General practitioners' management of symptomatic uncomplicated diverticular disease of the colon by using rifaximin, a non-adsorbable antibiotic.

OBJECTIVE: Symptomatic uncomplicated diverticular disease of the colon (SUDD) is generally managed by gastroenterologists rather than General Practitioners (GPs). The aim of this study was to assess the efficacy of the treatment of SUDD with rifaximin, a non-absorbable antibiotic, in a primary care setting by GPs. PATIENTS AND METHODS: This retrospective, observational study investigated the use of rifaximin at a dose of 400 mg b.i.d. for 5, 7 or 10 days monthly, up to 3 months. The symptoms were reported by the patients using a visual analogic scale (VAS) of 0-10. RESULTS: 286 SUDD patients were enrolled (44.4% of men, average age 70.92±10.98). Respectively, 15 (5.2%) patients received the treatment for 5 days, 205 (71.7%) for 7 days and 66 (23.1%) for 10 days. After three months, a significant reduction of VAS score was observed in almost all symptoms assessed: 135 (47.2%) patients reported no abdominal pain (p<0.001) and 23 (8.1%) reported no symptom. Adverse events related to the treatment were recorded in 3 (1.04%) patients, all of them mild and not requiring interruption of the treatment. Acute diverticulitis occurred in 9 (3.1%) patients, but only 2 of them [0.7% (n=2)] underwent surgery due to complicated diverticulitis. Analysis within the different treatment groups (5, 7 and 10 days) shows that rifaximin treatment is effective in reducing the severity of symptoms in almost all groups except for the constipation in the 5-day group. CONCLUSIONS: Rifaximin can be effectively used by GPs in real-life for the management of SUDD.

Variations in stable isotope ratios in lamb blood fractions following dietary changes: a preliminary study.

RATIONALE: In meat production it is common practice to use finishing diets based on concentrates, even for those animals previously raised on pasture. No studies have investigated the variations of stable isotope ratios in lamb plasma and erythrocytes, following a switch from pasture to a concentrate-based diet during the last days before slaughter. For meat traceability it is important to verify how and whether these parameters are affected in blood fractions. METHODS: Blood of ten male Italian Merino lambs, whose diet was switched from pasture to concentrate, was sampled 8 times (days 1, 2, 3, 4, 5, 6, 7 and 14) in the last 14 days before slaughter. The variations in the δ(13)C, δ(15)N, δ(18)O and δ(34)S values of blood plasma and erythrocytes were investigated. The stable isotope ratios of the samples were measured using a stable isotope mass spectrometer coupled with an elemental analyser (C, N, S) and a CO2/H2O equilibration system (O(plasma)). RESULTS: The δ(13) C(plasma), δ(18)O(plasma) and δ(34)S(plasma) values were shown to be different 7 days after the abrupt variation in the diet. The comparison between erythrocytes and plasma stable isotope ratios could be suitable for verifying whether the animal was actually pasture-raised and could merit a higher price. The erythrocytes isotopic signature was not affected by very short finishing periods in previously grazed animals and maintained the pasture-raised fingerprint, while the analysis of plasma could detect very short finishing periods with concentrate and hay. CONCLUSIONS: The present study has demonstrated that the combination of blood plasma and erythrocytes stable isotope ratios of carbon, nitrogen, oxygen and sulphur can be used to infer the dietary background of lambs and thus offers a tool for the authentication of the animal production system.

Stable isotope ratios of blood components and muscle to trace dietary changes in lambs.

Multielemental stable isotope ratio (SIR) analysis was used in lamb plasma, erythrocytes and muscle to detect the switch from a pasture- to a concentrate-based diet, with the aim of verifying the possibility to trace the change of feeding in animal tissues. During 89 days of experimental feeding, lambs were subjected to four dietary treatments: pasture (P), pasture followed by concentrate in the stall for either 14 days (P-S14) or 37 days (P-S37) or concentrate in the stall (S). Pasture and concentrate diets comprised C3 plants only and had different values of 13C/12C, 18O/16O, 2H/1H and 34S/32S ratios. Muscle 13C/12C and 34S/32S and plasma 13C/12C and 18O/16O ratios in P, P-S14 and P-S37 lambs were significantly different. A multivariate analytical approach revealed that 13C/12C and 18O/16O ratios in plasma were the most powerful variables for the discrimination among the dietary treatments.

Prevalencia de Síndrome metabólico en niños y adolescentes según diferentes criterios diagnósticos y su correlación con niveles de leptina y adiponectina / Prevalence of Metabolic Syndrome in Children and Adolescents by Different Diagnostic Criteria and their Correlation with Levels Leptin and Adiponectin

Los objetivos del trabajo fueron detectar sujetos con obesidad, sobrepeso y con afecciones que componen el Síndrome Metabólico (SM) en una población infantojuvenil. Determinar la frecuencia de SM según distintos criterios y comparar entre ellos, los valores de leptina y adiponectina. Se evaluó a 700 sujetos entre 6 y 19 años mediante encuestas, medidas antropométricas y registros de presión arterial. En aquellos con 1 o más componentes del SM (n: 138-20 %) se efectuaron dosajes de glucosa, insulina, perfil lipídico, leptina y adiponectina. El SM se definió de acuerdo a Cook, a De Ferranti y a Weiss. El análisis estadístico comprendió el estudio descriptivo de medias e intervalos del 95 % de confianza (IC) y el de asociación mediante test t y chi cuadrado con un nivel de significación del 5 %. De acuerdo al índice de masa corporal, el 14 % de la muestra presentó obesidad y el 22 %, sobrepeso. Según la circunferencia de cintura, el 15 % tuvo obesidad y 6 % sobrepeso. Hubo asociación significativa entre individuos obesos o con sobrepeso con la hipertensión arterial y en menor grado con otros parámetros como el índice HOMA, c-HDL y triglicéridos. La frecuencia de SM fue según Cook del 15 %, De Ferranti de 18 % y Weiss de 14 %. La mayor proporción que se obtuvo con los criterios de De Ferranti, se debe probablemente a que los percentiles y los valores de corte son más estrictos. La media de leptina fue significativamente mayor y la media de adiponectina fue significativamente menor en los pacientes con diagnóstico de SM de acuerdo las tres clasificaciones que se utilizaron (p < 0,01). Es necesario establecer criterios uniformes para diagnosticar al SM en la infancia y adolescencia ya que no existe acuerdo respecto a su definición, pues el desarrollo y crecimiento a estas edades, dificultan el establecimiento de valores de referencia precisos. Los autores declaran no poseer conflictos de interés.

The study aims were to detect subjects with obesity, overweight and components of Metabolic Syndrome (MS) in a child and adolescent populations. Also to determine the frequency of MS according to different criteria and compare them with Leptin and Adiponectin levels. 700 subjects between 6 and 19 years through standardized surveys, anthropometric and blood pressure measurements were studied. In those with 1 or more components of MS (n: 138-20 %), blood glucose, insulin, lipid profile, leptin and adiponectin were analyzed. MS were defined according criteria of Cook, or De Ferranti or Weiss. A descriptive statistical analysis showing the mean and 95 % confidence intervals (CI) were made. The association analysis was performed by t and chi-square tests with a significance level of 5 %. In the population studied by body mass index there were a 14 % of obesity and 22 % of overweight and through a waist circumference 15 % of obesity and 6 % of overweight. There was a strong association between overweight/obesity with hypertension and in a lesser degree, with other risk factors as HOMA index, HDL-cholesterol and triglycerides. The prevalence of MS according Cook was 15 %, according to De Ferranti 18 % and Weiss was 14 %. We speculate that the major percentage was obtained with the De Ferranti criteria, because the percentiles and cut-offs are more demanding. The mean value of leptin was significantly higher and the mean value of adiponectin was significantly lower in patients with MS according to the three criteria used (p < 0.01). It is necessary to establish a uniform standards and criteria to characterize MS in childhood and adolescence because there is no agreement on its definition, due to changes during growth and development that prevent the establishment of precise cut-off values. The authors do not have conflicts of interest.

Análisis de los registros de presión arterial en recién nacidos pretérminos en consultorio de control ambulatorio / Analysis of records of blood pressure in preterm infants in an outpatient clinic control

El registro de PA en controles ambulatorios de los niños nacidos pretérminos no es una práctica habitual. Los objetivos de este estudio fueron: Evaluar PA y prevalencia de HTA de RNPT en control ambulatorio. Asociar HTA a factores de riesgo y patologías perinatales. POBLACIÓN. RNPT < 36 semanas (sem) dados de alta de UTIN y atendidos en consultorio ambulatorio. Período agosto 2008 a febrero 2009. Las variables estudiadas fueron edad gestacional, edad actual corregida, medidas antropométricas al nacimiento y al momento del registro: peso, talla. Patologías en UTIN. Se midió PA con tensiómetro oscilométrico manual con auscultación y palpación del pulso. Se siguió técnica y definición de PA, pre HTA e HTA 1 Y 2 de la 4a Task Force. Diseño descriptivo de corte transversal. Análisis estadístico simple y de asociación. RESULTADOS: 36 RNPT<36 s fueron estudiados, 57 por ciento de sexo femenino. Los promedios observados al nacer fueron; EG de 31.3 s IC 95 por ciento (30;32), PN 1533 gr IC95 por ciento (1397;1668), TN 40 cm (38.8; 41.3). Al momento del registro, EAC 11.8 m IC 95 por ciento (8.9;14.7), PA 8594 gr IC95 por ciento (7763; 9424). 19 por ciento con BPEG; 16 por ciento con TBEG; 3 po ciento TAEG. Se registró PAS a 32 niños (86,5 por ciento) , 6 por ciento fueron Pre-HTAS (P90-95); 6 por ciento HTAS grado I y 6 por ciento HTAS grado 11. En 50 por ciento se registró PAD, 6 por ciento pre HTAD; 25 por ciento con HTAD 1; 6% con HTAD 2. 27 niños tuvieron algún antecedente patológico perinatal, CAU 19 por ciento, 57 por ciento EMH, 51 por ciento sepsis, 41 por ciento ARM, 14 por ciento HIV, esta última se asoció significativamente con HTA (p=0.01). DISCUSIÓN Y CONCLUSIONES: En los más pequeños fue difícil registrar PA con este método. Encontramos mayor prevalencia de HTA en este grupo y asociación de HTA con HIV. El seguimiento será fundamental...

The registration of BP (Blood Pressure) in ambulatory monitoring of children born pre-term is not common practice. The objectives of this study were: to evaluate BP and Hypertension of newborns in outpatient control, associate Hypertension risk factors and perinatal pathology. POPULATION: pre term newborns of 36 weeks discharged from NICU and treated at an outpatient clinic. PERIOD: August 2008 to February 2009. The variables studied were: gestational age, corrected current age, anthropometric measurements at birth and the time of recording: weight, height. Pathologies in NICU. BP (Blood Pressure) was measured with an oscillometric blood pressure monitor with manual auscultation and pulse palpation. It was followed by technique and definition of BP, pre Hipertension, e Hipertension 1 y 2 of the fourth Task Force. Cross sectional descriptive design. Simple and association statistical analysis. RESULTS: 36 newbons 36 weeks were studied, 57 per cent female. The averages observed at birth were: GA (Gestational Age) 31.3 CI (Confidence Interval) 95 per cent (30:32), WB (Weight at Birth) 1533 gr 95 per cent (1397, 1668), HB (Height at Birth) 40 cm (38.8; 41.3). At the time of registration: CCA (Corrected Current Age) 118 m 95 per cent (8.9; 14.7), 8594 BP (Blood Pressure) 95 per cent gr (7763, 9424). 19 per cent in LWGA (Low Weight for Gestational Age), LHGA (Low Height for Gestational Age) 16 per cent, RHGA (Right Height for Gestational Age) 3 per cent. SBP (Systolic Blood Pressure) was recorded in 32 children (86,5 per cent), 6 per cent were pre-HBPs (P 90-95), 6 per cent HBP grade 1, and 6 per cent were HBP grade II...

Exposure to pesticides residues from consumption of Italian blood oranges.

This paper reports the results of a 5-year study to evaluate pesticide levels, derived from orchard activities, on Italy's most common orange cultivar (Citrus sinensis, L. Osbeck, cv. Tarocco). Using a Bayesian approach, the study allowed both the qualitative (number) and quantitative distributions (amount) of pesticides to be determined with its own probability value. Multi-residue analyses of 460 samples highlighted the presence of ethyl and methyl chlorpyrifos, dicofol, etofenprox, fenazaquin, fenitrothion, imazalil, malathion and metalaxil-m. A total of 30.5% of samples contained just one pesticide, 2.16% two pesticides and 0.65% of samples had three pesticides present simultaneously. The most common residue was ethyl chlorpyrifos followed by methyl chlorpyrifos. Estimated daily intake (EDI) values for ethyl and methyl chlorpyrifos, as well as the distance from the safety level (non-observed adverse effect level, NOAEL), were calculated. The risk was differentiated (1) to take account of the period of actual citrus consumption (180 days) and (2) to discriminate the risk derived from eating oranges containing a certain level of chlorpyrifos from unspecified pesticides. The most likely EDI values for ethyl chlorpyrifos derived from Italian blood orange consumption are 0.01 and 0.006 mg/day calculated for 180 and 365 days, respectively. Considering the probability of the occurrence of ethyl chlorpyrifos, these EDI values are reduced to 2.6 x 10(-3) and 1.3 x 10(-3) mg/day, respectively. For methyl chlorpyrifos, the most likely EDI values are 0.09 and 0.04 mg/day, respectively; considering the probability of its occurrence, the EDI values decrease to 6.7 x 10(-3) and 3.4 x 10(-3) mg/day, respectively. The results confirmed that levels of pesticides in Italian Tarocco oranges derived from a known controlled chain of production are safe.

Characterization of 2 novel and 2 recurring BRCA1 germline mutations in breast and/or ovarian carcinoma patients from the area of Naples.

We have analyzed 18 families with high incidence of breast cancer or breast and ovarian cancer for the presence of BRCA1 mutations. We identified 4 mutations in the BRCA1 gene in 4 unrelated probands who belong to families with at least 1 case of breast and 1 case of ovarian cancer. Two of the mutations reported in this study are novel (GAA(1172)-->TAA in family Naples 14, GAA(1765)-->TAA in family Naples 20) whereas the others are already present in the Breast Cancer Information Core Electronic Database (http://nchgr.nih.gov/ Intramural research/Lab transfer/Bic/) (5382insC in family Naples 18 and 2080delA in family Naples 19). Conversely, no mutation in the BRCA1 gene was detected in 14 families characterized by 2 or more cases of breast cancer only, even if bilateral and with early-onset. These results indicate that germline mutations in the BRCA1 gene highly predispose for a cancer syndrome that involves the presence of both breast and ovarian cancer.

Differential divergence of three human pseudoautosomal genes and their mouse homologs: implications for sex chromosome evolution.

The human pseudoautosomal region 1 (PAR1) is essential for meiotic pairing and recombination, and its deletion causes male sterility. Comparative studies of human and mouse pseudoautosomal genes are valuable in charting the evolution of this interesting region, but have been limited by the paucity of genes conserved between the two species. We have cloned a novel human PAR1 gene, DHRSXY, encoding an oxidoreductase of the short-chain dehydrogenase/reductase family, and isolated a mouse ortholog Dhrsxy. We also searched for mouse homologs of recently reported PGPL and TRAMP genes that flank it within PAR1. We recovered a highly conserved mouse ortholog of PGPL by cross-hybridization, but found no mouse homolog of TRAMP. Like Csf2ra and Il3ra, both mouse homologs are autosomal; Pgpl on chromosome 5, and Dhrsxy subtelomeric on chromosome 4. TRAMP, like the human genes within or near PAR1, is probably very divergent or absent in the mouse genome. We interpret the rapid divergence and loss of pseudoautosomal genes in terms of a model of selection for the concentration of repetitive recombinogenic sequences that predispose to high recombination and translocation.

MECP2 gene mutation analysis in the British and Italian Rett Syndrome patients: hot spot map of the most recurrent mutations and bioinformatic analysis of a new MECP2 conserved region.

Rett syndrome (RTT) is an X-linked dominant neurological disorder, which appears to be the most common genetic cause of profound combined intellectual and physical disability in Caucasian females. This syndrome has been associated with mutations of the MECP2 gene, a transcriptional repressor of unknown target genes. We report a detailed mutational analysis of a large cohort of RTT patients from the UK and Italy. This study has permitted us to produce a hot spot map of the mutations identified. Bioinformatic analysis of the mutations, taking advantage of structural and evolutionary data, leads us to postulate the existence of a new functional domain in the MeCP2 protein, conserved among brain-specific regulatory factors.

Multiple pathogenic and benign genomic rearrangements occur at a 35 kb duplication involving the NEMO and LAGE2 genes.

The X-linked dominant and male-lethal disorder incontinentia pigmenti (IP) is caused by mutations in a gene called NEMO (IKK-gamma). We recently reported the structure of NEMO and demonstrated that most IP patients carry an identical deletion that arises due to misalignment between repeats. Affected male abortuses with the IP deletion had provided clues that a second, incomplete copy of NEMO was present in the genome. We have now identified clones containing this truncated copy (Delta NEMO) and incorporated them into a previously constructed physical contig in distal Xq28. Delta NEMO maps 22 kb distal to NEMO and only contains exons 3-10, confirming our proposed model. A sequence of 26 kb 3' of the NEMO coding sequence is also present in the same position relative to the Delta NEMO locus, bringing the total length of the duplication to 35.5 kb. The LAGE2 gene is also located within this duplicated region, and a similar but unique LAGE1 gene is located just distal to the duplicated loci. Mapping and sequence information indicated that the duplicated regions are in opposite orientation. Analysis of the great apes suggested that the NEMO/LAGE2 duplication occurred after divergence of the lineage leading to present day humans, chimpanzees and gorillas, approximately 10-15 million years ago. Intriguingly, despite this substantial evolutionary history, only 22 single nucleotide differences exist between the two copies over the entire 35.5 kb, making the duplications >99% identical. This high sequence identity and the inverted orientations of the two copies, along with duplications of smaller internal sections within each copy, predispose this region to various genomic alterations. We detected four rearrangements that involved NEMO, Delta NEMO or LAGE1 and LAGE2. The high sequence similarity between the two NEMO/LAGE2 copies may be due to frequent gene conversion, as we have detected evidence of sequence transfer between them. Together, these data describe an unusual and complex genomic region that is susceptible to various types of pathogenic and polymorphic rearrangements, including the recurrent lethal deletion associated with IP.

Survival of male patients with incontinentia pigmenti carrying a lethal mutation can be explained by somatic mosaicism or Klinefelter syndrome.

Incontinentia pigmenti (IP), or "Bloch-Sulzberger syndrome," is an X-linked dominant disorder characterized by abnormalities of skin, teeth, hair, and eyes; skewed X-inactivation; and recurrent miscarriages of male fetuses. IP results from mutations in the gene for NF-kappaB essential modulator (NEMO), with deletion of exons 4-10 of NEMO accounting for >80% of new mutations. Male fetuses inheriting this mutation and other "null" mutations of NEMO usually die in utero. Less deleterious mutations can result in survival of males subjects, but with ectodermal dysplasia and immunodeficiency. Male patients with skin, dental, and ocular abnormalities typical of those seen in female patients with IP (without immunodeficiency) are rare. We investigated four male patients with clinical hallmarks of IP. All four were found to carry the deletion normally associated with male lethality in utero. Survival in one patient is explained by a 47,XXY karyotype and skewed X inactivation. Three other patients possess a normal 46,XY karyotype. We demonstrate that these patients have both wild-type and deleted copies of the NEMO gene and are therefore mosaic for the common mutation. Therefore, the repeat-mediated rearrangement leading to the common deletion does not require meiotic division. Hypomorphic alleles, a 47,XXY karyotype, and somatic mosaicism therefore represent three mechanisms for survival of males carrying a NEMO mutation.

A recurrent deletion in the ubiquitously expressed NEMO (IKK-gamma) gene accounts for the vast majority of incontinentia pigmenti mutations.

Incontinentia pigmenti (IP) is an X-linked dominant disorder characterized by abnormal skin pigmentation, retinal detachment, anodontia, alopecia, nail dystrophy and central nervous system defects. This disorder segregates as a male lethal disorder and causes skewed X-inactivation in female patients. IP is caused by mutations in a gene called NEMO, which encodes a regulatory component of the IkappaB kinase complex required to activate the NF-kappaB pathway. Here we report the identification of 277 mutations in 357 unrelated IP patients. An identical genomic deletion within NEMO accounted for 90% of the identified mutations. The remaining mutations were small duplications, substitutions and deletions. Nearly all NEMO mutations caused frameshift and premature protein truncation, which are predicted to eliminate NEMO function and cause cell lethality. Examination of families transmitting the recurrent deletion revealed that the rearrangement occurred in the paternal germline in most cases, indicating that it arises predominantly by intrachromosomal misalignment during meiosis. Expression analysis of human and mouse NEMO/Nemo showed that the gene becomes active early during embryogenesis and is expressed ubiquitously. These data confirm the involvement of NEMO in IP and will help elucidate the mechanism underlying the manifestation of this disorder and the in vivo function of NEMO. Based on these and other recent findings, we propose a model to explain the pathogenesis of this complex disorder.

Identification of novel RP2 mutations in a subset of X-linked retinitis pigmentosa families and prediction of new domains.

X-linked Retinitis Pigmentosa (XLRP) shows a huge genetic heterogeneity with almost five distinct loci on the X chromosome. So far, only two XLRP genes have been identified, RPGR (or RP3) and RP2, being mutated in approximately 70% and 10% of the XLRP patients. Clinically there is no clearly significative difference between RP3 and RP2 phenotypes. In the attempt to assess the degree of involvement of the RP2 gene, we performed a complete mutation analysis in a cohort of patients and we identified five novel mutations in five different XLRP families. These mutations include three missense mutations, a splice site mutation, and a single base insertion, which, because of frameshift, anticipates a stop codon. Four mutations fall in RP2 exon 2 and one in exon 3. Evidence that such mutations are different from the 21 RP2 mutations described thus far suggests that a high mutation rate occurs at the RP2 locus, and that most mutations arise independently, without a founder effect. Our mutation analysis confirms the percentage of RP2 mutations detected so far in populations of different ethnic origin. In addition to novel mutations, we report here that a deeper sequence analysis of the RP2 product predicts, in addition to cofactor C homology domain, further putative functional domains, and that some novel mutations identify RP2 amino acid residues which are evolutionary conserved, hence possibly crucial to the RP2 function.

Longins: a new evolutionary conserved VAMP family sharing a novel SNARE domain.

This article describes the discovery of a novel SNARE domain that might be involved in the regulation of membrane fusion. This domain is shared by a novel family of VAMPs called long VAMPs or longins. Members of this family are more conserved among eukaryotes than are classical VAMPs, possibly because of their underlying basic SNARE function.

Mutation analysis of the MECP2 gene in British and Italian Rett syndrome females.

Rett syndrome is an X-linked dominant neurological disorder, which appears to be the commonest genetic cause of profound combined intellectual and physical disability in Caucasian females. Recently, this syndrome has been associated with mutations of the MECP2 gene, a transcriptional repressor of still unknown target genes. Here we report a detailed mutational analysis of 62 patients from UK and Italian archives, representing the first comparative study among different populations and one of the largest number of cases so far analyzed. We review the literature on MECP2 mutations in Rett syndrome. This analysis has permitted us to produce a map of the recurrent mutations identified in this and previous studies. Bioinformatic analysis of the mutations, taking advantage of structural and evolutionary data, leads us to postulate the existence of a new functional domain in the MeCP2 protein, which is conserved among brain-specific regulatory factors.

[Monitoring of tinzaparin in a ten day treatment dose in elderly patients]. / Surveillance d'un traitement par la tinzaparine à dose curative pendant dix jours chez le sujet âgé.

PURPOSE: Renal impairment, which is frequently observed in elderly patients, raises the question of low molecular weight heparins treatment dose adjustment in this population. Thus, we conducted a prospective study to determine whether tinzaparin, administered subcutaneously at treatment dose (175 anti-Xa IU/kg) once daily for 10 days, does accumulate in patients older than 70 years of age. METHODS: Accumulation criteria were an increase of plasma anti-Xa and anti-IIa levels determined prior to the first injection and on days 2, 5, 7 and 10. The characteristics of the 30 consecutive included patients receiving tinzaparin at treatment dose (six men, 24 women) were: age 87.0 +/- 5.9 years (range: 71-96 years), body weight: 62.7 +/- 14.6 kg (range: 38-90 kg) and creatinine clearance 40.6 +/- 15.3 mL/min (range: 20-72 mL/min). RESULTS: None of the patients required a dose adjustment of tinzaparin over the 10-day treatment period. Anti-Xa and anti-IIa activity levels on day 2 were 0.66 +/- 0.20 IU/mL (range: 0.26-1.04 IU/mL) and 0.33 +/- 0.10 IU/mL (range: 0.18-0.55 IU/mL), respectively. These levels did not significantly change over the 10 days. These results favor the absence of the accumulation effect of tinzaparin. There was no correlation between anti-Xa and anti-IIa activities and age, weight, or creatinine clearance. Concerning the side-effects, only one minor hematoma at the injection site was reported. CONCLUSION: Tinzaparin may thus be administered in older patients with renal impairment, at a treatment dose (175 anti-Xa IU/kg/d) for a 10-day treatment period, without accumulation effect nor hemorrhagic side-effect in patients with creatinine clearance greater than 20 mL/min.

Elderly patients treated with tinzaparin (Innohep) administered once daily (175 anti-Xa IU/kg): anti-Xa and anti-IIa activities over 10 days.

Since low molecular weight heparins (LMWH) are partly eliminated by renal excretion, their pharmacodynamic profile may be modified in very elderly patients with age-related renal impairment. The aim of this prospective study was to determine whether tinzaparin (Innohep) 175 anti-Xa IU/kg administered subcutaneously once daily over 10 days does accumulate in hospital patients greater than 70 years of age. Plasma anti-Xa and anti-IIa amidolytic levels and APTT were determined prior to the first injection (day 0), and then, at peak level i.e. 5 h after the second injection (day 2) and subsequently on days 5, 7 and 10. Thirty consecutive inpatients (6 men, 24 women) requiring LMWHs at a curative dose for acute thromboembolic disease were included. Patients' characteristics (mean +/- SD) were: age 87.0+/-5.9 years (range 71-96), body weight 62.7+/-14.6 kg (range 38-90) and creatinine clearance 40.6+/-15.3 mL/min (range 20-72). The mean actual dose of tinzaparin delivered was 174.8 anti-Xa IU/kg. Since no patient had an anti-Xa activity above 1.5 IU/mL, the dose of tinzaparin remained fixed over 10 days. Anti-Xa and anti-IIa peak levels measured on day 2 were 0.66+/-0.20 IU/mL (range 0.26-1.04) and 0.33+/-0.10 IU/mL (range 0.18-0.55), respectively. Ex vivo anti-Xa/anti-IIa ratios were close to 2.1. APTT ratios (patient/control) were strongly correlated with anti-IIa activity (p <0.01). There was no progressive increase of the anti-Xa and anti-IIa activities after repeated administration of tinzaparin over the 10 day treatment period. No correlation was found between anti-Xa and anti-IIa activities and age, weight, or creatinine clearance. No major bleeding occurred during the study and only one minor haematoma at the injection site was reported. No thrombo-embolic complication or death occurred. Tinzaparin may thus be administered safely at a treatment dose (175 anti-Xa IU/kg) in older patients with age-related renal impairment. Neither dose adjustment, nor serial anti-Xa activity monitoring seems to be required in patients with creatinine clearance above 20 mL/min during the first ten day treatment.

Human dbl proto-oncogene in 85 kb of xq26, and determination of the transcription initiation site.

The dbl oncogene is generated by substitution of the 5' portion of its normal counterpart with an unrelated human sequence. To analyze the genomic structure and transcriptional regulation of the dbl proto-oncogene, we have isolated human genomic clones containing the entire human proto-dbl gene, localized in Xq26. Restriction mapping of a 600kb YAC clone (yWXD311) placed proto-dbl about 50kb telomeric to the coagulation Factor IX gene. The genomic DNA fragment containing the 5' end of proto-dbl was subcloned into plasmid vectors and the nucleotide sequences of exon 1, the flanking intronic region and genomic DNA 5' of the first codon were determined. Sequence analysis of 85119bp from the region revealed the genomic structure of proto-dbl. It contains 25 exons coding for a 4.7kb transcript including large 5'- and 3'- (1218bp and 701bp, respectively) untranslated regions (UTRs). RNase protection and primer extension assays on RNA from medullary thyroid carcinoma (TT) cells, which normally express dbl, revealed a transcription start site 1218bp upstream of the ATG of the first exon. A 1.6kb genomic 5' of the translation start sites drives the expression of a CAT-reporter in transient transfections in the TT cell line, though lacking TATA or CAAT boxes.