Co-localization of neurotransmitter immunoreactivities in putative nitric oxide synthesizing neurones of the cat brain stem

The distribution of nitric oxide producing neurones in the medulla oblongata of the cat was investigated using nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase histochemistry, and nitric oxide synthase (NOS) immunohistochemistry. The pattern of staining obtained with both methods was found to be similar. Strongly diaphorase and NOS reactive neurones were present in the paramedian and lateral tegmental fields, including the regions occupied by the Al/C1 catecholamine cell groups, the nucleus ambiguus and lateral reticular nucleus, and in a number of sensory nuclei including the nucleus of the tractus solitarius and the dorsal column nuclei. The extent of co-localization of NADPH-diaphorase with a number of neuropeptides and neurotransmitters was investigated by combining NADPH-diaphorase histochemistry with immunocytochernisty for neuropeptide Y, somatostatin, glutamate, cholecystokinin and tyrosine hydroxylase. NADPH-diaphorase reaction product was observed in neurones immunoreactive for glutamate and somatostatin. These double-labelled cells were found in the paramedian region, lateral reticular field, the nucleus prepositus hypoglossi and in the rostral nucleus of the tractus solitarius. In the rostral ventrolateral medulla NADPH-diaphorase/somatostatin immunoreactive cells were found in the paragigantocellular nucleus. NADPHdiaphorase/glutamate immunoreactive cells overlapped the nucleus ambiguus, the lateral reticular nucleus and the A1/C1 catecholaminergic cell groups. In addition, a few NADPH-diaphorase/glutamate immunoreactive cells were found in the paraolivary area and gigantocellular tegmental field, in the external cuneate and infratrigerninal nuclei. The functional implications of the co-localization of nitric oxide with these neurotransmitters in areas of the medulla concerned with cardiovascular regulation is discussed.     

Protective effect of a direct renin inhibitor in acute murine model of cardiotoxicity and nephrotoxicity

This study aimed to investigate the possible protective effects of aliskiren against doxorubicin (DXR)‐induced cardiorenal injury and to identify the mechanisms involved. Intraperitoneal administration of DXR (15 mg/kg, body weight, as a single dose) caused significant induction in the levels of angiotensin I, caspase‐3, lactate dehydrogenase (LDH), lipid peroxidation malondialdehyde (MDA), urea, and creatinine. Concomitant decline in the levels of albumin and total protein in plasma, reduction in reduced glutathione (GSH), and antiperoxidative enzyme superoxide dismutase (SOD) levels followed by ultrastructural alterations in the myocardial and renal tissues were also observed. Oral administration of aliskiren (100 mg/kg, for a period of 14 days) significantly prevented all these DXR‐induced adverse effects and maintained the rats near to normal status. However, telmisartan (10 mg/kg) pretreatment has shown slight protection in DXR‐induced renal injury as evidenced by broadening of podocyte foot process and narrowing of slit pore diameter. The results of aliskiren were compared with telmisartan which was used as reference in this study. These results suggested that aliskiren has protective effects against acute model of DXR‐induced cardiotoxicity and nephrotoxicity, implying that plasma renin activity plays a role in DXR‐induced cardio‐renal injury.     

Mitochondrial genome diversity at the Bering Strait area highlights prehistoric human migrations from Siberia to northern North America

The patterns of prehistoric migrations across the Bering Land Bridge are far from being completely understood: there still exists a significant gap in our knowledge of the population history of former Beringia. Here, through comprehensive survey of mitochondrial DNA genomes retained in ‘relic'' populations, the Maritime Chukchi, Siberian Eskimos, and Commander Aleuts, we explore genetic contribution of prehistoric Siberians/Asians to northwestern Native Americans. Overall, 201 complete mitochondrial sequences (52 new and 149 published) were selected in the reconstruction of trees encompassing mtDNA lineages that are restricted to Coastal Chukotka and Alaska, the Canadian Arctic, Greenland, and the Aleutian chain. Phylogeography of the resulting mtDNA genomes (mitogenomes) considerably extends the range and intrinsic diversity of haplogroups (eg, A2a, A2b, D2a, and D4b1a2a1) that emerged and diversified in postglacial central Beringia, defining independent origins of Neo-Eskimos versus Paleo-Eskimos, Aleuts, and Tlingit (Na-Dene). Specifically, Neo-Eskimos, ancestral to modern Inuit, not only appear to be of the High Arctic origin but also to harbor Altai/Sayan-related ancestry. The occurrence of the haplogroup D2a1b haplotypes in Chukotka (Sireniki) introduces the possibility that the traces of Paleo-Eskimos have not been fully erased by spread of the Neo-Eskimos or their descendants. Our findings are consistent with the recurrent gene flow model of multiple streams of expansions to northern North America from northeastern Eurasia in late Pleistocene–early Holocene.     

A critical role for fibroblast growth factor-7 during early alveolar formation in the neonatal rat

Mesenchymal cell-derived FGF-7 (fibroblast growth factor-7) induces proliferation in both epithelial and endothelial cells. We found FGF-7 to be expressed in the lungs of neonatal rats from birth to d 14 of age. A role for FGF-7 in early postnatal lung growth and alveolar formation, by an action on type II pneumocytes, has been excluded by the work of others. However, a role through an action of FGF-7 on other cell types has not been excluded. We used intraperitoneal injections of neutralizing antibodies on d 3, 4, and 5 of life to inhibit binding of FGF-7 to its receptors, and assessed alveolar formation on d 6 of life. This intervention inhibited DNA synthesis in, and number of, alveoli-forming secondary crests, resulting in a significantly reduced alveolar number. This failure of alveolar formation was associated with a reduction in the number of small blood vessels in the lung periphery. We conclude that FGF-7, most likely through its effect on the vascular bed, is required for normal early postnatal alveolar formation from secondary crests.     

Characteristics of Unscheduled and Scheduled Outpatient Palliative Care Clinic Patients at a Comprehensive Cancer Center

Context

There is limited literature regarding outpatient palliative care and factors associated with unscheduled clinic visits.

Differential secretion of proteins and glycoproteins by livers of immature and adult rats. Effect of antimicrotubule drugs

This study was initiated to re-examine reported differences in the action of antimicrotubule agents on plasma protein secretion from livers of immature versus adult rats. The aim was (1) to determine the composition and to monitor the secretion of various plasma proteins and glycoproteins from liver slices labeled in vitro with specific amino acids and sugar residues, and (2) to correlate observed differences in secretion of these proteins with structural changes in the hepatocytes of the different aged animals. For the most part, slices of liver from fetal (term), neonatal (4- to 5 days old), and adult rats (70 days old) were incubated with radioactive amino acids or various tritiated sugars specific for N-linked core oligosaccharide and/or N-linked terminal oligosaccharide chains. Our findings indicate that liver slices of fetal and neonatal rats are efficient in synthesizing plasma proteins including fully glycosylated glycoproteins. The secretion of glycosylated and nonglycosylated proteins believed to be processed through Golgi complexes was inhibited to the same extent (approximately 70-80%) by antimicrotubule agents, regardless of the age of the host animal. However, other proteins and glycoproteins secreted by livers of immature rats were found to be relatively insensitive (i.e. inhibited to only 30-40%) to the action of various antimicrotubule drugs. The glycoproteins were found to lack N-linked terminal sugars (although the glycoproteins did contain N-linked core sugars), and it is likely that the drug-insensitive proteins bypassed critical glycosylating sites in the Golgi compartment prior to release. Overall, these findings support earlier data showing that antimicrotubule drugs have a special impact on Golgi-associated events in liver cells. To what extent these findings are related to the action of microtubules remains to be seen.     

A phase I study of oral LY293111 given daily in combination with irinotecan in patients with solid tumours

Summary Background: LY293111 is an oral agent known to be a leukotriene B4 (LTB4) receptor antagonist and a 5-lipoxygenase inhibitor resulting in selective inhibition of the lipoxygenase pathway. Lipoxygenases metabolize arachidonic acid and have been involved in cancer cell proliferation and survival. In addition, LY293111 has been found to be a peroxisome proliferator activated receptor-gamma (PPAR-γ) agonist. Antineoplastic activity of LY293111 has been identified in preclinical models both alone and in combination with chemotherapy agents including irinotecan. The NCIC Clinical Trials Group studied LY293111 in combination with irinotecan to determine the recommended dose of the combination and to describe its tolerability and pharmacokinetic interaction. In addition the anti-tumour activity of LY293111 in combination with irinotecan was documented. Patients and methods: Twenty-eight patients with advanced solid tumours were treated on seven dose levels with the combination of irinotecan and LY293111. Irinotecan was administered intravenously every 21-days as a single dose. LY293111 was administered twice daily continuously by mouth. Results: Dose limiting toxicity (DLT) of grade 3 diarrhea was seen in two patients with doses of irinotecan 300 mg/m² IV every 21-days in combination with LY293111 300 mg BID. Subsequently the dose of irinotecan was decreased to 250 mg/m² IV every 21-days with escalating doses of LY293111. A DLT of grade 3 abdominal pain was seen at dose 600 mg BID of LY293111 with irinotecan 250 mg/m². The pharmacokinetics (PK) indicated that the administration of LY293111 did not have an effect on the PK of irinotecan or its metabolite SN-38. No responses were seen; seven patients had stable disease of a median duration of 4.4 months (range 2.8–13 months). Conclusion: The recommended phase II dose of LY293111 is 600 mg orally BID in combination with irinotecan 250 mg/m² IV every 21-days. Gastrointestinal adverse effects were common but could be well managed.