The warm knee sign--an evaluation

The presence of an area of warmth at the knee has been described in cases of arterial occlusion at the popliteal fossa. A study was carried out to evaluate the significance of this sign by comparing clinical and thermographic findings with arteriographic results in a group of 30 patients. The clinical and thermographic findings were described with reference to the symptomatic limb. Clinically, 14/30 (47%) and thermographically, 16/30 (53%) had "positive" warm knee signs. The overall agreement between clinical impressions and thermographic findings was 28/30 (93%). The commonest arteriographic finding in patients with a positive warm knee sign was that the occlusion or stenosis ended at the adductor hiatus. Comparing this arteriographic finding with a positive warm knee sign, sensitivity, specificity, positive and negative predictive values of 73%, 75%, 79% and 69% respectively were obtained suggesting that this is a useful sign, is of proven value and deserves its place in the initial screening of patients with peripheral vascular disease.     

Serological identification of thymocyte differentiation antigens

We have examined subfractions of human thymocytes for the expression of novel differentiation antigens. Non-HLA alloantisera procured from multiparous women served as antibody probes. Thymocytes from five individuals were sequentially separated by discontinuous Percoll density gradient centrifugation and a peanut agglutinin (PNA) panning technique. Subfractions were selected and examined for their relative intensity of HLA class I and CD1 antigens as determined by cytofluorometric analysis. Two subfractions were characterized as follows: an immature population (Fr6 PNA-) expressed a high level of CD1 (OKT6 binding) antigen and a low level of class I HLA antigen; and a more mature fraction (Fr3 PNA-) expressed minimal amounts of CD1 antigen and relatively high levels of HLA class I molecules. Fr6 PNA+ and Fr3 PNA- thymocytes were tested for their reactivity with a panel of non-HLA alloantibodies as determined by cytofluorometric analysis. We observed that three alloantibodies demonstrated strong fluorescence staining with Fr6 PNA+ thymocytes only, whereas three other alloantibodies reacted with both the Fr6 PNA+ and the Fr3 PNA- subfractions. All six alloantibodies failed to react with peripheral T cells. However, the six antibodies did react with a panel of cultured T lymphoblastoid leukemic cells and fresh leukemic T cells. Blocking studies demonstrated that these alloantibodies do not bind beta 2-microglobulin-associated determinants. These results suggest that the alloantibodies detect thymocyte differentiation antigens (TDA) that are shared by or are cross-reactive with antigens expressed on certain leukemia T cells. The non-beta 2m-associated TDA antigens are not expressed on normal resting T cells.     

Enterohepatic circulation of nonconjugated bilirubin in rats fed with human milk

To test the hypothesis that enhanced intestinal absorption of bilirubin may contribute to prolonged nonconjugated hyperbilirubinemia in human milk-fed infants, we studied a cross-section of 36 healthy infants and mothers. Milk from mothers and serum from infants were collected at 16.3 +/- 2.4 days. Milk was studied for its effect on the absorption of bilirubin labeled with carbon 14 in rats and compared with buffer and iron-fortified infant formula (Similac With Iron). The percentage of a 1 mg bilirubin dose absorbed by the rat was 25.29 +/- 4.0% when it was administered into the duodenum with buffer, 4.67 +/- 2.4% with Similac formula, and 7.7 +/- 2.9% with human milk. Linear regression analysis, using the infant's serum nonconjugated bilirubin level as the dependent variable and the percentage of (14C)bilirubin absorbed by the rat with the corresponding mother's milk as the independent variable, revealed a significant correlation (r = 0.40; p = 0.016). Inspection of the data suggested that absorptive permissiveness correlated closely with infant serum bilirubin values greater than 24 mumol/L (1.4 mg/dl) (r = 0.55; p = 0.007), whereas in those with bilirubin values less than or equal to 24 mumol/L, there was no apparent correlation. Milk was also analyzed for beta-glucuronidase, nonesterified fatty acids, and the ability to inhibit glucuronosyltransferase activity of rat liver microsomes in vitro, none of which correlated with the infant's serum bilirubin. These data support the theory that enhanced intestinal absorption of bilirubin contributes to the jaundice associated with breast-feeding.     

Is phenytoin contraindicated in patients receiving cranial irradiation ?

Three recent publications have reported the development of erythema multiforme and Stevens-Johnson syndrome in patients receiving cranial irradiation and sodium phenytoin. Some authors have recommended that patients receiving whole brain radiation therapy and who have had seizures should not be prescribed phenytoin but an alternative anticonvulsant. This article reviews the current literature pertaining to the development of this potentially lethal complication in patients receiving whole brain radiation and phenytoin, with reference to the single recorded case of Stevens-Johnson syndrome in a patient receiving cranial irradiation and phenytoin in Auckland, New Zealand. While the clinical picture in the 16 patients reported in the literature and the current case report differed from the classical form of erythema multiforme, a similar pattern of presentation and outcome appeared in all patients reviewed, suggesting that the combination of phenytoin, cranial irradiation and the gradual reduction of concomitant steroids seem to lead to the development of erythema multiforme and/or Stevens-Johnson syndrome. The data presented, although sparse, suggest that phenytoin should not be prescribed in patients receiving cranial irradiation.     

Intestinal permeability in the newborn

Passive intestinal permeability in 33 newborn babies was studied using feeds containing lactulose and mannitol. Each marker is thought to pass across the gut wall by a different route; lactulose by a paracellular and mannitol by a transcellular pathway. Neither is metabolised and both are wholly and solely excreted by the kidney; urinary recovery is a measure of the intestinal uptake. Babies born before 34 weeks' gestation exhibited a higher intestinal permeability to lactulose than more mature babies, and all preterm babies showed an appreciable decline in lactulose absorption during the first week of oral feeds. Babies of 34 to 37 weeks' gestation achieved a 'mature' intestinal permeability to lactulose within four days of starting oral feeds. These findings may reflect the immaturity of the gut of the preterm baby rather than a process essential to adaptation to enteral nutrition.     

Soluble adhesion molecules (E-selectin,ICAM-1 and VCAM-1) in breast carcinoma

Adhesion molecules are important in cell-cell and cell-basement membrane interactions. They are intimately involved in inflammatory reactions and a role in tumour progression has been postulated. E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) play a role in cell adhesion to the vascular endothelium, and may have a role in tumour cell dissemination. Soluble forms of these molecules have been described and this study was established to examine these adhesion molecules in patients with breast carcinoma. Serum was obtained from 92 patients with breast carcinoma and 31 age-matched patients with benign breast disease. All samples were obtained prior to surgery. Soluble levels of E-selectin, ICAM-1, and VCAM-1 were significantly elevated in patients with Stage 4 disease compared with controls. (E-selectin 88.6 (47.9) versus 51.4 (18.4) ng/ml; P<0.001: ICAM-1 447 (249) versus 244 (79) ng/ml; P<0.001: VCAM-1 779 (159) versus 552 (135) ng/ml; P<0.001 results expressed on mean (SEM) SD placed above this.). The prognostic value of the adhesion molecules was examined. In patients with Stage 2 disease, elevated VCAM-1 was predictive of decreased survival, even when corrected for T and N status. Adhesion molecules are elevated in patients with advanced disease and elevation in VCAM-1 has prognostic significance in patients with breast carcinoma.     

Ki-ras mutations are an early event and correlate with tumor stage in transplacentally-induced murine lung tumors

A previous study from this laboratory demonstrated that treatment of pregnant mice with 3-methylcholanthrene (MC) caused lung tumors in the offspring at 1 year after birth, the incidence of which correlated with fetal inducibility of Cyp1a1. Analysis by PCR amplification and allele- specific hybridization (ASO) of paraffin-embedded tumors generated from that study revealed the presence of point mutations in exon 1 of the Ki- ras gene. This work has now been expanded by PCR amplification and ASO analysis of 31 additional lesions. Point mutations were found in 37 of the 47 (79%) lesions analyzed in this and the previous study, the majority of which were G-->T transversions in the first or second base of codon 12. The mutational spectrum appeared to be dependent on the relative stage of differentiation of the lesion, as both the incidence of mutation and type of mutation produced correlated with malignant progression. Mutations occurred in 60% of the hyperplasias, 80% of the adenomas and 100% of the adenocarcinomas. In the lesions with mutations, GLY12-->CYS12 transversions occurred in 100% of the hyperplasias, 42% of the adenomas and 14% of the adenocarcinomas. The GLY12-->VAL12 transversions occurred in none of the hyperplasias, 42% of the adenomas and 57% of the adenocarcinomas. The remaining mutations, which consisted of ASP12 transitions and ARG13 transversions, occurred only in adenomas (17%) and adenocarcinomas (29%). Between this study and our previous analyses, the identity of the mutations obtained by ASO were confirmed by sequence analysis of eight of the 37 lesions that harbored mutations at the Ki-ras gene locus. There were no differences in the type or incidence of mutations relative to the metabolic phenotype or sex of the mice. These data suggest that mutational activation of the Ki-ras gene locus is an early event in transplacental lung tumorigenesis, and that the type of mutations produced by exposure to chemical carcinogens can influence the carcinogenic potential of the tumor. This may have prognostic significance in determining the malignant progression of the neoplasm.