Quantitative MRI of the brain in children with sickle cell disease reveals abnormalities unseen by conventional MRI

Conventional MRI (cMRI) has shown that brain abnormalities without clinical stroke can manifest in patients with sickle cell disease (SCD). We used quantitative MRI (qMRI) and psychometric testing to determine whether brain abnormalities can also be present in patients with SCD who appear normal on cMRI. Patients 4 years of age and older with no clinical evidence of stroke were stratified by cMRI as normal (n = 17) or abnormal (n = 13). Spin-lattice relaxation time (T1) of gray and white matter structures was measured by the precise and accurate inversion recovery (PAIR) qMRI method. Patient cognitive ability was assessed with a standard psychometric instrument (WISC-III or WISC-R). In all 30 patients with SCD, qMRI T1 was lower than in 24 age- and race-matched controls, in cortical gray matter (P < .0006) and caudate (P < .0009), as well as in the ratio of gray-to-white matter T1 (P < .008). In the 17 patients who were shown to be normal by cMRI, qMRI T1 was still lower than in controls, in both cortical gray matter (P < .02) and caudate (P < .004). Histograms of voxel T1 show that the proportion of voxels with T1 values intermediate between gray and white matter (ie, consistent with encephalomalacia) was 9% higher than controls in patients shown to be normal by cMRI (P < .05) and 15% higher than controls in patients shown to be abnormal by cMRI (P < .0005). The full scale intelligence quotient (FSIQ) of all patients with SCD was 75, compared to the FSIQ of 88 in a historical control group of patient siblings (P < .001). The FSIQ of patients shown to be normal by cMRI was 79, significantly lower than the FSIQ of patient siblings (P < .04). The FSIQ of 71 in patients shown to be abnormal by cMRI was significantly lower than both the patient siblings (P < .005) and the patients shown to be normal by cMRI (P < .04). Patients shown to be abnormal by cMRI scored lower than patients shown to be normal by cMRI, specifically on the subtests of vocabulary (P = .003) and information (P = .03). Cognitive impairment is thus significant, even in patients with SCD who were shown to be normal by cMRI, suggesting that cMRI may be insensitive to subtle neurologic damage that can be detected by qMRI. Because cognitive impairment can occur in children normal by cMRI, our findings imply that prophylactic therapy may be needed earlier in the course of SCD to mitigate neurologic damage.     

A comparision of brain biopsy and CSF-PCR in the diagnosis of CNS lesions in AIDS patients

Twenty patients with AIDS who had intracranial lesions underwent both brain biopsy and cerebro-spinal fluid (CSF) examination to compare histological diagnosis with the polymerase chain reaction (CSF-PCR) for the identification of infectious agents. CSF-PCR was performed for herpes simplex virus, varicella zoster virus, cytomegalovirus (CMV), JC virus (JCV), Epstein-Barr virus (EBV), Toxoplasma gondii and Mycobacterium tuberculosis. A definitive diagnosis was obtained by brain biopsy in 14 patients (2 with astrocytoma, 12 with brain infection). CSF-PCR was positive for EBV DNA in 3 of 3 cases of primary cerebral lymphoma, positive for JCV DNA in 6 of 7 biopsy-proven (and one autopsy-proven) cases of progressive multifocal leukoencephalopathy (PML). CSF-PCR was positive for CMV DNA in one biopsy-proven and one autopsy-proven case of CMV encephalitis (the former also had PML) and positive for M. tuberculosis DNA in one case of tuberculous encephalitis. None of the five toxoplasmic encephalitis cases (one definite, four presumptive) were T. gondii DNA positive. There was close correlation between histology and CSF-PCR for CMV encephalitis, PML and PCL. Antitoxoplasma therapy affected the sensitivity of both histological and CSF-PCR methods. Received: 8 November 1995 Received in revised form: 9 July 1996 Accepted: 19 July 1996     

Expression of c-fos, fos B, and egr-1 in the medial preoptic area and bed nucleus of the stria terminalis during maternal behavior in rats

The spatial and temporal pattern of expression of the protein products of immediate early genes (IEGs) c-fos, fos B, and egr-1 were mapped in medial preoptic area (MPOA) and ventral bed nucleus of stria terminalis (VBST) during maternal behavior in rats. Immunocytochemical analysis indicated significant increases in the number of cells expressing c-Fos after 2 h of pup exposure, while Fos B levels showed a delayed response, reaching maximal levels after 6 h.     

Recruitment of quiescent (G0) cells following epidermal injury is initiated by activation of the phosphoinositol cycle

Under normal circumstances, the rate of production of new cells by the epidermis is rather low, but injury results in a burst of mitotic activity that continues until repair is complete. It is now recognized that most cells of the germinative population are in a resting (G0) state, and "postinjury cell renewal" is the consequence of G0 cells entering the mitotic cycle. The biochemical events triggering this process, however, are unknown. Here we show that phorbol myristate acetate (PMA) is able to induce G0 mobilization in the epidermis of the nude mouse. Further, we demonstrate that amiloride (an inhibitor of the membrane Na+-H+ pump), applied topically to human skin, abolishes almost completely the regenerative response after experimental injury. We suggest that activation of the phosphoinositol cycle may initiate recruitment of G0 cells in the epidermis.     

The role of hyperthermic perfusion as a first step in the treatment of soft tissue sarcoma of the extremities

Eighty-six patients with locally advanced, high-grade soft tissue sarcomas of the extremities were studied prospectively in order to determine the efficacy of hyperthermic perfusion (HP) or hyperthermic antiblastic perfusion (HAP) as the first step of a combined multimodality therapy. The immediate response was evaluated in terms of tumor regression, and results confirmed the in vivo sensitivity of human sarcomas to the selective antineoplastic action of heat alone or combined with drugs (melphalan, actinomycin D, and cis-platinum). HAP has been shown to be simpler and safer than HP, and it is now currently routinely employed. As far as the long-term cure is concerned, all the patients have been evaluated for functional results, locoregional control, and survival, according to the different treatment schedules. The first clinical trials employed HP or HAP followed by delayed surgery alone. In 11 of 17 evaluable patients treated with HP, and in 17 of 29 treated with HAP, conservative surgery could be performed. A high incidence of locoregional relapse (24%) occurred, with low overall survival rates: 50.1% and 31.7% at 5 and 10 years after HP plus surgery, and 47.9% after HAP plus surgery at both 5 and 10 years. The protocol was, therefore, modified to include continuous intraarterial infusion of Adriamycin® (ADR) (17 patients) or radiotherapy (9 patients) before surgery. The results obtained thus far may be summarized as follows: (a) conservative surgery with functional limb-salvage was possible in all patients; (b) the percentage of locoregional failure decreased to approximately 12% after HAP + ADR infusion + excision, the 5- and 10-year overall survival rates both being 77.6 %, and the 5- and 10-year disease-free rates both being 57.8%; (c) no local recurrences occurred in the group treated with HAP + radiotherapy + excision with a 5-year overall survival rate of 71.5% and a 5-year disease-free rate of 50.4%. In conclusion, the combined multimodality approaches employed appear to have improved both functional results and long-term cure, even though these must be further confirmed on a larger series of patients.

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Resumen Ochenta y seis pacientes con sarcomas de los tejidos blandos de las extremidades, de alto grado histológico, e invasión local avanzada fueron estudiados en forma prospectiva con el objeto de determinar la eficacia de la perfusión hipertérmica (PH) o la perfusión hipertérmica antiblástica (PHA) como primer paso dentro de una terapia combinada multimodal.La respuesta inmediata fue valorada en términos de la regresión tumoral, y los resultados confirmaron la sensibilidad in vivo de los sarcomas humanos a la acción antineoplásica selectiva del calor sólo o combinado con drogas (melfalán, actinomicina D, y cis-platino). La PHA ha demostrado ser más sencilla y más segura que la PH y actualmente es utilizada en forma rutinaria.En lo referente a curación a largo plazo, todos los pacientes han sido evaluados en cuanto a resultados funcionales, control locorregional, y supervivencia, de acuerdo a los diferentes programas terapéuticos.En los primeros ensayos clínicos se utilizó PH o PHA seguida de cirugía solamente. En 11 de 17 pacientes valorables tratados con PH y 17 con PHA, fue posible realizar cirugía conservadora. Se presentó una incidencia alta de relapso locorregional (24%), con tasas bajas de supervivencia global: 50.1% y 31.7% a 5 y 10 años con PH y cirugía, y 47.9% con PHA y cirugía tanto a 5 como a 10 años.El protocolo fue consecuentemente modificado para incluir una infusión intraarterial continua de Adriamicina® (ADR) (17 pacientes) o radioterapia (9 pacientes) antes de la cirugía.Los resultados logrados hasta el momento pueden ser resumidos así: (a) la cirugía conservadora con salvamento del miembro fue posible en la totalidad de los pacientes; (b) el porcentaje de falla locorregional disminuyó aproximadamente 12% después de PHA + infusión de ADR + resección, con supervivencias globales a 5 y 10 años de 77.6%, y tasas de estado libre de enfermedad a 5 y 10 años de 57.8%; (c) no se presentaron recurrencias locales en el grupo tratado con PHA + radioterapia + resección, con una tasa de supervivencia global a 5 años de 71.5% y una tasa de estado libre de enfermedad a 5 años de 50.4%.En conclusión, los aproches con terapia combinada multimodal empleados parecen haber mejorado tanto los resultados funcionales como las tasas de curación a largo plazo, aunque estos resultados aún deben ser reconfirmados en una serie mayor de pacientes.

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Résumé Une étude prospective concernant 86 malades qui présentaient un sarcome des parties molles des membres de stade évolutif avancé a été entreprise pour déterminer l'efficacité de la perfusion hyperthermique ou de la perfusion hyperthermique antiblastique en tant que première étape d'un traitement à modalités multiples.La réponse immédiate a été appréciée en fonction de la régression tumorale. Les résultats ont confirmé la sensibilité in vivo des sarcomes humains à l'action antinéoplasique sélective de la chaleur employée isolemment ou combinée avec des drogues (melphalan, actinomycine D, et cis-platinum). La perfusion hyperthermique antiblastique s'est montrée plus simple et plus sûre que la perfusion hyperthermique, et de ce fait est devenue une méthode thérapeutique normalement employée.Pour apprécier l'action thérapeutique à long terme tous les malades ont été étudiés en tenant compte des résultats fonctionnels, du contrôle loco-régional, et de la survie obtenus selon les différentes thérapeutiques appliquées.Les premiers essais ont eu recours à l'hyperthermie thermique ou à l'hyperthermie thermique antiblastique suivie d'une intervention chirurgicale. Chez 11 des 17 malades traités par l'hyperthermie thermique, et chez 17 des 29 malades soumis à l'hyperthermie antiblastique le traitement chirurgical conservateur a pu être réalisé. Les résultats furent les suivants: fréquence importante des récidives loco-régionales (24%); taux global de survie bas: 50.1% et 31.7% à 5 ans et 10 ans après perfusion hyperthermique suivie de chirurgie, ce taux étant de 47.9% après perfusion hyperthermique antiblastique suivie de chirurgie à 5 ans et 10 ans.En fonction de ces résultats le protocole thérapeutique fut modifié en y ajoutant une transfusion intra-artérielle continue d'Adriamycine® (17 malades) ou de la radiothérapie (9 malades) avant l'intervention.Les résultats obtenus à ce jour peuvent se résumer ainsi: (a) la chirurgie conservatrice permettant de sauver un membre fonctionnel est toujours possible; (b) la poucentage d'échec régional décroit environ jusqu' à 12% après perfusion hyperthermique antiblastique associée à la perfusion d'Adriamycine® et l'excision, le taux global de survie à 5 ans et 10 ans étant de 77.6%, le taux d'absence de la maladie à 5 ans et 10 ans étant de 57.8%; (c) aucune récidive locale n'est survenue dans le groupe traité par perfusion hyperthermique antiblastique associé à la radiothérapie et à l'exérèse, le taux global de survie à 5 ans étant de 71.5% et le taux d'absence de la maladie à 5 ans étant de 50.4%.En conclusion le traitement qui a été employé associant plusieurs modalités thérapeutiques a entrainé une amélioration des résultats fonctionnels et de la cure à long terme encore que ce fait demande a été confirmé par une étude étendue à un plus grand mombre de malades.

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Supported by Special Project Hyperthermia from the Italian Ministry of Health.     

Proteinuria in IgA nephropathy

Clinicopathological data in 74 patients with IgA nephropathy were analyzed with special attention to level of proteinuria and its prognostic significance in this disease. Excretion rates exceeding 3 g per day (heavy), in the range of 1 to 2.9 g (moderate) and under 1 g per day (mild) each occurred in approximately equal proportions of patients. One-sixth of those with more than 1 g developed end-stage renal failure, while serum creatinine never exceeded 2 mg/dl in any with mild proteinuria. "Renal survival" (serum creatinine of 2 mg/dl or less) at five years after presentation was 100% in patients with persistently mild proteinuria, 87% in those whose protein excretion reached the moderate range, and 69% when heavy or nephrotic range proteinuria developed. Of significance, only rarely did mild proteinuria at presentation increase to higher levels. A correlation existed between level of protein excretion and severity of mesangial, segmental or global proliferation, glomerulosclerosis, podocyte effacement, interstitial infiltration, tubular atrophy and vascular sclerosis, even in patients with unimpaired renal function. Moderate or heavy proteinuria typically preceded the onset of hypertension and occurred prior to the development of renal insufficiency. Our results underscore magnitude of proteinuria as an early marker of glomerular damage in the prognosis of IgA nephropathy.     

Reproductive studies of C57B/6 male mice treated with TCDD-contaminated soils from a 2,4,5-trichlorophenoxyacetic acid manufacturing site

Reproduction was studied in male C57B/6 mice treated with contaminated soils from a 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) manufacturing site in Newark, New Jersey, and a metal scrap yard where equipment from the manufacturing site was recycled. The soils contained a wide variety of contaminants including 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD). Treated males were mated to females given decontaminated soil. No acute toxicity was observed in treated males. 2,3,7,8-TCDD (up to 90 g/kg) or 2,3,7,8-TCDD from the contaminated soils (up to 288 g/kg) had no adverse effect on reproduction when the male mouse was treated. However, treatment of males with soil from the 2,4,5-T manufacturing site was associated with a marked decrease in viable litters at whelping and a decrease in pup survival. This toxicity may be associated with TCDD in combination with other toxic compounds that are present on the soil.     

Protection of chlordecone-potentiated carbon tetrachloride hepatotoxicity and lethality by partial hepatectomy

Chlordecone (CD) pretreatment is known to markedly potentiate CCl₄ hepatotoxicity. Previous studies have shown that prior exposure to CD obtunds the increased hepatocellular regeneration and repair observed in non-treated rats challenged with a single, low dose of CCl₄. These observations allowed us to hypothesize that suppression of hepatic regeneration and tissue repair by CD + CCl₄ combination treatment might be involved in this interaction. To test this hypothesis, CCl₄ hepatotoxicity was evaluated in actively regenerating livers using CD-treated (10 ppm in the diet for 15 days), surgically partially hepatectomized (PH) male Sprague-Dawley rats. Rats undergoing no surgical manipulation (CTRL) and sham operation (SH) were included as appropriate controls. Surgical manipulations were conducted on day 15 of the dietary protocol. Based on liver-to-body weight ratios (LW/BW), mitotic indices, hepatic cytochrome P-450 content, and hepatic glutathione (GSH and GSSG) levels, PH-induced hepatocellular regeneration was not affected by pretreatment with CD. Thus, the PH model was considered valid for assessing the effects of CD + CCl₄ combination treatment. CCl₄ (100 l/kg; i.p.) was administered 1, 2, 4 or 7 days after the surgical manipulations. Hepatotoxicity was assessed 24 h later by measuring LW/BW and serum enzymes (SGPT, SGOT and ICD) in all four groups. Hepatic histopathological, histomorphometric and lethal effects were assessed in animals receiving CCl₄ 1 or 7 days after the surgical manipulations. CCl₄-induced increases in LW/BW were observed in CD + PH rats receiving CCl₄ 4 or 7 days post-PH, but not in the 1 or 2 day post-PH groups in which the hepatocellular regeneration was maximal. CCl₄-induced serum enzyme elevations were significantly less in the CD + PH rats as compared to CD + SH. This decrease in the serum enzyme elevations was most prominent in the 1 day post-PH group, where the hepatocellular mitotic activity was most pronounced. CCl₄ lethality, assessed in the 1 day post-surgical manipulation group, was also decreased in the CD + PH rats in comparison to CD + SH rats. Such a protection was not observed in rats receiving CCl₄ 7 days post-PH. These data are consistent with and are supportive of the hypothesis that a suppression of otherwise normally stimulated hepatocellular regeneration following low-dose CCl₄ administration is involved in the marked amplification of CCl₄ toxicity by CD.Abbreviations CD chlordecone - GSH reduced glutathione - GSSG oxidized glutathione - PH partial hepatectomy - SH shamhepatectomy - CTRL control, not surgically manipulated - N normal diet - LW/BW liver weight-to-body weight ratio - SGPT serum glutamic; pyruvic transaminase - SGOT serum glutamic oxaloacetic transaminase - ICD isocitrate dehydrogenase These studies were made possible by a grant from the US Environmental Protection Agency R-811072A preliminary report of these findings was presented at the 70th Annual Meetings of the Federation of American Societies for Experimental Biology at St. Louis, MO (Fed Proc 45: 1051, 1986)A. N. Bell is a Predoctoral Toxicology Trainee and Robert A. Young is a Postdoctoral Trainee supported by Toxicology Training grant from National Institute of Environmental Health Science ES-07045     

Clinical significance of intraoperative cultures of aneurysm walls and contents in elective abdominal aortic aneurysmectomy

To investigate the clinical significance of intraoperative cultures in elective abdominal aortic aneurysmectomy, we cultured the aneuryrymml wall and contents in 90 patients undergoing vascular graft surgery. Prosthetic graft infection was documented in 1 out of 62 patients with negative cultures and in none of 28 patients with positive cultures (x² = 0.4, p > 0.1). Bacterial growth was seen in neither of 2 inflammatory aneurysms, 3 of 14 atherosclerotic aneurysms and 2 of 5 aneurysms without specific features. A retrospective analysis of patients' charts aimed at finding possible risk factors failed to identify any correlation between results of cultures and length of hospitalization before surgery, time interval between angiography and surgery, route of angiography procedure or minutes of surgery before sample collection. We conclude that positive cultures may not imply clinical infection at the time of surgery and that prolonged post-operative organism-specific antibiotic therapy does not appear necessary to prevent graft contamination in patients undergoing elective abdominal aortic aneurysmectomy.     

Phenotypic and functional characteristics of tumor-associated lymphocytes in patients with malignant ascites receiving intraperitoneal infusions of recombinant interleukin-2 (rIL-2)

In the course of a phase I trial, in which recombinant IL-2 (rIL-2) was infused intraperitoneally (i.p.) in patients with peritoneal carcinomatosis, we evaluated the effect on "tumor-associated lymphocytes" (TAL) isolated from the ascitic fluid. No major changes in the percentages of cells expressing the CD3, CD4, CD8, Leu-7, OKM1 and WT-31 antigens were detected either in TAL or in peripheral blood lymphocytes (PBL) after 7 days of rIL-2 infusion. In contrast the percentages of TAL (but not PBL) expressing surface IL-2 receptor (Tac), or LAK-1 antigen were sharply increased. Analysis of cytolytic functions showed a potentiation of the lytic activity against natural-killer (NK) sensitive K562 target cells and the de novo appearance of lytic activity against fresh melanoma cells. In one patient IFN-gamma was detected in the ascitic fluid following rIL-2 infusion. T-cell clones derived from the patient were analyzed for the IFN-gamma production. While only approximately 40% of PB-derived control clones produced medium to low amounts of IFN-gamma, all of the TAL-derived clones produced medium to high amounts of the lymphokine.