Apolipoprotein e4 allele and cognitive decline in elderly men

OBJECTIVES: To determine whether polymorphism of apolipoprotein E--notably, the e4 allele--predicts cognitive deterioration in the general population. DESIGN: Population based cohort investigated in 1990 and in 1993. SETTING: Zutphen, the Netherlands. SUBJECTS: Representative cohort of 538 Dutch men aged 70-89 at baseline. MAIN OUTCOME MEASURES: Cognitive function assessed by mini mental state examination, change in cognitive function and incidence of impaired cognitive function at three years. RESULTS: The baseline prevalence of impaired cognitive function (mini mental state examination score < or = 25) was higher among carriers of the e4 allele compared with men without the allele (41.0% (55) v 31.1% (122) P = 0.03), and this result was still valid after adjustment for age, occupation, smoking, alcohol use, and cardiovascular diseases. The decline in cognitive function at three years was largest in men homozygous for e4 (-2.4 points), intermediate in those heterozygous for e4 (-0.7 points), and lowest in men without e4 (-0.1 points), and it was independent of other risk factors (P = 0.02). The risk of developing impaired cognitive function during follow up was significantly increased in allele carriers compared with non-carriers (27.6% (16/58) v 15.5% (32/207)). The adjusted odds ratio was 2.87 (95% confidence interval 1.29 to 6.42). Twenty two per cent of the risk of developing impaired cognitive function in this population may be attributable to the e4 allele. CONCLUSIONS: The apolipoprotein e4 allele predisposes to cognitive decline in a general population of elderly men.     

Prothoracicotropic hormone in Manduca sexta: localization by a larval assay

1. A new method for the assay of insect prothoracicotropic hormone (PTTH) is described, using fourth instar larvae of Manduca sexta. Larvae neck-ligated at a critical time to prevent release of PTTH from the head fail to undergo the next larval moult. Such ligated larvae moult to fifth instar larvae or larval-pupal intermediates after injection of brain homogenates from Manduca larvae, pupae or pharate adults. The degree of response is proportional to the concentration of brain homogenate injected. 2. The source of PTTH in the pupal brain is the dorsal region of the protocerebrum containing the lateral neurosecretory cells. Microhomogennates of single pieces of brain showed activity with this method. 3. PTTH activity in partially purified extracts is water soluable, stable to boiling for 10 min, and is destroyed by Pronase or trypsin.     

Studies of prosody perception by cochlear implant patients

Prosodic information is conveyed to normally-hearing listeners by variations in acoustic fundamental frequency, amplitude envelope, and duration of speech segments. This study measured cochlear implant patients' sensitivity to these parameters in electrically coded speech. The psychophysical discrimination of electric parameters used to code prosodic information, were examined, together with prosody perception using speech processing strategies which modified the contributions of these parameters. Patients were implanted with the Cochlear Limited prosthesis and used the MPEAK speech processing strategy. In the psychophysical studies, difference limens were measured for steady-state and time-varying stimuli, of different pulse rates and pulse durations, over a series of different stimulus durations. These limens were obtained using an adaptive procedure which converged on the 50 per cent correct point. In the prosody perception studies, performance was measured for the MPEAK strategy and for strategies which modified the contributions of pulse rate and pulse duration. Data were collected for five tests of prosodic contrasts. Difference limens for steady-state pulse rates were larger at higher rates (17 per cent at 400 pulses/s) than at lower rates (6 per cent at 100 pulses/s). For some patients, limens for the time-varying pulse rates were larger than those for the steady-state pulse rates while for the other patients, the limens were similar. Difference limens for pulse duration were 0.3 dB, corresponding to 4 per cent of the dynamic range, for steady-state stimuli and doubled in size for the time-varying stimuli. Prosody perception performance was generally poorer for the modified strategies than for the MPEAK strategy, suggesting that the removal of information coded by pulse rate and pulse duration reduced the perception of prosodic contrasts.     

Targeting the receptor-Gq interface to inhibit in vivo pressure overload myocardial hypertrophy

Hormones and neurotransmitters may mediate common responses through receptors that couple to the same class of heterotrimeric guanine nucleotide-binding (G) protein. For example, several receptors that couple to Gq class proteins can induce cardiomyocyte hypertrophy. Class-specific inhibition of Gq-mediated signaling was produced in the hearts of transgenic mice by targeted expression of a carboxyl-terminal peptide of the alpha subunit Galphaq. When pressure overload was surgically induced, the transgenic mice developed significantly less ventricular hypertrophy than control animals. The data demonstrate the role of myocardial Gq in the initiation of myocardial hypertrophy and indicate a possible strategy for preventing pathophysiological signaling by simultaneously blocking multiple receptors coupled to Gq.     

MR imaging of symptomatic osteochondromas with pathological correlation

Presentation of antigenic peptides by major histocompatibility complex (MHC) class I molecules depends on translocation of cytosolic peptides into the endoplasmic reticulum (ER) by transporters associated with antigen processing (TAP). Peptide transport by TAP is thought to include at least two steps: initial binding of peptide to TAP, and its subsequent translocation requiring ATP hydrolysis. These events can be monitored in peptide binding and transport assays. Previous studies have shown that the efficiency of peptide transport by human, mouse and rat transporters varies according to the C-terminals of peptide substrates in an allele and species-specific manner. However, it has not been clear during which step of peptide interaction with TAP selection occurs. We used an assay monitoring the peptide binding step to study the binding affinity of a library of 199 peptides for human TAP and the two major allelic rat TAP complexes. We observed a dominant influence of the C-terminus on peptide binding affinity for all transporters, and highly restrictive selection of peptides with aliphatic and aromatic C-terminals by rat TAP1/TAP2u complexes. The selectivity of peptide binding to rat TAP complexes is in full accordance with published data on selective peptide transport and on control of antigen presentation by rat TAP. These results strongly suggest that (i) peptide selection by TAP occurs exclusively in the initial binding step; (ii) all factors involved in peptide selection by TAP are present in insect cells.     

Genetic transformation of germinated conidia of the thermophilic fungus Humicola grisea var. thermoidea to hygromycin B resistance

Dihydrotestosterone decreased alcohol dehydrogenase (ADH) activity and enzyme-protein in rat hepatocytes in culture. This effect was observed after the hepatocytes had been exposed to dihydrotestosterone for 3 days at concentrations of 0.5 micromol/L or higher. Dihydrotestosterone did not decrease alcohol dehydrogenase messenger RNA (mRNA) but, rather, resulted in small increases in ADH mRNA after 3 days of exposure. To further determine the mechanism for the effects of dihydrotestosterone in decreasing the enzyme, the turnover of ADH was determined after incorporation of [3H]-leucine into the enzyme protein. Dihydrotestosterone did not alter the initial 2-hour incorporation of [3H]-leucine into the enzyme protein. Dihydrotestosterone, however, resulted in an increase in the fractional rate of degradation (Kd) of the enzyme from 0.12 +/- 0.013 to 0.23 +/- 0.004 per hour (P < .001) accompanied by a much smaller increase in the fractional rate of synthesis (Ks) from 0.12 +/- 0.028 to 0.17 +/- 0.031 per hour (P > .05). Hence, the mechanism for the fall in ADH in the presence of dihydrotestosterone is an increase in enzyme degradation which is not accompanied by a sufficient increase in enzyme synthesis.     

Antibody to epitope tag induces internalization of human muscarinic subtype 1 receptor

The degree to which a startle response to a loud noise is inhibited by a weak prestimulus is an operational measure of sensorimotor gating. Prepulse inhibition (PPI) can be measured across species and is reduced in schizophrenia patients and dopamine (DA)-activated rats. The ability of DA antagonists to restore PPI in apomorphine (APO)-treated rats correlates highly with their clinical antipsychotic potency. We compared the ability of systemic- vs. intracerebrally (i.c.)-administered haloperidol (HAL) to restore PPI in APO-treated rats. Consistent with previous studies, systemic administration of HAL completely restored PPI in rats treated with APO (0.5 mg/kg s.c.), with an ED50 of approximately 0.02 mg/kg. In an otherwise identical paradigm, HAL failed to fully restore PPI after infusion into either the nucleus accumbens (NACcore or NACshell), NACcore + caudate nucleus (CN), ventral subiculum (VS), medial prefrontal cortex (MPFC), or ventral tegmentum (VTA). A subtotal, but statistically significant restoration of PPI was achieved after HAL infusion into all regions, except the NACshell. Statistically significant effects of i.c. HAL tended to be observed at doses that were only approximately 5-10-fold lower than those at which significant effects were observed after systemic administration. The results suggest that systemically administered HAL may restore PPI in APO-treated rats through its action distributed throughout multiple levels of PPI-regulatory circuitry.