Increase of Plasma Transforming Growth Factor Beta (TGFβ) During Immunotherapy with IL-2

Interleukin-2 (IL-2) is a lymphokine with pleiotropic activities on the immune system. When administered in vivo, besides inducing unrestricted tumor cytotoxicity, it is also responsible for the secondary release of other lymphokines, such as IL-1, TNF, and marrow growth factors, which may mediate some of the clinical toxicities (as well as therapeutic effects) seen during IL-2 immunotherapy. Among the clinical effects of IL-2, we previously reported thrombocytopenia and IL-2-induced in vitro inhibition of platelet aggregatiori accompanied by rapid secretion of alpha-granule components such as platelet factor 4 (PF4) and beta-thromboglobulin. Platelets coiistitute one of the largest storage forms of TGFβ. Preliminary evaluation of this factor in patients receiving IL-2 had indicated that plasma TGFβ activity increased in cancer patients following IL-2 therapy. We report a more detailed study of the quantitation of TCFβ activity, in the plasma of 23 cancer patients treated with IL-2 immunotherapy. Of interest, we found that although elevation of the bioactive form of TGFβ occurred in most patients during IL-2 therapy, it was significantly higher in patients with clinical regression of tumor (p =,004). In the first 2 weeks of therapy increase of plasma TGFP activity appeared to correlate with a decrease of platelet counts, suggesting that the factor may derive from the storage form of TGFβ contained therein.     

Role of Broviac catheters in infections in children with cancer

In a 3-year period 157 single lumen Broviac catheters were inserted in 145 children with various neoplastic diseases. The overall duration of the catheter courses was 30,533 days (median, 171; range, 2 to 647). Sixty-five percent of the catheter courses (102 of 157) were complicated by at least 1 febrile episode, for a total of 157 episodes. According to European Organization for Research on Treatment of Cancer criteria, 79 febrile episodes (50%) were classified as microbiologically documented infections, 57 (36%) with and 22 (14%) without septicemia; 31 (20%) as clinically documented infections; and 47 (30%) as possible infections. Of the 79 microbiologically documented infections 21 were catheter-related infections (CRI), 32 were catheter-unrelated infections and 26 were infections of unknown source. Only 48% of CRI occurred during neutropenia (less than 1000 neutrophils/mm3), compared with 88% of catheter-unrelated infections and 96% of infections of unknown origin (P = 0.00007). Gram-positive microorganisms (56% staphylococci) accounted for 78% of all isolates in CRI, 47% in catheter-unrelated infections and 43% in infections of unknown origins (P = 0.03). Fungi represented 12% of all isolates. Clinical and microbiologic resolution without removal of the catheter was achieved in 12 of 21 CRI (57%) and no patient died from a CRI. This study indicates that over 3 of 4 of CRI are caused by Gram-positive bacteria, occur in neutropenic and non-neutropenic patients (approximately 50%) and can be successfully treated without removing the catheter.     

Activation of mGlu1 but not mGlu5 metabotropic glutamate receptors contributes to postischemic neuronal injury in vitro and in vivo

In order to investigate the involvement of mGlu1 and mGlu5 metabotropic glutamate receptors in the development of postischemic neuronal death, we examined the effects of selective agonists and antagonists in models of cerebral ischemia in vitro and in vivo. In murine cortical cell cultures and rat organotypic hippocampal slices exposed to oxygen and glucose deprivation (OGD), the mGlu1 antagonists 1-aminoindan-1,5-dicarboxylic acid (AIDA; 300 microM), (S)-(+)-2-(3'-carboxybicyclo[1.1.1]pentyl)-glycine (CBPG; 300 microM), 7-hydroxyiminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester (CPCCOEt; 10-30 microM) and (+)-2-methyl-4-carboxyphenylglycine (LY367385; 30-100 microM) reduced neuronal loss when added to the medium during OGD and the subsequent 24-h recovery period. On the contrary, the potent and selective mGlu5 antagonist methyl-6-(phenylethynyl)-pyridine (MPEP; 0.1-1 microM) did not exhibit neuroprotection in any of these in vitro models. Incubation with the nonselective mGlu1 and mGlu5 agonist 3,5-dihydroxyphenylglycine (3,5-DHPG; 300 microM) but not with the mGlu5 agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG; 1 mM) enhanced the severity of OGD-induced neuronal damage. In gerbils subjected to global ischemia, intracerebroventricular administration of AIDA (100 nmol two times) or CBPG (300 nmol, two times) afforded consistent protection against CA1 pyramidal cell death, whereas MPEP (10 pmol i.c.v two times and 10 mg/kg i.p two times) failed to reduce postischemic hippocampal damage. Our results suggest that activation of mGlu1 but not mGlu5 receptor contributes to postischemic neuronal injury.     

Metabotropic glutamate 1 (mGlu1) receptor antagonists enhance GABAergic neurotransmission: a mechanism for the attenuation of post-ischemic injury and epileptiform activity?

Selective antagonists of mGlu1 metabotropic glutamate receptors attenuate neuronal death in models of cerebral ischemia. Because GABAergic mechanisms have recently been proposed to contribute to these neuroprotective effects, we examined the effects of selective mGlu1 antagonists characterized in our laboratory on GABAergic transmission in three different models of neuropathology. In rat organotypic hippocampal slices exposed to oxygen-glucose deprivation, the mGlu1 antagonists AIDA, CBPG and 3-MATIDA reduced CA1 pyramidal cell loss when added to the medium during the insult and the subsequent recovery period. This effect was mimicked by the GABA(A) and GABA(B) agonists muscimol and baclofen and partially prevented by the antagonists bicuculline and CGP 55845. In gerbils subjected to global ischemia, protection of CA1 pyramidal cells by transdialytic perfusion of AIDA and CBPG was associated with a significant increase in the basal and ischemic output of GABA and minor changes in the output of glutamate. In a mouse cortical wedge model, both muscimol and 3-MATIDA reduced the frequency of spontaneous bursts induced by 4-aminopyridine and this reduction was prevented by co-perfusion with bicuculline. Taken together, our results suggest that the release of GABA, and the subsequent activation of GABA receptors, may contribute to the attenuation of post-ischemic neuronal damage and epileptiform activity induced by mGlu1 receptor antagonists.     

Antiretroviral activity and cytotoxicity of novel zidovudine (AZT) derivatives and the relation to their chemical structure

Zidovudine (AZT) was the first nucleoside analogue licensed for the treatment of HIV infection. Efforts have continuously been made to improve the therapeutic characteristics of this drug, most of them focussed on prodrugs design. Here we describe the anti-HIV-1 activity and cytotoxicity of six novel AZT derivatives namely 3'-azido-3'-deoxy-5'-O-oxalyl-N-valinethymidine, 3'-azido-3'-deoxy-5'-O-oxalyl-N-leucinethymidine, 3'-azido-3'-deoxy-5'-O-oxalyl-N-isoleucinethymidine, 3'-azido-3'-deoxy-5'-O-oxalyl-N-phenylalaninethymidine, 3'-azido-3'-deoxy-5'-O-oxalylthymidine acid, 3'-azido-3'-deoxy-5'-O-isonicotinoylthymidine and 5-chloro-6-hydroxy-5,6-dihydro-3'-azido-3'-deoxythymidine which were perfectly characterized. AZT-Val, AZT-Leu, AZT-iLeu, AZT-Phen, AZT-Ac and AZT-Iso have shown a similar or higher selectivity index than that of AZT itself, in one or both of the different cell cultures used (PBMC and MT2). However, AZT-ClOH showed no anti-HIV activity. These results suggest that using amino acids in the design of AZT derivatives improves AZT activity.     

Clinical aspects of the AIDS dementia complex in relation to histopathological and immunohistochemical variables

To correlate cerebral histopathological and immunohistochemical changes in the neuroclinical features of the AIDS dementia complex (ADC), autopsy results of 28 ADC patients were related, in a retrospective analysis, to scores on a standardised neurological examination performed at neurologic onset. From a histopathological point of view, the cases were classified as follows: 9 cases of HIV leucoencephalopathy (HIVL; diffuse myelin damage and rare microglial nodules), 7 cases of HIV encephalitis (HIVE; several microglial nodules and no myelin damage) and 12 cases of mixed HIVL and HIVE (HIVL-E). The groups differed significantly with respect to symptoms and CD4 count at neurologic onset, survival and neurological impairment. Immunohistochemically, the interstitial component (p24-positive cells scattered singly within the white matter) was significantly more prevalent in HIVL, and the micronodular component (p24-positive cells confined within microglial nodules) in HIVE. Neurological damage was worse in cases with a high prevalence of interstitial component or a low prevalence of micronodular component. HIVE, HIVL and HIVL-E are distinct clinical forms of ADC. Neurological impairment is related to white matter damage.     

Costello syndrome: a cancer predisposing syndrome?

Costello Syndrome is a specific MCA/MR syndrome mainly characterized by dysmorphic facial features, peculiar biphasic growth pattern, motor and mental retardation, ectodermal anomalies involving skin and nails, and age dependent development of nasal and perianal papillomata. Heart malformations and/or hypertrophic cardiomyopathy are frequently observed. We report a 4-year-old girl with Costello syndrome who developed an intrathoracic ganglioneuroblastoma. In previous reports two patients with ectodermal tumours have been described, a ganglioneuroblastoma of the adrenal gland and an epithelioma. This third report suggests that neural crest neoplasia may be a significant risk factor for children with Costello syndrome.     

Type-III acrocephalosyndactylia (Saethre-Chotzen syndrome). Description of 2 cases

The acrocephalosyndactylia III is a syndrome, which follows an autosomal dominant mode of inheritance, characterized by premature fusion of the cranial sutures in association with mild cutaneous syndactyly. The authors describe two cases recently come to their observation and point out the usefulness of the imaging diagnostics (CT, MRI) in finding anomalies specific of this affection.     

L-2-Hydroxyglutaric aciduria: MRI in seven cases

The MRI findings in 7 patients with L-2-Hydroxyglutaric aciduria (L-2-OHG aciduria) are described and compared with previous neuroradiological reports and the only three published pathological cases. Signal abnormalities involved peripheral subcortical white matter, basal ganglia and dentate nuclei. Cerebellar atrophy was present. Although similar appearances may be seen in other metabolic disorders, the distribution of signal abnormalities in L-2-OHG aciduria is highly characteristic and may suggest the correct diagnosis. Received: 5 January 1998 Accepted: 22 April 1998