Role of insulin and atrial natriuretic peptide in sodium retention in insulin-treated IDDM patients during isotonic volume expansion

Because insulin shows an antinatriuretic effect in healthy humans, insulin therapy resulting in circulating hyperinsulinemia may lead to sodium retention and in turn to hypertension in individuals with insulin-dependent diabetes mellitus (IDDM). Moreover, it has been proved that atrial natriuretic peptide (ANP) plays a major role in modulating natriuresis in humans. This study investigated the relationship between insulin and ANP in modulating sodium metabolism in normotensive and hypertensive IDDM subjects compared with control groups of normotensive and hypertensive nondiabetic subjects. IDDM normotensive and hypertensive subjects had mean +/- SE duration of IDDM of 7 +/- 2 and 8 +/- 2 yr, respectively, and had no clinical features of diabetic nephropathy. All subjects received a saline infusion (2 mmol.kg-1.90 min-1) during euglycemia. IDDM normotensive and hypertensive subjects received a subcutaneous insulin infusion (15 mU.kg-1.h-1), resulting in twofold higher plasma free-insulin levels (16 +/- 2 and 19 +/- 3 microU/ml, respectively) than in nondiabetic normotensive and hypertensive subjects (7 +/- 2 and 8 +/- 2 microU/ml, respectively). During saline challenge, sodium excretion increased by 22 +/- 4% in normotensive and 49 +/- 9% in hypertensive nondiabetic subjects but by only 11 +/- 0.4% in normotensive (P less than 0.01) and 8 +/- 2% in hypertensive (P less than 0.01) IDDM subjects. The impaired natriuretic response to saline challenge was mainly due to greater rates of sodium reabsorption by kidney proximal tubules in IDDM than nondiabetic subjects. At baseline, plasma ANP concentrations were significantly higher in both IDDM groups than in control groups (normotensive IDDM and control subjects: 38 +/- 4 and 19 +/- 2 pg/ml, respectively, P less than 0.01; hypertensive IDDM and control subjects: 45 +/- 6 and 27 +/- 4 pg/ml, respectively, P less than 0.05). After saline challenge, ANP concentrations rose to 39 +/- 4 pg/ml in normotensive and 49 +/- 5 pg/ml in hypertensive control subjects, whereas no significant change above baseline value was seen in IDDM subjects. Both IDDM groups showed a 10-12% greater exchangeable Na+ pool than control subjects regardless of the presence of hypertension. Subcutaneous insulin infusion, resulting in circulating plasma free-insulin levels in normotensive control subjects comparable to those in IDDM patients, inhibited natriuresis, increased proximal tubule sodium reabsorption at the level of the kidney, and inhibited an adequate ANP stimulation by saline challenge. We conclude that hyperinsulinemia leads to increased proximal tubule sodium reabsorption and impaired ANP response during saline administration. Both mechanisms account for sodium retention in normotensive and hypertensive IDDM patients.(ABSTRACT TRUNCATED AT 400 WORDS)     

Expression and distribution of vascular endothelial growth factor protein in human brain tumors

Marked neovascularization is a hallmark of many neoplasms in the nervous system. Recent reports indicate that the endothelial mitogen vascular endothelial growth factor (VEGF) may play a critical role in the regulation of vascular endothelial proliferation in malignant gliomas. Using novel monoclonal antibodies to the VEGF polypeptide we have determined the expression and cellular distribution of VEGF protein in a representative series of 171 human central nervous system (CNS) tumors by immunohistochemistry and immunoblotting. In agreement with previous in situ hybridization data, 19 out of 20 glioblastomas (95%) showed immunoreactivity for VEGF, whereas both the percentage of immunoreactive tumors and the extent of immunoreactivity for VEGF were significantly lower in astrocytomas. Of the pilocytic astrocytomas (WHO grade I) 44% were immunoreactive for VEGF, but we observed several cases with pronounced vascular proliferates in the absence of VEGF. In ependymomas, meningiomas, hemangioblastomas, and primitive neuroectodermal tumors, there was no correlation between VEGF expression, vascular endothelial proliferation and the grade of malignancy. Oligodendrogliomas and the oligodendroglial component of mixed gliomas lacked immunoreactive VEGF, indicating that endothelial growth factors other than VEGF may regulate tumor angiogenesis in these neoplasms. Western blot analysis showed a predominant VEGF protein species of 23 kDa and confirmed the immunohistochemical data in all cases. Our findings demonstrate that VEGF is expressed in a wide spectrum of brain tumors in which it may induce neovascularization. However, other angiogenic factors also appear to contribute to the vascularization of CNS neoplasms. Received: 18 April 1996 / Revised, accepted: 20 August 1996     

Antibiotic resistance in exopolysaccharide-forming Staphylococcus epidermidis clinical isolates from orthopaedic implant infections

The opportunistic pathogen Staphylococcus epidermidis is able to produce biofilm and to frequently cause implant infections. In recent years, it has also exhibited an increasing antimicrobial drug resistance. Here, the resistance to a panel of 16 different antibiotics in 342 clinical strains of S. epidermidis from orthopaedic implant infections has been investigated. The isolates were pheno- and genotyped for extracellular polysaccharide production, relevant to staphylococcal biofilm formation, in order to ascertain possible associations with antibiotic resistance. Approximately 10% of the isolates were found to be sensitive to all screened antibiotics. In all, 37-38% were resistant to beta-lactams such as oxacillin and imipenem, while the resistance to penicillin, ampicillin, cefazolin, cefamandole, was consistently observed in over 80% of the strains. Erythromycin- and clindamycin- resistant strains were approximately 41% and 16%, respectively. Of the isolates, 10% was resistant to chloramphenicol, 23% to sulfamethoxazole and 26% to ciprofloxacin. Resistance to vancomycin was never observed. Interestingly, exopolysaccharide-producing strains exhibited a significantly higher prevalence in the resistance to the four aminoglycosides (gentamicin, amikacin, netilmicin, tobramycin), to sulfamethoxazole and to ciprofloxacin with respect to non-producing isolates. Moreover, multiple resistance to antibiotics was more frequent among exopolysaccharide-forming strains.     

4′ -epi-doxorubicin in advanced lung cancer

Summary Fifty evaluable patients with advanced lung cancer (28 small cell and 22 non-small cell carcinomas), mainly pretreated by chemotherapy, received 4-epi-doxorubicin 90 mg/m² every 3 weeks. Two partial responses were obtained in small cell lung cancer patients, which lasted 153 and 168 days. Leukopenia, emesis and alopecia were the most frequent side effects. Two patients who previously received anthracyclines died suddenly of cardiac failure, another patient had severe congestive heart failure, and four others had minor cardiac dysfunctions. 4-epi-doxorubicin has a modest activity in advanced lung cancer, mainly pretreated by chemotherapy and is not devoid of significant cardiotoxicity in this patient population.     

The impact of basic fibroblast growth factor on photoreceptor function and morphology.

PURPOSE: To assess the impact of basic fibroblast growth factor (bFGF) on photoreceptor function and morphology. METHODS: Impact was assessed in two models. In one, the endogenous expression of bFGF in photoreceptors was raised by sectioning one optic nerve of rats 3 to 4 weeks before study. In the other, bFGF was injected into the vitreous chamber in rats and cats. Retinal function was assessed from the electroretinogram (ERG), and retinal morphology was studied using DNA dyes, immunolabeling, and in situ hybridization. RESULTS: In both models of bFGF upregulation, the ERG b-wave was suppressed over a wide stimulus range and in light- and dark-adapted conditions. The a-wave was not suppressed by either procedure and at the brightest intensities was enhanced by both procedures. In nerve-sectioned eyes, outer retina appeared normal histologically, but levels of bFGF protein in the inner and outer nuclear layers were raised, whereas bFGF mRNA levels remained unchanged. In both models, levels of synaptophysin in the outer plexiform layer and of cytochrome oxidase in inner segments were raised in association with increases in bFGF protein levels. CONCLUSIONS: bFGF increased the ability of photoreceptors to respond to light but attenuated the transmission of this response to inner retinal cells, presumably by blocking the photoreceptor-bipolar synapse. If the expression of bFGF protein is upregulated in human photoreceptor dystrophies, it may contribute a reversible component to the loss of vision. The relationship between these actions of bFGF and its ability to protect photoreceptors from stress remains to be established.     

Conservative surgery for Stage I ovarian carcinoma in women of childbearing age

Objective To assess the results of a policy of tailored conservative surgical management for young women with stage I ovarian carcinomas.
Design Retrospective study.
Participants Ninety-nine women aged 40 years or younger who underwent either primary surgery in our department or were referred after primary surgery performed elsewhere.
Methods Of the 99 women in our study, 56 underwent fertility-sparing surgery and 43 more radical surgery. Minimal requirements for conservative management were adequate staging and complete information about the therapeutic options. Factors important in the choice of the treatment were, age, wish to preserve fertility, histologic type and grade, and the stage of the tumour.
Results Conservative treatment was conducted in 84% of nulliparous and in 33% of parous women; 62% of grade 1 tumours, 48% of grade 2, and 50% of grade 3 were treated conservatively. With a median follow up of seven years, we observed five recurrences (9%) of carcinoma in women treated conservatively and five (12%) in those treated more radically. Two women (one in each treatment arm) were saved after recurrence. Two recurrences after conservative surgery involved the residual ovary (3.6%). Two women developed borderline tumour in the contralateral ovary and both were treated by surgery.
Conclusion After adequate staging and accurate information is given to the patient, conservative treatment may be safe in some women with early ovarian cancer. The risk of recurrence in the contralateral ovary is low. Conservative surgery may be also considered in some Stage I grade 3 tumours and in some women with stage IC tumours.     

FGFR1 Expression and FGFR1-FGF-2 Colocalisation in Rat Retina: Sites of FGF-2 Action on Rat Photoreceptors

Aim : To identify sites of FGF-2 action on photoreceptors of the rat retina, by localizing FGFR1 in the intact retina, and to assess the colocalisation of FGF-2 with FGFR1. Methods : Immunohistochemistry and confocal microscopy were used to localise FGF-2 and FGFR1 in cryosections of the rat retina, both normal retina and retina stressed by exposure to bright continuous light (1000 lux, 24 h). Antibodies to synaptophysin (SY), cytochrome oxidase (CO) and opsin were used to relate FGFR1-labelling to synaptic vesicles, mitochondria and the photoreceptor cell membrane. Electron microscopy was used to demonstrate the location of synapses within the outer plexiform layer (OPL). Results : FGFR1 was most prominent in the outer nuclear layer (ONL), as diffuse labelling of photoreceptor cytoplasm and as granules between photoreceptor somas. FGFR1 labelling was also observed in the outer synapse-rich sublayer of the OPL where it colocalised with SY, but not with CO-labelled mitochondria. In stressed retina, both at the edge of normal retina and after light stress, FGFR1 expression was upregulated in both the ONL and the OPL. Colocalisation of FGFR1 with FGF-2 could not be demonstrated in unstressed retina, but was demonstrable in stressed retina, in both the ONL and OPL. Conclusions : FGFR1 is prominent in the cytoplasm of photoreceptors, and in their axon terminals, where it is closely associated with synaptic vesicles. Colocalisation of FGFR1 and FGF-2 could be demonstrated in stressed retina, in the cytoplasm and the axon terminals of photoreceptors. The known protective action of FGF-2 may be exerted at the photoreceptor soma. The action of FGF-2 in inhibiting the ERG b-wave may be exerted at the axon terminal.