Bolusvs. continuous hepatic arterial infusion of cisplatin plus intravenous 5-fluorouracil chemotherapy for unresectable colorectal metastases

A multicenter, randomized Phase 2 study that compared patients, affected by colorectal liver metastases, who received intrahepatic arterial infusion with two different schedules of cisplatin, bolusvs. continuous infusion, and systemic 5-fluorouracil. PURPOSE: The aim of this study was to validate results of a previous Phase 2 trial on bolus cisplatin intrahepatic arterial infusion, which reported a 47 percent response rate and a 32 percent 4-year survival rate for Gennari's Stage 2 patients, with a high rate of neurologic, gastrointestinal, and hematologic toxicity. METHODS: One hundred nine patients were randomized in a Phase 2 study to receive cisplatin intrahepatic arterial infusion (24 mg/m²/day, 15, bolusvs. continuous infusion) and systemic intravenous 5-fluorouracil (250, 375, or 500 mg/m²/day, 15; escalating doses, respectively, at cycles I, II, III, and VI). To avoid neurotoxicity a maximum of six cycles was administered. RESULTS: Preliminary results for the 78 evaluable patients are similar to those of the previous study: response rate 46 percent and at a median follow-up of 16.5 months, the overall survival was 16.5 months, with 45 percent of the patients who received more than 3 cycles alive at 3 years. Toxicity, evaluable in 99 patients, showed a decreased incidence of neurotoxicity and a tolerable gastrointestinal and hematologic toxicity, lower in the cisplatin continuous infusion arm. CONCLUSION: This study clearly shows that cisplatin intrahepatic arterial infusion is able to provide a good palliative effect with a tolerable toxicity.This study was supported in part by Pharmacia-Deltec, Italy.     

The pentose phosphate pathway and pyruvate carboxylation after neonatal hypoxic-ischemic brain injury

The neonatal brain is vulnerable to oxidative stress, and the pentose phosphate pathway (PPP) may be of particular importance to limit the injury. Furthermore, in the neonatal brain, neurons depend on de novo synthesis of neurotransmitters via pyruvate carboxylase (PC) in astrocytes to increase neurotransmitter pools. In the adult brain, PPP activity increases in response to various injuries while pyruvate carboxylation is reduced after ischemia. However, little is known about the response of these pathways after neonatal hypoxia-ischemia (HI). To this end, 7-day-old rats were subjected to unilateral carotid artery ligation followed by hypoxia. Animals were injected with [1,2-¹³C]glucose during the recovery phase and extracts of cerebral hemispheres ipsi- and contralateral to the operation were analyzed using ¹H- and ¹³C-NMR (nuclear magnetic resonance) spectroscopy and high-performance liquid chromatography (HPLC). After HI, glucose levels were increased and there was evidence of mitochondrial hypometabolism in both hemispheres. Moreover, metabolism via PPP was reduced bilaterally. Ipsilateral glucose metabolism via PC was reduced, but PC activity was relatively preserved compared with glucose metabolism via pyruvate dehydrogenase. The observed reduction in PPP activity after HI may contribute to the increased susceptibility of the neonatal brain to oxidative stress.     

The Association of Beliefs About Heredity with Preventive and Interpersonal Behaviors in Communities Affected by Podoconiosis in Rural Ethiopia

Little is known about how beliefs about heredity as a cause of health conditions might influence preventive and interpersonal behaviors among those individuals with low genetic and health literacy. We explored causal beliefs about podoconiosis, a neglected tropical disease (NTD) endemic in Ethiopia. Podoconiosis clusters in families but can be prevented if individuals at genetically high risk wear shoes consistently. Adults (N = 242) from four rural Ethiopian communities participated in qualitative assessments of beliefs about the causes of podoconiosis. Heredity was commonly mentioned, with heredity being perceived as (1) the sole cause of podoconiosis, (2) not a causal factor, or (3) one of multiple causes. These beliefs influenced the perceived controllability of podoconiosis and in turn, whether individuals endorsed preventive and interpersonal stigmatizing behaviors. Culturally informed education programs that increase the perceived controllability of stigmatized hereditary health conditions like podoconiosis have promise for increasing preventive behaviors and reducing interpersonal stigma.     

Family history and its association to curve size and treatment in 1,463 patients with idiopathic scoliosis

Purpose

To study family history in relation to curve severity, gender, age at diagnosis and treatment in idiopathic scoliosis.

Methods

A self-assessment questionnaire on family history of scoliosis was administered to 1,463 untreated, brace or surgically treated idiopathic scoliosis patients.

Results

Out of the 1,463 patients, 51 % had one or more relatives with scoliosis. There was no significant difference between females and males, nor between juvenile and adolescent study participants in this respect (p = 0.939 and 0.110, respectively). There was a significant difference in maximum curve size between patients with one or more relatives with scoliosis (median 35°, interquartile range 25) and patients without any relative with scoliosis (median 32°, interquartile range 23) (p = 0.022). When stratifying patients according to treatment (observation, brace treatment or surgery), we found that it was more common to have a relative with scoliosis among the treated patients (p = 0.011). The OR for being treated was 1.32 (95 % CI 1.06–1.64) when the patient had a relative with scoliosis, compared to not having.

Conclusions

Larger curve sizes were found in patients with a family history of scoliosis than in the ones without. No relation between family history and gender or between family history and age at onset of idiopathic scoliosis was found. Although the presence of a family history of scoliosis may not be a strong prognostic risk factor, it indicates that these patients are at higher risk of developing a more severe curve.     

The purine salvage enzyme hypoxanthine guanine xanthine phosphoribosyl transferase is a major target antigen for cell-mediated immunity to malaria

Although there is good evidence that immunity to the blood stages of malaria parasites can be mediated by different effector components of the adaptive immune system, target antigens for a principal component, effector CD4(+) T cells, have never been defined. We generated CD4(+) T cell lines to fractions of native antigens from the blood stages of the rodent parasite, Plasmodium yoelii, and identified fraction-specific T cells that had a Th1 phenotype (producing IL-2, IFN-gamma, and tumor necrosis factor-alpha, but not IL-4, after antigenic stimulation). These T cells could inhibit parasite growth in recipient severe combined immunodeficient mice. N-terminal sequencing of the fraction showed identity with hypoxanthine guanine xanthine phosphoribosyl transferase (HGXPRT). Recombinant HGXPRT from the human malaria parasite, Plasmodium falciparum, activated the T cells in vitro, and immunization of normal mice with recombinant HGXPRT reduced parasite growth rates in all mice after challenge.     

Leishmania immune adherence reaction in vertebrates

In normal human blood, C3-opsonized Leishmania promastigotes immune adhere to erythrocytes, a mechanism believed to enhance their clearance from blood and phagocytosis. Given the potential importance of this reaction in host defence against infection, the promastigote-erythrocyte interaction was studied in blood of individuals from one avian and 12 mammalian genera; [111In]-labelled promastigotes were found to bind only to primate erythrocytes. Nevertheless, previous experiments coincubating platelets isolated from nonprimate mammals with C3-opsonized promastigotes led to promastigote-platelet adherence. To ascertain whether this is a natural mechanism in nonprimate Leishmania infection, normal blood from members of Leishmania animal models of interest, dog, guinea-pig, hamster, mouse and rabbit, was infected ex vivo with promastigotes. Within 1 min of blood contact, the promastigote surface was loaded with platelets, rapidly evolving into large aggregates. These results confirm the physiological nature of the reaction and demonstrate that promastigote-erythrocyte and promastigote-platelet binding are the first parasite-host cell encounters after Leishmania invasion of primates and nonprimate mammals, respectively. Leishmania immune adherence shares the characteristics of the nonanticipatory immune systems, and we consider it should be viewed as an innate vertebrate host effector mechanism.