Principal neuron spiking: neither necessary nor sufficient for cerebral blood flow in rat cerebellum

Neuronal activity, cerebral blood flow, and metabolic responses are all strongly coupled, although the mechanisms behind the coupling remain unclear. One of the key questions is whether or not increases in spiking activity in the stimulated neurons are sufficient to drive the activity-dependent rises in cerebral blood flow (CBF) that form the basis of the signals used in functional neuroimaging such as the blood oxygen level-dependent (BOLD) signal. To this end the present study examined the effect of enhanced spike activity per se on CBF in rat cerebellar cortex under conditions of disinhibition, achieved by blocking GABA_A receptors using either bicuculline or picrotoxin. Purkinje cell spiking activity and local field potentials were recorded by glass microelectrodes, and laser Doppler flowmetry was used to monitor CBF. Disinhibition increased Purkinje cell spiking rate to 200–300% of control without incurring any increase in basal CBF. This demonstrates that increased spike activity per se is not sufficient to affect basal CBF. The neurovascular coupling between excitatory synaptic activity and CBF responses evoked by inferior olive (climbing fibre) stimulation was preserved during disinhibition. Thus, the unchanged basal CBF in the presence of the dramatic rise in Purkinje cell spiking rate was not explained by impaired synaptic activity–CBF coupling. On the basis of our previous and the present studies, we conclude that increased spiking activity of principal neurons is neither sufficient nor necessary to elicit CBF responses and in turn BOLD signals, and that activation-dependent vascular signals reflect excitatory synaptic activity.     

An HLA study in 74 Danish haemochromatosis patients and in 21 of their families

HLA-A and -B alleles in 74 Danish patients and 21 homozygous relatives with idiopathic haemochromatosis (IH) were compared with those in a sample of 1719 chromosomes from healthy Danish control subjects. The following alleles occurred with higher frequencies in IH compared to controls: A3: 53.6% vs. 15.1% (Pc less than 0.001); B7: 33.1% vs. 15.6% (Pc less than 0.001); B14: 6.9% vs. 3.0% (Pc greater than 0.05); B38: 5% vs. 0.9% (Pc greater than 0.05); B47: 4.0% vs. 0.4% (Pc greater than 0.05). Pedigree analyses disclosed 19 different haplotypes in IH subjects, compared to 286 haplotypes in controls. The following haplotypes occurred with higher frequency in IH compared to controls: A3,B5: 10.3% vs. 0.3% (Pc less than 0.001); A3,B7: 25.6% vs. 6.6% (Pc = 0.001); A3,B14: 3.4% vs. 0.6% (Pc greater than 0.05); A3,B47: 6.9% vs. 0.2% (Pc greater than 0.05). The major IH marker HLA-A3 was found in 56% of the haplotypes. The patterns of HLA-alleles associated with IH in Denmark show similarities to those in Central Europe, Australia, USA and Canada, being A3,B7 dominated and those in Central Sweden, England and Ireland, being A3,B14 dominated.     

Increased gamma delta T cells in acute Plasmodium falciparum malaria

The T cell receptor of gamma delta is normally expressed on a small percentage of peripheral lymphocytes. Although the role of gamma delta T cells in the physiologic immune response is still unknown, there is accumulating evidence that gamma delta T cells may participate in the immune response to mycobacterial and other infectious organisms. In this study, we have quantitated the number of circulating gamma delta T cells during acute Plasmodium falciparum malaria. The results indicate that gamma delta T cells are elevated during the acute infection and remain elevated for at least 4 weeks during convalescence. T cells may participate in the immune response against P. falciparum by functioning as non-MHC restricted cytotoxic cells against intraerythrocytic parasites. Alternatively, lymphokines may be produced on antigen stimulation which may have antiparasitic activity.     

Peptide motifs of closely related HLA class I molecules encompass substantial differences.

The peptides presented by major histocompatibility complex class I molecules adhere to strict rules concerning peptide length and occupancy by certain amino acid residues at anchor positions. Peptides presented by HLA-A*0201 molecules, for example, are generally nonapeptides requiring Leu or Met at position 2 and an aliphatic residue, predominantly Val, at position 9. A closely related molecule, HLA-A*0205, differing from the former at four amino acid residues, has a related but substantially different peptide motif. A*0205-presented peptides are still nonapeptides, and position 9 is still aliphatic, although it is preferentially occupied by Leu instead of Val. Position 2 not only allows aliphatic residues but also polar ones. Occupancy at position 6, considered as an auxiliary anchor in A*0201, as well as non-anchor residues at positions 3, 4, and 8 are relatively well conserved between the two peptide motifs. Thus, although a number of the T cell epitopes presented by the two HLA-A2 forms is expected to be identical, a considerable number of epitopes should be different.     

Changes during eating in oxygen consumption, cardiac function and body fluids of sheep

1. A study was made of the changes taking place in O₂ consumption, cardiac function and the volume and composition of the body fluids of sheep while they consumed a meal of hay.

2. During eating P_{a, CO2} and P_{v, CO2} both increased, pH decreased and free plasma [HCO₃^-] increased. Venous haematocrit increased sharply at the beginning of the meal, and declined slowly after feed was removed.

3. Arterial P_O2 did not change significantly during eating. However P_{v, O2} fell slightly but significantly. The O₂ saturation of venous blood fell due to the decline in pH. Estimated CO₂ in arterial blood increased as a consequence of increased haemoglobin content. The net effect was to increase arteriovenous difference in O₂ content from 4·4 ml./100 ml. before eating to 6·0 ml./100 ml. at the end of the meal.

4. O₂ consumption increased about 60% during eating and fell rapidly thereafter. Heart rate followed a similar pattern. Cardiac output however increased only about 17%, from 6 to 7 l./min. Consequently stroke volume declined throughout the meal from 76 to 52 ml./beat.

5. Plasma volume, estimated from measurements of T-1824, declined sharply by about 300 ml. at the beginning of the meal and recovered slowly after feed was removed. Blood volume declined less because of a rise in circulating erythrocytes.

6. Extracellular fluid volume was estimated from measurements of thiocyanate and thiosulphate spaces. Thiocyanate space measurements were abandoned after thiocyanate was found to be concentrated in saliva. Considerable random variation occurred in measurements of changes in extracellular fluid from thiosulphate disappearance but the results did reveal a significant fall of 1000-1500 ml. in extracellular fluid volume during eating.

7. The significance of these interrelated changes is discussed in relation to the maintenance of homoeostasis during eating in the sheep.

     

Effects of cold, eating, efferent nerve stimulation and angiotensin on heart rate in sheep before and after autonomic blockade

1. Effects of the natural stimuli of cold exposure and feeding on heart rate were tested in conscious sheep in which blockade of the cardiac efferent nerves was achieved by administration of propranolol and atropine. Effects of direct nerve stimulation, isoproterenol and angiotensin on heart rate before and after autonomic blockade were studied in acute preparations anaesthetized with pentobarbitone sodium.2. Propranolol reduced the extent of cardioacceleration induced both by exposure to cold and by eating. Heart rate in propranolol treated animals exposed to cold did not exceed about 120 beats/min. During eating, heart rate in propranolol treated animals showed no upper limit and increased on occasions to over 170 beats/min.3. Heart rate in conscious sheep following administration of atropine and propranolol was about 110 beats/min; in anaesthetized sheep following vagal section and propranolol it was usually about 120 beats/min. This was taken as intrinsic heart rate.4. Angiotensin administered to normal anaesthetized sheep usually reduced heart rate. After vagal section and propranolol, angiotensin injection usually, and angiotensin infusion invariably, increased heart rate.5. It was concluded that there exists in sheep a mechanism which during eating elevates heart rate by a means other than through the parasympathetic and sympatho-adrenal systems. It is suggested that this mechanism involves a direct chronotropic effect of angiotensin secreted in association with eating.     

A quantitative method for measuring in vitro synthesis of IgA and IgG by human rectal mucosa: studies on normal controls and patients with hypogammaglobulinaemia.

A quantitative technique has been developed for measurement of immunoglobulin production by human rectal mucosa in vitro. The technique overcomes the problem of serum proteins trapped in the tissue by parallel measurements of Ig and human serum albumin (HSA) over a 6 day period. IgG, IgA, IgM and HSA were measured in supernatant fluids using sensitive radioimmunoassays. The technique has demonstrated IgG and IgA synthesis by rectal mucosa in vitro. The conclusion that the observed IgA and IgG was synthesized in vitro was supported by the demonstration that the production could be increased by pokeweed mitogen and blocked by emetine. This culture system has been applied to measure Ig synthesis by the rectal mucosa of immunodeficient patients.     

Antiinflammatory effects of endotoxin. Inhibition of rabbit polymorphonuclear leukocyte responses to complement (C5)-derived peptides in vivo and in vitro.

Although capable of provoking a variety of inflammatory effects, endotoxin (bacterial lipopolysaccharide) paradoxically has been reported to be antiinflammatory. The authors have found that single intravenous injections of Escherichia coli endotoxin, 24 hours before challenge, inhibit almost completely the vascular permeability changes and exudation of polymorphonuclear leukocytes induced in rabbit skin by reversed passive Arthus reactions. Whereas intravenous injections of endotoxin also caused modest inhibition of the vascular permeability changes induced in rabbit skin by the synthetic peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP), exudation of polymorphonuclear leukocytes was unaffected. Polymorphonuclear leukocytes from rabbits given single injected doses of endotoxin exhibited markedly diminished chemotactic and degranulation responses to complement (C5)-derived peptides in vitro. Responses of these cells to FMLP, however, were normal. These data suggest that selective suppression of polymorphonuclear leukocyte responses to C5-derived peptides accounts, in part, for the antiinflammatory effects of endotoxin.