Commensal microflora and interferon‐γ promote steady‐state interleukin‐7 production in vivo

IL‐7 is a major regulator of lymphocyte homeostasis; however, little is known about the mechanisms that regulate IL‐7 production. To study Il7 gene regulation in vivo, we generated a novel IL‐7‐reporter mouse, which allows the non‐invasive quantification of Il7 gene activity in live mice and, additionally, the simultaneous activation/inactivation of target genes in IL‐7‐producing cells. With these IL‐7‐reporter mice, we identify thymus, skin and intestine as major sources of IL‐7 in vivo. Importantly, we show that IFN‐γ and the commensal microflora promote steady‐state IL‐7 production in the intestine. Furthermore, we demonstrate that the blockade of IFN‐γ signaling in intestinal epithelial cells strongly reduces their IFN‐γ‐driven IL‐7 production. In summary, our data suggest a feedback loop in which commensal bacteria drive IFN‐γ production by lymphocytes, which in turn promotes epithelial cell IL‐7 production and the survival of IL‐7‐dependent lymphocytes.     

Single Enteral Loading Dose of Phenobarbital for Achieving Its Therapeutic Serum Levels in Neonates

Aim

To investigate whether therapeutic serum drug levels may be achieved with a single enteral loading dose of phenobarbital.

Methods

The study was performed at the Mersin University Hospital in Turkey between April 2004 and August 2006, and included 29 newborn babies with seizure. After the acute treatment of the seizure with midazolam at a dose of 0.1 mg/kg, phenobarbital was administered by orogastric route at a loading dose of 20 mg/kg. Serum phenobarbital concentrations were measured at 0.5, 3, 6, and 12 hours after the loading. Serum phenobarbital levels between 10-30 μg/mL were considered as the therapeutic range.

Results

The serum phenobarbital levels reached therapeutic values in 9 (31%), 19 (66%), 21 (72%), and 23 (79%) patients at 0.5, 3, 6, and 12 hours after loading, respectively, while they did not reach therapeutic values in 6 patients (21%) after 12 hours. Four of the patients in whom there was no increase in serum phenobarbital levels had hypoxic-ischemic encephalopathy.

Conclusion

Enteral loading of phenobarbital can achieve therapeutic serum levels in the large majority of newborn babies with seizure and may be safely used in babies with the intact gastrointestinal tract.Seizures are the most common neurological emergency in newborn babies, in whom they occur more frequently than in adolescents or adults. The incidence of neonatal seizures varies between 0.1% and 8.6% (1-5) and depends in part on the gestational age and the nature of the studied population. The long-term outcome of infants with seizures has been associated primarily with the cause of seizures, but reports on both laboratory animals and newborn infants suggest that seizures themselves may have a deleterious effect (6-10). Although phenobarbital is commonly accepted as the first-choice treatment for seizures in newborns, there is no consensus regarding the most appropriate treatment (11-13). There is considerable evidence that phenobarbital achieves clinical and electrographic control in one third to one half of babies within a few hours, and most physicians choose it to treat neonates with seizures (11-15).Studies evaluating the efficacy of phenobarbital have been done using the intravenous form of the drug and all therapeutic recommendations have been based on the data obtained from these studies. Seizure is usually treated with a single intravenous dose of midazolam in the acute period, followed by intravenous administration of phenobarbital, and the treatment is continued with intravenous phenytoin. Unfortunately, intravenous formulations of phenobarbital are not available in some countries, and intravenous phenytoin loading or midazolam infusion is usually the first choice of second line antiepileptic drugs. In some of these countries, phenobarbital is typically administered by enteral loading, but as far we know, no study has been published evaluating the efficacy of this method. The aim of this study was to investigate whether enterally loaded phenobarbital reaches therapeutic serum levels in newborn babies with seizure.     

Addition of rituximab to chop does not increase the risk of cardiotoxicity in patients with non-Hodgkin’s lymphoma

Background The addition of rituximab to doxorubicin-containing standard chemotherapy significantly improves response to therapy and reduces the risk of death in B-cell non-Hodgkin’s lymphoma (NHL) patients. However, the impact of this approach on doxorubicin-induced cardiotoxicity has not been elucidated. Methods Patients who had been planned to receive CHOP or rituximab plus CHOP (R-CHOP) combination chemotherapy with a diagnosis of NHL were included in the study. In all patients, systolic and diastolic parameters were measured by using conventional and pulsed-wave tissue Doppler echocardiography, which is more sensitive than conventional lead-dependent techniques, both before and in the sixth month of therapy. Results There were 28 (M/F; 14/14) patients on CHOP and 33 (M/F; 16/17) patients on R-CHOP. Median age in CHOP and R-CHOP was 49 and 50 years (P = 0.44), respectively. Cumulative doxorubicin doses were 280 and 286 mg/m² on CHOP and R-CHOP (P = 0.65), respectively. None of the patients developed clinically evident congestive heart failure. Parameters of systolic function such as LVEF and FS did not significantly change in any patients. In both arms, tissue Doppler parameters of diastolic function such as lateral E and septal E velocity of mitral annulus decreased significantly after therapy (P < 0.001). However, the decrease in diastolic function was similar in both arms (P > 0.05). Conventional Doppler echocardiography yielded consistent findings. Conclusion Both CHOP and R-CHOP cause diastolic dysfunction in the early period following their administration. The addition of rituximab to CHOP chemotherapy does not significantly increase the risk of doxorubicin-induced cardiotoxicity during this period.     

Doxorubicin-induced second degree and complete atrioventricular block.

Doxorubicin is one of the most effective chemotherapeutic agents used in the treatment of malignancies. Cardiotoxicity is the most important dose-limiting toxicity of doxorubicin. Although cardiomyopathy is the most well known side effect of doxorubicin, it usually occurs many years after the treatment and relates to cumulative doxorubicin dosage. Another form of doxorubicin cardiotoxicity is arrhythmia which may occur at any time and after any dosage. However, doxorubicin-induced arrhythmia is rarely a life-threatening side effect. In this report, we present a case in which there were doxorubicin-induced life-threatening arrhythmias.