Thyroid function in normal aged subjects or with auricular fibrillation

Free T4, free T3 and TSH before and 30 min after TRH administration have been evaluated in 35 elderly patients with atrial fibrillation (AF), in 35 elderly normal subjects (AN) and compared with results obtained in 36 young men (YN). No significant differences were evidenced between AF and AN, especially no mild hyperthyroidism was discovered in AF. In comparison with YN, there was no alteration of free T4 with age but free T3 is dramatically decreased; concerning TSH, there is a significant decrease before and after TRH in AN males whereas TSH levels in other subgroups are similar to those in YN.     

Early activation defects in T lymphocytes from aged mice

Summary: Aging affects both calcium signals and protein kinase cascades in mouse T lymphocytes. The decline in calcium signal development largely represents differences between naive and memory T cells: the latter are resistant to increases in calcium concentration, and are more common in aged mice. Aging leads to declines in phosphorylation of a wide range of substrates in T cells stimulated by either anti-CD 3 antibodies or by substances, such as phorbol myristate acetate (PMA) or ionomycin, that act at intracellular sites, but some phosphoproteins respond only in old T cells, and others respond regardless of age, Tyrosine phosphorylation of die CD3ζ chain declines with age, both in resting T cells and after activation. but the proportion of Zap-70 that is bound to CD3C increases in T cells from old mice, Zap-70 function and phosphorylation of CD3ζ-associated Zap-70 change only slightly after stimulation of T cells by anti-CD3 and aiHi-CD4, and are at similar levels in activated old and young T cells. Nonetheless, induction of Raf- l, MEK, and ERK kinase activity declines with age in CD4T cells. The effect of aging on T-cell activation is not simply an overall decline in signal intensity, but a set of qualitative changes that differ among subsets and depend at least partly on the nature of the stimulus.     

Genetic and structural polymorphism of complement receptor 1 in normal Indian subjects

The human complement receptor 1 (C3b/C4b receptor, CD35, CR1), a polymorphic membrane bound glycoprotein, is differentially expressed on erythrocytes, eosinophils, monocytes, B and T-lymphocytes, dendritic cells and kidney podocytes. It also occurs in the plasma as soluble CR1 (sCR1) and in urine as urinary CR1 (uCR1). Different population studies have suggested the functional and physiological significance of the structural (CR1-A/190, CR1-B/220, CR1-C/160 and CR1-D/250 kDa) and genomic (HH, high erythrocyte CR1 expression, HL, intermediate and LL, low expression) polymorphisms in health and disease. However, simultaneous study on the structural and genomic polymorphism in the same group of study subjects is lacking. This is the first study on both quantitative and structural polymorphism in 101 healthy volunteers from different parts of India by random sampling. In our study, AA phenotype was found to be expressed in 84.2% of individuals and 14.8% carried AB phenotype. One individual (0.9%) was found to possess BB phenotype. Homozygous BB pattern was identified for the first time in Indian subjects. The relative gene frequencies for A and B allele were found to be 0.916 and 0.084, respectively. Pertaining to quantitative polymorphism, percentage distribution for HH, HL and LL phenotypes was found to be 23.7, 54.45 and 21.79%, respectively and the gene frequencies were 0.51 and 0.49 for H and L allele, respectively. The observations for quantitative as well as structural polymorphism showed a good probability of fitness with Hardy-Weinberg equilibrium, thus proving that both the types of CR1 polymorphic forms are encoded by autosomal co-dominant alleles. We found a higher frequency of HL and AA phenotypes in the study subjects. Our findings are unique as we found that gene frequencies for structural and quantitative polymorphism in our study subjects were a combination of those found in Caucasian and Oriental populations.     

Traumatic brain injury in aged animals increases lesion size and chronically alters microglial/macrophage classical and alternative activation states

Traumatic brain injury (TBI) causes chronic microglial activation that contributes to subsequent neurodegeneration, with clinical outcomes declining as a function of aging. Microglia/macrophages (MG/M?) have multiple phenotypes, including a classically activated, proinflammatory (M1) state that might contribute to neurotoxicity, and an alternatively activated (M2) state that might promote repair. In this study we used gene expression, immunohistochemical, and stereological analyses to show that TBI in aged versus young mice caused larger lesions associated with an M1/M2 balance switch and increased numbers of reactive (bushy and hypertrophic) MG/M? in the cortex, hippocampus, and thalamus. Chitinase3-like 3 (Ym1), an M2 phenotype marker, displayed heterogeneous expression after TBI with amoeboid-like Ym1-positive MG/M? at the contusion site and ramified Ym1-positive MG/M? at distant sites; this distribution was age-related. Aged-injured mice also showed increased MG/M? expression of major histocompatibility complex II and NADPH oxidase, and reduced antioxidant enzyme expression which was associated with lesion size and neurodegeneration. Thus, altered relative M1/M2 activation and an nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase)-mediated shift in redox state might contribute to worse outcomes observed in older TBI animals by creating a more proinflammatory M1 MG/M? activation state.     

Astrocyte mitogenic activity in aged normal and Alzheimer's human brain

Purified cultures of neonatal rat cortex astrocytes can be used to measure astrocyte mitogenic activity in human brain extracts. A microassay permits the strict comparison of multiple samples. Human brain mitogenic activity was 2 to 4-fold that found in comparable extracts from rat brain. A 1.3-fold increase in specific mitogenic activity was observed in extracts from Alzheimer's disease cortex when compared to normal aged or adult tissue. This small increase was due to the lower amount of extractable protein in Alzheimer's tissue.     

Topographic distribution of the 40 Hz auditory evoked-Related potential in normal and aged subjects

Summary Galambos, Makeig and Talmachoff (1981) described what they called the 40 Hz event-related potential (ERP). This steady-state response is an EEG following response to repetitive auditory stimulation which becomes sinusoidal in form and maximal in amplitude at rates between 35 and 45 Hz. The present study was designed to examine the scalp topography of the 40 Hz ERP in order to complement previous magnetoencephalographic studies which implicate auditory cortex in the generation of the response. In addition, this study was designed to collect normative data on an aged sample in order to assess the effects of aging on the response. 40 Hz ERP's were recorded from a group of seven audiometrically and neurologically normal elderly subjects (mean age = 69.6 years) and a younger group of five normal adults (mean age = 38.0 years), using 1000 Hz tones presented binaurally at 40 per second. A 21 channel recording system was used to obtain a comprehensive picture of the scalp distribution of the response. Recorded ERP's were Fourier transformed to enhance the signal-to-noise ratio. No significant differences were found in phase or amplitude of the 40 Hz ERP between the two age groups, indicating that the normal aging process does not have an effect on this response. Topographic maps of the 40 Hz ERP showed reversals of electrode potential in temporal regions, supporting an interpretation of bilateral sources in temporal cortex. The data presented in this study complement previous studies of the 40 Hz event-related magnetic field and support the position that temporal cortex is involved in the generation of the response.This study was funded in part by N.S.E.R.C., D.O.D. and the Gerontology Research Centre, Simon Fraser University.     

Regional distributions of brain glutamate and glutamine in normal subjects

Glutamate (Glu) and glutamine (Gln) play an important role in neuronal regulation and are of value as MRS‐observable diagnostic biomarkers. In this study the relative concentrations of these metabolites have been measured in multiple regions in the normal brain using a short‐T_E whole‐brain MRSI measurement at 3 T combined with a modified data analysis approach that used spatial averaging to obtain high‐SNR spectra from atlas‐registered anatomic regions or interest. By spectral fitting of high‐SNR spectra this approach yielded reliable measurements across a wide volume of the brain. Spectral averaging also demonstrated increased SNR and improved fitting accuracy for the sum of Glu and Gln (Glx) compared with individual voxel fitting. Results in 26 healthy controls showed relatively constant Glu/Cr and Gln/Cr throughout the cerebrum, although with increased values in the anterior cingulum and paracentral lobule, and increased Gln/Cr in the superior motor area. The deep gray‐matter regions of thalamus, putamen, and pallidum show lower Glu/Cr compared with cortical white‐matter regions. Lobar measurements demonstrated reduced Glu/Cr and Gln/Cr in the cerebellum as compared with the cerebrum, where white‐matter regions show significantly lower Glu/Cr and Gln/Cr as compared with gray‐matter regions across multiple brain lobes. Regression analysis showed no significant effect of gender on Glu/Cr or Gln/Cr measurement; however, Glx/Cr ratio was found to be significantly negatively correlated with age in some lobar brain regions. In summary, this methodology provides the spectral quality necessary for reliable separation of Glu and Gln at 3 T from a single MRSI acquisition enabling generation of regional distributions of metabolites over a large volume of the brain, including cortical regions. Copyright © 2016 John Wiley & Sons, Ltd.     

Effect of house dust mite on serum complement activation and total haemolytic activity in vitro in normal subjects and in patients with bronchial asthma

House dust mite (Dermatophagoides farinae) has been shown to activate the complement system in vitro by both the classical and alternative pathways in normal serum and in two groups of (skin test positive and skin test negative) patients with bronchial asthma. The activation was dose dependent in the lower range of allergen concentrations. Skin test positive asthmatic subjects showed the maximum activation. Skin test negative patients had activation between skin test positive patients and normal subjects. However, at the higher allergen concentration normal serum and bronchial asthma patients showed similar results.     

Activation of early components of complement targets myelin and oligodendrocytes in the aged rhesus monkey brain

The disruption and loss of myelin in the white matter are some of the major changes that occur in the brain with age. In vitro studies suggest a role of the complement system in the catabolic breakdown of myelin membranes. This study presents findings on activation of the early components of complement cascade in the brains of both young and aged rhesus monkeys with evidence of increased complement activation in aged animals. Complement containing oligodendrocytes (CAOs) containing C3d and C4d complement activation products bound to oligodendrocytes and myelinated fibers were found in the brain of normal young and old animals. The CAOs, which also contained activated microglia, were distributed throughout the whole brain and in significantly greater numbers in the aged monkeys. These findings, together with the demonstration of covalent binding of the C3 fragments to myelin, suggest the initiation of the complement cascade by myelin and oligodendrocytes, which are known classical complement activators. Activation of terminal complement components was not demonstrable in the CAOs. Taken together the findings support the concept that activation of early components of complement in the brain may be a normal biological process that involves the metabolism of myelin and oligodendrocytes and up-regulates with age.     

Differential expression of platelet activation markers in aspirin-sensitive asthmatics and normal subjects

Background Activation of platelets and expression of adhesion molecules (e.g. CD62P and CD63) which mediate interactions between platelets and other cells may be important in the pathogenesis of aspirin-sensitive asthma. Objective To determine the expression of CD62P and CD63 on platelets from aspirinsensitive asthmatic (ASA +), aspirin-tolerant asthmatic (ASA-) and normal subjects and to assess the modulatory effect of aspirin on platelet CD62P and CD63 expression following stimulation with either platelet-activating factor (PAF), arachidonic acid (AA) or collagen (COL). Methods Platelet-rich plasma was obtained from 10 ASA +, 10 ASA—and 10 normal control subjects, and expression of CD62P and CD63 was measured by flow cytometry. Platelets were stimulated with PAF (10, 80 nM), AA (0.1, 1 mM) or COL (80, 800 μg/mL) with or without aspirin (concentration range 0.4–4 mg/mL). Results In the absence of aspirin, CD62P expression induced by AA and COL was greater in ASA+ patients compared with control subjects (P<0.001) while CD62P expression with PAF, AA and COL was reduced in ASA—when compared wilh ASA+ and control subjects (P < 0.001). CD63 expression with PAF and AA was reduced in both ASA+ and ASA- patients compared with control subjects (P<0.001). Aspirin inhibited the expression of both CD62P and CD63 after agonist stimulatitin. Greater inhibition of CD62P expression was observed in ASA+ compared with ASA- patients (P<0.001) and normal subjects (P<0.05) while greater inhibition of CD63 expression was observed in normal subjects compared with both ASA+ and ASA- patients (P<0.05). In ASA+ patients and normal subjects, stimulation with PAF and COL resulted in only one platelet population while in contrast with 1 mM AA two populations were observed. Conclusions Fnhanced AA- and collagen-induced platelet CD62P expression in ASA+ patients compared with normal subjects and greater inhibition by aspirin of CD62P expression in ASA+ may be relevant to the pathogenesis of this syndrome. Reduced expression of CD62P and CD63 in platelets of ASA- patients following stimulation with PAF and AA may also have implications for the role of platelets and these mediators in the pathogenesis of other forms of asthma.     

SSRI Treatment suppresses dream recall frequency but increases subjective dream intensity in normal subjects

Clinical lore and a small number of published studies report that the selective serotonin reuptake inhibitors (SSRIs) intensify dreaming. This study examines the dream effects of paroxetine and fluvoxamine in order to both increase clinical knowledge of these agents and to test an important potential method for probing the relationship between REM sleep neurobiology and dreaming in humans. Fourteen normal, paid volunteers (4 males, 10 females; mean age 27.4 year, range 22--39) free of medical or neuropsychiatric symptoms as well as of psychotropic or sleep affecting drugs completed a 31-day home-based study consisting of: 7 days drug-free baseline; 19 days on either 100 mg fluvoxamine (7 Ss) or 20 mg paroxetine (7 Ss) in divided morning and evening doses; and 5 days acute discontinuation. Upon awakening, subjects wrote dream reports, self-scored specific emotions in their reports and rated seven general dream characteristics using 5-point Likert scales. Dream reports were independently scored for bizarreness, movement and number of visual nouns by three judges. REM sleep-related measures were obtained using the Nightcap ambulatory sleep monitor. Mean dream recall frequency decreased during treatment compared with baseline. Dream report length and judge-rated bizarreness were greater during acute discontinuation compared with both baseline and treatment and this effect was a result of the fluvoxamine-treated subjects. The subjective intensity of dreaming increased during both treatment and acute discontinuation compared with baseline. Propensity to enter REM sleep was decreased during treatment compared with baseline and acute discontinuation and the intensity of REM sleep increased during acute discontinuation compared with baseline and treatment. The decrease in dream frequency during SSRI treatment may reflect serotonergic REM suppression while the augmented report length and bizarreness during acute SSRI discontinuation may reflect cholinergic rebound from serotonergic suppression.     

Early events in initiation of alternative complement pathway activation by the capsule of Cryptococcus neoformans.

The capsule of Cryptococcus neoformans is a powerful activator of the alternative complement pathway. This study examined the manner in which the cryptococcal capsule influences initiation of and early events in complement activation by C. neoformans. These studies examined the effects of the classical and alternative pathways on the kinetics and early sites for deposition of C3 fragments on encapsulated cryptococci, nonencapsulated cryptococci, and zymosan. The results showed that nonencapsulated cryptococci and zymosan are qualitatively and quantitatively similar in the manner in which they initiate complement activation. Both utilize the classical and alternative pathways. Initiation via the classical pathway occurs suddenly and simultaneously at sites distributed over the entire cell surface. Initiation of the alternative pathway by zymosan and nonencapsulated cryptococci is characterized by a lag of 6 to 8 min before appreciable amounts of C3 accumulate on the cells. Alternative pathway initiation by zymosan and nonencapsulated cryptococci occurs at a limited number of focal initiation sites that expand with alternative pathway amplification to cover the cell surface. Presence of the cryptococcal capsule blocks classical pathway initiation, which would normally occur at the cryptococcal cell wall, and produces an initiation that is dependent solely on the alternative pathway. Initiation of the alternative pathway by the cryptococcal capsule is characterized by a lag in C3 accumulation and the appearance of a limited number of focal initiation sites which resemble those observed when the alternative pathway is activated by zymosan and nonencapsulated cryptococci.     

NGF restores decrease in catalase and increases glutathione peroxidase activity in the brain of aged rats.

The effects of subchronic administration of nerve growth factor (NGF) into the lateral ventricle on catalase and selenium-dependent glutathione-peroxidase (GSH-Px) activity in several areas of the brain in 3-, 12- and 24-month-old rats were studied. NGF given daily (1 microgram for 28 consecutive days) produced in all brain areas studied a significant increase in catalase activity in 12- and 24-month-old rats. The most important finding was a complete restoration in 12- and 24-month-old rats of catalase activity to levels similar to those occurring in young (3-month-old) rats. In addition, NGF produced in comparison to 3-month-old rats and to same age vehicle-treated rats a significant increase in selenium-dependent GSH-Px in all the brain areas studied in 12- and 24-month-old animals, whereas selenium-independent GSH-Px was unaffected. In conclusion, the present results show that long-term administration of NGF into the lateral ventricle significantly increases in old animals the activity of key enzymes involved in the metabolic degradation of hydrogen peroxide.     

Local reflex mechanisms: influence on basal genioglossal muscle activation in normal subjects

STUDY OBJECTIVES: To define the influence of topical nasopharyngeal anesthesia on genioglossal EMG responsiveness to both negative pressure and basal muscle activity. The effects on airway mechanics (resistance and collapsibility) were also determined. PARTICIPANTS: 18 normal adult subjects (9 males and 9 premenopausal females) DESIGN AND MEASUREMENTS: Genioglossal EMG (GG EMG) was measured with intramuscular electrodes. Basal phasic and tonic GG EMG were defined, in addition to the muscle response to multiple brief applications of negative airway pressure (-10 to 12 cm H2O). Airflow resistance (at 0.2 L/second and peak flow) plus airway collapsibility were also determined. All measurements were completed with and without dense nasopharyngeal anesthesia (lidocaine). RESULTS: Following nasopharyngeal anesthesia, peak GG EMG response to negative pressure fell from 28.1+/-4.3 (SE) to 19.6+/-3.4% of maximum (p<0.01). This was associated with a significant fall in both peak phasic and tonic GG EMG under basal conditions (phasic: 20.2+/-3.2 to 15.9+/-2.7% of maximum, tonic: 13.9+/-2.5 to 9.8+/-1.8% of maximum). Falling muscle activity led to a trend of rising airflow resistance and increasing airway collapsibility. CONCLUSIONS: Local, topical receptor mechanisms located in the nasopharynx importantly modulate upper airway dilator muscle activity in humans during normal tidal breathing. Therefore, the mechanisms exist for the airway to respond to local events which would tend to compromise airway patency.