iPSC-derived cortical neurons to study sporadic Alzheimer disease: A transcriptome comparison with post-mortem brain samples.

Alzheimer's disease (AD) is the most common cause of dementia, characterized by the progressive impairment of cognition and memory loss. Sporadic AD (sAD) represents approximately 95 % of the AD cases and is induced by a complex interplay between genetic and environmental factors called "Alzheimerogens". Heavy metals (e.g. copper) and pesticides (e.g. fipronil) can affect many AD-related processes, including neuroinflammation (considered as AD-inducing factor). Research would benefit from in vitro models to investigate effects of Alzheimerogens. We compared transcriptomics changes in sAD induced pluripotent stem cell (iPSC) derived cortical neurons to differentially expressed genes (DEGs) identified in post-mortem AD brain tissue. These analyses showed that many AD-related processes could be identified in the sAD iPSC-derived neurons, and furthermore, could even identify more DEGs functioning in these processes than post-mortem AD-brain tissue. Thereafter, we exposed the iPSCs to AD-inducing factors (copper(II)chloride, fipronil sulfone and an inflammatory cytokine cocktail). Cytokine exposure induced expression of immune related genes while copper-exposure affected genes involved in lipid and cholesterol metabolism, which are known AD-related processes. Fipronil-exposure did not result in significant transcriptomic changes, although prolonged exposures or higher doses may be necessary. Overall, we show that iPSC-derived cortical neurons can be beneficial in vitro models to identify Alzheimerogens and AD-related molecular mechanisms.

Determining the effects and challenges of incorporating genetic testing into primary care management of hypertensive patients with African ancestry.

People of African ancestry (Blacks) have increased risk of kidney failure due to numerous socioeconomic, environmental, and clinical factors. Two variants in the APOL1 gene are now thought to account for much of the racial disparity associated with hypertensive kidney failure in Blacks. However, this knowledge has not been translated into clinical care to help improve patient outcomes and address disparities. GUARDD is a randomized trial to evaluate the effects and challenges of incorporating genetic risk information into primary care. Hypertensive, non-diabetic, adults with self-reported African ancestry, without kidney dysfunction, are recruited from diverse clinical settings and randomized to undergo APOL1 genetic testing at baseline (intervention) or at one year (waitlist control). Providers are educated about genomics and APOL1. Guided by a genetic counselor, trained staff return APOL1 results to patients and provide low-literacy educational materials. Real-time clinical decision support tools alert clinicians of their patients' APOL1 results and associated risk status at the point of care. Our academic-community-clinical partnership designed a study to generate information about the impact of genetic risk information on patient care (blood pressure and renal surveillance) and on patient and provider knowledge, attitudes, beliefs, and behaviors. GUARDD will help establish the effective implementation of APOL1 risk-informed management of hypertensive patients at high risk of CKD, and will provide a robust framework for future endeavors to implement genomic medicine in diverse clinical practices. It will also add to the important dialog about factors that contribute to and may help eliminate racial disparities in kidney disease.

Adenomas and carcinomas missed in routine colonoscopy: a prospective study in resected colon segments.

Colonoscopy is the standard technique in the diagnosis and treatment of colorectal neoplasia, but small adenomas and even advanced lesions can be missed during the procedure. With large scale screening colonoscopy programs installed, information on quality of colonoscopy in primary care is essential, but scarcely available. Over a period of 45 months, we prospectively included all those patients in our study, who underwent major colonic surgery at our institution and who had undergone a colonoscopy within 42 days prior to the operation. 89 men and 100 women, median age 71 years, were included. The majority of these operations were performed for colorectal carcinoma (125), other malignant tumors (4), suspected malignancies (6) or large adenomas (14). The pathologist inspected the resected colonic segment, and we compared his findings with the colonoscopy report. Colonoscopies had been performed by 22 doctors in 13 institutions. Median length of the resected colonic segments was 20 cm (range 3 to 135 cm), total length was 41,21 metres. In 14 segments the pathologist identified 28 neoplastic lesions not described in the endoscopy report. Colonoscopy had missed 2 carcinomas, both in the right colon, and a 12 mm tubulo-villous adenoma with high-grade dysplasia. Another 25 tubular adenomas had been missed, 2 measuring 10 mm, 7 between 5 and 9 mm and 16 smaller than 5 mm. We conclude that primary care colonoscopy misses neoplastic lesions in a significant number of procedures. Most of the missed lesions in our high risk group of patients would have been of little clinical consequence. In a small, but clinically important number of cases, however, advanced adenomas and even colorectal carcinomas were missed by endoscopy.

"Nanoparticle-in-alloy" approach to efficient thermoelectrics: silicides in SiGe.

We present a "nanoparticle-in-alloy" material approach with silicide and germanide fillers leading to a potential 5-fold increase in the thermoelectric figure of merit of SiGe alloys at room temperature and 2.5 times increase at 900 K. Strong reductions in computed thermal conductivity are obtained for 17 different types of silicide nanoparticles. We predict the existence of an optimal nanoparticle size that minimizes the nanocomposite's thermal conductivity. This thermal conductivity reduction is much stronger and strikingly less sensitive to nanoparticle size for an alloy matrix than for a single crystal one. At the same time, nanoparticles do not negatively affect the electronic conduction properties of the alloy. The proposed material can be monolithically integrated into Si technology, enabling an unprecedented potential for micro refrigeration on a chip. High figure-of-merit at high temperatures (ZT approximately 1.7 at 900 K) opens up new opportunities for thermoelectric power generation and waste heat recovery at large scale.

Changes in open-field activity and novelty-seeking behavior in periadolescent rats neonatally treated with monosodium glutamate.

Monosodium glutamate (MSG) treatment of neonatal rodents leads to degeneration of the neurons in the arcuate nucleus, inner retinal layers and various other brain areas. It also causes various changes in the motor activity, sensory performance and learning abilities. We have previously shown that MSG treatment delays the appearance of some reflexes during neurobehavioral development and leads to temporary changes in reflex performance and motor coordination. Investigation of novelty-seeking behavior is of growing importance for its relationship with sensitivity to psychomotor stimulants. Perinatal administration of numerous toxic agents has been shown to influence novelty-seeking behavior in rats, but little is known about the influence of neonatal MSG treatment on the novelty-seeking behavior. The aim of the present study was to compare changes in locomotor, spontaneous exploratory and novelty-seeking behavior in periadolescent rats neonatally treated with MSG. Newborn rats were treated with 4 mg/g MSG subcutaneously on postnatal days 1, 3, 5, 7 and 9. Open-field behavior was tested at 2, 3, 4, 6 and 8 weeks of age. We found that MSG administration led to only temporary increases in locomotor behavior, which was more pronounced during the first few postnatal weeks, followed by a subtle hypoactivity at 2 months of age. Novelty-seeking was tested in four 5-min trials at 3 weeks of age. Trial 1 was in an empty open-field, two identical objects were placed in the arena during trial 2 and 3, and one of them was replaced to a novel object during trial 4. We found that the behavioral pattern of MSG-treated rats was the opposite in all tested signs in the novelty exploration test compared to control pups. In summary, our present study shows that neonatal MSG treatment leads to early temporary changes in the locomotor activity followed by hypoactivity at 2 months of age. Furthermore, MSG-treated rats show a markedly disturbed novelty-seeking behavior represented by altered activity when subjected to a novel object.

HESS observations of the galactic center region and their possible dark matter interpretation.

The detection of gamma rays from the source HESS J1745-290 in the Galactic Center (GC) region with the High Energy Spectroscopic System (HESS) array of Cherenkov telescopes in 2004 is presented. After subtraction of the diffuse gamma-ray emission from the GC ridge, the source is compatible with a point source with spatial extent less than 1.2;{'}(stat) (95% C.L.). The measured energy spectrum above 160 GeV is compatible with a power law with photon index of 2.25+/-0.04(stat)+/-0.10(syst) and no significant flux variation is detected. It is finally found that the bulk of the very high energy emission must have non-dark-matter origin.

Fast variability of tera-electron volt gamma rays from the radio galaxy M87.

The detection of fast variations of the tera-electron volt (TeV) (10(12) eV) gamma-ray flux, on time scales of days, from the nearby radio galaxy M87 is reported. These variations are about 10 times as fast as those observed in any other wave band and imply a very compact emission region with a dimension similar to the Schwarzschild radius of the central black hole. We thus can exclude several other sites and processes of the gamma-ray production. The observations confirm that TeV gamma rays are emitted by extragalactic sources other than blazars, where jets are not relativistically beamed toward the observer.

Effects of systemic PACAP treatment in monosodium glutamate-induced behavioral changes and retinal degeneration.

The present article investigated effects of systemic pituitary adenylate cyclase-activating polypeptide (PACAP) treatment in monosodium glutamate (MSG)-induced retinal degeneration and neurobehavioral alterations in neonatal rats. It was found that the dose of PACAP that effectively enhances neurobehavioral development in normal rats was able to counteract the retarding effect of MSG on righting, forelimb placing, and grasp reflexes and caused a significant amelioration of the righting and gait reflex performance and motor coordination at 2 weeks of age. In the retina, significant amelioration of neuronal loss in the inner retinal layers was achieved, but it was much less than that observed by local administration.

A low level of extragalactic background light as revealed by gamma-rays from blazars.

The diffuse extragalactic background light consists of the sum of the starlight emitted by galaxies through the history of the Universe, and it could also have an important contribution from the 'first stars', which may have formed before galaxy formation began. Direct measurements are difficult and not yet conclusive, owing to the large uncertainties caused by the bright foreground emission associated with zodiacal light. An alternative approach is to study the absorption features imprinted on the gamma-ray spectra of distant extragalactic objects by interactions of those photons with the background light photons. Here we report the discovery of gamma-ray emission from the blazars H 2356 - 309 and 1ES 1101 - 232, at redshifts z = 0.165 and z = 0.186, respectively. Their unexpectedly hard spectra provide an upper limit on the background light at optical/near-infrared wavelengths that appears to be very close to the lower limit given by the integrated light of resolved galaxies. The background flux at these wavelengths accordingly seems to be strongly dominated by the direct starlight from galaxies, thus excluding a large contribution from other sources-in particular from the first stars formed. This result also indicates that intergalactic space is more transparent to gamma-rays than previously thought.

Discovery of very-high-energy gamma-rays from the Galactic Centre ridge.

The source of Galactic cosmic rays (with energies up to 10(15) eV) remains unclear, although it is widely believed that they originate in the shock waves of expanding supernova remnants. At present the best way to investigate their acceleration and propagation is by observing the gamma-rays produced when cosmic rays interact with interstellar gas. Here we report observations of an extended region of very-high-energy (> 10(11) eV) gamma-ray emission correlated spatially with a complex of giant molecular clouds in the central 200 parsecs of the Milky Way. The hardness of the gamma-ray spectrum and the conditions in those molecular clouds indicate that the cosmic rays giving rise to the gamma-rays are likely to be protons and nuclei rather than electrons. The energy associated with the cosmic rays could have come from a single supernova explosion around 10(4) years ago.

A phase I trial of stereotactic external beam radiation for subfoveal choroidal neovascular membranes in age-related macular degeneration.

Effective treatment for neovascular age-related macular degeneration (AMD) is currently limited. Radiation therapy, a therapeutic approach with known antiangiogenic properties, has been investigated as a modality to prevent severe visual loss in AMD. Most of the studies using external beam radiation employed <25 Gy to the whole eye, which is below the dose of radiation that is toxic to the retina and optic nerve ( approximately 50 Gy and approximately 59 Gy, respectively). Stereotactic fractionated external beam radiation (St-EBR) is a method that allows radiation to be delivered to a small, defined area. We investigated the effects of St-EBR in incremental doses up to 40 Gy on neovascular AMD. Patients with clinical signs and fluorescein angiography demonstrating neovascular AMD, visual acuity (VA) better than 20/400 and ineligible for laser treatment (MPS criteria) or who refused to have laser photocoagulation were enrolled in the study. Each patient was treated with radiation at incremental dosages from 20 Gy to 40 Gy. After completion of the radiation course, all patients were followed-up at 3 and 7 weeks and 3, 6, and 12 months. Best-corrected VA (ETDRS), slit-lamp and fluorescein angiographic evaluations were performed at each visit. 94 eyes of 89 patients were treated from October 1997 to April 2000. The VA was 0.82+/-0.35 before treatment, 0.83+/-0.36 at 6 months, and 0.89+/-0.33 at 12 months. No patients suffered any significant acute side effects. No significant benefits in either VA or in membrane size were derived from increasing the doses of radiation. Our results are consistent with trends of a palliative benefit of radiotherapy in neovascular AMD and support further investigation of radiotherapy. Since there is no evidence that therapeutic effectiveness is dose dependent, our data provide no justification for potentially dangerous escalations in radiation dosage for treating neovascular AMD.

Effects of ketanserin and DOI on spontaneous and 5-HT-evoked peristalsis of the pig ureter in vivo.

1. The influence of 5-hydroxytryptamine (5-HT) receptor agonists and antagonists on the ureter motility was investigated in vivo on intact ureters of anaesthetized pigs. Drugs were administered intravenously or topically. 2. 5-HT induced a dose-dependent increase in the frequency of ureter contractions in anaesthetized pigs when given intravenously (0.0001-1 mg kg(-1); ED(50) 0.066 mg kg(-1)) or topically (0.001-1 mg ml(-1); EC(50) 0.043 mg ml(-1)). Significant increases in heart rate and blood pressure were observed when the drug was given intravenously but not topically. 3. The 5-HT(2A) agonist, DOI (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane) increased the frequency of ureteral contractions in a dose-dependent manner (1-300 microg kg(-1) i.v.). Calculation of ED(50) indicated this compound to be about 1.5 times more potent with an efficacy of 23% compared to 5-HT. 4. The 5-HT(2A/2C) antagonist, ketanserin (0.5 mg kg(-1)) and the 5-HT(2C) antagonist, methysergide (1 mg kg(-1)) antagonized the 5-HT-induced ureter peristalsis when given intravenously. Contraction amplitude, blood pressure and heart rate were not affected by the antagonists. 5. Intravenous (0.0001-1 mg kg(-1)) and topical (0.0001-1 microg ml(-1)) ketanserin significantly decreased the frequency of spontaneous ureteral contractions to about 30% of controls, which could be partly reversed by 5-HT (0.3 mg kg(-1) i.v.). The contraction amplitude, contractions of the contralateral, saline perfused ureter, heart rate and mean arterial blood pressure were not affected. 6. Thus, contractility of porcine ureter is mediated by 5-HT(2) receptors. Their antagonists ketanserin and methysergide seem to be promising drugs for treatment of acute ureteric colic or in preparing the ureter for ureteroscopy.

An electronic database for outcome studies that includes digital radiographs.

We report on acquisition of key data from the clinical medical record, surgical data, radiologic studies, and patient surveys for a novel digital total hip arthroplasty (THA) registry that includes electronic capture of digital radiographic images into a database on an internet platform for query. We now have the ability to collect demographic and operative data, including the operative note, discharge summary, surgery data, and Digital Imaging Communications in Medicine (DICOM) radiology images. Steps are being completed to assemble office encounters, hospital procedural codes, and implant bar codes. Two examples include a THA surgery record and a THA outcome study with plain radiograph set. Analysis of such data could suggest ways to improve clinical practice.

[Occult cutaneous mastocytosis]. / Okkulte kutane Mastozytose.

Mastocytosis is diagnosed without difficulty if it presents with easily recognizable lesions of urticaria pigmentosa. Recently, we have identified hardly visible skin lesions of mastocytosis in Hymenoptera venom allergic patients ("occult mastocytosis"). In addition, in approximately 15% of the patients with typical cutaneous lesions, urticaria pigmentosa was at first mistaken for other conditions and thus not linked to simultaneous symptoms of systemic mastocytosis. In most patients with unrecognized mastocytosis, the diagnosis was supported by raised basal serum tryptase levels. Cutaneous mastocytosis is often overlooked and more frequent than assumed. Measurement of basal serum tryptase concentrations can make an important contribution to the diagnosis of mastocytosis, but it does not replace a meticulous skin examination.

Constitutively raised serum concentrations of mast-cell tryptase and severe anaphylactic reactions to Hymenoptera stings.

Anaphylactic IgE-mediated reactions to Hymenoptera stings vary in their severity for reasons that are not clear. We investigated patients with a history of systemic anaphylatic reactions to honeybee or wasp stings. Nine (75%) of 12 patients with raised tryptase concentrations but only 28 (28%) of 102 patients with lower tryptase concentrations, had a history of severe sting reactions (p=0.004). Raised baseline serum concentrations of mast-cell tryptase and mastocytosis are potential risk factors for severe allergic reactions to Hymenoptera venom.

Mast cells in an angiosarcoma complicating xeroderma pigmentosum in a 13-year-old girl.

A cutaneous angiosarcoma, a rare tumor that occurs almost exclusively in sun-exposed skin of individuals older than 50 years, developed in an adolescent with Xeroderma pigmentosum (XP). As this is the second report of a child with angiosarcoma and XP, ultraviolet-induced DNA damage may be involved in the pathogenesis of this tumor. Strongly increased numbers of mast cells were found, particularly in the peripheral tumor area, which may reflect with the requirement of mast cells for the growth of vascular structures or a role for mast cells in the antitumor immune response.

The emerging role of physician assistants in the delivery of dermatologic health care.

The NAMCS provides a wealth of information on use of PAs in all practices, including dermatology. Two important points regarding the NAMCS and SDPA data are addressed here: the number of visits to PAs for dermatologic symptoms and the expected growth of PA use in dermatologists' offices. Dermatologic symptoms were evaluated frequently by PAs, accounting for 14% of PA visits. These statistics do not address the number of referrals those PAs made to dermatologists. Perhaps PAs as a group should be targeted for increased dermatologic education, particularly stressing the need for appropriate referral to a dermatologist. PAs could increase the number of dermatology referrals from primary care offices with improved understanding of the importance of the dermatologist in the management of patients' overall skin health. At projected growth rates, the number of PAs employed by dermatologists should exceed 500 by the end of 2000. Most of this growth has been in private practices and rarely in HMOs or in large multispecialty clinics. There are a number of reasons for this growth, as follows: A PA may help reduce the patient load on the dermatologist, especially with sameday appointments and drop-ins. Some dermatologists are moving away from clinical dermatology into cosmetics, which not only leaves a vacuum in clinical dermatology, but also creates job opportunities for PAs in cosmetic dermatology. Regarding managed care growth, PAs can have a positive impact on the problem of having to see more patients for less money. PAs are cost-effective. In the 1998 SDPA survey, the ratio of billings generated (production) to gross income for the average dermatology PA ranged from 3:1 to 6:1. Even with inexperienced PAs new to dermatology, this ratio was usually at least 2:1 at the end of the first year. PAs can cover satellite offices, allowing for practice expansion. Effective with the new Medicare laws of January 1, 1998, PAs can now see new Medicare patients or Medicare patients with new conditions without the physician being on site, opening up the possibility for satellite offices in remote areas. Just as dermatologists may move toward specialization in surgery, cosmetics, or medical dermatology, PAs may do the same, filling a niche in a particular practice. As in other specialties, patient acceptance of seeing dermatology PAs has not been a significant problem. Continued access to the dermatologist remains unfettered, but, over time, many patients become willing to see either. Are PAs likely to become future competitors of dermatologists? Genuinely concerned dermatologists worry that a dermatology-trained PA will become part of a gatekeeper system that impedes patient access to dermatologists. This is not happening and is not at all likely to become a trend, for a number of reasons. First, primary care cannot compete with dermatology practices in remuneration for PAs. Just as financial benefits in high-production specialty practices entice physicians, the same benefits entice PAs as well. Second, according to member surveys of the SDPA, virtually 100% of fellow members work with dermatologists. Although PAs can work in any type of practice and evaluate dermatologic symptoms just as a general practitioner would, PAs who specialize in dermatology primarily practice with dermatologists, a collegial association most PAs seek out. PAs have steadfastly maintained their dependent, noncompetitive relationship with physicians and would not have it any other way. Although PAs see a good number of patients (2.8 million) with dermatologic symptoms, the NAMCS data indicate that most (72%) of these patients are also seen by a physician. Third, physicians are ultimately responsible for the actions of their PA employee. A general practitioner not trained to perform excisions or manage certain dermatologic conditions should not allow a PA to perform such duties. Similar to much of medicine, the PA profession continues to evolve, with many members moving awa

Biomechanical evaluation of dual-energy X-ray absorptiometry for predicting fracture loads of the infant femur for injury investigation: an in vitro porcine model.

OBJECTIVE: The purpose of this study was to determine the ability of bone mineral density (BMD) measured by dual-energy x-ray absorptiometry (DXA) and geometry measured by biplanar x-ray to predict fracture mechanics in vitro in an immature femur model. DESIGN: Prospective analysis of radiographic and biomechanical data was performed. SETTING: In vitro experimentation. INTERVENTIONS: Bone geometry and DXA data were obtained before mechanical testing. Twenty-two porcine femora from males and females (age 3 to 12 months; body weight 3.6 to 7.0 kilograms) were fractured. Mechanical tests were performed on the diaphysis of the femora in two loading configurations: (a) three-point bending to simulate loads that result in transverse fractures; and (b) torsion to simulate twisting injuries that result in spiral fractures. MAIN OUTCOME MEASURES: Correlation of radiographic data with the experimentally determined bone strength. RESULTS: Three-point bending consistently resulted in transverse fractures. Femoral diaphysis BMD (mean, 0.304 grams per square centimeter; SD, 0.028 grams per square centimeter) strongly correlated (r2 = 0.938) to fracture load in bending. Load at failure ranged from 530 to 1,024 N (mean, 726 N; SD, 138 N), consistent with the findings of Miltner. Empirically derived strength parameters coupling BMD with geometry accurately predicted bending loads (r2 = 0.84, p < 0.001) and energy to failure (r2 = 0.88, p < 0.05). Torsional loading failed to generate spiral fractures consistently, resulting in either end plate or diaphyseal fractures. Load at failure for torsion ranged from 1,383 to 3,559 Newton-millimeters (mean, 2,703 Newton-millimeters; SD, 826 Newton-millimeters). Because of these inconsistent fracture results, empirical strength parameters for torsion could not be derived. CONCLUSION: BMD coupled with geometry is a strong predictor of bending fracture loads in the immature femoral diaphysis. A similar relationship could not be shown for torsion because of inconsistent failure results. This study represents an initial attempt at developing a methodology for predicting the strength of young bones from radiographic measures. Further research is required to establish this methodology and to show the necessary correlation with immature human bone.