A late Eemian aridity pulse in central Europe during the last glacial inception.

Investigating the processes that led to the end of the last interglacial period is relevant for understanding how our ongoing interglacial will end, which has been a matter of much debate (see, for example, refs 1, 2). A recent ice core from Greenland demonstrates climate cooling from 122,000 years ago driven by orbitally controlled insolation, with glacial inception at 118,000 years ago. Here we present an annually resolved, layer-counted record of varve thickness, quartz grain size and pollen assemblages from a maar lake in the Eifel (Germany), which documents a late Eemian aridity pulse lasting 468 years with dust storms, aridity, bushfire and a decline of thermophilous trees at the time of glacial inception. We interpret the decrease in both precipitation and temperature as an indication of a close link of this extreme climate event to a sudden southward shift of the position of the North Atlantic drift, the ocean current that brings warm surface waters to the northern European region. The late Eemian aridity pulse occurred at a 65 degrees N July insolation of 416 W m(-2), close to today's value of 428 W m(-2) (ref. 9), and may therefore be relevant for the interpretation of present-day climate variability.

Experimental evidence of cerebral injury from profound hypothermia during cardiopulmonary bypass.

Choreoathetosis, seizures, and impaired mental development continue to occur in children undergoing cardiopulmonary bypass (CPB) and profound hypothermia with or without circulatory arrest. Although there is some evidence that the hypothermia itself may be causing these neurologic problems, skepticism remains because of lack of evidence from experimental studies simulating the clinical setting. In this experimental study, we examined the effect of profound and moderate hypothermia on the brain while maintaining normal flow rates during CPB. Ten adult mongrel dogs equally divided into two groups were anesthetized and subjected to CPB and varying levels of hypothermia (group 1, < or = 15 degreesC; group 2, < or = 2 degreesC). Both groups were kept at the desired temperature for 1 hour prior to rewarming and discontinuation of CPB. The dogs were euthanized 4-6 weeks later and neuropathologic studies were performed. The mean CPB flow rates during cooling and at the desired rectal temperature were comparable in both groups: group 1, 108 +/- 10 ml/kg/min versus 106 +/- 7 ml/kg/min in group 2 (p = NS) and 95 +/- 12 ml/kg/min in group 1 versus 101 +/- 5 ml/kg/min in group 2 (p = NS). Because of the difference in temperature between the two groups, the mean cooling time (onset of CPB to desired rectal temperature) was longer in group 1 (70 +/- 14 minutes) than in group 2 (28 +/- 11 minutes, p = 0.007). Hence, the total mean CPB time was also longer in group 1 (198 +/- 25 minutes) than in group 2 (143 +/- 13 minutes, p = 0.002). The lowest mean blood and rectal temperature achieved in group 1 were 11 +/- .9 degreesC and 12 +/- 1 degreesC versus 29 +/- .4 degreesC (p < 0.001) and 30 +/- .6 degreesC (p = 0.001), respectively, in group 2 (p = 0.001). Neuronal loss and degeneration was noted in all dogs in group 1 ranging from 2 to 8 cells per 1000 cells counted compared to none in group 2 (p = 0.05). These lesions occurred in both the basal ganglia and the cortex, although they were more marked in the caudate when compared to the cortex and cerebellum. Both in the cortex and in the caudate, neuronal loss was more marked around the capillaries. We conclude that the use of profound hypothermia of < or =15 degreesC and maintenance of normal flow rates during cooling at this temperature for 1 hour produces neuronal loss and degeneration in the brain. These lesions being more marked around capillaries points to the vulnerability of the neurons, probably because of their high lipid content to injury from the cold perfusate.

Factors influencing coronary vascular resistance during hypothermia.

Factors influencing total coronary vascular resistance (CVR) during hypothermia were studied in 30 mongrel dogs. Complete isolation of the heart in situ was achieved by transection of all cardiac neural and vascular connections in 15 dogs (denervated, Group I). Cardiac innervation was maintained in the other 15 dogs using systemic normothermic cardiopulmonary bypass (innervated, Group II). The aortic root was perfused with heparinized oxygenated blood at a constant flow rate at variable myocardial temperatures. Electromechanical arrest was achieved using potassium chloride (KCl) (25 meq/liter) added to the coronary perfusate. In each group, 5 dogs were maintained at a flow rate of 10 cc/kg/min without KCl and allowed to beat spontaneously, another 5 at a flow rate of 10 cc/kg/min and arrested with KCl, and the remaining 5 at a flow rate of 5 cc/kg/min with KCl. Total coronary vascular resistance was calculated from aortic root pressure, right atrial pressure, and flow rate and expressed in units per 100 grams of cardiac tissue. At 37 degrees C, resistance was lower in the denervated arrested (1.3 +/- 0.2) than in the innervated arrested hearts (2.1 +/- 0.2) (P less than 0.001). Preservation of spontaneous electromechanical activity in the innervated hearts resulted in a lower resistance (0.4 +/- 0.1) (P less than 0.001). A progressive decrease in myocardial temperature to 15 degrees C resulted in a corresponding decrease in coronary vascular resistance to a plateau value (0.5 to 0.7 U) in all arrested groups. The data suggest that at normothermia, innervation increases vascular tone in the coronary vascular bed, while electromechanical activity decreases it.(ABSTRACT TRUNCATED AT 250 WORDS)

Ontogeny of adenosine 3',5'-monophosphate metabolism in guinea pig cerebral cortex. II. Development of responses to L-glutamate in the presence of adenosine or histamine.

The effects of L-glutamate and other dicarboxylic amino acids on the accumulation of adenosine 3',5'-monophosphate (cyclic AMP) in slices of cerebral cortex from strain 2 guinea pigs were examined using tissue from animals at 39 days gestation to 7 days after birth. Responses to glutamate were inhibited completely by adenosine deaminase or theophylline unless histamine was present. When tested in the presence of adenosine, glutamate increased cyclic AMP accumulation up to 10-fold at 39 days gestation; the response was maximal at 52 days gestation, and both the efficacy and potency of glutamate declined thereafter. While the effects of glutamate were smaller in the presence of histamine plus theophylline, the developmental pattern was similar to that in the presence of adenosine. The relative potencies of D-aspartate, kainate, and alpha-methyl-DL-glutamate were much greater in fetal than in adult tissue. Glutamic acid diethyl ester, N-acetyl glutamate or 2,3-diaminopropionate had no effect in fetal tissue either in the presence or absence of glutamate. Responses to glutamate in adult tissue were much more dependent upon the presence of calcium ions than were those in fetal tissue. It was concluded that responses to glutamate involve mechanisms that differ in fetal and adult tissue.

Evidence for cross-linking of cyclic AMP to constituents of brain tissue by aldehyde fixatives: potential utility in histochemical procedures.

The amount of cyclic AMP recovered from unfixed tissue sections of brain carried through immunohistochemical procedures was found to be small (less than 2 pmoles/mg protein) and constant despite wide variations in the amount accumulated prior to freezing and sectioning. However, treatment of brain slices with glutaraldehyde or formaldehyde in buffered sucrose solutions for one to two hours at 0 degrees rendered insoluble as much as 60% of the total accumulated cyclic AMP as judged by filtration of homogenates of treated tissue. Immunoreactive cyclic AMP was recovered from filters by extraction with warm, dilute acid. The fraction of filter-bound cyclic AMP was relatively constant over a wide range of initial tissue levels. The persistence of insoluble cyclic AMP was greatest in homogenates of slices treated with formaldehyde when maintained above pH 8.5; about 40% of this fraction was lost after two hours at 0 degrees. Incubation of tissue homogenates with formaldehyde and radioactive nucleoside or nucleotide derivatives of adenine, guanine, and cytosine resulted in a time-dependent appearance of insoluble radioactivity; compounds lacking an amino function were inactive. Pure proteins, including polylysine, also reacted with formaldehyde and 3H-cyclic AMP to produce radioactivity resistant to adsorption by charcoal. The reaction between cyclic AMP or adenosine, formaldehyde, and alkyl amines was examined using UV spectrometry. It is tentatively concluded that at 0 degrees formaldehyde is capable of rapidly producing a methylene-bridged adduct between primary alkylamines and the N6-amino function of purine nucleosides or nucleotides. Application of these results to the development of immunohistochemical procedures for the cellular localization of cyclic AMP will require the generation of antibody preparations with high reactivity for cyclic AMP derivatized at the N6-position.

A kinetic analysis of the cyclic nucleotide phosphodiesterase regulation by the endogenous protein activator. A study of rat brain and frog sympathetic chain.

The effect of the endogenous protein activator on the kinetic characteristics of a highly purified, activator-deficient rat brain phosphodiesterase (EC 3.1.4.-) of a highly purified, activator-deficient rat brain phosphodiesterase (EC 3.1.4-) was studied. This enzyme preparation has only a high Km for cyclic AMP and a low Km for cyclic GMP. In the presence of 20 muM Ca2+, saturating concentrations of the activator decreased the Km of this enzyme for cyclic AMP from 350 muM to about 80 muM, without changing the V. The phosphodiesterase activator did not change the Km of phosphodiesterase for cyclic GMP; however, amoderate increase of V was seen. The activator lacks species specificity; the activator isolated from the bullfrog sympathetic chain produced the same qualitative and comparable quantitative changes in the kinetic properties of the purified rat brain phosphodiesterase. Cyclic GMP is a potent competitive inhibitor of the phosphodiesterase activation by the activator (Ki=1.8 muM), using cyclic AMP as a substrate. Cyclic AMP inhibits slightly the hydrolysis of cyclic GMP by phosphodiesterase in the presence of activator (Ki=155 muM) only.

A neurobiological role for a protein activator of cyclic nucleotide phosphodiesterase.

This work supports the idea that PDEA is bound and stored in brain particulate fraction. The release of PDEA into cytosol where the activator-sensitive PDE is located, is the first event in the process of the regulation of cAMP metabolism and inactivation. PDEA is released by cAMP-dependent phosphorylation of the activator-binding sites. This process is Ca2+ independent and does not occur in the presence of cGMP and cGMP-dependent phosphorylation. The free, soluble PDEA activates the high Km PDE in the presence of micromolar concentrations of Ca2+. This protein decreases severalfold the Km for cAMP of the high Km activator-sensitive PDE. PDEA regulates cAMP metabolism when the concentration of cAMP is elevated by a transsynaptic activation of adenylate cyclase. The rate of synthesis and the release of PDEA might be a part of the process of receptor sub- and supersensitivity, which has been reported during denervation or as a result of chronic treatment with drugs.