A recurrent nova super-remnant in the Andromeda galaxy.

The accretion of hydrogen onto a white dwarf star ignites a classical nova eruption1,2-a thermonuclear runaway in the accumulated envelope of gas, leading to luminosities up to a million times that of the Sun and a high-velocity mass ejection that produces a remnant shell (mainly consisting of insterstellar medium). Close to the upper mass limit of a white dwarf3 (1.4 solar masses), rapid accretion of hydrogen (about 10-7 solar masses per year) from a stellar companion leads to frequent eruptions on timescales of years4,5 to decades6. Such binary systems are known as recurrent novae. The ejecta of recurrent novae, initially moving at velocities of up to 10,000 kilometres per second7, must 'sweep up' the surrounding interstellar medium, creating cavities in space around the nova binary. No remnant larger than one parsec across from any single classical or recurrent nova eruption is known8-10, but thousands of successive recurrent nova eruptions should be capable of generating shells hundreds of parsecs across. Here we report that the most frequently recurring nova, M31N 2008-12a in the Andromeda galaxy (Messier 31 or NGC 224), which erupts annually11, is indeed surrounded by such a super-remnant with a projected size of at least 134 by 90 parsecs. Larger than almost all known remnants of even supernova explosions12, the existence of this shell demonstrates that the nova M31N 2008-12a has erupted with high frequency for millions of years.

Alzheimer's disease as an autoimmune disorder of innate immunity endogenously modulated by tryptophan metabolites.

Introduction: Alzheimer's disease (AD) is characterized by neurotoxic immuno-inflammation concomitant with cytotoxic oligomerization of amyloid beta (Aß) and tau, culminating in concurrent, interdependent immunopathic and proteopathic pathogeneses. Methods: We performed a comprehensive series of in silico, in vitro, and in vivo studies explicitly evaluating the atomistic-molecular mechanisms of cytokine-mediated and Aß-mediated neurotoxicities in AD.  Next, 471 new chemical entities were designed and synthesized to probe the pathways identified by these molecular mechanism studies and to provide prototypic starting points in the development of small-molecule therapeutics for AD. Results: In response to various stimuli (e.g., infection, trauma, ischemia, air pollution, depression), Aß is released as an early responder immunopeptide triggering an innate immunity cascade in which Aß exhibits both immunomodulatory and antimicrobial properties (whether bacteria are present, or not), resulting in a misdirected attack upon "self" neurons, arising from analogous electronegative surface topologies between neurons and bacteria, and rendering them similarly susceptible to membrane-penetrating attack by antimicrobial peptides (AMPs) such as Aß. After this self-attack, the resulting necrotic (but not apoptotic) neuronal breakdown products diffuse to adjacent neurons eliciting further release of Aß, leading to a chronic self-perpetuating autoimmune cycle.  AD thus emerges as a brain-centric autoimmune disorder of innate immunity. Based upon the hypothesis that autoimmune processes are susceptible to endogenous regulatory processes, a subsequent comprehensive screening program of 1137 small molecules normally present in human brain identified tryptophan metabolism as a regulator of brain innate immunity and a source of potential endogenous anti-AD molecules capable of chemical modification into multi-site therapeutic modulators targeting AD's complex immunopathic-proteopathic pathogenesis. Discussion:  Conceptualizing AD as an autoimmune disease, identifying endogenous regulators of this autoimmunity, and designing small molecule drug-like analogues of these endogenous regulators represents a novel therapeutic approach for AD.

Studies on HDL associated enzymes under experimental hypercholesterolemia: possible modulation on selenium supplementation.

BACKGROUND: Atherosclerosis is a chronic disorder of the arterial wall that starts by formation of fatty streaks and gradually evolves into atherosclerotic plaques. High-density lipoproteins (HDL) blood levels are inversely correlated with atherosclerosis. This beneficial effect of HDL has been partly attributed to its antioxidant properties mediated by paraoxonase1 (PON1) or platelet-activating factor acetylhydrolase (PAF-AH). The present study was aimed to study HDL associated enzymes i.e. PON1 and PAF-AH under experimental hypercholesterolemia and their possible modulation on selenium (Se; an antioxidant) supplementation. Male Sprague Dawley rats were divided into three groups and fed on the control diet, high fat diet (HFD) and HFD + Se respectively for the period of 4 months. RESULTS: Cholesterol, triglycerides, HDL and LDL levels were significantly increased by HFD feeding. Selenium supplementation lowered the triglyceride level, whereas the other lipid values remained unchanged. Serum selenium levels were reduced by 31% and ROS levels in the liver were 2-fold increased by HFD. Se supplementation, however, diminished the HFD-induced ROS levels by 29%. Furthermore, Se also improved the HFD-mediated reduction of serum PON1 enzyme activity by 34% and PON1 protein levels by 21%. However, no significant effect of Se was detected on the reduced PAF-AH proteins levels in HFD fed rats. mRNA expression of PON1 and PAF-AH in the liver was not affected in the Se treated groups. CONCLUSION: Se supplementation appears to be protective in hypercholesterolemia by restoring the antioxidant properties of the HDL associated enzyme i.e. PON1 whereas biological system aims towards maintaining the same PAF-AH levels even on selenium supplementation indicating its probable role in both anti and pro-atherogenic activities. Therefore, Se supplementation might be a valuable approach to limit the adverse effects of hypercholesterolemia and may need further investigations.

Obesity and type 2 diabetes are important risk factors underlying previously undiagnosed cirrhosis in general practice: a cross-sectional study using transient elastography.

BACKGROUND: Rising cirrhosis incidence and mortality in the United Kingdom has been attributed predominantly to excess alcohol consumption. However, metabolic risk factors such as Type 2 diabetes and obesity may also be important. AIM: To screen at-risk individuals in general practice for undetected cirrhosis using transient elastography and study the risk factors underlying these cases. METHODS: The study was undertaken in 4 general practices (adult patient population 20 868) between February 2012 and September 2014. Patients with defined risk factors for chronic liver disease (hazardous alcohol use and/or Type 2 diabetes) were identified from the General Practice electronic records and invited for transient elastography. Elevated liver stiffness was defined as ≥8 kPa. Cirrhosis was confirmed by established histological, radiological and biochemical methods. RESULTS: Two thousand three hundred and sixty eight patients were invited for transient elastography and 899/919 who attended (97.8%) had valid measurements. Of these 230 patients had elevated liver stiffness (25.6%) and 27 had cirrhosis (2.9%). Risk factors for new cirrhosis diagnoses were obesity and/or Type 2 diabetes in 16 patients (59.3%), alcohol alone in 3 (11.1%) and both alcohol and obesity and/or diabetes in eight (29.6%). Presence of cirrhosis was significantly increased in obese patients with Type 2 diabetes or hazardous alcohol use compared to non-obese (odds ratio 9.4 [95% CI 2.2-40.9] and 5.6 [95% CI 1.6-19.7] respectively). CONCLUSIONS: The number of new cases of cirrhosis diagnosed clearly demonstrates that existing estimates of prevalence are likely to be gross underestimates. Obesity was an important risk factor for cirrhosis within both alcohol users and diabetics.

Use of protein A to remove immunoglobulins from serum in hybridoma culture media.

The levels of protein A-reactive immunoglobulin (PA-Ig) in foetal bovine serum were measured in commercial batches. For tissue culture media incorporating 10% foetal bovine serum, the levels of bovine PA-Ig were of a similar order to those of mouse monoclonal antibodies produced by hybridomas grown in such media. The equilibrium constants were calculated for the binding to protein A-Sepharose of a number of mouse monoclonal antibodies, and of PA-Ig in foetal bovine serum and normal mouse serum. The average affinity of the mouse PA-Ig was 10 times higher than that of the bovine PA-Ig, suggesting that the two could be separated by affinity chromatography on protein A-Sepharose. The mouse monoclonal antibodies, however, displayed a range of affinity 1.5-100 times that of the bovine PA-Ig, indicating that such separation could not be generally applied. The optimal technique involved removing PA-Ig from bovine serum before its inclusion in the culture medium and then purifying the monoclonal antibody on a second protein A-Sepharose column.

The production of high affinity monoclonal antibodies to human growth hormone.

The primary aim of this work was to produce specific monoclonal antibodies to human growth hormone (hGH) for use in a diagnostic RIA of hGH levels in serum. Three different schedules were used for immunization of BALB/c mice and the splenocytes from each mouse were fused with myeloma cells Sp 2/0 Ag 14. Each fusion resulted in the production of hundreds of hybridomas secreting hGH-directed antibodies. Six antibodies have been fully characterized and have been grouped into pairs which recognize 3 different epitopes on the hGH molecule. One pair exhibits no cross reaction with the structurally related placental hormone, human placental lactogen (hPL), a second pair has low cross reaction with hPL (1.6-3%) and a third pair reacts equally well with hGH and hPL indicating binding to a common epitope in the 2 molecules. The highest affinity antibody, 74/6, which has an affinity constant of 4.4 X 10(10) l/mol and 3% cross-reactivity with hPL, has been used to establish a RIA for serum hGH measurements. Evidence is provided that hGH levels measured in this assay correlate well with those obtained in a conventional rabbit antiserum assay.

Contrasting effects of thymopentin and splenopentin on the capacity of female mice to reject syngeneic male skin.

The TP-5 pentapeptide analog of thymopoietin and the SP-5 pentapeptide analog of splenin, which differ only in substitution of Glu for Asp and represent positions 32-36 of the parent molecules, were compared for effects on the capacity of C3H/HeJ female mice to reject C3H/HeJ male skin (the H-Y rejection response). The actions of these TP-5 and SP-5 analogs of respective thymic and splenic products were already known to differ in other functional systems, neuromuscular and immunological, in vitro and in vivo. The H-Y rejection response of young thymus-intact female mice was heightened by TP-5 and by SP-5. Neither TP-5 nor SP-5 affected the raised H-Y rejection response of splenectomized female mice. Whereas TP-5 lowered the raised H-Y rejection response of thymectomized female mice, as reported elsewhere, SP-5 did not. Thus, not only do these structurally very similar immunoregulators differ in their particular functions, but the overall effect of these functions in vivo depends on the immune status of the recipient.

The production of monoclonal antibodies to human chorionic gonadotrophin and its subunits.

The difficulties encountered in producing highly specific antisera to human chorionic gonadotrophin (hCG) were overcome by the use of hybridoma technology. A panel of monoclonal antibodies directed toward hCG and its subunits was produced. Of the four antibodies which were fully characterized, one recognized the intact hCG molecule only, a second recognized only the free beta-subunit, a third recognized only the free alpha-subunit and the fourth bound to the beta-subunit of hCG both when it was in the free form and when it was associated with the alpha-subunit forming the intact hCG molecule. There was no significant cross-reaction of any of these antibodies with the pituitary glycoprotein hormones. The four antibodies had high binding affinities which should permit their use in immunoassays for measurement of circulating levels of hCG and its subunits.

Extending functional life span.

Average life expectancy at birth is a rough measure of the span of healthy, productive life--the functional life span. In the developed countries average life expectancies at birth now range from 76-79 years, six to nine years less than the limit of about 85 years imposed by aging. Aging is the accumulation of changes that increase the risk of death. Aging changes can be attributed to development, genetic defects, the environment, disease, and the inborn aging process. The latter is the major risk factor for disease and death after age 28 in the developed countries. The free radical theory of aging arose in 1954; it postulated that aging changes were caused by free radical reactions. There is now a growing consensus, largely based on the results of measures to minimize more-or-less random endogenous free radical reactions, that such reactions are a major cause of aging, possibly the only one. Some of these studies are presented following a brief discussion of free radical reactions.

Free radical theory of aging: history.

Aging is the accumulation of changes responsible for the sequential alterations that accompany advancing age and the associated progressive increases in the chance of disease and death. These changes can be attributed to disease, environment, and the inborn aging process. The aging process is now the major risk factor for disease and death after about age 28. The free radical theory of aging arose in 1954 from a consideration of aging phenomenon from the premise that a single common process, modifiable by genetic and environmental factors, was responsible for the aging and death of all living things. The theory postulates that aging is caused by free radical reactions, i.e., these reactions may be involved in production of the aging changes associated with the environment, disease and the intrinsic aging process. The origination of the theory and its application to the problem of increasing the functional life span are discussed. Support for the free radical theory of aging has increased progressively and now includes: 1) studies on the origin of life and evolution, 2) studies on the effect of ionizing radiation on living things, 3) dietary manipulations of endogenous free radical reactions, 4) the plausible explanations it provides for aging phenomena, and 5) the growing numbers of studies that implicate free radical reactions in the pathogenesis of specific diseases. The rapidly growing number of scientists involved in studies on the role of free radical reactions in biological systems should assure future significant increases in the healthy, useful, life span of man.

The clinical gerontologist.

A major objective now and in the future should be that of maximizing health and well-being during our essentially fixed span of life. It is proposed that this objective be delegated to a new field of medicine, perhaps to be known as clinical gerontology--a combination of preventive medicine and geriatrics.

Free radical theory of aging: effect of age, sex and dietary precursors on rat-brain docosahexanoic acid.

Increasing the peroxidizability of dietary fat has an adverse effect on the function of the central nervous system (CNS) in the rat. This effect may be influenced by the level of docosahexanoic acid, a highly unsaturated fatty acid, selectively concentrated in the phospholipids of brain membranes. This study was aimed at determining the influence of age, sex, and the nature of a dietary lipid supplement - linolenic acid (18:3w3), docosahexanoic acid (22:6w3), or the same amount of 22:6w3 in the form of menhaden oil triglycerides - on the rate of increase in the percentage of 22:6w3 in the whole-brain fatty acids of rats between the ages of 1 and 12 months. The dietary lipid supplements were reflected in linear increases in the brain 22:6w3 of female rats throughout the study. Between 6 and 12 months of age, the rate of incorporation of dietary 22:6w3 and its precursors into the brain 22:6w3 of male rats dropped. At 12 months it was about half that for females in the case of 22:6w3 and menhaden oil, and about zero for 18:3w3. It is suggested that dietary 22:6w3 and its precursors may modify CNS function by altering membrane function and peroxidizability through changes in the concentration of 22:6w3 in membrane phospholipids.

Free radical theory of aging: inhibition of amyloidosis in mice by antioxidants; possible mechanism.

The antioxidants, alpha-tocopherol acetate and a quinolone derivative (Santoquin), inhibited the development of amyloidosis when added to the diet of casein-injected C3HeB/FeJ male mice. Santoquin, and to a lesser extent butylated hydroxytoluene (BHT), also depressed the appearance of a plasma protein fraction in these mice; the effect of alpha-tocopherol was not determined. Consideration of the current knowledge of amyloid, in the light of these antioxidant studies, prompted the following hypothesis. Amyloidosis is largely the result of an enhanced rate of oxidative degradation of a connective-tissue glycoprotein(s) coupled with oxidative/enzymatic changes in the plasma, both of the tissue-derived substances and of immunoglobulins, to form the amyloid fibril protein subunits (AL and AA) which subsequently aggreagate to form the amyloid fibrils.

Free radical theory of aging: effect of dietary fat on central nervous system function.

Free radical reactions have been implicated in aging. A rise in the level of random free radical reactions in a biologic system might have a greater effect on the central nervous system (CNS) than elsewhere, partly because of the presence of glial cells and the unique connections between neurons. To evaluate this possibility, some animal experiments were conducted. The initial experiment involved old male Sprague-Dawley rats fed (since shortly after weaning) with semisynthetic diets characterized by fat differing in amount or degree of unsaturation. The number of errors made in a Hebb-Williams maze was determined and found to be higher as the amount or degree of unsaturation of the fat was increased. Likewise rats aged 6 and 9 months, fed semisynthetic diets containing 20 percent by weight of lard, oleinate, or safflower oil +alpha-tocopherol performed significantly better in a discrimination learning situation (Skinner box) than did rats fed a diet containing 20 percent by weight of safflower oil. The diets employed in these studies did not have a significant effect on the mortality rates. These results are compatible with the possibility that enhancing the level of lipid peroxidation has an adverse effect on the CNS, out of proportion to the effect on the body as a whole, as measured by the mortality rate.

Aging: phenomena and theories.

Aging is the accumulation of diverse adverse changes that increase the risk of death. These changes can be attributed to development, genetic defects, the environment, disease, and the inborn aging process. The chance of death at a given age serves as a measure of the number of accumulated aging changes, that is, of physiologic age, and the rate of change of this measure, as the rate of aging. As living conditions in a population approach optimum, the curve of the logarithm of the chance of death versus age shifts towards a limit determined by the sum of (1) the irreducible contributions to the chance of death by aging changes that can be prevented to varying degrees, and (2) those due to the intrinsic aging process. In the developed countries living conditions are now near optimum, and the ALE-Bs are about 6-9 years less than the potential maximum of around 85 years. The inborn aging process is now the major risk factor for disease and death after about age 28. By age 28 only 1 to 2% of a cohort is dead, the remaining 98 to 99% die at an exponentially increasing rate determined by the aging process. This process ensures that few reach 100 years and none exceed about 122 years. Many theories have been advanced to account for the aging process. No single theory is generally accepted. Theories that can contribute to the important practical goal of increasing the healthy, useful span of humans will endure.

Aging: overview.

Aging is a universal process that began with the origination of life about 3.5 billion years ago. Accumulation of the diverse deleterious changes produced by aging throughout the cells and tissues progressively impairs function and can eventually cause death. Aging changes can be attributed to development, genetic defects, the environment, disease, and an inborn process--the aging process. The chance of death at a given age serves as a measure of the average number of aging changes accumulated by persons of that age, that is, of physiologic age, and the rate of change of this measure as the rate of aging. Chances for death are decreased by improvements in general living conditions. As a result, during the past two millennia average life expectancy at birth (ALE-B), determined by the chances for death, of humans has risen from 30 years, in ancient Rome, to almost 80 years today in the developed countries. Chances for death in the developed countries are now near limiting values and ALE-Bs are approaching plateau values that are 6-9 years less than the potential maximum of about 85 years. Chances for death are now largely determined by the inherent aging process after age 28. Only 1.1% of female cohorts in Sweden die before this age; the remainder die off at an exponentially increasing rate with advancing age. The inherent aging process limits ALE-B to around 85 years, and the maximum life span (MLS) to about 122 years. Past efforts to increase ALE-B did not require an understanding of aging. Such knowledge will be necessary in the future to significantly increase ALE-B and MLS, and to satisfactorily ameliorate the medical, economic, and social problems associated with advancing age. The many theories advanced to account for aging should be used, to the extent it is feasible, to help with these important practical problems, including applications of the free radical theory of aging. Past measures evolved by societies to ensure adequate care for older individuals are rapidly becoming inadequate because of changes in life style, the growing percentage of older people, declining fertility rates, and the diminishing size of the work forces to provide for the elderly. Measures are being advanced to help with this problem. Prospects are bright for further increases in the span of functional life and improvements in the lives of the elderly.

The trapezius musculocutaneous flap in head and neck reconstruction: potential pitfalls.

Defects resulting from bulky tumor resection of the head and neck region represent a reconstructive challenge. The trapezius musculocutaneous paddle flap based on the transverse cervical vessels is a useful tool for the reconstructive surgeon. Failure to recognize the variable anatomy is discussed in relation to other musculocutaneous flaps used for the purpose of head and neck reconstruction. The trapezius muscle has a variably located vasculature and diverse nomenclature. The knowledge of the variance of its anatomical vasculature is essential in the successful use of the trapezius musculocutaneous flap.

Ocular histopathology in animals experimentally infected with Mycobacterium leprae and M. lepraemurium. 1. Mycobacterium leprae and M. lepraemurium infections in the mouse. 2. Mycobacterium leprae infections in the 9-banded armadillo (Dasypus novemcinctus L.).

At varying periods of time following the successful establishment of systemic infections with Mycobacterium leprae or M. lepraemurium in the mouse and the nine-banded armadillo eyes were examined by light microscopy. Inoculation of bacilli was by the intravenous or intraperitoneal route or directly into the hind footpads; eyes were not directly inoculated in this study. During periods of up to 3 years under laboratory conditions no animal showed evidence of impaired vision or blindness, and the external appearance of both eyes was normal. The ocular histopathology and the sites of accumulation of bacilli are described. In immunologically normal mice infected with M. lepraemurium bacilli were much commoner in extraorbital tissues, but they were, nevertheless, found in various tissues within the orbit, including the ciliary body and sclera. In immunologically normal mice (and one rat) injected with M. leprae of human origin no bacilli were found in the eye, but in mice immunologically depressed by thymectomy and total body irradiation considerable numbers of bacilli were present in the iris and ciliary body and also in the limbal cornea. In the armadillo bacilli were found in large numbers in virtually all tissues except the lens, retina, optic nerve, and aqueous and vitreous humours, but the uveal tract was heavily involved. Findings are discussed in relation to the great frequency of ocular involvement and the importance of immune-complex disease in patients with lepromatous leprosy, and to factors wihch may favour the localisation and multiplication of Mycobacterium leprae in the eye.

Combined sedation and topical anesthesia for cataract surgery.

PURPOSE: To determine whether lidocaine jelly is as efficacious as tetracaine drops for obtaining ocular anesthesia and to evaluate sublingual lorazepam as premedication for sedation in cataract surgery. SETTING: An ambulatory surgical center dedicated to ophthalmic surgery. METHODS: The study was divided into 2 phases. In the first, 100 patients were divided into 2 groups of 50 each. The first group received tetracaine 0.5% drops for anesthesia. The second group received lidocaine 2% jelly for topical anesthesia. In the second stage, 100 patients were divided into 2 groups of 50 each. The first 50 patients were given 1 mg of sublingual lorazepam before surgery. The second group had cataract surgery without sublingual lorazepam. All patients were operated on by the same surgeon in an ambulatory surgical center. The technique was temporal clear corneal cataract surgery with foldable intraocular lens implantation. Exclusions from the study were the need to convert to peribulbar or retrobulbar anesthesia, intraocular complications, and altered mental status. RESULTS: In the first phase of the study, lidocaine 2% jelly was as efficacious as tetracaine 0.5% drops for topical anesthesia in cataract surgery. In the second phase of the study, overall, patients in the lorazepam group had less anxiety, greater amnesia, and lower blood pressure than those not receiving lorazepam as sedation for topical anesthesia. CONCLUSIONS: Lidocaine 2% jelly combined with sublingual lorazepam provided excellent cost-effective anesthesia and sedation for topical anesthesia in cataract surgery and enhanced patient satisfaction with the procedure.