[Incidence of skin and non-skin cancers in Afro-Caribbean renal transplant recipients: Guadeloupe data from 2004 to 2011]. / Incidence des cancers cutanés et non cutanés chez les transplantés rénaux afro-caribéens : données guadeloupéennes de 2004 à 2011.

BACKGROUND: Cancer is the main complication of transplantation surgery. The literature concerning renal transplant recipients among the Afro-Caribbean population is scant. The aim of this study was to determine the incidence of cancer in these patients, with the secondary objective being to identify predisposing factors for cancer. PATIENTS AND METHODS: This was an epidemiological and retrospective study that included all Guadeloupians of phototype V-VI undergoing renal transplantation from 01/01/2004 to 31/12/2011. Skin cancer screening was performed before transplantation and during an annual dermatological consultation following transplantation. Screening for non-cutaneous cancers was guided by clinical symptoms or by the results of the screening examinations recommended in the current guidelines. At the study time-point (31/12/2011), all patients were examined by a dermatologist. RESULTS: One hundred and two patients were included : 42 women and 60 men (mean age: 52.1±11.6 years at transplantation). Eight cancers were diagnosed. The cumulative incidence of cancer was 7.8% at 3 years. Three factors were associated with more rapid onset of cancer: personal history or familial history of cancer, and genital lesion induced by HPV. CONCLUSION: Our results suggest a low incidence of cancer in Afro-Caribbean renal transplant patients. Personal or family history of cancer and HPV-induced genital lesions would appear to accelerate the onset of cancer in this population.

How many times can parvovirus B19-related anemia recur in solid organ transplant recipients?

Parvovirus B19 (PB19) infection is known to cause acute erythroblastopenia-mediated anemia in solid organ transplant (SOT) recipients. Intravenous immunoglobulins (IVIg) and the decrease of immunosuppression level are supposed to induce a long-term remission, although no consensus exists about the dose and the schedule of IVIg administrations. However, a few reports have shown that PB19-related anemia can recur despite this treatment, with a maximum of 3 recurrences reported. In this report, we describe in detail the cases of 2 kidney recipients with PB19 infection. They experienced, respectively, 9 and 7 PB19-related anemia recurrences. Immunosuppression level was decreased and IVIg were administered at each recurrence followed by a transitory normalization of hemoglobin level and a decrease of serum PB19 viral load. Episodes were separated by several months. These patients raise an original therapeutic management question about a frequent viral infection in SOT recipients. One patient is currently receiving IVIg every 3 months as a secondary prophylaxis without recurrence to date. These 2 case reports are followed by a review of the literature.

Synergistic effect of carbapenem-teicoplanin combination during severe Rhodococcus equi pneumonia in a kidney transplant recipient.

Rhodococcus equi is a bacterial pathogen of domestic animals that can infect immunocompromised patients, especially those with impaired cellular immunity, such as transplant recipients. No standard treatment has been established, but therapy must be prolonged, as relapses are common and can occur at the initial site or distant locations. Here we report a case of R. equi-associated pulmonary abscess in a renal transplant recipient successfully treated with a combination of carbapenem and teicoplanin. This combination was shown to be synergistic. It has minimal side effects in transplant recipients and appears to be an effective initial treatment for this severe infection.

Pharmacokinetics of cyclosporine in heart and lung transplant candidates and recipients with cystic fibrosis and Eisenmenger's syndrome.

OBJECTIVE: To compare the pharmacokinetics of cyclosporine in patients with either cystic fibrosis or Eisenmenger's syndrome. METHODS: Patients in the study were heart and lung transplant candidates with either cystic fibrosis (n = 6) or Eisenmenger's syndrome (n = 5), as well as patients who received heart and lung transplantation for either cystic fibrosis (n = 13) or Eisenmenger's syndrome (n = 7). This was no experimental pharmacokinetic study in transplant candidates and an exploratory population pharmacokinetic study in transplant recipients. RESULTS: Patients with cystic fibrosis showed higher blood cyclosporine clearance, higher apparent oral clearance, shorter mean residence time, and more erratic absorption. The coefficient of variation of pharmacokinetic parameters was higher in patients with cystic fibrosis. There were no significant differences in metabolite indexes between the two groups of patients after either oral or intravenous administration. A significant negative correlation was found between cyclosporine clearance and hematocrit (r = 0.81 [95% confidence interval, -0.95 to -0.4.1]). Dose-normalized predose blood concentration measurements were lower in patients with cystic fibrosis after transplantation. There was a significant correlation between hematocrit and log dose-normalized cyclosporine concentration (r = 0.40 [95% confidence interval, 0.30 to 0.49]). The total daily dose per 100 ng/ml trough blood concentration required was estimated to be 2.36 times (95% confidence interval, 1.96 to 2.84) higher in patients with cystic fibrosis. CONCLUSIONS: Cyclosporine pharmacokinetics is more variable in patients with cystic fibrosis. The difference in cyclosporine clearance between the two groups is accounted for by differences in binding in blood rather than metabolism. The findings suggest that patients with cystic fibrosis could be conservatively given initial oral doses that are 1.5 times higher than those for patients who receive transplants because of Eisenmenger's syndrome.

Safety of subcutaneous clodronate and efficacy in hypercalcemia of malignancy: a novel route of administration.

Bisphosphonates have become standard treatment in management of malignancy-induced hypercalcemia and malignant bone pain. One obstacle to the routine use of bisphosphonates in palliative patients is that oral bisphosphonates have low bioavailability and a degree of gastrointestinal toxicity that may explain poor compliance. Intravenous administration can be cumbersome in patients admitted to long-term care settings or at home. We have developed and tested a new way of administering clodronate via subcutaneous infusion. This retrospective cohort study evaluated 150 patients admitted to a tertiary palliative care unit from May 1996 to May 2000 who received 254 subcutaneous infusions of clodronate for hypercalcemia or bony complications. Data were collected by chart review and specifically evaluated site toxicity and biochemistry. There was minimal local toxicity and only 2 infusions needed to be discontinued because of pain at the subcutaneous site. Clodronate showed efficacy in normalizing the serum calcium within 5 days post-infusion in 32 of 43 infusions given for hypercalcemia. This study shows that subcutaneous clodronate is safe and can lower serum calcium levels in malignant hypercalcemia.

Silent myocardial ischaemia and risk factors in a diabetic Afro-Caribbean population.

AIMS: In Guadeloupe, an island in the French West Indies, diabetes has a prevalence recently reported to be 10%. Myocardial ischaemia is more frequently silent in diabetics, and needs to be screened for and monitored, once identified. This study aimed to evaluate the prevalence of silent myocardial ischaemia (SMI) in a diabetic population and to analyze its associated cardiovascular risk (CVR) factors. METHODS: This was a cross-sectional study of 147 patients with associated CVR factors, defined according to the 2004 SFC/ALFEDIAM guidelines. Exercise stress tests, myocardial performance imaging and stress echocardiography were performed. Ancova and logistic regression were used in the statistical analyses. RESULTS: The patients' mean age was 62 years, and 53% were male. Mean duration of diabetes was 14 years. Overall, 23.1% had SMI, and these patients more frequently had a personal history of cardiovascular disease vs those without SMI. On multivariate logistic-regression analyses, the adjusted odds ratios of SMI were significantly increased in patients with a personal history of cardiovascular disease (4.36, 95% CI: 1.36-13.96; P=0.01) and left ventricular hypertrophy (LVH) (2.46, 95% CI: 1.03-5.86; P=0.04). CONCLUSION: The prevalence of SMI in our Afro-Caribbean diabetic population was 23.1%. Searching for a personal history of cardiovascular disease and LVH may help to identify patients who need to be screened for SMI.

Left ventricular hypertrophy in hypertensive type 2 diabetic patients according to renal function.

AIM: Cardiovascular disease is the main cause of death in diabetic patients undergoing haemodialysis. Dialysis and hypertension increase left ventricular hypertrophy (LVH), a strong predictor of cardiovascular events. This study evaluated left ventricular structure and function in three groups of hypertensive type 2 diabetic patients with different renal function, and assessed the factors associated with LVH, in an Afro-Caribbean population. METHODS: Left ventricular structure and function were measured by ultrasonography. Group 1 consisted of 150 patients with normal renal function, group 2 included 183 patients with renal dysfunction and the third group comprised 75 dialysis patients. RESULTS: Left ventricular mass/height(2.7) increased from group 1 to groups 2 and 3 (49.00g/m(2.7), 57.12g/m(2.7) and 59.75g/m(2.7), respectively; P<0.0001). The prevalences of LVH were 48.3% in group 1, 64.8% in group 2 and 70.3% in the dialysis patients (P=0.001). LVH was more concentric than eccentric in groups 2 and 3. The factors significantly associated with LVH were obesity in groups 1 and 2, and an increase of 10mmHg in pulse pressure in groups 2 and 3, according to multivariate logistic-regression analysis. CONCLUSION: Our study confirmed that, in a population of Afro-Caribbean hypertensive type 2 diabetic patients, renal failure was associated to an increased left ventricular mass/height(2.7). The data show that the variables associated with LVH differ according to renal profile. This finding will be of value in the treatment and follow-up of these patients.

Regulation of the macrolide-lincosamide-streptogramin B resistance gene ermD.

The erythromycin resistance gene ermD, which encodes an rRNA methylase protein, has an unusually long leader region (354 nucleotides). Previously, a single promoter-proximal leader peptide coding sequence was recognized from the nucleotide sequence, and erythromycin-induced ribosome stalling in this sequence was proposed to be required for the induction of methylase translation. We characterized spontaneously occurring and in vitro-constructed leader region mutations in an effort to understand the function of various segments of the long ermD leader region. A second leader peptide coding sequence was identified, and the location of insertion and point mutations that expressed ermD methylase constitutively suggested that translation of the second leader peptide is controlled by ribosome stalling in the first leader peptide. From Northern RNA blot analysis of ermD transcription, it appears that regulation of ermD expression is not by transcriptional attenuation.

Effect of ermC leader region mutations on induced mRNA stability.

Induction of translation of the ermC gene product in Bacillus subtilis occurs upon exposure to erythromycin and is a result of ribosome stalling in the ermC leader peptide coding sequence. Another result of ribosome stalling is stabilization of ermC mRNA. The effect of leader RNA secondary structure, methylase translation, and leader peptide translation on induced ermC mRNA stability was examined by constructing various mutations in the ermC leader region. Analysis of deletion mutations showed that ribosome stalling causes induction of ermC mRNA stability in the absence of methylase translation and ermC leader RNA secondary structure. Furthermore, deletions that removed much of the leader peptide coding sequence had no effect on induced ermC mRNA stability. A leader region mutation was constructed such that ribosome stalling occurred in a position upstream of the natural stall site, resulting in induced mRNA stability without induction of translation. This mutation was used to measure the effect of mRNA stabilization on ermC gene expression.

An intron in the thymidylate synthase gene of Bacillus bacteriophage beta 22: evidence for independent evolution of a gene, its group I intron, and the intron open reading frame.

The thymidylate synthase gene (thy) (EC 2.1.1.45) of Bacillus subtilis bacteriophage beta 22 has a self-splicing, group I intron inserted into a highly conserved region of the coding sequence. The intron is very similar to one that is inserted 21 bp further downstream in the homologous thymidylate synthase gene (td) of Escherichia coli bacteriophage T4. In contrast, the amino acid sequences of the bacteriophage thymidylate synthases are highly divergent. The beta 22 intron has a fragmentary open reading frame (ORF) that encodes a putative helix-turn-helix DNA-binding motif, similar to one at the carboxyl terminus of the homing endonuclease (I-TevI) encoded by the T4 td intron. The td ORF and the thy ORF fragments are inserted into different regions of their respective intron structures. These results suggest that the thymidylate synthase genes, their introns, and their respective intron-ORFs all have separate evolutionary histories and that the acquisition of the intron could not have occurred by a simple homing event.

A polypurine sequence that acts as a 5' mRNA stabilizer in Bacillus subtilis.

A segment of early RNA from Bacillus subtilis bacteriophage SP82 was shown to function as a 5' stabilizer in B. subtilis. Several heterologous RNA sequences were stabilized by the presence of the SP82 sequence at the 5' end, and expression of downstream coding sequences was increased severalfold. The SP82 RNA segment encodes a B. subtilis RNase III cleavage site, but cleavage by B. subtilis RNase III was not required for stabilization. The sequence that specifies 5' stabilizer function was localized to a polypurine sequence that resembles a ribosome binding site. The ability of the SP82 sequence to stabilize downstream RNA was dependent on its position relative to the 5' end of the RNA. These results demonstrate the existence of a new type of 5' stabilizer in B. subtilis and indicate that attack at the 5' end is a principal mechanism for initiation of mRNA decay in B. subtilis.

In vitro processing activity of Bacillus subtilis polynucleotide phosphorylase.

A phosphate-dependent exonuclease activity was identified in purified protein fractions from Bacillus subtilis that were selected for binding to poly(I)-poly(C) agarose. Based on the characteristics of the degradation products and the absence of this activity in a pnpA strain, which contains a transposon insertion in the B. subtilis PNPase gene (Luttinger et al., 1996--accompanying paper), this exonuclease activity was shown to be due to polynucleotide phosphorylase (PNPase). Processive 3'-to-5' exonucleolytic degradation of an SP82 phage RNA substrate was stalled at a particular site. Structure probing of the RNA showed that the stall site was downstream of a particular stem-loop structure. A similar stall site was observed for an RNA that comprised the intergenic region between the B. subtilis rpsO and pnpA genes. The ability to initiate degradation of a substrate that had a stem structure at its 3' end differed for the B. subtilis and Escherichia coli PNPase enzymes.

Cross-correlation of cyclosporine concentrations and biochemical measures of kidney and liver function in heart and heart-lung transplant recipients.

Cross-correlation of cyclosporine concentrations with results of biochemical tests of renal and liver function, measured during the first three months post-operatively, was carried out retrospectively in 24 heart and eight heart-lung transplant recipients to assess the temporal relationship between cyclosporine treatment and the development of possible toxic side-effects. We found a statistically significant negative correlation (95% confidence interval of the mean correlation coefficient did not overlap zero) between the five-day mean concentration of cyclosporine in whole blood (but not plasma) as measured with nonselective (NSRIA) and selective radioimmunoassays (SRIA) and the mean reciprocal creatinine concentration measured in the subsequent five days. In 15 of 32 (47%) patients the negative correlation coefficient exceeded 0.7 (high susceptibility), whereas in 11 of 32 (34%) it was between 0.5 and 0.7 (medium susceptibility), and in only six of 32 (19%) was it less than 0.3 (low susceptibility). We found no consistent correlations between cyclosporine measurements and results of other renal-function tests or liver-function tests. This suggests that therapeutic doses of the drug are not hepatotoxic in most patients. There was, however, a significantly correlated decrease in the NSRIA/SRIA ratio and in serum bilirubin concentration with time post-operatively, reflecting improvement in hepatic function and clearance of the cyclosporine metabolites that are detected by NSRIA. Assays of cyclosporine in whole blood, but not in plasma, are of value in anticipating changes in renal function after heart and heart-lung transplantation.

Studies on the mechanism of coumarin-induced toxicity in rat hepatocytes: comparison with dihydrocoumarin and other coumarin metabolites.

Single doses of coumarin (125 mg/kg, ip) produced a depletion of hepatic nonprotein sulfhydryl groups (mainly reduced glutathione; GSH) in young male Sprague-Dawley rats after 2 hr and increased liver weight and produced hepatic centrilobular necrosis after 24 hr. Coumarin also produced time- and dose-dependent toxic effects in primary rat hepatocyte cultures. A marked reduction of GSH levels was also observed in vitro and this was not due either to the formation of oxidized glutathione (GSSG) or to the leakage of GSH and/or GSSG from the hepatocytes. Coumarin-induced toxicity in rat hepatocytes could be inhibited by the cytochrome P450 inhibitors ellipticine and metyrapone and potentiated by depleting hepatocyte GSH levels with diethyl maleate. In contrast to coumarin, dihydrocoumarin--which lacks the 3,4-double bond--produced little toxicity in rat hepatocytes either in vivo (127 and 254 mg/kg, ip) or in vitro. Similarly, coumarin was more toxic to rat hepatocytes than a number of known coumarin metabolites including 3- and 7-hydroxycoumarin and o-hydroxyphenylacetic acid. The results of these studies demonstrate a good in vivo/in vitro correlation for the effects of coumarin and dihydrocoumarin in rat hepatocytes. Furthermore, the data suggest that coumarin hepatoxicity in the rat is due to coumarin bioactivation by cytochrome P450-dependent enzymes to a toxic metabolite(s), which may be a coumarin 3,4-epoxide intermediate. GSH appears to protect against coumarin-induced toxicity possibly by the formation of conjugates with the toxic coumarin metabolite(s).

Blood cyclosporin concentrations and the short-term risk of lung rejection following heart-lung transplantation.

1. The relationship between blood cyclosporin concentration (CyACb) and a patient's risk of organ rejection following heart-lung (HL) transplantation was investigated. 2. Longitudinal data were collected for 90 days post-operation for 31 HL transplant recipients. Following exploratory analysis, a multiple logistic regression model with a binary outcome variable representing presence or absence of lung rejection (as defined on biopsy findings and/or intention to treat) in the next 5 days was fitted to the data. 3. A significant interaction between time post-transplant and CyACb was found. During weeks 1-3, the relative risk (RR) of rejection per unit increase in log(e) (5-day mean CyACb) was reduced: RR = 0.29, 95% confidence interval (CI) = (0.12, 0.72). After 3 post-operative weeks, this trend was reversed: RR = 1.61, 95% CI = (0.96, 2.70). Increases in cyclosporin dose (CyAD) and in coefficient of variation (CV) for both CyAD and CyACb over the previous 10 days significantly increased the risk of rejection: RR per unit increase in log(e) (5-day mean CyAD) = 2.72, 95% CI = (1.18, 6.25); RR per increase of 10% (i.e. from, say, 20% to 30%) in the CV for CyAD = 1.20, 95% CI = (1.07, 1.36); RR if the CV for CyACb > 40% = 1.51, 95% CI = (1.01, 2.27). Administration of high dose steroids in the previous 5 days was found to protect against further rejection: RR if steroid treatment was given = 0.23, 95% CI = (0.13, 0.38).(ABSTRACT TRUNCATED AT 250 WORDS)

Blood cyclosporin concentrations but not doses correlate with acute changes in renal function following heart and heart-lung transplantation.

The relationship between changes in cyclosporin (CyA) dose or CyA blood concentration and the reciprocal creatinine concentration was investigated by cross-correlation analysis over the first 3 postoperative months in 32 consecutive heart and heart-lung recipients. Exploratory analysis suggested that early changes in renal function, probably attributable to recovery from preoperative cardiac failure, obscured later underlying correlations. Therefore, all data up to the first nadir in plasma creatinine following transplantation were excluded from the analysis. Five-day mean CyA doses or blood concentrations were cross-correlated with 5-day mean reciprocal creatinine concentrations measured either in the same 5-day period or with the creatinine measured up to two 5-day periods later. Although a significant correlation was found between CyA dose and blood concentration (the 95% confidence interval of the population correlation coefficient did not overlap zero), there was no relationship between dose and changes in renal function. The blood CyA concentration, however, correlated significantly with the reciprocal creatinine concentration measured in the same 5-day period and was also predictive of changes in creatinine measured in the subsequent 5-day period. Thus, a major criterion for therapeutic drug monitoring had been fulfilled: CyA dosage adjustment based on blood CyA concentrations, as the intermediate therapeutic end point, is helpful in the management of acute nephrotoxicity in heart and heart-lung transplant recipients because of the lack of a dose-effect relationship. Regular CyA monitoring and appropriate dosage adjustment is essential for the management of acute nephrotoxicity in the first 3 months following heart or heart-lung transplantation.

Altered pharmacokinetics of cyclosporin in heart-lung transplant recipients with cystic fibrosis.

The cyclosporin dose versus blood concentration relationship for 11 heart-lung transplant recipients with cystic fibrosis was studied retrospectively. Eleven patients, closely matched for age and gender, who received heart-lung transplantation for other diseases were selected as controls. Cystic fibrosis patients received 16.7 (SD 7.2) mg/kg/day of oral cyclosporin compared with 8.2 (SD 1.9) mg/kg/day given to the control patients (p less than 0.01). Nine of the cystic fibrosis patients received higher mean daily doses of cyclosporin. Mean blood cyclosporin concentrations were, however, not significantly different (p = 0.58), and there were no apparent differences in clinical outcome in terms of rejection, infection, and nephrotoxicity in the two groups. The apparent oral clearance of cyclosporin was significantly higher (p less than 0.01) in cystic fibrosis patients. Cyclosporin dosage individualization with the aid of cyclosporin blood concentration measurements is critically important in this subpopulation of heart-lung transplant recipients.