A novel treatment of childhood lymphoblastic non-Hodgkin's lymphoma: early and intermittent use of teniposide plus cytarabine

We treated 24 children and adolescents with stage III or IV lymphoblastic non-Hodgkin's lymphoma, using a protocol designed for patients with poor-prognosis acute lymphoblastic leukemia (ALL). Early therapy consisted of teniposide plus cytarabine administered before and immediately after prednisone, vincristine, and asparaginase. The two- drug combination was also given intermittently with continuous 6- mercaptopurine and methotrexate during the first year of continuation chemotherapy. Periodic intrathecal methotrexate and delayed cranial irradiation were used to prevent central nervous system involvement. Anthracycline compounds, alkylating agents, high-dose methotrexate, and involved-field irradiation were not used in any phase of treatment. Twenty-two (96%) of the 23 evaluable patients achieved complete remission. With a median follow-up of 2 1/2 years, only four patients have relapsed; the remainder have been disease-free for eight months to more than five years. The projected four-year continuous complete remission rate is 73% for all patients and 79% for the 19 with mediastinal involvement at diagnosis. These results demonstrate that use of teniposide plus cytarabine with an otherwise conventional plan of ALL therapy is an effective approach to the treatment of childhood lymphoblastic lymphoma.     

Recombinant human milk fat globule-EGF factor 8 produces dose-dependent benefits in sepsis

Purpose  

Animal milk fat globule-EGF factor 8 (MFG-E8) has been shown to be beneficial in attenuating the inflammatory response in sepsis. In this study, we examined the effect of recombinant human MFG-E8 (rhMFG-E8) in an animal model of sepsis in an effort to develop it as a potential therapy against sepsis in humans.     

Anal infections with concomitant <Emphasis Type="Italic">Chlamydia trachomatis</Emphasis>genotypes among men who have sex with men in Amsterdam,the Netherlands

Background  

Lymphogranuloma venereum (LGV) proctitis is caused by Chlamydia trachomatis (Ct) genotype L and is endemic among men who have sex with men (MSM) in western society. Genotype L infections need to be distinguished from non-LGV (genotypes A-K) Ct infections since they require prolonged antibiotic treatment. For this purpose, an in-house developed pmpH based LGV polymerase chain reaction (PCR) test is used at the Amsterdam STI outpatient clinic. We investigated retrospectively the anal Ct genotype distribution, and the frequency of concomitant genotype infections in MSM infected with LGV and non-LGV Ct infections. To detect concomitant Ct genotype infections, the pmpH LGV PCR and genoTyping Reverse Hybridization Assay (Ct-DT RHA) were used.     

Structure-activity relationship of resveratrol and its analogue, 4,4'-dihydroxy-trans-stilbene, toward the endothelin axis in human endothelial cells

Resveratrol inhibits endothelin-1, a vascular tension regulator. We synthesized the resveratrol analogue 4,4'-dihydroxy-trans-stilbene with 2 hydroxyl groups in the 4 and 4' position to obtain a molecule more active than resveratrol (3,4',5-trihydroxy-trans-stilbene). The results demonstrate that 4,4'-dihydroxy-trans-stilbene led to a significant decrease in total endothelin-1 secretion and in endothelin-1 messenger RNA (mRNA) levels in human endothelial cells. In addition, resveratrol and its analogue decreased endothelin-converting enzyme-1 mRNA levels and further reduced the activity of the enzyme. 4,4'-dihydroxy-trans-stilbene was more active than resveratrol because the new molecule exerted greater activity at the level of endothelin synthesis and conversion, even at a lower concentration. Although 4,4'-dihydroxy-trans-stilbene and resveratrol inhibited formation of reactive oxygen species and lipid peroxidation, the treatment of cells with different oxidant agents did not modify the endothelin-1 release. This finding suggests that the inhibition of endothelin-1 secretion is independent of the antioxidant properties of the 2 compounds. On the basis of these results, the resveratrol analogue 4,4'-dihydroxy-trans-stilbene could be a promising chemopreventive agent against cardiovascular diseases.     

Transitory peaked waveforms with elevated velocities in Doppler sonography after renal transplant

Vascular complications after a renal transplant are rare and critical. Duplex Doppler evaluation constitutes the primary imaging modality in renal transplant. Early diagnosis and appropriate intervention to address potential complications are crucial in graft survival. This report describes a 25-year-old woman who underwent a live-donor renal transplant. During a routine study 4 hours after surgery, she was found to have high peak flow velocities suggestive of stenosis. An angiogram obtained as a result of this finding showed no abnormalities. A repeat duplex Doppler sonogram performed 12 hours later revealed normal waveforms and velocities. Postrenal transplant vascular complications are rare but may represent a significant morbidity factor for patients and grafts. Peak wave forms, elevated velocities, and a tardus-parvus configuration are suggestive of vascular disorders that require aggressive evaluation. In our patient, the Doppler ultrasound, angiogram, and lack of clinical signs were compatible with a renal artery vasospasm. This entity, despite its reversibility in the majority of instances, may cause severe graft injury if it does not regress promptly.     

Post-treatment with the combination of 5-aminoimidazole-4-carboxyamide ribonucleoside and carnitine improves renal function after ischemia/reperfusion injury

Renal ischemia/reperfusion (I/R) injury is a major clinical problem where main metabolic pathways are compromised and cellular homeostasis crashes after ATP depletion. Fatty acids are major energy source in the kidneys. Carnitine palmitoyltransferase I (CPT1), a mitochondrial membrane enzyme, utilizes carnitine to transport fatty acids to mitochondria for the process of β-oxidation and ATP generation. In addition, CPT1 activity is indirectly regulated by adenosine monophosphate-activated protein kinase, which can be activated by 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR). We hypothesized that administration of carnitine and AICAR could reestablish the energetic balance after reperfusion and ameliorate renal I/R injury. Male adult rats were subjected to renal I/R by bilateral renal pedicle clamping for 60 min, followed by administration of saline (vehicle), carnitine (250 mg/kg BW), AICAR (30 mg/kg BW), or combination of both drugs. Blood and renal tissues were collected 24 h after reperfusion for various measurements. Renal carnitine levels decreased 53% after I/R. The combined treatment significantly increased CPT1 activity and ATP levels and lowered renal malondialdehyde and serum TNF-α levels against the vehicle group. It led to improvement in renal morphology and histological damage score associated with diminution in serum creatinine, blood urea nitrogen, and aspartate aminotransferase levels. Moreover, the combined treatment significantly improved the survival rate in comparison to the vehicle group. In contrast, administration of either drug alone did not show a significant improvement in most of the measurements. In conclusion, enhancing energy metabolism by combination of carnitine and AICAR provides a novel modality to treat renal I/R injury.     

The challenges of liver transplantation for hepatocellular carcinoma on cirrhosis

Hepatocellular carcinoma (HCC) is a major cause of cancer mortality worldwide and liver transplantation (LT) has potentials to improve survival for patients with HCC. However, expansion of indications beyond Milan Criteria (MC) and use of bridging/downstaging procedures to convert intermediate‐advanced stages of HCC within MC limits are counterbalanced by graft shortage and increasing use of marginal donors, partially limited by the use of donor‐division protocols applied to the cadaveric and living‐donor settings. Several challenges in technique, indications, pre‐LT treatments and prioritization policies of patients on the waiting list have to be precised through prospective investigations that have to include individualization of prognosis, biological variables and pathology surrogates as stratification criteria. Also, liver resection has to be rejuvenated in the general algorithm of HCC treatment in the light of salvage transplantation strategies, while benefit of LT for HCC should be determined through newly designed composite scores that are able to capture both efficiency and equity endpoints. Innovative treatments such as radioembolization for HCC associated with portal vein thrombosis and molecular targeted compounds are likely to influence future strategies. Accepting this challenge has been part of the history of LT and will endure so also for the future.