Buccodental side effects of sunitinib in patients with metastatic renal cell carcinoma.

BACKGROUND: Sunitinib is a tyrosine kinase inhibitor approved for the treatment of renal cell carcinoma (RCC). Few data evaluated severe buccodental adverse events. The aim of this study was to evaluate sunitinib buccodental toxicity in patients with metastatic RCC and to compare it with that of standard chemotherapy in patients with other solid cancers. METHODS: Patients with RCC treated with sunitinib and patients with other solid tumours treated with chemotherapy were followed for 3 months. Data on dental appliances, oral hygiene/care practices before and during treatment were collected. RESULTS: A total of 116 patients were included (58 RCC treated by sunitinib: group S, and 58 treated by chemotherapy: group C). No differences in dental care habits were noted before treatment. In group S, patients reported significantly more frequent pain (P<0.01), teeth instability (P=0.01), gingival bleeding (P=0.01) and change in teeth colour (P=0.02). In all, 58% of patients in this group had to modify their diet (P<0.01). Frequency of dentist visits for teeth removal was increased (25% vs 8%, P=0.01). CONCLUSION: Sunitinib seems to increase buccodental toxicity as compared with chemotherapy. This finding emphasises the need for optimal dental care and standardised dental follow-up in patients treated with sunitinib.

From a dull enzyme to something else: facts and perspectives regarding aldose reductase.

Aldose Reductase (ALR2) is defined as the first enzyme of the "polyol pathway". As such, ALR2 would convert glucose to sorbitol through an NADPH dependent reaction. Considered a promoter of osmotic imbalance under hyperglycemic conditions, the enzyme has been under intense investigation as a critical target to prevent and control diabetic complications through the inhibition of its activity. Further characterization of ALR2 suggests its participation in cell detoxification mechanisms through the reduction of toxic aldehydes. Moreover, intriguing is the apparent involvement of the enzyme in the signalling machinery of inflammatory cell response. Here, the structural and functional assessment of ALR2 as an aldose/aldehyde reducing enzyme, and its involvement in various aspects of cell function from sugar metabolism to redox homeostasis and cell signaling are presented.

Rectal intussusception: can high resolution three-dimensional ano-rectal manometry compete with conventional defecography?

BACKGROUND: Three-dimensional high-resolution anorectal manometry (3DHRAM), used for exploring anorectal disorders, was recently developed, providing interesting topographic data for the diagnosis of pelvic floor disorders such as excessive perineal descent. The aim of our study was to define a diagnostic strategy based on selected 3DHRAM parameters to identify rectal intussusceptions (RI), considering conventional defecography (CD) as the gold standard. METHODS: All patients referred to our center in the previous 6 months for 3DHRAM to explore fecal incontinence or constipation, and who previously achieved CD, were eligible. 3DHRAM results were obtained for all classical parameters and the presence of a narrow band of high pressure in the anal canal during attempted defecation, which was recently found to be associated with RI in some studies. The sensitivity, specificity, and positive and negative predictive values were calculated for various 3DHRAM criterion in order to propose a diagnostic strategy for RI. KEY RESULTS: Twenty-six patients (66%) presented with RI on CD. On 3DHRAM, according to our diagnostic strategy, the most relevant manometric criterion for the diagnosis of RI was the association of an anterior additional high-pressure area and an excessive perineal descent, with a positive predictive value of 100% [81.5-100], a specificity of 100% [75.3-100] and a sensibility of 69.2% [48.2-85.7]. CONCLUSIONS & INFERENCES: In this study, 3DHRAM was used to diagnose RI, and we confirmed its use in the diagnosis of pelvic floor disorders. Further studies will be necessary to define classifications for these new anatomic data from 3DHRAM.

In vitro recycling of alpha-D-ribose 1-phosphate for the salvage of purine bases.

In this paper, we extend our previous observation on the mobilization of the ribose moiety from a purine nucleoside to a pyrimidine base, with subsequent pyrimidine nucleotides formation (Cappiello et al., Biochim. Biophys. Acta 1425 (1998) 273-281). The data show that, at least in vitro, also the reverse process is possible. In rat brain extracts, the activated ribose, stemming from uridine as ribose 1-phosphate, can be used to salvage adenine and hypoxanthine to their respective nucleotides. Since the salvage of purine bases is a 5-phosphoribosyl 1-pyrophosphate-dependent process, catalyzed by adenine phosphoribosyltransferase and hypoxanthine guanine phosphoribosyltransferase, our results imply that Rib-1P must be transformed into 5-phosphoribosyl 1-pyrophosphate, via the successive action of phosphopentomutase and 5-phosphoribosyl 1-pyrophosphate synthetase; and,in fact, no adenosine could be found as an intermediate when rat brain extracts were incubated with adenine, Rib-1P and ATP, showing that adenine salvage does not imply adenine ribosylation, followed by adenosine phosphorylation. Taken together with our previous results on the Rib-1P-dependent salvage of pyrimidine nucleotides, our results give a clear picture of the in vitro Rib-1P recycling, for both purine and pyrimidine salvage.

In vitro assessment of salvage pathways for pyrimidine bases in rat liver and brain.

In this paper we extend our previous observation on the mobilization of the ribose moiety from guanosine to xanthine catalyzed by rat liver extracts (Giorgelli et al., Biochim. Biophys. Acta 1335 (1997) 16-22). The data show that in rat liver and brain extracts the activated ribose, stemming from inosine and guanosine phosphorolysis as ribose 1-phosphate, can be used to salvage uracil to uracil nucleotides. Uridine is an intermediate. The salvage process occurs even in the presence of excess inorganic phosphate suggesting that uridine phosphorylase may function in vivo as an anabolic enzyme. Ribose 5-phosphate cannot substitute for inosine, guanosine or ribose 1-phosphate as ribose donor. When inorganic phosphate was substituted with arsenate, hindering the formation of ribose 1-phosphate, no ribose transfer could be observed. A similar pathway occurs at the deoxy level. The deoxyribose moiety of deoxyinosine can be used to salvage thymine to thymine nucleotides, again in the presence of excess inorganic phosphate. Our results introduce a novel aspect of the salvage pathway, in which ribose 1-phosphate seems to play a pivotal role.

Ribose 1-phosphate and inosine activate uracil salvage in rat brain.

The purpose of this study was to determine the mechanism by which inosine activates pyrimidine salvage in CNS. The levels of cerebral inosine, hypoxanthine, uridine, uracil, ribose 1-phosphate and inorganic phosphate were determined, to evaluate the Gibbs free energy changes (deltaG) of the reactions catalyzed by purine nucleoside phosphorylase and uridine phosphorylase, respectively. A deltaG value of 0.59 kcal/mol for the combined reaction inosine+uracil <==> uridine+hypoxanthine was obtained, suggesting that at least in anoxic brain the system may readily respond to metabolite fluctuations. If purine nucleoside phosphorolysis and uridine phosphorolysis are coupled to uridine phosphorylation, catalyzed by uridine kinase, whose activity is relatively high in brain, the three enzyme activities will constitute a pyrimidine salvage pathway in which ribose 1-phosphate plays a pivotal role. CTP, presumably the last product of the pathway, and, to a lesser extent, UTP, exert inhibition on rat brain uridine nucleotides salvage synthesis, most likely at the level of the kinase reaction. On the contrary ATP and GTP are specific phosphate donors.

Purine nucleoside phosphorylase from bovine lens: purification and properties.

Purine nucleoside phosphorylase (purine nucleoside: orthophosphate ribosyltransferase, EC 2.4.2.1) was purified 38,750-fold to apparent electrophoretic homogeneity from bovine ocular lens. The enzyme appears to be a homotrimer with a molecular weight of 97,000, and displays non-linear kinetics with concave downward curvature in double-reciprocal plots with orthophosphate as variable substrate. The analysis of the kinetic parameters of bovine lens purine nucleoside phosphorylase, determined both for the phosphorolytic activity on nucleosides and for ribosylating activity on purine bases, indicates the occurrence of a rapid equilibrium random Bi-Bi mechanism with formation of abortive complexes. The effect of pH on the enzyme activity and on the sensitivity of the enzyme to photoinactivation, as well as the effect of thiol reagents on the enzyme activity and stability, strongly suggest the involvement of histidine and cysteine residues in the active site. From the measurements of the kinetic parameters at different temperatures, heats of formation of the enzyme-substrate complex for guanosine, guanine, orthophosphate and ribose 1-phosphate were determined. Activation energies of 15,250 and 14,650 cal/mol were obtained for phosphorolysis and synthesis of guanosine, respectively.

Synthesis, activity, and molecular modeling of a new series of tricyclic pyridazinones as selective aldose reductase inhibitors.

Three new series of tricyclic pyridazinones have been synthesized and tested in vitro in order to assess (i) their ability to inhibit aldose reductase enzyme (ALR2) and (ii) their specificity toward the target enzyme with respect to other related oxidoreductases, such as aldehyde reductase, sorbitol dehydrogenase, and glutathione reductase. The inhibitory capability of the most effective compounds (IC50 values ranging from 6.44 to 12.6 microM) appears to be associated with a rather significant specificity for ALR2. Molecular mechanics and molecular dynamic calculations performed on the ALR2-inhibitor complex give indications of specific interaction sites responsible for the binding, thus providing information for the design of new inhibitors with improved affinity for the enzyme.

Kinetics of human thrombin inhibition by two novel peptide inhibitors (Hirunorm IV and Hirunorm V).

A study on the kinetics of human thrombin inhibition by two novel synthetic peptides (Hirunorm IV and Hirunorm V) and a comparison with recombinant hirudin and a commonly used thrombin inhibitor, Hirulog-1, are reported. The dissociation constants for Hirunorm IV and Hirunorm V were determined by varying the concentration of inhibitors at fixed concentrations of the chromogenic substrate Chromozym-TH (N-tosylglycyl-L-prolyl-L-arginine 4-nitroanilide acetate). Both inhibitors behaved as reversible tight-binding inhibitors of amidolytic thrombin activity. The apparent dissociation constants determined showed a linear dependence on the concentration of substrate; this finding, which indicates that the inhibition was competitive, made possible the estimation of the dissociation constants (KI) for Hirunorm IV and Hirunorm V, which were 0.134 +/- 0.014 nM and 0.245 +/- 0.016 nM, respectively. Similar dissociation constants were also obtained for the two inhibitors when thrombin activity was measured with fibrinogen in the clotting assay. When tested for resistance to thrombin proteolytic activity, both inhibitors were inviolate to cleavage by thrombin. The data obtained demonstrate that both Hirunorm IV and Hirunorm V are potent and stable inhibitors of human thrombin activity.

High-dose sequential chemotherapy with stem cell support for non-metastatic breast cancer.

The importance of dose-intensity has been suggested in breast cancer. The aim of this study was to evaluate the feasibility of a high-dose intensity doxorubicin-cyclophosphamide regimen with supporting G-CSF and blood stem cells. Twenty-five patients with non-metastatic breast cancer received four cycles of doxorubicin (75 mg/m2) and cyclophosphamide (3000 mg/m2) at 3 week intervals. Apheresis was performed after the first cycle and if necessary after the second cycle. Stem cells were reinfused after the third and fourth cycles. G-CSF was started on day 3 of each cycle (5 microg/kg/day) and was stopped the day before the last apheresis or when absolute neutrophil count was above 0.5 x 10(9)/l. Median received dose-intensity was respectively 25 mg/m2/week (range 22-26) and 1000 mg/m2/week (range 904-1065) for doxorubicin and cyclophosphamide. Grade IV thrombocytopenia occurred in 8% of cycles. Two patients needed platelets and 12 red cell transfusion. Fifteen patients were readmitted for a median duration of 4 days (range 1-7). We have established a safe, outpatient, high-dose intensity doxorubicin-cyclophosphamide regimen with supporting G-CSF and blood stem cells which can be submitted for comparison with the current standards.

Leaving work to smoke.

Work-place smoking bans have not only reduced work-day cigarette consumption but also been associated with going outside to smoke during working hours. We examined the extent of "exiled smoking", estimated how much work-day cigarette consumption can be attributed to it, and examined proximal predictors of both these two variables. Some 794 smokers from 42 medium-sized work-places were surveyed as the baseline for an intervention study. A self-completed questionnaire assessed smoking behaviour on work and non-working days, leaving work to smoke, and beliefs and opinions about smoking and smoking bans. Multiple regressions were used to examine predictors of leaving work to smoke, and of the amount smoked when doing so. Smokers reported consuming an average of 5.4 cigarettes during work breaks, 3.5 of which were associated with deliberately seeking opportunities to smoke; 39% reported leaving work to smoke one or more times per day during non-break periods. Indices of addiction were significant predictors of both leaving work to smoke and of cigarette consumption while doing so. Leaving work to smoke is in part an activity of addicted smokers, presumably to maintain blood nicotine levels. There is the potential to further reduce rates of cigarette consumption associated with work-place smoking bans if this "exiled smoking" can be reduced. This may be easier to achieve in light smokers.

Modulation of aldose reductase activity through S-thiolation by physiological thiols.

The glutathionyl-modified aldose reductase (GS-ALR2) is unique, among different S-thiolated enzyme forms, in that it displays a lower specific activity than the native enzyme (ALR2). Specific interactions of the bound glutathionyl moiety (GS) with the ALR2 active site, were predicted by a low perturbative molecular modelling approach. The outcoming GS allocation, involving interactions with residues relevant for catalysis and substrate allocation, explains the rationale behind the observed differences in the activity between GS-ALR2 and other thiol-modified enzyme forms. The reversible S-glutathionylation of ALR2 observed in cultured intact bovine lens undergoing an oxidative/non oxidative treatment cycle is discussed in terms of the potential of ALR2/GS-ALR2 inter-conversion as a response to oxidative stress conditions.

Thiol and disulfide determination by free zone capillary electrophoresis.

A rapid, sensitive and simple method for the determination of reduced and oxidized glutathione, cysteine, cystine, cysteamine, cystamine and their respective mixed disulfides is described. The compounds were separated and identified in a single step by capillary zone electrophoresis. The method was used to follow the thiol-disulfide interconversion and to measure glutathione levels in lens extracts.

Purine salvage as a metabolite and energy saving mechanism in the ocular lens.

The ocular lens is an organ which depends mainly on anaerobic processes to obtain the metabolic energy required for the maintenance of its physiological functions. In these circumstances, the purine salvage pathway enzymes, by using preformed purine rings, and allowing the utilization of the activated ribose moiety of nucleosides, might be of relevance as an energy saving device. In this paper we show that the calf lens possesses many enzymes of the purine salvage pathway, with a particularly high specific activity of purine nucleoside phosphorylase (EC 2.4.2.1), and that the isolated lens epithelium can actively convert adenine and adenosine into adenine nucleotides. In addition, as in bacteria and red blood cells, inosine and adenosine in the lens, acting as ribose donors, exert a profound effect on the process of adenine conversion into ATP.

Predictors of attendance at a relocatable mammography service for rural women.

This study aimed to identify factors that predicted attendance at a relocatable screening mammography service in a rural centre in Victoria. A cohort design was used whereby 180 women from the target population were interviewed by telephone two weeks before the service moved to the area for a 10-week period of operation. Attendance data were ascertained from service records. Fifty per cent of the sample attended the service. Significant predictors of attendance were: mammographic history, with women who reported previous screening mammography being less likely to attend than women who had not had a previous mammogram (odds ratio (OR) 0.38, 95% confidence interval (CI) 0.17 to 0.83); perception of personal risk for breast cancer, with women who perceived at least some risk being more likely to attend than women who perceived no risk (OR 2.73, CI 1.07 to 6.99); stated intention of attending (OR 2.01, CI 1.49 to 2.71); knowing the correct location of the service (OR 3.08, CI 1.37 to 6.89); and education, with higher education being associated with a lower likelihood of attending (OR 0.65, CI 0.44 to 0.96). Our study raised some issues, including the high prevalence of rural women who reported a previous screening mammogram, although BreastScreen services had not previously been available in their area; factors underlying perceptions of personal risk for breast cancer; and the generalisability of our finding of an inverse relationship between higher education and attendance for screening.

Molecular epidemiology by ribotyping and PCR-ribotyping of Enterococcus faecium strains isolated from intercontinental areas.

In this study classical ribotyping based on hybridization of an enteroccocal ribosomal operon previously cloned from Enterococcus hirae (Sechi and Daneo-Moore, 1993) with XbaI cut chromosomal DNA and PCR-ribotyping were used to characterize the molecular epidemiology of 131 Enterococcus faecium, with high-level resistance to gentamicin, isolated from different hospitals in Italy and the United States. The ribotyping was able to differentiate all 131 clinical isolates into 96 family patterns. These family patterns appeared to be useful in establishing epidemiological spread. The results obtained were in agreement with those previously published, suggesting the presence of five to six operons in the Enterococcus genus (Sechi et al., 1994). We performed PCR-ribotyping, based on conserved sequences at the 3' end of the enterococcal 16S rrn and the 5' end of the 23S rrn, on 131 clinical isolates as well as on several enterococcal ATCC strains tested. The results were then compared with those obtained with the classical ribotyping method. The results suggest the presence of at least four classes of intergenic spacers among enterococci, but these classes are not helpful in differentiating between Enterococci or among Enterococcal isolates.

Uridine 5'-diphosphoglucuronic acid (UDPGLcUA) in the human fetal liver, kidney and placenta.

The endogenous concentration of uridine 5'-diphosphoglucoronic acid (UDPGLcUA), the endogenus substrate of UDP-glucuronosyltransferase, was measured in the human fetal and adult liver and kidney and in the placenta. The concentrations (mumol/Kg wet weight) of UDPGLcUA were 59.4 +/- 11.3 (fetal liver), 301 +/- 119 (adult liver), 11.9 +/- 3.2 (fetal kidney), 17.4 +/- 3.0 (adult kidney), 17.8 +/- 1.8 (mid-term placenta) and 17.0 +/- 1.7 (term placenta). UDPGLcUA is present in the human fetal liver at a concentration 5-fold lower than in the adult liver indicating a potential limiting factor for glucuronidation ind the human fetus.

[Pseudotumoral pulmonary AL amyloidosis]. / Amylose AL pulmonaire de forme pseudo-tumorale.

INTRODUCTION: Thoracic involvement in amyloidosis is rare. An isolated pseudotumor without extra-thoracic disease suggests a malignant process. We present the case of a patient with pseudonodular AL amyloidosis, confirmed by lobar lung resection. CASE REPORT: A 57-year-old woman, with a 25-pack-year smoking history, presented with a nodular opacity on chest x-ray. Physical examination was normal. Thoracic CT-scan revealed an isolated spiculated nodule in the right upper lobe. A whole body positron emission tomography (PET) scan revealed high FDG activity in this nodule, without evidence of metastatic disease. Bronchoscopy was negative. Lobectomy revealed lambda L-chain amyloidosis. Investigation for systemic extension was negative. Follow up has been unremarkable. CONCLUSION: A spiculated lung nodule on conventional imaging (radiography, scanner) is cancer until proven otherwise. The use of PET scan in this context is sensitive but not specific. Definitive diagnosis must be obtained by histological examination. Nodular lung amyloidosis must be included in the differential diagnosis of lung nodules and false-positive FDG PET.

Postnatal Growth Patterns in a Chilean Cohort: The Role of SES and Family Environment.

Objective. This study examined how family environmental characteristics served as mediators in the relationship between socioeconomic conditions and infant growth in a cohort of Chilean infants. Methods. We studied 999 infants, born between 1991 and 1996, from a longitudinal cohort which began as an iron deficiency anemia preventive trial. SES (Graffar Index), the Life Experiences Survey, and the Home Observation for Measurement of the Environment (HOME) were assessed in infancy. Using path analysis, we assessed the relationships between the social factors, home environment, and infant growth. Results. During the first year, weight and length gain averaged 540 grams/month and 6.5 cm/month, respectively. In the path analysis model for weight gain, higher SES and a better physical environment were positively related to higher maternal warmth, which in turn was associated with higher average weight gain. Higher SES was directly related to higher average length gain. Conclusions. In our cohort, a direct relationship between SES and length gain developed during infancy. Higher SES was indirectly related to infant weight gain through the home environment and maternal warmth. As the fastest growing infants are at risk for later obesity, new strategies are needed to encourage optimal rather than maximal growth.