Complex segregation analysis of familial amyloidosis in Oriental shorthair cats.

Amyloidosis in Siamese/Oriental cats is a lethal condition with variable age of clinical onset. There is no sex predisposition and clinical signs of disease usually become apparent by 1-7 years of age. In the terminal stages, the liver is enlarged and pale, and contains parenchymal hemorrhages. In the present study, pedigree data from 17 cats with clinical signs consistent with amyloidosis underwent genetic analysis. Necropsy and histopathological data were available for 10 of the 17 cats. Necropsy findings included pale, fragile and enlarged livers with capsular ruptures and parenchymal hemorrhages, and sanguineous effusions in the abdominal cavity. Congo red staining with birefringence confirmed systemic amyloidosis mostly involving the liver and thyroid gland. In four of the 10 cases, protein deposits were classified as amyloid A protein (AA-amyloid) by immunostaining. Pedigree data for all 17 affected cats indicated a familial trait. Animal threshold model analysis demonstrated that the heritability for amyloidosis was 0.56 ± 0.09 (standard error). Complex segregation analysis was used for statistical comparisons among models to determine environmental or sex dependent effects, and Mendelian, polygenic, or mixed Mendelian and polygenic inheritance patterns. A mixed model with a Mendelian and polygenic component provided the best fit to the data and thus was most likely. All other models of inheritance were rejected due to their insufficient ability to explain segregation of amyloidosis. In conclusion, we found evidence for a complex genetic basis for amyloidosis in Oriental shorthair cats.

Validation of an algorithm of time-dependent electro-clinical risk stratification for electrographic seizures (TERSE) in critically ill patients.

OBJECTIVE: The clinical implementation of continuous electroencephalography (CEEG) monitoring in critically ill patients is hampered by the substantial burden of work that it entails for clinical neurophysiologists. Solutions that might reduce this burden, including by shortening the duration of EEG to be recorded, would help its widespread adoption. Our aim was to validate a recently described algorithm of time-dependent electro-clinical risk stratification for electrographic seizure (ESz) (TERSE) based on simple clinical and EEG features. METHODS: We retrospectively reviewed the medical records and EEG recordings of consecutive patients undergoing CEEG between October 1, 2015 and September, 30 2016 and assessed the sensitivity of TERSE for seizure detection, as well as the reduction in EEG time needed to be reviewed. RESULTS: In a cohort of 407 patients and compared to full CEEG review, the model allowed the detection of 95% of patients with ESz and 97% of those with electrographic status epilepticus. The amount of CEEG to be recorded to detect ESz was reduced by two-thirds, compared to the duration of CEEG taht was actually recorded. CONCLUSIONS: TERSE allowed accurate time-dependent ESz risk stratification with a high sensitivity for ESz detection, which could substantially reduce the amount of CEEG to be recorded and reviewed, if applied prospectively in clinical practice. SIGNIFICANCE: Time-dependent electro-clinical risk stratification, such as TERSE, could allow more efficient practice of CEEG and its more widespread adoption. Future studies should aim to improve risk stratification in the subgroup of patients with acute brain injury and absence of clinical seizures.

Detecting abnormal electroencephalograms using deep convolutional networks.

OBJECTIVES: Electroencephalography (EEG) is a central part of the medical evaluation for patients with neurological disorders. Training an algorithm to label the EEG normal vs abnormal seems challenging, because of EEG heterogeneity and dependence of contextual factors, including age and sleep stage. Our objectives were to validate prior work on an independent data set suggesting that deep learning methods can discriminate between normal vs abnormal EEGs, to understand whether age and sleep stage information can improve discrimination, and to understand what factors lead to errors. METHODS: We train a deep convolutional neural network on a heterogeneous set of 8522 routine EEGs from the Massachusetts General Hospital. We explore several strategies for optimizing model performance, including accounting for age and sleep stage. RESULTS: The area under the receiver operating characteristic curve (AUC) on an independent test set (n = 851) is 0.917 marginally improved by including age (AUC = 0.924), and both age and sleep stages (AUC = 0.925), though not statistically significant. CONCLUSIONS: The model architecture generalizes well to an independent dataset. Adding age and sleep stage to the model does not significantly improve performance. SIGNIFICANCE: Insights learned from misclassified examples, and minimal improvement by adding sleep stage and age suggest fruitful directions for further research.

Decision analysis of intracranial monitoring in non-lesional epilepsy.

PURPOSE: Up to one third of epilepsy patients develop pharmacoresistant seizures and many benefit from resective surgery. However, patients with non-lesional focal epilepsy often require intracranial monitoring to localize the seizure focus. Intracranial monitoring carries operative morbidity risk and does not always succeed in localizing the seizures, making the benefit of this approach less certain. We performed a decision analysis comparing three strategies for patients with non-lesional focal epilepsy: (1) intracranial monitoring, (2) vagal nerve stimulator (VNS) implantation and (3) medical management to determine which strategy maximizes the expected quality-adjusted life years (QALYs) for our base cases. METHOD: We constructed two base cases using parameters reported in the medical literature: (1) a young, otherwise healthy patient and (2) an elderly, otherwise healthy patient. We constructed a decision tree comprising strategies for the treatment of non-lesional epilepsy and two clinical outcomes: seizure freedom and no seizure freedom. Sensitivity analyses of probabilities at each branch were guided by data from the medical literature to define decision thresholds across plausible parameter ranges. RESULTS: Intracranial monitoring maximizes the expected QALYs for both base cases. The sensitivity analyses provide estimates of the values of key variables, such as the surgical risk or the chance of localizing the focus, at which intracranial monitoring is no longer favored. CONCLUSION: Intracranial monitoring is favored over VNS and medical management in young and elderly patients over a wide, clinically-relevant range of pertinent model variables such as the chance of localizing the seizure focus and the surgical morbidity rate.

[Neurodevelopmental outcome of very low birth weight infants born at the Perinatal Centre in Ulm, Germany]. / Entwicklungsneurologische Nachuntersuchung von sehr unreifen Frühgeborenen im Perinatalzentrum Ulm.

BACKGROUND: Since 2006 an assessment of the neurodevelopmental outcome of very low birth weight infants (VLBWI) at a corrected age of 2 years is mandatory for every perinatal centre in Germany. The aim of our study was to check how complete these assessments were performed in our population of infants born at our perinatal centre and receiving treatment within our local neonatal network. Furthermore, the data obtained will be used for prenatal consultations. Another objective was to identify risk factors for adverse neurodevelopmental outcomes. METHODS: All VLBWI were invited for a follow-up exam using the Bayley Scales of Infant Development II (BSID-II) or III (BSID-III), or Griffiths Mental Developmental Scales) at 2 years corrected age. The results of children assessed by other institutions were collected. RESULTS: 142 (69.3%) of the 205 VLBWI, born and finally discharged alive at the perinatal centre in Ulm were assessed at a median (minimum - maximum) corrected age of 23 (18-27) months. The BSID-II Psychomotor Development Index (PDI) 91 was (< 50-128) (n=115), the BSID-II Mental Development Index (MDI) was 87 (< 50-134) (n=96), BSID-III MDI 95 (60-112) (n=29) and the Griffiths Score was 93 (67-140) (n=17). Severe disability was diagnosed in 36 (25.4%) of the children studied. Gestational age and higher grade intraventricular haemorrhage were associated independently with severe disability. CONCLUSIONS: It is very difficult to achieve a high rate of follow-up examinations in preterm infants <1,500 g in a neonatal network. Severe impairment in VLBWI is not rare. Improving neurodevelopmental outcome remains a challenge.

Design, synthesis and properties of synthetic chlorophyll proteins.

A chemoselective method is described for coupling chlorophyll derivatives with an aldehyde group to synthetic peptides or proteins modified with an aminoxyacetyl group at the epsilon-amino group of a lysine residue. Three template-assembled antiparallel four-helix bundles were synthesized for the ligation of one or two chlorophylls. This was achieved by coupling unprotected peptides to cysteine residues of a cyclic decapeptide by thioether formation. The amphiphilic helices were designed to form a hydrophobic pocket for the chlorophyll derivatives. Chlorophyll derivatives Zn-methyl-pheophorbide b and Zn-methyl-pyropheophorbide d were used. The aldehyde group of these chlorophyll derivatives was ligated to the modified lysine group to form an oxime bond. The peptide-chlorophyll conjugates were characterized by electrospray mass spectrometry, analytical HPLC, and UV/visible spectroscopy. Two four-helix bundle chlorophyll conjugates were further characterized by size-exclusion chromatography, circular dichroism, and resonance Raman spectroscopy.

[Sleep disorders--what can be done when hypnotics no longer help? Overview and case report]. / Schlafstörungen--Was tun, wenn Schlafmittel nicht mehr helfen? Ubersicht und Fallvorstellung.

We report on the case of a 45-year old female with chronic insomnia and refractory to hypnotics, who also has a - polygraphically documented - tolerance to the imidazopyridine "zolpidem". We discuss the main differential diagnosis and demonstrate a therapeutic regimen which allows a step-by-step replacement of hypnotics by sedative antidepressants. This interval replacement treatment reduces on the one hand the risk of developing a severe withdrawal syndrome. On the other hand the replacement by sedative antidepressants improves insomnia and insomnia-associated depressive symptoms. Finally, the clinical implications and rationale of a therapeutic approach with sedative antidepressants in chronic insomnia are discussed.

Inhibition of macrophage-dependent low density lipoprotein oxidation by nitric-oxide donors.

We have previously shown that nitric oxide donors inhibit the oxidation of low density lipoprotein (LDL) initiated by copper ions or by azo-bis-amidinopropane (Hogg et al., 1993. FEBS Lett. 334: 170-174). In this study, the nitric oxide donors S-nitroso-N-acetylpenicillamine (SNAP), spermine NONOate, and sodium nitroprusside were tested for their ability to inhibit macrophage-dependent oxidation of LDL. SNAP and spermine NONOate inhibited macrophage-dependent oxidation of LDL in a time- and concentration-dependent manner. We propose that nitric oxide is acting as a chain-breaking antioxidant that can inhibit the progression of lipid peroxidation in cell dependent-oxidation of LDL. By this mechanism nitric oxide could be an endogenous defense against atherogenesis. In contrast, sodium nitroprusside enhanced cell-mediated oxidation of LDL by a mechanism dependent on superoxide production and transition metal ions. Sodium nitroprusside also enhanced LDL oxidation by cell culture medium alone by a similar mechanism. The use of sodium nitroprusside as a nitric oxide donor in cellular systems appears to be complicated by the release of iron leading to an enhanced oxidative stress. Thus the effects of sodium nitroprusside in such systems may be unrelated to nitric oxide release.

Role of apolipoprotein B-derived radical and alpha-tocopheroxyl radical in peroxidase-dependent oxidation of low density lipoprotein.

The peroxidation of low density lipoprotein (LDL) may play an important role in the modification of the lipoprotein to an atherogenic form. The oxidation of LDL by peroxidases has recently been suggested as a model for in vivo transition metal ion-independent oxidation of LDL (Wieland, E., S. Parthasarathy, and D. Steinberg. 1993. Proc. Natl. Acad. Sci. USA. 90: 5929-5933). It is possible that in vivo the peroxidase activities of proteins, such as prostaglandin synthase and myeloperoxidase, promote LDL oxidation. We have used horseradish peroxidase (HRP) and H2O2 as a model of peroxidase-dependent oxidation of LDL and we observed the following during HRP/H2O2-initiated LDL oxidation. i) The oxidation of alpha-tocopherol occurred with the concomitant formation of alpha-tocopheroxyl radical. This was followed by the production of an apolipoprotein B (apoB)-derived radical. The apoB radical and the alpha-tocopheroxyl radical were formed under both aerobic and anaerobic conditions. ii) Inclusion of N-t-butyl-alpha-phenylnitrone (PBN) did not inhibit alpha-tocopheroxyl radical formation. The ESR spectrum of a PBN/LDL-lipid derived adduct was observed after prolonged incubation. iii) There was formation of conjugated dienes, lipid hydroperoxides and thiobarbituric acid reactive substances. Our data indicate that HRP/H2O2 oxidizes both alpha-tocopherol and apoB to the corresponding radicals and concomitantly initiates lipid peroxidation.

Nitric oxide donor compounds inhibit the toxicity of oxidized low-density lipoprotein to endothelial cells.

Photo-oxidized low-density lipoprotein is cytotoxic to bovine aortic endothelial cells in a concentration-dependent manner. Total cell killing occurs at a concentration of 600 mumol/l lipid hydroperoxide (LOOH). Selenium deficiency enhances the toxicity of LOOH such that 300 mumol/l LOOH is cytotoxic. This toxicity is inhibited by desferrioxamine, a transition metal ion chelator, and by butylatedhydroxytoluene, a potent inhibitor of lipid peroxidation. Toxicity is also inhibited by the nitric oxide donors S-nitrosoglutathione and spermine NONOate but not by reduced or oxidized glutathione and spermine. We propose that nitric oxide, released from these compounds, is inhibiting the toxicity of LOOH to selenium-deficient endothelial cells. Furthermore we hypothesize that the mechanism for this inhibition of toxicity is the scavenging of the propagatory peroxyl and alkoxyl free radicals, by nitric oxide, that are generated during peroxidation of cell membranes.

Inhibition of low-density lipoprotein oxidation by nitric oxide. Potential role in atherogenesis.

The effects of nitric oxide (.NO) and nitrovasodilators on the oxidation of low-density lipoprotein (LDL) have been studied. S-Nitroso-N-acetylpenicillamine (SNAP) and sodium nitroprusside (SNP) inhibited Cu(2+)- and 2,2'-azobis-2-amidinopropane hydrochloride-dependent oxidation of LDL as monitored by oxygen consumption and the formation of thiobarbituric acid-reactive substances, conjugated dienes, and lipid hydroperoxides. In the case of SNP, inhibition of LDL oxidation occurred only when the incubation mixture was irradiated with visible light. SNAP, however, exerted a dose-dependent inhibition of Cu(2+)-catalyzed oxidation of LDL even in the dark. Addition of .NO dissolved in deoxygenated buffer also inhibited the progression of LDL oxidation. Mouse peritoneal macrophages were less able to degrade LDL that had been oxidized in the presence of SNAP. Using an .NO electrode, it was estimated that a continuous production of .NO (< or = 760 nM/min) could retard the progression of LDL oxidation. We propose that .NO can inhibit LDL oxidation by acting as a chain-breaking antioxidant that is capable of scavenging carbon-centered and peroxyl radicals. Biological implications of this novel .NO antioxidant property are discussed in relation to atherogenesis and contrasted to the prooxidant property of .NO when generated in the presence of superoxide.

Intracellular catalase inhibition does not predispose rat heart to ischemia-reperfusion and hydrogen peroxide-induced injuries.

The objective of this study was to determine whether inhibition of intracellular catalase would decrease the tolerance of the heart to ischemia-reperfusion and hydrogen peroxide-induced injuries. Isolated bicarbonate buffer-perfused rat hearts were used in the study. Intracellular catalase was inhibited with 3-amino-1,2,4-triazole (ATZ, 1.5 g/kg body weight, two hours prior to heart perfusion). In the ischemia-reperfusion protocol, hearts were arrested with St. Thomas'II cardioplegic solution, made ischemic for 35 min at 37 degrees C, and reperfused with Krebs-Henseleit buffer for 30 min. The extent of ischemic injury was assessed using postischemic contractile recovery and lactate dehydrogenase (LDH) leakage into reperfusate. In the hydrogen peroxide infusion protocol, hearts were perfused with increasing concentrations of hydrogen peroxide (inflow rates 0.05-1.25 mumol/min). Inhibition of catalase activity (30.4 +/- 1.8 mU/mg protein in control vs 2.4 +/- 0.3 mU/mg in ATZ-treated hearts) affected neither pre-ischemic aerobic cardiac function nor post-ischemic functional recovery and LDH release in hearts subjected to 35 min cardioplegic ischemic arrest. Myocardial contents of lipid hydroperoxides were similar in control and ATZ-treated animals after 20 min aerobic perfusion, ischemia, and ischemia-reperfusion. During hydrogen peroxide perfusion, there was an increase in coronary flow rate followed by an elevation in diastolic pressure and inhibition of contractile function in comparison with control hearts. The functional parameters between control and ATZ-treated groups remained unchanged. The concentrations of myocardial lipid hydroperoxides were the same in both groups. We conclude that inhibition of myocardial catalase activity with ATZ does not predispose the rat heart to ischemia-reperfusion and hydrogen peroxide-induced injury.

[Somnambulism and pavor nocturnus--review and case report]. / Somnambulismus und Pavor nocturnus--Ubersicht und Falldarstellung.

A case of night terror with sleepwalking in an adult patient is described. Sleep polygraphic data are presented. The literature related to sleepwalking, night terror and its treatment is reviewed. The psychopathologic patterns of sleepwalking and night terror are illustrated and the differentiations of parasomnias and epileptic seizures discussed. The clinical applications of these findings are described and practical recommendations made for the management of NON-REM parasomnia.

Primary electron transfer kinetics in bacterial reaction centers with modified bacteriochlorophylls at the monomeric sites BA,B.

The primary electron transfer has been investigated by femtosecond time-resolved absorption spectroscopy in two chemically modified reaction centers (RC) of Rhodobacter sphaeroides, in which the monomeric bacteriochlorophylls BA and BB have both been exchanged by 13(2)-hydroxybacteriochlorophyll a or [3-vinyl]-13(2)-hydroxybacteriochlorophyll a. The kinetics of the primary electron transfer are not influenced by the 13(2)-hydroxy modification. In RCs containing [3-vinyl]-13(2)-hydroxybacteriochlorophyll a the primary rate is reduced by a factor of 10.

Effects of n-3 fatty acids on renal function and renal prostaglandin E metabolism.

The present study was performed to investigate the effects of dietary fish oil supplements on renal function and renal prostaglandin (PG) E metabolism. The usual "western" diet of 10 healthy volunteers (six female and 4 male) aged between 21 and 35 years was supplemented with 6 g/day of n-3 polyunsaturated fatty acids [3.6 g of eicosapentaenoic acid (EPA) and 2.4 g of docosahexaenoic acid (DHA)] for six weeks. Supine arterial blood pressure (BP) and heart rate (HR), renal hemodynamics, renal excretory function and urinary excretion of PGE2 and PGE3 were determined before and at the end of the fish oil supplementation period. No changes could be observed in BP and HR while renal plasma flow (RPF), determined as the clearance of PAH, significantly increased from 559 +/- 44 to 738 +/- 47 ml/min (P less than 0.001) with the fish oil supplements. This was associated with a decrease in renal vascular resistance from (8.11 +/- 0.54).10(-2) to (6.37 +/- 0.38).10(-2) mm Hg.min.ml-1 (P less than 0.01). Glomerular filtration rate (GFR), determined as the clearance of inulin, increased from 97 +/- 3 to 107 +/- 3 ml/min (P less than 0.01), resulting in a decrease in filtration fraction from an average of 0.19 +/- 0.01 to 0.15 +/- 0.01 (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Modified reaction centers from Rhodobacter sphaeroides R26. 2: Bacteriochlorophylls with modified C-3 substituents at sites BA and BB.

Monomeric bacteriochlorophylls BA and BB in photosynthetic reaction centers from Rhodobacter sphaeroides R26 were exchanged with (13(2)-hydroxy-)bacteriochlorophylls containing a 3-vinyl- or 3-(alpha-hydroxyethyl)-substituent instead of the 3-acetyl group. The corresponding binding sites must be tolerant to the introduction of the polar residue at C-13(2) and modifications of the 3-acetyl group. According to HPLC analysis, the exchange with both pigments amounts to less than or equal to 50% of the total BChl contained in the complex, corresponding to less than or equal to 100% of the monomeric BChl alpha BA,B. The absorption spectra show significant changes in the QX and QY-region of the monomeric bacteriochlorophylls. By contrast, the absorption of the primary donor (P870) and reversible photobleaching is retained. The circular dichroism is also unchanged in the 870 nm region. The positive cd band located at around 800 nm in native reaction centers, shifts with the (blue-shifted) QY absorption(s) of BA and/or BB, whereas the position of the negative one remains nearly unaffected. The data indicate that the latter is the upper excitonic band of the primary donor, and that there is little interaction of the monomeric BA/BB with the primary donor.

Fish oil and baroreceptor function in man.

The present study was designed to investigate the effects of dietary fish oil supplements on blood pressure, the pressor response to norepinephrine, and sensitivity of the arterial baroreceptor reflex. 10 normotensive volunteers (six female and 4 male) aged between 21 and 35 years were given 6 g/day of n-3 polyunsaturated fatty acids (3.6 g of eicosapentaenoic acid and 2.4 g of docosahexaenoic acid) during six weeks in addition to their usual diet. Resting blood pressure (BP), blood pressure response to exogenous norepinephrine (NE), and changes in heart rate (HR) associated with the blood pressure increase during NE infusion were determined before and at the end of the fish oil supplementation period. No changes in BP could be observed following the n-3 fatty acid supplements as compared to control values (110.7 +/- 2.4/63.5 +/- 2.9 mmHg vs. 110.6 +/- 1.9/60.1 +/- 1.3 mmHg). Blood pressure values during infusion of 0.1 micrograms/kg body weight of NE were 119.8 +/- 2.4/67.4 +/- 1.7 mmHg before the fish oil supplementation period and were also unchanged (119.9 +/- 2.0/70.5 +/- 1.9 mmHG) after the fish oil diet. HR during NE infusion was significantly (p less than 0.01) more suppressed after the fish oil supplementation period. During control, HR decreased in parallel with the rise in blood pressure from 69.2 +/- 2.8 min-1 to 63.9 +/- 2.4 min-1 (difference of 5.3 +/- 0.5 min-1), while after the fish oil supplementation HR fell from 68.1 +/- 3.5 min-1 to 56.2 +/- 2.6 min-1 (difference of 11.9 +/- 1.5 min-1).(ABSTRACT TRUNCATED AT 250 WORDS)