PULMONARY ADENOMA AND ENDOCRINE CELL HYPERPLASIA IN SYRIAN GOLDEN HAMSTER TREATED WITH 4-NITROQUINOLINE 1-OXIDE

Chronic effects of 4-nitroquinoline 1-oxide (4 NQO) on the lungs of Syrian golden hamsters were studied. 4 NQO was subcutaneously injected weekly for 3 weeks at a dose of 20 mg/kg body weight. The animals were sacrificed at the 65th and 80th experimental weeks. Two cases of pulmonary adenomas were demonstrated in the 10 4 NQO-treated animals at the 80th week, and the tumor cells contained cytoplasmic lamellar inclusion bodies. In a previous study, we reported 4 NQO- induced pulmonary endocrine cell hyperplasias in the 4 NQO-treated hamster after the 20th experimental week (Jpn. J. Cancer Res., 77,1986). In the present study, 12 pulmonary endocrine cell hyperplasias were recognized in serial sections of the 24 treated animals. The hyperplastic lesions showed positive immunoreactivity to calcitonin. The hyperplastic lesion did not develop to pulmonary endocrine cell neoplasm. ACTA PATHOL JPN 38 : 1097∼1104, 1988.     

Time-resolved fluorometric assay for the detection of endostatin in chromatographically separated extracts of natural peptides

We present a heterogeneous non-competitive immunological detection assay for peptide and protein antigens from crude extracts of biological sources. This time-resolved fluoroimmunoassay (TR-FIA) has been designed in a solid-phase mode using 96-well microtiter plates. Using the rare-earth metal europium as a fluorescent marker, a highly sensitive, selective and efficient procedure was developed. This technique prevents from interferences of intrinsic protein fluorescence which is highly important for antigen measurement in complex matrices. The TR-FIA has been applied for the detection of circulating forms of the potential anti-tumor agent endostatin, a C-terminal fragment of collagen XVIII, and its close homolog collagen XV (restin) from hemofiltrate. Endostatin was detected with a limit of detection of 3 ng (150 fmol/well) and a broad dynamic range from 10-1000 ng/well.     

The renal nerves in the newborn rat

Immunocytochemical methods were used to investigate the distribution of afferent [calcitonin gene-related peptide-(CGRP) immunoreactive and substance P-immunoreactive] nerves and efferent (neuropeptide Y-immunoreactive and dopamine -hydroxylase-immunoreactive) nerves in the kidneys of rats within the 1st day of life. The newborn rat kidney possesses an afferent and efferent innervation. Both afferent and efferent nerves reach the kidney in the same bundles. The afferent sensory fibers predominate overwhelmingly in the renal pelvis and ureter while the efferent fibers clearly predominate in the vasculature. The corticomedullary connective tissue contains both types of innervation with a more prominent afferent innervation (CGRP immunoreactive). Only afferent arterioles of perihilar nephrons were innervated by efferent sympathetic fibers. The distribution and extent of afferent and efferent innervation is consistent with the renal nerves playing a significant role in the transition from fetal to newborn life. The close proximity between afferent and efferent fibers suggests a possible interaction between the two systems.     

Early and delayed cardioprotection by heat stress is mediated by calcitonin gene-related peptide

Brief ischaemia or heat stress protects the myocardium against ischaemia-reperfusion injury. Heat stimulus evokes release of sensory nerve transmitters, including calcitonin gene-related peptide (CGRP). Since CGRP has been shown to play an important role in the mediation of ischaemic preconditioning, the present study examined whether early or delayed preconditioning induced by retrograde hyperthermic perfusion in vitro or by whole-body hyperthemia in vivo also involves endogenous CGRP. Isolated rat hearts were perfused in the Langendorff mode and subjected to 30 min global ischaemia and 30 min reperfusion. Heart rate, coronary flow, left ventricular pressure and its first derivatives (±dp/dt) were recorded and the CGRP-like immunoreactivity (CGRP-LI) content and the release of creatine kinase (CK) during reperfusion were measured. Retrograde hyperthermic perfusion (42 °C) for 5 min improved the recovery of cardiac function, decreased the release of CK and elevated the content of CGRP-LI in the coronary effluent. CGRP_8–37 (10^–7 mol/l), a selective CGRP receptor antagonist, abolished the cardioprotection by heat stress. Pretreatment with capsaicin (50 mg/kg s.c.), which specifically depletes sensory nerve transmitter content, abolished both the cardioprotection and the increased release of CGRP-LI. Whole-body hyperthermia (42 °C for 15 min) caused an increase in the plasma concentration of CGRP-LI. Early or delayed protection was shown in the hearts obtained from the animals subjected to whole-body hyperthermia 10 min or 48 h before the experiments. The early or delayed protection by heat stress was also abolished by pretreatment with capsaicin. The present study suggests that, in the rat, the early and delayed cardioprotection induced by heat stress involves endogenous CGRP. Received: 31 December 1998 / Accepted: 6 April 1999     

Active transport of polypeptides in rabbit nasal mucosa: Possible role in the sampling of potential antigens

Transepithelial pathways of macromolecule transport have been studied in vitro in rabbit nasal respiratory mucosa, maintained at 27° C. Transepithelial electrical potential difference, short-circuit current and resistance were 3.4±0.5mV (submucosa positive), 65.0±6.7 A cm^–2 and 52.1±5.6 cm^–2 respectively (n=15). These electrical characteristics are those of a leaky epithelium allowing macromolecules to permeate paracellularly. A detailed permeation study of a polypeptide (elcatonin, M _w=3362) was also undertaken. Elcatonin mucosa-submucosa (J _ms) and submucosa-mucosa (J _sm) fluxes were measured by radioimmunoassay. With 10 g/ml elcatonin, J _ms was significantly larger than J _sm for the whole 120-min period of observation; net flux showed a maximum in the first 30 min (J _ms=13.6±1.0 ng cm^–2 h^–1, J _sm=1.4±0.1 ng cm^–2 h^–1, n=10). J _ms fell towards the value of J _sm if the temperature was reduced to 4°C or if the mucosa was simultaneously treated with 0.1 mM dinitrophenol and 3 mM monoiodoacetate. J _ms and J _net followed saturation kinetics with increasing elcatonin concentrations. Adrenocorticotropic hormone (M _r=4500) produced a similar pattern to elcatonin. However, J _ms and J _sm were not significantly different from each other at any time either for [³H]sucrose (M _w=342) or for [¹⁴C]polyethyleneglycol-4000 (M _w=4000) when present in the bathing medium at 500 M concentration. The results show active transport of polypeptides in parallel with passive permeation (possibly through leaky intercellular junctions). Active transport does not appear to be related to nonspecific pinocytosis but to receptor-mediated endocytosis. The latter may be important for the sampling of potential antigens from the nasal lumen.     

Mechanisms governing the differentiation of a serotonergic phenotype in culture

The blood–brain barrier prevents the entry of many potentially therapeutic peptide drugs to the brain. Glycosylation has shown potential as a methodology for improving delivery to the CNS. Previous studies have shown improved bioavailability and improved centrally mediated analgesia of glycosylated opioids. In this study we investigate the effect of glycosylation on the cyclic opioid peptide [ -Cys^2,5,Ser⁶,Gly⁷] enkephalin. The peptide was glycosylated on the Ser⁶ via an O-linkage with various sugar moieties and alignments. The peptides were then investigated for receptor binding, physiochemical attributes, in situ brain uptake in female Sprague–Dawley rats and antinociception in male ICR mice. Glycosylation resulted in a slight decrease in affinity to the δ-opioid receptor, and mixed effect on binding to the μ-opioid receptor. There was a significant decrease in lipophilicity resulting from glycosylation and a slight reduction in binding to bovine serum albumin. In situ perfusion showed that brain uptake was improved by up to 98% for several of the glycosylated peptides, and the nociceptive profiles of the peptides, in general, followed the rank order of peptide entry to the brain with up to a 39-fold increase in A.U.C.     

Radioiodinated somatostatin analogue RC-160: preparation,biological activity,in vivo application in rats and comparison with [123I-Tyr3]octreotide

We have evaluated the potential usefulness of the radioiodinated octapeptide RC-160, a somatostatin analogue, which might serve as a radiopharmaceutical for the in vivo detection of somatostatin receptor-positive tumours. For this purpose, iodine-123 and iodine-125 labelled RC-160 was tested for biological activity and applied in vivo in rats bearing the transplantable rat pancreatic tumour CA20948, which expresses somatostatin receptors. Our group has recently described the in vivo visualization of such tumours in rats and in humans with the radioiodinated somatostatin analogue [Tyr³]octreotide. Like [¹²³I-Tyr³]octreotide, ¹²³I-RC-160 showed uptake in and specific binding in vivo to somatostatin receptor-positive organs and tumours. However, blood radioactivity (background) was higher, resulting in a lower tumour to blood (background) ratio. We therefore conclude that in this animal model ¹²³I-RC-160 has no advantage over [¹²³I-Tyr³]octreotide as a radiopharmaceutical for the in vivo use as a somatostatin receptor imager, although, like [¹²³I-Tyr³]octreotide, ¹²³I-RC-160 shows specific binding to different somatostatin receptor-positive organs. Recently differences were reported in affinity between somatostatin and its analogues for somatostatin receptors expressed in different human cancers, like those of the breast, ovary, exocrine pancreas, prostate and colon. Therefore ¹²³I-RC-160 might be of interest for future use in humans as a radiopharmaceutical for imaging octreotide receptor-negative tumours. Correspondence to: W.A.P. Breeman, Department of Nuclear Medicine, University Hospital Dijkzigt, Dr. Molewaterplein 40, NL-3015 GD Rotterdam, The NetherlandsThe authors wish to thank Dr. Wil Kort, Ineke Hekking-Weyma, Reno Mekes, Marcello Harms and Ina Loeve for their expert assistance during the experiments.     

血清PCT与hs-CRP对新生儿细菌感染性肺炎的诊断价值

目的 比较血清降钙素原(PCT)和超敏C反应蛋白(hs-CRP)对新生儿细菌感染性肺炎的诊断价值.方法 选择2015年1月至2016年6月期间我院收治的新生儿肺炎90例为研究对象,根据病原体的不同分为细菌性肺炎组(n=46)与非细菌性肺炎组(n=44),比较两组患儿血清PCT和hs-CRP阳性率,以及细菌性肺炎患儿治疗后血清PCT和hs-CRP阳性率的变化.结果 细菌性肺炎组患儿的hs-CRP、PCT阳性率分别为71.74%、91.30%,明显高于非细菌性肺炎组患儿的18.18%和4.55%,差异均有统计学意义(P<0.05);细菌性肺炎患儿治疗1周后,PCT阳性率为32.61%,高于hs-CRP的13.04%,差异均有统计学意义(P<0.05);治疗2周后PCT和hs-CRP阳性率分别为4.35%和2.17%,差异无统计学意义(P>0.05).结论 血清PCT对于新生儿细菌性肺炎具有更好的诊断及鉴别诊断价值,且PCT有助于评估治疗效果并指导抗菌药物的应用.     

The Analgesic Role of Calcitonin Following Osteoporotic Fracture

Osteoporosis is a systemic skeletal condition characterized by decreased bone strength with consequent increased susceptibility to bone fracture. Fragility fractures in osteoporosis are often painful and result in loss of quality of life and disability. Salmon calcitonin (SCT) is a natural hormone that may assist in the management of osteoporotic patients following fracture by reducing fracture risk and decreasing pain. SCT is an antiresorptive agent which has been shown to reduce the risk of vertebral fractures (by 36%) in postmenopausal women with osteoporosis and previous fractures, with a safety profile comparable to placebo over long-term use. Clinical evidence suggests that SCT (with either subcutaneous and intranasal delivery) is an analgesic for the acute pain following osteoporotic fracture. Pain relief with SCT occurs after 1 week or less of treatment. Associated with this pain relief, vertebral fracture patients receiving SCT have been observed to have earlier mobilization compared with those receiving a placebo. Both preclinical and clinical data suggest a central analgesic effect for SCT. The mechanism(s) by which SCT induces pain relief has (have) not been conclusively shown. Neither a direct receptor-mediated action nor an indirect endorphin-mediated effect can be ruled out. Received: 26 October 2001 / Accepted: 17 June 2002 Correspondence and offprint requests to: Stuart Silverman, MD, 8641 Wilshire Blvd, Suite 301, Beverly Hills, CA 90211, USA. e-mail: stuarts@omcresearch.org