Folic acid lowers elevated plasma homocysteine in chronic renal insufficiency: possible implications for prevention of vascular disease.

To explore interrelations between folic acid and methionine metabolism in chronic renal insufficiency, we measured plasma amino acids in 21 patients with mean serum creatinine +/- SD of 560 +/- 240 mumol/L, after a ten-hour overnight fast, before and after administration of 5 mg of oral folic acid daily for 15 +/- 6 days. Mean plasma homocysteine was 12.9 +/- 6.8 mumol/L in the patients and 4.2 +/- 0.8 mumol/L in 24 normal controls (P less than .001), and after folic acid administration it declined in the patients to 6.8 +/- 2.8 mumol/L (P less than .0001) in linear proportion (r = .92) to the prefolate homocysteine level. Methionine concentrations were normal in the patients and did not change after folate administration, nor did elevated cysteine and creatinine. Plasma serine was lower (88.3 +/- 17.2 v 121 +/- 25 mumol/L, P less than .41) and declined further to 67.8 +/- 16.4 (P less than .0001) after folate, while prefolate glycine levels increased from 273.3 +/- 61.2 to 313.2 +/- 97.5 mumol/L (P less than .01). Serum and red-cell folate levels were normal in the patients before treatment. The results show that homocysteine levels are increased in chronic renal insufficiency, but may be lowered by folate enhancement of remethylation of homocysteine to methionine. Since elevated plasma homocysteine is associated with premature vascular disease, folic acid may reduce cardiovascular risk in chronic renal insufficiency.

Endotoxaemia, fever and clinical status in immunosuppressed patients: a preliminary study.

A prospective study was performed in order to find out whether endotoxaemia assays are clinically relevant in neutropenic patients. In a group of 10 immunocompromised patients, serial haematological, bacteriological and clinical investigations were done in parallel with serial plasma endotoxin assays. The chromogenic modification of the Limulus amoebocyte lysate (LAL) assay for endotoxin used in this study had a sensitivity of less than 10 pg endotoxin per ml plasma. It was found that endotoxaemia was associated with Gram-negative bacteraemia but infection with Gram-negative bacteria did not always produce endotoxaemia. Furthermore, infections with Gram-positive bacteria and administration of blood products may lead to raised endotoxin values. Endotoxin assays may be of value for elucidating mechanisms of fever in immunocompromised patients but it seems unlikely that routine assays of endotoxin will help in the clinical management of these patients.

Right vocal cord paralysis after internal jugular vein cannulation.

Neurological complications are rare after central venous cannulation. We report a case of right vocal cord paralysis after internal jugular vein cannulation. The mechanism of neural injury is discussed.

Skin cancer and immunosuppression.

7 (14%) out of 51 kidney-allograft recipients developed a total of 19 malignant skin tumours four to forty-five months after transplantation. Immunosuppressive treatment, known to be associated with an increased risk of development of tumours of lymphoreticular type, also enhances the occurrence of squamous-cell carcinoma. Under the influence of immunosuppression cutaneous hyperkeratoses more rapidly evolve into squamous-cell carcinoma, multiple skin cancers occur in some patients, and keratoacanthoma is not only more frequent but also prone to early recurrence.

The complement system in infectious mononucleosis.

The complement system was investigated in 34 patients with infectious mononucleosis. Three had specific complications: one haemolytic anaemia, one severe arthralgia/myalgia and one proliferative glomerulonephritis. Complement changes consistent with classical pathway consumption were seen in ten of the uncomplicated group and the patients with haemolytic anaemia and arthralgia/myalgia. The patient with glomerulonephritis showed evidence of alternative pathway utilisation including C3 splitting activity and the deposition of properdin on renal biopsy. The complement findings suggest that circulating immune complexes are common in such patients and are likely to play a role in the pathogenesis of the complications. It is proposed that both complement pathways may be required for the effective clearance of viral material from the circulation.

Idiopathic retroperitoneal fibrosis presenting with back pain.

We describe 2 cases of idiopathic retroperitoneal fibrosis presenting with back pain. Additional features included weight loss, constitutional symptoms and elevated erythrocyte sedimentation rate (ESR). One patient had sacroiliitis and was HLA-B27 positive. A further finding was obstruction of the superior mesenteric artery which has not been previously described in retroperitoneal fibrosis. The importance of considering idiopathic retroperitoneal fibrosis in the differential diagnosis of back pain has not been emphasized in the rheumatological literature.

Immunoglobulin E in renal disease.

Samples of renal tissue from 373 patients were examined for the presence of immunoglobulin E (IgE) by immunofluorescent techniques. Only trace to ++ amounts ( on a scale of ++++) were found in 20 patients: 4/9 with post-streptococcal acute glomerulonephritis (GN), 5/30 with GN associated with systemic lupus erythematosus, 3/20 with membranous GN, 1/4 with Goodpasture's syndrome, 2/18 with recurrent microhematuria and focal GN, 1/5 with hemolytic anemia and uremia, 3/73 with renal homografts, and 1/5 with dermatomyositis. No IgE was found in 18 patients with lipoid nephrosis, 8 of whom were being treated with prednisone, nor in 5 patients with focal glomerular sclerosis and the nephrotic syndrome. Serum IgE was measured in 9 of the 20 patients with glomerular deposits of this globulin. With one exception, levels of IgE were within the range generally considered to be normal. However, they were greater than the mean of this range in all but two and near the highest limits of normal in most. Neither the amounts of serum IgE nor the degree of proteinuria could be related to the intensity of stain for IgE in the glomeruli of these patients.

Measles infection. Involvement of the complement system.

The complement system was examined in fifty patients with acute, apparently uncomplicated measles; forty-six were children less than 10 years old. Twenty showed evidence of pathological complement activation. In thirteen of these the pattern was consistent with activation of the classical pathway while in the other seven data suggested utilization of an alternative pathway. An additional eleven patients had isolated reduction in Clq without alteration in concentration of other components; these were excluded from the classical pathway group. No patient had detectable immune complexes or C3 splitting activity in serum; however, it is suggested that the abnormal complement patterns observed are likely to indicate the presence of circulating immune complexes in a high percentage of patients with this infection.

Impairment of acute protein reactivity in chronic renal failure.

The acute phase protein response was studied after elective surgery in 13 normal subjects and 9 patients with severe chronic renal failure. Total haemolytic complement reactivity (CH50) and serum concentrations of C1q, C1s, C4, C3, factor B, properdin, C5, C9, C-reactive protein (CRP), caeruloplasmin, alpha1-acid glycoprotein and haptoglobin were measured preoperatively and on days 2, 4 and 6 after operation. Abnormalities were seen in the group with chronic renal failure. Firstly, there was no significant acute phase response of C1s, C3, C5, C9 and CH50 and a significant reduction in the response of factor B. Secondly, CRP showed prolonged elevation in the post-operative period in contrast to the transient rise seen in the control group. With the possible exception of alpha1-acid glycoprotein, the behaviour of the non-complement proteins (caeruloplasmin and haptoglobin) was comparable for the two groups. These defects could impair the physiological response to infection in patients with severe chronic renal failure.

Angiography in the diagnosis of renal allograft dysfunction.

We reviewed retrospectively 75 renal transplant arteriograms done during a 7-year period. Acute rejection and vasomotor nephropathy were not differentiated. Generalized cortical ischemia was diagnosed correctly in 23 of 30 cases but there were 7 falsely negative results. Renal artery stenosis was found in 7 of 17 cases in which the main indication for arteriography was hypertension. We conclude that the major role of transplant arteriography is in the diagnosis of larger vessel disease.

Cyclical neutropenia and T8 lymphocyte mediated stimulation of granulopoiesis.

A 33-year-old female with cyclical neutropenia and a reciprocally cycling T8 (suppressor/cytotoxic) lymphocytosis was investigated. T8 lymphocytes ranged between 1.4 and 5.6 X 10(9)/l and a significant proportion (50-75%) were preactivated (1a+). Fc gamma receptors were detected in only a minority (7-10%). Functional studies on the lymphocytes indicated that despite their phenotype, little natural killer and reduced suppressor activities were present. Anti-granulocyte antibodies were not detectable in the serum. Production of colony stimulating activity (CSA) was assessed in the patient and control subjects' lymphocytes. Using a methylcellulose marrow culture system, the CSA production by the patient's lymphocytes was markedly increased compared with the control. Monoclonal antibody cytotoxic experiments confirmed that the T8 lymphocytes were responsible. As peaks of circulating T8 lymphocytes were synchronous with granulopoietic activity in the marrow, the above findings may represent a homeostatic mechanism which is attempting to compensate for an underlying stem cell defect.

A new approach to the classification of human leukaemias: measurement of the relative abundance of a specific RNA sequence by means of molecular hybridisation.

A recombinant plasmid library representing polyadenylated RNAs in the leucocytes of a Ph1-positive chronic granulocytic leukaemia (CGL) has been constructed. One recombinant (designated pCG14) isolated from this library contains a DNA sequence complementary to a small polyadenylated RNA that is abundant in RNA from CGL leucocytes. The relative concentrations of pCG14 RNA in the RNAs from a variety of normal and leukaemic leucocytes and human haemopoietic cell lines have been measured with a molecular hybridisation assay. This has shown that pCG14 RNA is 10 to 50 times more abundant in RNA from CGL leucocytes than in the RNAs from these other cells. The data indicate that the occurrence of pCG14 RNA in high abundance is sufficiently characteristic of a CGL leucocyte population to distinguish it from other populations of leucocytes. They suggest that the measurement of the concentrations of specific RNA species in leucocyte RNA by means of molecular hybridisation with cloned complementary DNAs may provide additional markers for the objective classification of human leukaemias which could be particularly useful since the method exploits a criterion different from any currently in use.