Peter W. Johnston

Chemical generation of nitric oxide in the mouth from the enterosalivary circulation of dietary nitrate.

High concentrations of nitrite present in saliva (derived from dietary nitrate) may, upon acidification, generate nitrogen oxides in the stomach in sufficient amounts to provide protection from swallowed pathogens. We now show that, in the rat, reduction of nitrate to nitrite is confined to a specialized area on the posterior surface of the tongue, which is heavily colonized by bacteria, and that nitrate reduction is absent in germ-free rats. We also show that in humans increased salivary nitrite production resulting from nitrate intake enhances oral nitric oxide production. We propose that the salivary generation of nitrite is accomplished by a symbiotic relationship involving nitrate-reducing bacteria on the tongue surface, which is designed to provide host defence against microbial pathogens in the mouth and lower gut. These results provide further evidence for beneficial effects of dietary nitrate.

Histochemical identification of cortical areas in the auditory region of the human brain.

Despite numerous studies stretching over the last 100xa0years there is still no general agreement on the number of auditory areas in the human cortex or even how to define them by histological methods. Full definition of these areas will require a combination of functional and histological methods but, by using six complementary histological methods, of which most have been used in the monkey, we provide a clearer description of these areas. The primary auditory area was located on the posteromedial two-thirds of the first transverse temporal (Heschl’s) gyrus and was distinguished by a dense band of cytochrome oxidase activity in layer IV and the base of layer III, as well as a relatively thick, pale layer V and VI. Layers V and VI together made up 40% of the cortical thickness. Acetylcholinesterase (AChE)-containing pyramidal cells were sparsely distributed within the primary auditory area. The anterolateral third of Heschl’s gyrus did not have a clear band of high cytochrome oxidase activity but contained a moderately high density of AChE-containing pyramidal cells and thus appeared to be part of the auditory belt. Within Heschl’s sulcus there was a third area, which had a band of high cytochrome oxidase activity and bands of high parvalbumin immunoreactivity and AChE activity in layer IV. This area appeared to be part of the auditory core. Thus the use of staining methods for cytochrome oxidase, AChE and parvalbumin provided additional information which allowed a clearer definition of auditory areas than Nissl or myelin staining alone. Our results suggest that there are two core areas surrounded by at least six belt areas in the human auditory region.

European development of clofarabine as treatment for older patients with acute myeloid leukemia considered unsuitable for intensive chemotherapy.

PURPOSEnTreatment options for older patients with acute myeloid leukemia (AML) who are not considered suitable for intensive chemotherapy are limited. We assessed the second-generation purine nucleoside analog, clofarabine, in two similar phase II studies in this group of patients.nnnPATIENTS AND METHODSnTwo consecutive studies, UWCM-001 and BIOV-121, recruited untreated older patients with AML to receive up to four or six 5-day courses of clofarabine. Patients in UWCM-001 were either older than 70 years or 60 to 69 years of age with poor performance status (WHO > 2) or with cardiac comorbidity. Patients in BIOV-121 were >or= 65 years of age and deemed unsuitable for intensive chemotherapy.nnnRESULTSnA total of 106 patients were treated in the two monotherapy studies. Median age was 71 years (range, 60 to 84 years), 30% had adverse-risk cytogenetics, and 36% had a WHO performance score >or= 2. Forty-eight percent had a complete response (32% complete remission, 16% complete remission with incomplete peripheral blood count recovery), and 18% died within 30 days. Interestingly, response and overall survival were not inferior in the adverse cytogenetic risk group. The safety profile of clofarabine in these elderly patients with AML who were unsuitable for intensive chemotherapy was manageable and typical of a cytotoxic agent in patients with acute leukemia. Patients had similar prognostic characteristics to matched patients treated with low-dose cytarabine in the United Kingdom AML14 trial, but had significantly superior response and overall survival.nnnCONCLUSIONnClofarabine is active and generally well tolerated in this patient group. It is worthy of further evaluation in comparative trials and might be of particular use in patients with adverse cytogenetics.

Protection against oral and gastrointestinal diseases: Importance of dietary nitrate intake, oral nitrate reduction and enterosalivary nitrate circulation.

Over the last 20 years, dietary nitrate has been implicated in the formation of methemoglobin and carcinogenic nitrosamines in humans. This has led to restrictions of nitrate and nitrite levels in food and drinking water. However, there is no epidemiological evidence for an increased risk of gastric and intestinal cancer in population groups with high dietary vegetable or nitrate intake. A reevaluation of our currently very negative perception of dietary nitrates comes from recent research into the metabolism and enterosalivary circulation of nitrate in mammals. These studies showed that nitrate is converted to nitrite in the oral cavity that then fuels an important mammalian resistance mechanism against infectious diseases. Moreover, there is now evidence that the conversion of nitrate into oxides of nitrogen prevents the formation carcinogenic nitrosamines.

CD4(+) T-cell responses to Epstein-Barr virus (EBV) latent membrane protein 1 in infectious mononucleosis and EBV-associated non-Hodgkin lymphoma: Th1 in active disease but Tr1 in remission

Primary infection with Epstein–Barr virus (EBV) in childhood is usually asymptomatic, whereas infection in adolescence may result in infectious mononucleosis (IM) often followed by a fatigue syndrome. EBV latent membrane protein 1 (LMP1) is expressed in latency and in many EBV‐associated tumours, including non‐Hodgkin lymphoma (NHL). Given the regulatory nature of the CD4+ T‐cell response against LMP1 previously reported in healthy donors, we investigated whether patients with active EBV‐driven disease can nevertheless mount effector [T‐helper cell, type 1 (Th1)] anti‐LMP1 responses. We therefore performed a longitudinal study of the nature of CD4+ T‐cell responses to LMP1 in four patients with IM, and five patients with NHL. In both groups, responses changed with time. During symptomatic infection or active tumour growth, responses were dominated by a Th1 effector phenotype, but switched to a regulatory interleukin‐10 response upon recovery. In addition, the fine specificities of the T cells driving these responses evolved. This study showed the dynamic nature of CD4+ T‐cell responses to LMP1, and demonstrated that, although patients can mount Th1 effector responses, recovery from IM and NHL is associated with regulatory responses.