EGF/EGF-R system and benign breast disease during and following the treatment of gynaecological pathologies with an analogue of LH-RH

Clinical and pathological changes of the mammary gland have been studied in 64 women affected by symptomatic Benign Breast Disease (BBD) coexisting with endometriosis or uterine leiomyomata. These patients were rendered hypoestrogenic by subcutaneous administration of the LH-RH analogue Goserelin depot [D-ser (tBu)6 Aza-Gly10-GnRH (ICI118630)] performed every 28 days, for six months. They were evaluated clinically and ultrasonographically before and after treatment to find possible changes of BBD as well as of endometriosis or uterine leiomyomata. Mammary biopsies were performed before and after treatment in all the patients to study the changes of EGF-R expression. Results showed that clinical improvement is accompanied with a reduction of EGF-R expression.     

Regeneration of active receptor recognition domains on the B subunit of cholera toxin by formation of hybrids from chemically inactivated derivatives

In order to test the hypothesis that binding sites of cholera toxin for its receptor, the monosialoganglioside GM1, are shared between adjacent beta-polypeptide chains, two inactive chemical derivatives of the B subunit of cholera toxin (CTB) were prepared and were subsequently used for the construction of hybrid CTB pentamers. One inactive derivative consisted of CTB specifically modified in the single essential Trp-88 residue of each beta-chain. This residue was modified by formylation, a treatment preserving the structural integrity of CTB. The other inactive derivative consisted of CTB specifically succinylated in three amino groups located in or near the receptor binding site. Using [1,4-14C]succinic anhydride for the site-specific succinylation and analysis of radiolabeled tryptic fragments of S-carboxymethylated [14C]sssCTB revealed that the amino groups specifically modified were the alpha-amino group of Thr-1 and the epsilon-amino groups of respectively Lys-34 and Lys-91. Upon submitting equal amounts of formylated CTB and site-specific succinylated CTB to a denaturation-renaturation cycle, hybrid pentamers were formed which in contrast to the parental compounds were able to bind GM1. The affinity of hybrid CTB for GM1, as estimated by a competitive solid-phase radiobinding assay was unexpectedly high and only 2.5-fold lower than that of its native counterpart. The number of active binding sites on hybrid CTB was determined from: (i) titration with the oligosaccharide moiety of GM1 (oligo-GM1) and monitoring the reversal of the Trp fluorescence quenching by iodide ions and (ii) rapid gel filtration over a superdex HR column of a mixture of hybrid CTB and an excess of 3H-labeled oligo-GM1. The data are in agreement with the formation of one active binding per four reconstituted binding sites in hybrid CTB, which is consistent with a random association of CTB monomers during the denaturation-renaturation cycle.     

Practical accuracy analysis of some existing effective channellength and series resistance extraction methods for MOSFET's

A method to analyze the accuracy of the extracted values for the channel length (L_eff) and series resistance (R_s) of MOSFET devices is presented. The analysis is based on a statistical argument being the variance σ of the extracted results. This variance is found to be a good measure for the accuracy of the particular extraction method used. It is shown that, in the case of deep submicron technologies, errors as large as 200 nm for ΔL can be made for these extraction methods depending on the process design and the process control. The use of a single transistor method is suggested as a possible solution to the low accuracy of the L-array methods     

Plasma mevalonate concentrations in uremic patients

Mevalonic acid (mevalonate or MVA), is an obligate precursor in the biosynthetic pathway of cholesterol. It is partially metabolized by the kidneys and its plasma concentrations are an index of endogenous cholesterol synthesis. The aim of the present study was to evaluate plasma MVA concentrations in uremic patients with different degrees of chronic renal failure (CRF; group A), and the effects of a single hemodialysis treatment on plasma MVA in a group of patients with end-stage renal disease (ESRD; group B). CRF patients exhibited a higher mean basal mevalonate concentration (13.3 +/- 6.5 ng/ml) than control subjects (4.68 +/- 1.32 ng/ml; P < 0.001). A statistically significant direct correlation was evident in CRF patients between mevalonate and creatinine plasma levels (r = 0.86; P < 0.001). A single hemodialysis treatment was associated with a significant reduction of plasma mevalonate concentrations four hours after the hemodialysis session (-57%; P < 0.001) and an increase up to the basal values 24 hours after the end of the treatment. In conclusion, our results demonstrated: (i) higher plasma MVA concentrations in patients with decreased renal function; (ii) a direct relationship between plasma MVA levels and the degree of kidney failure as expressed by creatinine plasma concentrations; and (iii) a clear cut reduction of elevated plasma MVA levels after a single hemodialysis treatment.     

Stability, in-Vitro and in-Vivo Release Studies from Metronidazole Ointments

The influence of ointment formulation on the stability, the in-vitro release and the in-vivo absorption through the skin of rabbits was investigated. The choice of the selected ointments has no influence on the drug stability with the exception of an acidified emulsion base. A good correlation between in-vitro release and in-vivo absorption was found revealing that metronidazole was quickly released and effectively absorbed from a polyethylene glycol base.     

Specific bronchial provocation tests with flour in the diagnosis of occupational bronchial asthma

The gold standard in the diagnosis of occupational asthma is the specific bronchial provocation test (sBPT), but other diagnostic criteria have been proven to have a similar sensitivity, mainly in asthma due to high molecular weight compounds. In order to assess wether some clinical findings can predict the positive response to sBPT, we studied 37 subjects (14 millers and 23 bakers) with suspected occupational asthma who underwent sBPT with wheat flour dust (dust exposure in a small cabin: geometric mean 12.1 mg/m3 for up to 30 min). A positive response to sBPT (FEV1 > 20%) was elicited in 20 subjects (11 early, 4 late, and 5 dual responses). There was no significant difference between subjects with positive or negative sBPT as regards mean age, smoking, length of employment, duration of symptoms, atopy (skin positivity to one or more common allergens) and PD20FEV1 methacholine. The percentage of subjects with work-related symptoms was significantly higher in subjects with positive sBPT with respect to subjects with negative sBPT (81% versus 41.2%, p < 0.01 by chi 2 test); furthermore, FEV1 was significantly lower in subjects with positive sBPT. The percentage of positive skin response to wheat flour extract (mean wheal diameter > or = 3 mm) was mildly but not significantly higher in subjects with positive sBPT (68.4% versus 41.2%). None of the following clinical factors (age < 35 years, asthma symptoms pre-existing occupational exposure, non smokers, atopy and bronchial hyperresponsiveness to methacholine), alone or in combination, were associated with higher prevalence of positive sBPT. We conclude that the response to sBPT in subjects with suspected occupational asthma due to flour dust can not be adequately predicted by other clinical, allergologic and functional data. Therefore, sBPT with flour dust should always be performed in subjects with suspected occupational asthma.     

Preparation of V/ZrO2 catalysts by the sol-gel method: Physical and structural characterization

Some zirconia-supported vanadium oxides have been prepared by sol-gel method and characterized by different techniques. The vanadium content exerts an effect on the area and pore-size of precursors and samples calcined. The presence of vanadium also affects the decomposition of precursors into ZrO₂ and to its phase transformation, as well as the formation of fibres, as shown by SEM-EDX. XPS analyses show the presence of two species of vanadium at the surface, V^5– and V⁴⁺, the percentage of each one depending on the load of vanadium in the catalyst.     

Randomized placebo trial of myeloprotection with goralatide in patients with squamous cell carcinoma of the upper respiratory and digestive tracts or esophagus, treated with a carboplatin-fluorouracil combination

Eighty-four patients with locally advanced, non metastatic squamous cell carcinoma of head and neck or esophagus, were included in a multicentric double-blind randomized trial, comparing goralatide (12.5 or 62.5 micrograms/kg/day, d1-d4) to placebo, associated with carboplatin (400 mg/m2, d1) and 5-fluorouracile (1 g/m2/d continuous IV over 96 hours). Haematological toxicity was analysed on 221 cycles of chemotherapy. All but one patient were evaluable because of early death without haematological toxicity. No significant difference was observed for mean nadir of leukocytes, granulocytes, platelets counts and hemoglobin level. Duration of haematological toxicity was no significantly different for the two groups of patients. Anemia and lymphopenia were more frequent in the goralatide treated patients. Clinical and biological tolerability of goralatide was excellent.     

Zollinger-Ellison syndrome and antral G-cell hyperfunction in patients with resistant duodenal ulcer disease

We measured basal and pentagastrin-stimulated acid secretion, as well as basal and meal-stimulated plasma gastrin concentration to determine, in 67 patients affected by resistant duodenal ulcer, whether their condition could be related to gastric acid secretion and/or gastrin-related syndromes. We then compared them to 46 duodenal ulcer control patients. The outpatients were investigated consecutively. The resistant duodenal ulcer patients differed from the controls only in their higher complication rates (bleeding or perforation, P < 0.05). We identified five patients in the resistant duodenal ulcer group with Zollinger-Ellison syndrome and 12 with antral G cell hyperfunction, whereas in the control group only one patient was affected by antral G cell hyperfunction. IgG anti-Helicobacter pylori antibodies were positive for the presence of infection in 7 of the hypergastrinaemic patients. When Zollinger-Ellison syndrome or antral G cell hyperfunction were excluded, no differences could be found in gastric acid secretion, or basal and meal-stimulated plasma gastrin levels, between the resistant and control duodenal ulcer patients, except for basal acid hypersecretion (resistant duodenal ulcer 16% vs duodenal ulcer 2% P = 0.0144). In the presence of duodenal ulcer disease resistant to H2-blockers, it is mandatory to measure basal plasma gastrin concentration since it was possible to diagnose the gastrin-related syndromes, Zollinger-Ellison syndrome and antral G cell hyperfunction, in 26% of this group of patients.     

Inhibitory effect of 9-(2-phosphonylmethoxyethyl)adenine on visna virus infection in lambs: a model for in vivo testing of candidate anti-human immunodeficiency virus drugs

The acyclic nucleoside phosphonate analog 9-(2-phosphonylmethoxyethyl)adenine (PMEA) was recently found to be effective as an inhibitor of visna virus replication and cytopathic effect in sheep choroid plexus cultures. To study whether PMEA also affects visna virus infection in sheep, two groups of four lambs each were inoculated intracerebrally with 10(6.3) TCID50 of visna virus strain KV1772 and treated subcutaneously three times a week with PMEA at 10 and 25 mg/kg, respectively. The treatment was begun on the day of virus inoculation and continued for 6 weeks. A group of four lambs were infected in the same way but were not treated. The lambs were bled weekly or biweekly and the leukocytes were tested for virus. At 7 weeks after infection, the animals were sacrificed, and cerebrospinal fluid (CSF) and samples of tissue from various areas of the brain and from lungs, spleen, and lymph nodes were collected for isolation of virus and for histopathologic examination. The PMEA treatment had a striking effect on visna virus infection, which was similar for both doses of the drug. Thus, the frequency of virus isolations was much lower in PMEA-treated than in untreated lambs. The difference was particularly pronounced in the blood, CSF, and brain tissue. Furthermore, CSF cell counts were much lower and inflammatory lesions in the brain were much less severe in the treated lambs than in the untreated controls. The results indicate that PMEA inhibits the propagation and spread of visna virus in infected lambs and prevents brain lesions, at least during early infection. The drug caused no noticeable side effects during the 6 weeks of treatment.