The role of cell-mediated cytotoxicity in acute GVHD after MHC-matched allogeneic bone marrow transplantation in mice.

The role of cell-mediated cytotoxicity in the complex pathophysiology of graft-versus-host disease (GVHD) has remained poorly defined for several decades. We transplanted T cells from Fas-ligand (FasL)-defective and perforin-deficient mutant donor mice into lethally irradiated MHC-matched allogeneic recipient mice to characterize the role of cell-mediated cytotoxicity in GVHD. Although recipients of allogeneic FasL-defective donor T cells underwent severe GVHD-associated cachexia, they exhibited only minimal signs of hepatic and cutaneous GVHD pathology. Recipients of perforin-deficient allogeneic donor T cells developed signs of acute GVHD, but the time of onset was significantly delayed. These findings demonstrate that Fas-mediated anti-recipient cytotoxicity may be critical for the development of hepatic and cutaneous GVHD, but is not required for GVHD-associated cachexia. In addition, perforin-mediated anti-recipient cytotoxicity appears to play an important role in the kinetics of GVHD pathophysiology, but is not required for GVHD-associated tissue damage.

The effect of cupric acetate on ethionine metabolism.

The addition of cupric acetate, a potent inhibitor of ethionine carcinogenesis, to a diet containing ethionine increased the ethionine toxicity. The concentration of S-adenosylethionine in liver was found to be significantly higher when compared to animals fed only ethionine in the diet. Ethionine forms a complex(es) with cupric acetate that is insoluble at a pH higher than 4; however, this complex can be solubilized at a low pH. Ethionine, if administered p.o. in the form of this complex, was absorbed from the intestinal lumen in the same order of magnitude as when administered alone; however, as the body weight increased over 200 g, the portion of absorbed ethionine decreased. The absorption of ethionine bound in the complex was completed within 16 hr compared to 2 hr for free ethionine. This time delay was accompanied by a shift in the concentration maximum of ethionine metabolities in the liver form 8 to 24 hr. When ethionine was administered alone, it was metabolized in the intestinal lumen as demonstrated by the analysis of the soluble intestinal contents; the presence of cupric acetate inhibited this process. The chromatographic analysis of ethionine metabolites in urine of rats treated by the complex revealed an increased excretion of ethionine sulfoxide and other ethionine metabolities at the expense of N-acetylethionine sulfoxide. The increased concentration of S-adenosylethionine in the liver in chronic experiments may be, at least partly, a result of a diminished capacity of the rat to detoxify (acetylate) ethionine sulfoxide, which is considered the main reserve pool of ethionine for the maintenance of a high level of S-adenosylethionine.

The influence of DL-methionine on the metabolism of S-adenosylethionine in rats chronically treated with DL-ethionine.

The concentration of S-adenosylethionine in the liver of ethionine-fed rats was increased gradually during the process of carcinogenesis. This increase may have been due to the decreased capacity of the treated rats to acetylate ethionine sulfoxide. Ethionine sulfoxide is considered as the main reserve pool of ethionine for the synthesis of S-adenosylethionine. When the ethionine diet was supplemented by DL-methionine (0.3 to 0.9%), the increase in the concentration of S-adenosylethionine during the period of observation (28 to 150 days) was lower and the acetylation of ethionine sulfoxide was significantly higher. The concentration of the total S-adenosyl compounds in the liver of rats on a diet supplemented with DL-methionine was increased over the concentration of S-adenosylethionine in rats fed ethionine alone, and the S-adenosylethionine portion of this fraction was only about 30% lower. The supplementation of the diet with methionine restored the diurnal oscillation of adenosine 5'-triphosphate in the liver, which had been absent in rats ingesting only ethionine.

Failure of pure 1-naphthylamine to induce bladder tumors in dogs.

1-Naphthylamine was administered p.o. to beagles for approximately 9 years at a daily dose of 15 mg/kg (5 days a week). At autopsy, no tumors or other pathological changes were observed in the bladders of any of these animals. With the possible exception of the excessive accumulation of lipofuscin in the hepatocytes of these dogs, no test compound-related pathological changes in other tissues of the body were observed. Analysis of the urine revealed the presence of small amounts of N-oxidation products (1-nitrosonaphthalene plus N-hydroxy-1-naphthylamine), ranging from 2.85 to 125 microgram, following a dose of 1-naphthylamine. The theoretical significance of these findings is discussed.

Prostate cancer progression, metastasis, and gene expression in transgenic mice.

We previously reported that a transgenic mouse line containing the fetal globin promoter linked to the SV40 T antigen (T Ag) viral oncogene (Ggamma/T-15) resulted in prostate tumors. In this study, we further explored tumor origin, frequency, invasiveness, androgen sensitivity, and gene expression pattern. T Ag was detected in adult but not fetal and neonatal prostates, suggesting a role for androgens in tumor progression. However, castration shortly after prostate morphogenesis did not prevent tumor development, suggesting an androgen-independent phenotype. Tumors originated within ventral or dorsal prostate lobes and involved intraepithelial neoplasia, rapid growth in the pelvic region, and metastasis to lymph nodes and distant sites. In addition, the primary cancers could be propagated in nude mice or nontransgenic mice. Seventy-five percent of hemizygous and 100% of homozygous transgenic males developed prostate tumors, suggesting a T Ag dosage effect. Biochemical characterization of advanced tumors revealed markers of both neuroendocrine and epithelial phenotypes; markers of terminal differentiation are lost early in tumorigenesis. Tumor suppressor genes (p53 and Rb), normally bound to T Ag, were up-regulated; bcl-2 proto-oncogene, which prevents apoptosis, was slightly up-regulated. Myc, a stimulus to cell cycle progression, was unchanged. We propose the Ggamma/T-15 transgenic line as a model of highly aggressive androgen-independent metastatic prostate carcinoma with features similar to end-stage prostate cancer in humans.

Growth hormone responses to hypoglycemia in postmenopausal depressed women.

Human growth hormone (HGH) responses to insulin-induced hypoglycemia were measured in ten postmenopausal women suffering from primary unipolar depressive illness, and in ten age-matched normal postmenopausal women. The mean maximal HGH response in the depressed patients was 4.6 plus or minus 4.4 ng/ml, and in the normals 13.3 plus or minus 9.8 ng/ml (P less than .05). All of the normal subjects had clinically adequate HGH responses, in contrast to only four of the depressed patients (P less than .01). The blood glucose responses were virtually the same in the two groups. Since brain catecholamines play a major role in mediating HGH responses to hypoglycemia, the findings are consistent with the hypothesis of diminished functional catecholaminergic activity in the depressed patients.

Prolactin responses to neuroleptics in normal and schizophrenic subjects.

The prolactin response to neuroleptics can serve as an index of dopamine blockade in humans. Plasma prolactin increments to single doses of chlorpromazine, and prolactin decrements to single doses of levodopa, were similar in normal and schizophrenic subjects. Antischizophrenic drugs of all chemical classes stimulated prolactin release,while chemically related drugs and other psychotropic agents ineffective in schizophrenia did not. The prolactin response to neuroleptic therapy occurred in all patients, and tolerance did not develop. Within subjects, prolactin responses were graded according to neuroleptic dose, but the upper limit of sensitivity of the response curve was achieved at doses below the therapeutic range. Relative prolactin-stimulating potency in humans of chlorpromazine, thioridazine, trifluoperazine, butaperazine, and haloperidol correlated well with their relative clinical potencies.

Thioridazine stimulates prolactin secretion in man.

Thioridazine, unlike most other effective antipsychotic drugs, appears to be only a weak dopamine antagonist in various regions of the brain. We decided to test, indirectly, thioridazine's effects on another brain dopaminergic system, the tuberoinfundibular tract, which regulates prolactin secretion by stimulating hypothalamic secretion of prolactin-inhibiting factor. Chlorpromazine and several other phenothiazines have been shown to stimulate prolactin secretion. Five healthy men ingested 50 mg of chlorpromazine concentrate on one occasion, and 50 mg of thioridazine concentrate on another. Both drugs noticeably stimulated prolactin secretion within two hours. It is concluded that thioridazine is a potent dopamine antagonist in the tuberoinfundibular system, and it is suggested that this system's regulation of prolactin secretion may provide a useful method for studying antipsychotic drug effects in man.

Human growth hormone response to levodopa. Relation to menopause, depression, and plasma dopa concentration.

After ingestion of 500 mg of levodopa, postmenopausal women had significantly diminished human growth hormone (HGH) responses (mean, 4.6 ng/ml), as compared with those of age-matched men (mean, 9.1 ng/ml; P smaller than .05). The differences between the groups were not related to plasma dopa concentrations. The HGH responses to levodopa of age-matched unipolar and bipolar depressed men, and of unipolar depressed postmenopausal women, did not differ significantly from their respective normal control groups. Depressive illness of these types does not appear to affect the HGH response to levodopa, once the effect of the menopause is taken into account.

Relation of plasma prolactin to clinical response in schizophrenic patients.

It has been suggested that, if dopamine antagonism is a necessary condition for the antischizophrenic action of neuroleptics, the prolactin response, as an index of dopamine blockade, would correlate with clinical response. Morning prolactin and clinical symptomatology were measured in 15 schizophrenic patients before neuroleptic therapy, and after three and six weeks of high-dose butaperazine or loxapine treatment. Prolactin levels were transiently elevated during the unmedicated admission period, probably reflecting a normal stress response. Prolactin increased in all patients during neuroleptic therapy. There was, however, no correlation between magnitude of prolactin changes and clinical response, probably because the prolactin response achieved a maximum at relatively low doses of neuroleptics.

Evolution of acute hepatitis B in homosexual men to chronic hepatitis B. Prospective study of placebo recipients in a hepatitis B vaccine trial.

To determine whether the frequency of chronic hepatitis B in homosexual men reflects the high rate of acute hepatitis B or an altered response to hepatitis B, 236 homosexual men were prospectively followed up after entry into the placebo group of a hepatitis B vaccine trial. Sixty-six participants (28.0%) developed hepatitis B ten to 18 months after entering the study. Only four (6.1%) of the 66 had persistence of hepatitis B beyond six months, similar to reports in nonhomosexual subjects. This study suggests that the high rate of acute hepatitis B is the major factor contributing to the high prevalence of chronic hepatitis B in homosexual men, rather than an altered host response. Clinical features of the acute illness could not be used to identify patients who developed chronic hepatitis B.

Sexual behavior before AIDS: the hepatitis B studies of homosexual and bisexual men.

Data on sexual practices, collected during studies of hepatitis B virus (HBV) infection in 1978 and 1979, were analyzed for 4910 homosexual and bisexual men from Chicago, Denver, Los Angeles, San Francisco, and St Louis. Data on sexual practices in 1978 showed that white participants had larger numbers of non-steady male sexual partners and engaged in oral-genital activities more frequently but were equally likely to engage in anal intercourse as black and Hispanic participants. San Francisco participants had more non-steady sex partners and were more likely to engage in receptive anal intercourse with non-steady partners than participants from all other sites. Analysis of data on 606 HBV-antibody-negative men interviewed on three occasions in 1978 and 1979 showed no changes in risk indices for insertive and receptive anal intercourse between these years, except in San Francisco where significant declines occurred in insertive anal intercourse and receptive anal intercourse without ejacultion in a small, highly select group of participants.

Cerebral aneurysmal arteriopathy in childhood AIDS.

OBJECTIVE: To identify cerebral aneurysmal arteriopathy in children with longstanding AIDS. BACKGROUND: Five cases are described from the authors' experience, and eight additional cases are reviewed from the literature. Details are presented in regard to the clinical picture as well as brain imaging with cerebral angiography and magnetic resonance angiography in some cases. Autopsy information is available in four cases, including one of the authors' patients. RESULTS: Seven patients acquired HIV infection perinatally, five patients were infected by blood transfusions, and one patient had both risk factors. In the four postmortem patients, the vascular pathology was similar, showing ectasia and aneurysmal dilatation confined to the large arteries of the circle of Willis. Medial fibrosis and loss of muscularis with destruction of the internal elastic lamina and intimal hyperplasia was common. The latency period following infection varied from 2 to 11 years. Once a diagnosis of aneurysmal arteriopathy was made, the patients deteriorated rapidly, with death occurring in less than 6 months. CONCLUSIONS: The development of cerebral aneurysmal arteriopathy in childhood AIDS tends to occur after a prolonged delay and is usually followed by death in a short period of time. The etiology for the vasculitis is unknown. Varicella zoster virus may be the etiology in some of the cases because of its potential to cause this pathology and the striking unilateral arterial involvement found in Case 5. HIV vasculitis is also a possibility, as suggested by the detection of HIV protein or genomic material in two of the four autopsy cases.

Topical fluorouracil. II. Postoperative administration in an animal model of glaucoma filtering surgery.

Unilateral posterior lip sclerectomies were performed in ten owl monkeys. Five milligrams of fluorouracil was injected subconjunctivally in each operated eye immediately after surgery. Three drops (approximately 2.4 mg/drop) of fluorouracil were instilled ten minutes apart in each operated eye twice daily on postoperative days 1 through 7 and once daily on postoperative days 8 through 15, 17, 19, and 21. One monkey died on the seventh postoperative day; its death could not be attributed to systemic fluorouracil toxicity. All of the operated eyes had filtering blebs after the full course of fluorouracil, but seven also had corneal epithelial defects. By the seventh postoperative week, two of the operated eyes manifested moderately severe corneal opacification. Ten weeks postoperatively, the electroretinographic a- and b-wave amplitudes averaged 17% and 12% less, respectively, in the seven operated eyes without clinically significant corneal opacification than in the unoperated fellow eyes. Only two eyes had blebs after the 12th postoperative week. Histopathologic examination was performed on five eyes, of which only two revealed patent sclerostomies. Although topical fluorouracil appears to delay bleb scarring, the corneal findings suggest that it may be more toxic than subconjunctival fluorouracil.

Bilateral aplasia of the optic nerves, chiasm, and tracts in an otherwise healthy infant.

PURPOSE: To report bilateral aplasia of the optic nerves, chiasm, and tracts in an otherwise healthy infant. METHOD: Case report. RESULTS: Ophthalmologic examination disclosed bilateral microphthalmos and optic nerve aplasia. Physical, neurologic, and genetic evaluations were otherwise normal. Magnetic resonance imaging of the brain and orbits disclosed bilateral aplasia of the optic nerves, chiasm, and tracts. CONCLUSION: Bilateral aplasia of the optic nerves, chiasm, and tracts may occur in an otherwise healthy infant.

MR and CT characteristics of gangliocytoma: a rare cause of epilepsy in children.

Three children were examined who had surgery to remove gangliocytomas in order to control seizures that were refractory to medical therapy. The CT characteristics of gangliocytomas are those of a hyperdense lesion that does not demonstrate contrast enhancement. The MR findings show a region of mixed signal intensity on T1-weighted and proton-density images, and decreased signal intensity on T2-weighted images. Little mass effect, if any, is seen with these lesions.

MR imaging of spinal dysraphism.

Spinal dysraphism includes anomalies of midline fusion involving bony, mesenchymal, and neural elements. MR imaging of the spine was performed as the initial imaging technique to determine its role in the evaluation of 31 children when spinal dysraphism was clinically suspected or when radiographs revealed errors of ossification of the posterior elements (spina bifida). Correlation of surgical findings in 17 of 18 abnormal examinations and metrizamide myelography with CT in six of these cases indicated that accurate diagnosis was provided by MR in all instances. Examples of spina bifida aperta (spina bifida cystica)--including myelomeningocele, myelocystocele, and lipomyelomeningocele--and those of occult spinal dysraphism--such as dorsal dermal sinus, spinal lipoma, and tight filum terminale (thickened filum)--are presented. These cases show MR to be a reliable technique in the initial evaluation of these disorders.

Holoprosencephaly classified by computed tomography.

Five cases are presented to demonstrate the computed tomographic (CT) spectrum of holoprosencephaly. The classifications of alobar, semilobar, and lobar types A and B holoprosencephaly are each represented, with an additional case of semilobar holoprosencephaly complicated by a subdural effusion.

Radiologic characteristics of primitive neuroectodermal tumors in children.

Radiographic findings are reviewed in 31 children with primitive neural ectodermal tumors seen at the Hospital for Sick Children from 1962 through 1983. Seventeen children were initially evaluated with computed tomography (CT). Ten of these had both CT studies and angiography. The tumors were large, irregular, typically iso- to hyperdense, and showed dense, heterogeneous contrast enhancement. Cysts were present in 65% and calcifications in 71% of cases. The angiographic findings were nonspecific, ranging from avascular to markedly vascular. Although these tumors were usually found in the cerebral hemisphere, particularly the frontal lobes, two cases are included of tumors arising elsewhere: one in the pineal and one in the suprasellar region. Epidemiologic data are reviewed.

Placement of intracerebral depth electrodes during excisional surgery for epilepsy: value of intraoperative ultrasound.

The authors describe the use of intraoperative US for directing placement of depth electrodes for the localization of seizure foci prior to temporal lobectomy. They used this technique in seven patients (six undergoing temporal and one frontal resection), and encountered no complications.