to the cell surface of P388D1 cells (211,000-359,000 sites/cell). Ligand blotting showed that all the HDL subfractions bound to membrane polypeptides at 60, 100, and 210 kDa. These HDL binding proteins may represent HDL receptors. In summary HDL particles, which differed principally in ratio of apolipoprotein A-I to apolipoprotein A-II behaved in a similar manner for both cholesterol efflux and cell surface binding.