Serotonergic receptors in the brain of in utero undernourished rats

In this study, we report that 5-HT(1A) receptors are already present in fractions of axonal growth cones, from the normal rat fetal brain (E-17). Also, in utero undernourished (UN) rat pups at birth show a noteworthy enhancement in the B(max) of [3H]5-hydroxytryptamine (5-HT) and [3H]8-hydroxy-(2-N,N-dipropilamin)-tetralin (([3H])8-OH-DPAT), in the brainstem and cerebral cortex up to the second week after birth. Afterwards, there is a significant decrease in the binding of these ligands. [125I]Cyanopindolo binding in the cerebral cortex only showed a decrease in the same period. An elevation of brain serotonin in both regions was also present. These findings together, suggest that the mechanisms of regulation of serotonergic receptors' expression during the period studied, may not depend on the amount of neurotransmitter in the synaptic cleft, because in the early UN brain it would be expected only a lower receptor's density due to the chronic serotonin increase. On this basis, we propose that developmental activation of brain serotonin biosynthesis observed in early UN animals may disrupt the mechanism regulating the expression of 5-HT receptors during development.     

Ninety-one Cases of Breast Cancer and Chronic Lymphoproliferative Neoplasm: A Retrospective Review of a Population at High Risk for Multiple Malignancies

Abstract: We performed a retrospective analysis of clinical course of 91 patients who developed both breast cancer and a chronic lymphoproliferative neoplasm and were seen at the M. D. Anderson Cancer Center between January 1, 1970 and December 30, 1991. The sample included 24 individuals who developed lymphoproliferative neoplasm first (Group A), 22 individuals with concurrent diagnosis of both malignancies (Group B), and 45 individuals who developed breast cancer first (Group C). The median time to diagnosis of secondary breast cancer and lymphoproliferative neoplasm was 66 months (range, 7–459) and 65 months (range, 0–334), respectively. A higher proportion of Group B lymphomas were low-grade (77% vs. 47% [Group A] vs. 37% [Group C] p = 0.009). Prior occurrence of either one of these malignancies did not affect the disease-specific survival from the second malignancy. However, continuing mortality from the first malignancy appeared to contribute to a poor overall survival following second malignancy. Group A included 8 patients who developed breast cancer following radiation therapy for Hodgkin's disease after a mean interval of 18 (± 4.3) years. Three of these individuals had coexisting ductal and lobular histology (vs. none of the individuals in Groups B and C, p = 0.02). Another interesting finding was the high incidence of multiple additional malignancies in this patient population. A total of 29 additional neoplasms occurred in 21 (23%) of the 91 study subjects. These malignancies involved a wide variety of organ sites and could not be attributed to the therapy for either the breast cancer or the lymphoma in most cases. The data suggest that individuals who develop both breast cancer and a lymphoproliferative neoplasm are at a high risk for multiple malignancies. Close surveillance of such individuals for additional malignancies and further studies to understand the molecular basis of this predisposition are warranted.?     

Biphasic Shocks Compared with Monophasic Damped Sine Wave Shocks for Direct Ventricular Defibrillation during Open Heart Surgery

Background: Biphasic waveform shocks are more effective than monophasic shocks for transchest ventricular defibrillation, atrial cardioversion, and defibrillation with implantable defibrillators but have not been studied for open chest, intraoperative defibrillation. This prospective, blinded, randomized clinical study compares biphasic and monophasic shock effectiveness and establishes intraoperative energy dose-response curves.

Methods: Patients undergoing cardiothoracic surgery with bypass cardioplegia were randomly assigned to the monophasic or biphasic shock group. Ventricular fibrillation occurring after aortic clamp removal was treated with escalating energies of 2, 5, 7, 10, and 20 J until defibrillation occurred. If ventricular fibrillation persisted, a 20-J crossover shock of the other waveform was used.

Results: Cumulative defibrillation success at 5 J, the primary end point of the study, was higher in the biphasic group than in the monophasic group (25 of 50 vs. 9 of 41 defibrillated;P = 0.011). In addition, the biphasic group required lower threshold energy (6.8 vs. 11.0 J;P = 0.003), less cumulative energy (12.6 vs. 23.4 J;P = 0.002), and fewer shocks (2.5 vs. 3.5;P = 0.002). Crossover-shock effectiveness did not differ between groups. Dose-response curves show biphasic shocks to have higher cumulative success rates at all energies tested.     

Effects on Behaviour and EEG of Single Chain Phospholipases A2 from Snake and Bee Venoms Injected into Rat Brain: Search for a Functional Antagonism

Abstract: Three phospholipase A₂ (PLA₂s), OS₁ and OS₁ purified from the taipan snake venom Oxyuranus scutellatus scutellatus and bee venom PLA₂ were injected to rats by the intracerebroventricular route. OS₁ showed no sign of neurotoxicity at doses at which OS₂ and bee venom PLA₂ produced multiform dose-dependent behavioural effects including motor disturbances (stereotyped movements), compulsive scratching, convulsions and breathing difficulties. EEG recordings showed at the very time when the animal was motionless the induction of several episodes of a low frequency hippocampal theta rhythm, index of long-term changes in synaptic neuroplasticity. Spike-wave discharges were also produced but the occurrence was not systematic. These seizures were often accompanied with behavioural convulsions. Blockers of NMDA receptors and drugs modifying the GABAergic transmission could not abolish the neurotoxic effects of PLA₂s except for diazepam (10 mg/kg intraperitoneally) that prevented only OS₂-induced disturbances. Blockers of L-type Ca²⁺ channels and K⁺ channel openers were also without effect. The toxicity of OS₂ and bee venom PLA₂ is probably due to their initial specific binding to their neuronal receptor sites.     

Morphological effects of a large single dose of cycloheximide on the intestinal epithelium of the rat

Adult male rats received 15 mg/kg cycloheximide and the subsequent morphological effects at three and six hours after injection were evaluated using histometry, light and electron microscopy, histological demonstration of terminal web and acid phosphatase, and radioautography with tritiated thymidine. Rapid atrophy of the villi took place, progressing from the villus tip by premature exfoliation of epithelial cells. The crypts also diminished by random exfoliation of many crypt cells and by partial or complete disintegration. Mitosis and epithelial cell migration were absent. By six hours, the area occupied by the villi and the crypts per unit length of histological section was decreased by about 70–90% in most of the small intestine but only by about 40–60% in the duodenum and the terminal ileum. In the upper half of the villi, the epithelium was strongly positive for acid phosphatase and contained large numbers of round bodies resembling primary lysosomes. In the lower half, the microvillous border and terminal web were found to be disrupted. Animals receiving only 5 mg/kg cycloheximide also showed the atrophy of villi and crypts, and the round bodies resembling lysosomes. Evidence from several sources has indicated that protein synthesis in normal villus epithelial cells subsides toward the villus tip and becomes minimal at exfoliation. At exfoliation, proteins responsible for epithelial cohesion probably fail because they are no longer replenished. Cycloheximide appears to accelerate this process.     

Circulating leucocyte subpopulations in sedentary subjects following graded maximal exercise with hypoxia

Summary Ten healthy sedentary subjects [age, 27.5 (SD 3.5) years; height, 180 (SD 5) cm; mass, 69.3 (SD 6.3) kg] performed two periods of maximal incremental graded cycle ergometer exercise in a supine position. Randomly ordered and using an open spirometric system, one exercise was carried out during normoxia [maximal oxygen consumption ( O_2max)=38.6 (SD 3.5) ml·min^–1·kg^–1; maximal blood lactate concentration, 9.86 (SD 1.85) mmol·l^–1; test duration, 22.6 (SD 2.7) min], the other during hypoxia [ O_2max=33.2 (SD 3.2) ml·min^–1· kg^–1; maximal blood lactate concentration, 10.38 (SD 2.02) mmol·l^–1; test duration, 19.7 (SD 2.8) min]. At rest, immediately (0 p) and 60 min (60 p) after exercise, counts of leucocyte subpopulations (flow cytometry), cortisol and catecholamine concentrations were determined. At 0 p in contrast to normoxia, during hypoxia there was no significant increase of granulocytes. There were no significant differences between normoxia and hypoxia in the increases from rest to 0 p in counts of monocytes, total lymphocytes and lymphocyte subpopulations [clusters of differentiation (CD), CD3⁺, CD4⁺CD45RO^–, CD4⁺CD45RO⁺, CD8⁺CD45RO^–, CD8⁺CD45RO⁺, CD3⁺HLA-DR⁺, CD3^–CD16/CD56⁺, CD3⁺CD16/CD56⁺, CD 19⁺] as well as adrenaline, noradrenaline and cortisol concentrations. The counts of CD3 ^–CD16/CD56⁺-and CD8 ⁺CD45RO⁺-cells increased most. At 60 p, CD3^–CD16/CD56⁺ and CD3⁺CD16/CD56⁺-cell counts were below pre-exercise levels and under hypoxia slightly but significantly lower than under normoxia. We concluded that the exercise-induced mobilization and redistribution of most leucocyte and lymphocyte subpopulations were unimpaired under acute hypoxia at sea level. Reduced increases of granulocyte counts during the study and reduced cell numbers of natural killer cells and cytotoxic, not major histocompatibility complex-restricted T-cells, only indicated marginal effects on the immune system.     

Chimaeric anti-CD4 monoclonal antibody cross-linked by monocyte Fcγ receptor mediates apoptosis of human CD4 lymphocytes

Previous studies have shown that murine anti-CD4 monoclonal antibody, cross-linked by rabbit anti-mouse immunoglobulin, could mediate apoptosis of murine CD4⁺ lymphocytes when they were stimulated by T cell receptor antibody. In this study, we have shown that the murine anti-CD4 monoclonal antibody, OKT4, can induce apoptosis in human CD4⁺ T cells stimulated by the recall antigen tuberculin purified protein derivative (PPD) only when cross-linked by rabbit anti-mouse immunoglobulin. The chimeric anti-CD4 monoclonal antibody, cM-T412 whose Fc fragment is human, was able to cause apoptosis without cross-linking by a second antibody. Similarly, abolition of PPD-induced proliferation of peripheral blood mononuclear cells by cM-T412 did not require cross-linking with rabbit anti-human immunoglobulin. Inhibition of proliferation by cM-T412 could be reduced by pre-treating monocytes with heat-aggregated human IgG. This suggested that monocyte Fcγ receptors might be cross-linking the human Fc of cM-T412. Propidium iodide staining together with immunofluorescence showed that the apoptotic cells were indeed CD4⁺ lymphocytes. It is proposed that during treatment with cM-T412 in autoimmune disease such as rheumatoid arthritis, cM-T412-coated CD4 T cells, when they are subsequently stimulated by the unknown arthritogenic antigen, may undergo apoptotic cell death through cross-linking of cM-T412 on Fey receptor-positive cells within the joint.