The mechanism of IL-2-mediated protection against GVHD in mice. II. Protection occurs independently of NK/LAK cells.

We have recently demonstrated that high-dose IL-2, when begun on the day of bone marrow transplantation, has a potent protective effect against graft-vs.-host disease mortality, especially when coadministered with T cell-depleted syngeneic bone marrow cells. Because several groups of investigators have demonstrated that lymphokine-activated killer cells can mediate GVHD protection, we hypothesized that the mechanism of protection by IL-2 administration might involve the in vivo activation of natural killer and/or LAK cells. In order to test this hypothesis, we evaluated the effect of IL-2 administration on the number of NK1+ cells and on NK-mediated cytotoxic activity in recipients of GVHD-producing inocula. Furthermore, we evaluated the effects on IL-2-induced GVHD protection of depleting NK cells and LAK precursor cells in vivo with mAb against NK1.1 or antiserum against asialo GM1. The results demonstrate that: (1) The number of NK1+ cells is not increased in spleens of IL-2-treated compared with control recipients of GVHD-producing inocula; (2) NK activity is not increased in IL-2-treated compared with control recipients of GVHD-producing inocula during or immediately following the period of IL-2 administration; (3) depletion of NK cells and LAK precursors from the donor and host influenced the time course of GVHD-related mortality in a complex fashion; and (4) IL-2-induced GVHD protection is largely independent of the activity of an NK or LAK cell population of donor or host origin. IL-2-induced GVHD protection therefore reflects primarily the activity of non-LAK protective cell populations, or it may be a direct inhibitory effect on responding donor cell populations as they encounter host antigen.     

Right ventricular-pulmonary arterial interactions

The application of pulsatile models to hemodynamic data has made possible a more complete understanding of the relationship of pulmonary pressure and flow. To review the genesis of these concepts, the unique characteristics of the pulmonary artery and right ventricle are outlined as a basis for understanding why differences in their pulsatile properties from the systemic circuit must exist. The pulmonary impedance spectrum is introduced and the concept of optimal right ventricular-pulmonary artery coupling is explored based on a review of extensive experimental data. Finally, available studies of normal pulmonary impedance in man and abnormal impedance in human disease states are reviewed, with emphasis on disturbances in optimal ventricular-vascular coupling. The important implications of these concepts for understanding and treatment of cardiovascular disease are developed.     

Immunocytochemical demonstration of neural cell adhesion molecule (NCAM) along the migration route of luteinizing hormone-releasing hormone (LHRH) neurons in mice.

Contact between the developing forebrain and the ingrowing central processes of the olfactory, vomeronasal and terminal nerves is preceded by a migration of neural cell adhesion molecule (NCAM)-immunoreactive cells from the epithelium of the olfactory pit and the formation of an NCAM-immunoreactive cellular aggregate in the mesenchyme between the olfactory pit and the forebrain. The axons of the olfactory, vomeronasal, and terminal nerves, also NCAM-immunoreactive, grow into the cellular aggregate, which as development proceeds, becomes continuous with the rostral tip of the forebrain. The lateral and more rostral part of the cellular aggregate receives the ingrowing axons of the olfactory nerves and becomes the olfactory nerve layer of the olfactory bulb. The medial, more caudal part receives the central processes of the vomeronasal and terminal nerves. The vomeronasal nerve ends in the accessory olfactory bulb. The central processes of the terminal nerve end in the medial forebrain. Luteinizing hormone-releasing hormone (LHRH)-immunoreactive neurons, like the vomeronasal and terminal nerves, originate from the medial part of the olfactory pit. These LHRH cells migrate into the brain along and within a scaffolding formed by the NCAM-immunoreactive axons of the vomeronasal and terminal nerves, and they are never seen independent of this NCAM scaffold as they cross the nasal lamina propria. The results suggest that: (1) NCAM is likely to be necessary for scaffold formation, and (2) the scaffold may be essential for the subsequent migration of LHRH neurons into the brain. Because they aggregate, migrating LHRH-immunoreactive neurons, on which we did not detect NCAM immunoreactivity, may interact via other cell adhesion molecules (CAM). Inasmuch as the interaction between the LHRH-immunoreactive neurons and the NCAM-immunoreactive scaffold is heterotypic, the possibility of a heterophilic (NCAM to other CAM) interaction is not ruled out. These findings focus our attention on the functional role of NCAM in this migratory system.     

Inhibition of human adult and fetal heme oxygenase by new synthetic heme analogues

Heme oxygenase (HO) is the rate-limiting enzyme for heme degradation, and elevated levels of HO may be associated with a variety of pathologic disturbances. A limited number of HO inhibitors such as the metalloporphyrins have been proposed as possible chemotherapeutic agents for the treatment of hyperbilirubinemia. We undertook the study of various natural newly synthesized heme analogues as possible inhibitors of HO in human adult and fetal liver microsomes. We investigated two compounds with substitutions at the 2 and 4 position of the porphyrin ring, iron deuteroporphyrin 2,4 disulfonic (1a) and iron deuteroporphyrin 2,4 bis glycol (1b), and two compounds with substitutions of aromatic groups on the methene bridges of the porphyrin molecule, meso-tetra-4-carboxyphenyl-porphine (2a) and meso-tetra-4-sulfonatophenyl-porphine (2b). When these heme analogues were incubated in the reaction media in the presence of heme, two of the analogues (1a) and (1b) inhibited the conversion of heme to bilirubin. This inhibition was 97% and 65% respectively for (1a) and (1b) when both were present in 30 microM concentrations. Both of these compounds exhibited competitive type inhibition. The kI for the more potent inhibitor, (1b), was determined to be 0.30 microM. Porphyrins with aromatic substitutions at the methene bridges (2a, 2b) did not inhibit the conversion of heme to bilirubin, even at relatively high concentrations. Furthermore, the specific activity of HO was significantly greater (5X) in fetal microsomes as contrasted with adult microsomes as contrasted with adult microsomes. Even though fetal microsomes had greater HO activity, 5 microM of compound (1b) caused a similar degree of inhibition in both adult and fetal preparations.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of chronic diuretic therapy on serum, lymphocyte and erythrocyte potassium, magnesium and calcium concentrations

Serum, lymphocyte and erythrocyte potassium, magnesium and calcium concentrations were measured in 31 patients with congestive cardiac failure and 14 patients with mild noncomplicated hypertension, who had been receiving either furosemide or chlorothiazide (with or without potassium supplementation) or a combination of hydrochlorothiazide and amiloride for more than 6 months. Lymphocyte potassium concentrations (pmol/100 cells +/- SE) were as follows: controls 18.1 +/- 1.5, furosemide 14.1 +/- 0.9 (p less than 0.001), furosemide + potassium 12.3 +/- 0.7 (p less than 0.001), chlorothiazide 13.1 +/- 1.0 (p less than 0.001) and hydrochlorothiazide + amiloride 18.6 +/- 0.7 (p = NS). There was a statistically significant relationship between the number of months the patients had been on diuretics and their lymphocyte potassium concentrations. Serum electrolytes, apart from the group receiving chlorothiazide who showed a significant fall in serum K, were unchanged.     

ACCESSORY SOLEUS MUSCLE: A PROBLEM OF AWARENESS

Reports of accessory soleus muscle are rare, perhaps as a result of it often remaining unrecognized. It presents as a swelling behind the ankle and may be mistaken for a tumour or inflammatory lesion, as occurred in the first of a series of three cases. The other two were incidental findings, one in a 30 year old man with an open tibial fracture and the other in a 9 month old child with a club foot. Patients present with either pain or a diagnostic problem. When large, it may make wearing of footwear difficult. Computerized tomography with electromyography enables confirmation of the diagnosis. Pain is relieved by epimysiotomy and when encountered incidentally during surgery, incision of the epimysium is all that is needed. Excision of the muscle may be considered only if wearing of footwear is difficult. The significance of its presence in a case of club foot is unknown. Disinsertion of its insertion was all that was required to obtain surgical correction of the deformity in the present case. Awareness of the condition will prevent unnecessary surgery in asymptomatic cases.     

Are intravenous corticosteroids required in status asthmaticus?

Seventy-seven patients with status asthmaticus were prospectively studied to compare oral with intravenous methylprednisolone. Patients were given methylprednisolone, either 160 or 320 mg orally or 500 or 1000 mg intravenously, daily in equally divided doses. They were randomly assigned to either group on a daily sequential basis. Spirometry was performed within one hour of the initial dose of steroids. The mean presenting forced expiratory volume in 1 s was 26% of the predicted value. Spirometry was then repeated every six hours for the first 24 hours and then every eight to 12 hours until discharge or 72 hours, whichever occurred first. There were no significant differences in the incidence of respiratory failure, forced expiratory volume in 1 s, days of hospitalization, rate of improvement in pulmonary function, or side effects. No patient who went into respiratory failure did so more than three hours after receiving the initial dose of steroids. We conclude that oral methylprednisolone is safe and effective in the treatment of status asthmaticus.