Infusion of diazoxide in severe hypertension during pregnancy.

Eight patients with severe pre-eclampsia or eclampsia were treated with diazoxide. The drug was administered on 3 occasions as a bolus injection (300 mg within 10 sec) and on 8 occasions as an infusion (15 mg/min, total amount 5 mg/kg body weight). The hypotensive effect at 30 and 60 min (stable hypotensive effect) and at 7 h (long-term effect) were the same with both modes of administration. The maximal decrease in blood pressure was reached in 5 min after bolus injection, compared to 25 min with the infusion. If diazoxide is used in severe pre-eclampsia and eclampsia, it should be administered preferably by the infusion method, because this results in a more gradual decline in blood pressure. Furthermore, the administration can easily be interrupted in cases of an exaggerated drop in blood pressure.

Diazoxide infusion in severe hypertension and hypertensive crisis.

Prompted by reports of hypotension with myocardial ischemia after bolus injection, we restudied the efficacy of diazoxide infusion (5 mg/kg, rate, 15 mg/min) in 35 hypertensive patients. In 20 patients with chronic hypertension, mean arterial pressure of 138 mm Hg was 110 (after 30 min) and 121 (after 8 hr). In 15 patients with hypertensive crisis, there was a fall from 159 to 126 (in 30 min) and 133 mm Hg (after 8 hr), similar to findings in 12 patients with hypertensive crisis treated with a 300-mg bolus injection (159, 130, 140 mm Hg). In the latter, the maximal systolic blood pressure decrease was greater (56 mm Hg, reached in 4 min) than in the 15 patients with hypertensive crisis treated by slow infusion (38 mm Hg in 28 min). Thus, infusion of diazoxide causes a gradual decline of blood pressure and is, in contrast to current opinion, also an effective treatment in hypertensive crisis.

Uretero-neo-cystostomy in renal transplantation. Is an antireflux mechanism mandatory?

We report a retrospective analysis of 120 kidney transplantations in which a simple end-to-end ureteric implantation in the bladder without antireflux mechanism was made. From this study no greater incidence of vesico-ureteric reflux could be demonstrated and, even when present, reflux neither interfered with graft function nor caused an increased incidence of recurrent urinary tract infections. The incidence of other urological complications (leakage, obstruction) being equal, this very simple technique yielded in our hands the best results and we recommend its use in kidney transplantation.

Inhibition of frusemide-induced natriuresis by indomethacin in patients with the nephrotic syndrome.

1. In four patients with nephrotic syndrome indomethacin not only reduced proteinuria but also inhibited the natriuretic effect of high doses of frusemide. 2. The inhibition of natriuresis by indomethacin could not be antagonized by albumin infusions. 3. Only the combined use of spironolactone and frusemide induced a natriuresis during indomethacin treatment. Spironolactone alone was ineffective. 4. It is suggested that inhibition of prostaglandin synthesis by indomethacin, in the presence of a stimulated renin-angiotensin system and hyperaldosteronism, may cause this strong tendency to sodium retention.

Juvenile diabetes mellitus, optic atrophy, hearing loss, diabetes insipidus, atonia of the urinary tract and bladder, and other abnormalities (Wolfram syndrome). A review of 88 cases from the literature with personal observations on 3 new patients.

A review of 88 cases from the literature with personal observations on 3 new patients is given of the syndrome featured by juvenile diabetes mellitus, optic atrophy, hearing loss, diabetes insipidus, atonia of the urinary tract and bladder and other abnormalities. The postmortem in one of our cases is mentioned. The pattern of inheritance is autosomal recessive. The interpretation of the data on diabetes insipidus from the literature and in our three patients is also discussed. It can only be stated that neurohypophyseal diabetes insipidus can be a component of the syndrome and that in many cases--particularly in the presence of lesions of the efferent urinary tract--the possibility of nephrogenous diabetes insipidus can not be excluded with certainty. It seems probable that the same mechanism can be held responsible for the lesions of the olfactory, optic, vestibular and cochlear nerves, the hypophyseal form of diabetes insipidus, retarded sexual maturation, abnormal pupillary reaction, myelopathy and the electro-encephalographic, electroneurological and electromyographic changes in the Wolfram syndrome. The process underlying this affection of neural structures remains obscure.

Successful haemodialysis and renal transplantation in a patient with haemophilia A.

A 19-year old male with severe haemophilia A (factor VIII activity less than 1%) developed terminal renal insufficiency and was subsequently dialysed via an external arteriovenous shunt for one year. To prevent bleeding he received cryoprecipitate (2000-2500 units of factor VIII) three times a week during dialysis. After one year of uneventful dialysis he received a kidney graft from a cadaver donor that was matched for the B locus antigens. During the first two weeks after transplantation his factor VIII level was kept at approximately 70% by daily cryoprecipitate infusions. Thereafter he was free from bleeding at a level of 20% with prophylactic cryoprecipitate treatment (1000 units 3 times a week). He was discharged from the hospital five weeks after transplantation with excellent renal function (ECC 75 ml/min). No rejection crisis occurred. His factor VIII requirements remained unchanged after transplantation, indicating that the human kidney does not substantially contribute to the production of clotpromoting factor VIII.

Hyperacute rejection of skin allografts in the mouse. Sensitivity of ingrowing skin grafts to the action of alloantibody and rabbit complement.

The destructive action of alloantiserum and exogenous complement on ingrowing skin allografts was studied. B6AF1 recipients of a B10.D2 skin graft received a single intravenous injection of B6AF1 anti-B10.D2 serum (antiserum to H-2K.31) together with rabbit complement (RC) within the first 10 days after transplantation. Different models were used: recipients without immunosuppression, recipients treated with antilymphocyte serum, x-irradiation, or enhancing antibody. If the injection was given between day 5 and 10 after grafting, hyperacute rejection occurred in all cases. The rejection seemed to be most violent when the injection was given on days 7 or 8. Injections given on days 1, 2 or 3 after grafting could not induce hyperacute-rejection, but resulted, on the contrary, in a prolongation of graft survival, probably due to immunological enhancement. Injections on day 4 produced patchy necrosis, but the grafts recovered and the residual tissue showed a prolonged survival. The results suggest that the presence of a functioning vascular network is a prerequisite for the occurrence of hyperacute rejection of skin allografts in the mouse.

Enhancement of skin grafts in the mouse. The combined used of specific and nonspecific immunosuppression.

Enhancement of skin grafts in mice by passively administered alloantiserum was examined in conjunction with the simultaneous use of other immunosuppressive regimens. It could be clearly shown that when a "weak" antilymphocyte serum (ALS) was used, a significant further prolongation of graft survival occurred over that obtained with the enhancing antiserum alone, and these two separate effects were synergistic. When a "strong" ALS was used, no synergistic effects were apparent unless the enhancing alloantiserum was given almost continuously. A similar, but less impressive synergism was seen when the enhancing alloantiserum and azathioprine were used together. Azathioprine, like ALS, presumably acts on T cells, whereas drugs directed against B cells, such as cyclophosphamide and prednisolone, failed to show any synergistic effect.

Isolation of pure IgG subclasses from mouse alloantiserum and their activity in enhancement and hyperacute rejection of skin allografts.

B6AF1 anti-B10.D2 ascites fluid was fractionated by molecular sieving. From the 7S fraction, IgG subclasses were isolated by affinity chromatography with specific antisera against mouse immunoglobulin subclasses coupled to CNRr-activated Sepharose 4B. Thus, 7S IgG1, 7S IgG2, 7S IgG2a, and 7S IgG2b were obtained which were completely pure by criteria of immunodiffusion and immunoelectrophoresis. In the in vitro tests the 7S IgG1 completely lacked cytotoxic activity. All the other subclasses were able to induce lysis of B10.D2 cells in the presence of rabbit complement. All subclasses were tested for their capacity to induce enhancement and hyperacute destruction of B10.DI skin grafts in B6AF1 recipient mice, and for the dose-dependency of these effects. 7S IgG1, although showing clearcut enhancing activity, was completely inactive in inducing hyperacute destruction of the grafts, even if high doses were administered. By contrast, 7S IgG2 (IgG2a as well as IgG2b) was not only able to induce enhancement but also hyperacute destruction of the frafts. The results obtained with 7S IgG2 demonstrate that opposite biologic activities can be present within a single subclass.

Hyperacute rejection and enhancement of mouse skin grafts by antibodies with a distinct specificity.

Pure 7S IgG2 was prepared from B6AF1 anti-B10.D2 ascites fluid by affinity chromatography. This preparation was extensively absorbed with B10.D2 red blood cells to remove the antibodies directed against the serologically defined antigens of the major histocompatibility complex. After absorption the serum had retained in vitro cytotoxic activity against 45 percent of B10.D2 spleen cells. The absorbed and unabsorbed 7S IgG2 antibodies were tested for their capacity to induce enhancement and, in the presence of rabbit complement, hyperacute rejection of B10.D2 skin grafts in B6AF1 recipient mice. The enhancing capacity of 7S IgG2 was completely unimpaired after absorption. However, the absorbed preparation was unable to induce hyperacute rejection of the grafts even if very high doses were administered. The results show that hyperacute rejection of skin grafts in this model is mediated by antibodies directed against the serologically defined antigens (i.e., H-2K antigens) of the H-2 complex. They further support the hypothesis that immunologic enhancement is mediated by antibodies directed against Ir-region-as-sociated antigens.

Ehancement and hyperacute rejection of skin grafts in the mousefailure to separate cytotoxic and enhancing antibodies from alloantiserum with physicochemical methods.

B6AF1 anti-B10.D2 ascites fluid was fractionated by molecular sieving and cation exchange chromatography in an attempt to separate cytoxic and enhancing antibodies. Five fractions were obtained which showed no overlap on analysis with isoelectric focusing. Despite this complete physicochemial separation all fractions contained detectable amounts of 7S IgG1 and 7S IgG2. Furthermore, exhancement of B10.D2 skin grafts in B6AF1 recipients could be induced with all the fractions. Cytotoxic activity was also present in the fractions. This was not only shown in vitro by the cytolysis of B10.02 lymphoid cells in the presence of rabbit complement, but also by the ability of the different fractions to induce hyperacute destruction of B10.02 skin grafted onto B6AF1 mice after i.v. injection together with rabbit complement. Thus, we were unable to separate the alloantiserum in cytotoxic and enhancing fractions by physicochemical means.