Alberta Leon

Intrahepatic cholestasis of pregnancy: new insights into its pathogenesis

Absract Aim: To search a specific gene expression profile in women with intrahepatic cholestasis of pregnancy (ICP) and to evaluate the maternal and foetal outcome. Methods: We consecutively enrolled 12 women with ICP and 12 healthy pregnant controls. The gene expression profile was assayed with the microarray technique including a panel of 5541 human genes. Microarray data were validated by real-time PCR technique. Results: Caesarean delivery was performed in eight patients with ICP versus three controls (p = 0.05). ICP women delivered at earlier gestational age than control (p < 0.001). Foetal distress was recorded in two babies, but we failed to find any correlation between bile salt concentration and foetal distress. Twenty genes potentially correlated with ICP were found differentially expressed (p < 0.05). Among these, three belong to genetic classes involved in pathogenic mechanisms of ICP: (1) pathophysiology of pruritus (GABRA2, cases versus controls = 2, upregulated gene); (2) lipid metabolism and bile composition (HLPT, cases versus controls = 0.6, down-regulated gene) and (3) protein trafficking and cytoskeleton arrangement (KIFC3, cases versus controls = 0.5, down-regulated gene). Conclusions: Different gene expression may contribute to the complex pathogenesis of ICP. An upregulation of GABRA2 receptor may indicate that GABA may play a role in the pathogenesis of pruritus in this condition.

Glutathione S-Transferase P1 Ile105Val Polymorphism is Associated with Haematological Toxicity in Elderly Rectal Cancer Patients Receiving Preoperative Chemoradiotherapy

AbstractBackground: Increasing evidence suggests that common gene polymorphisms may influence the toxicity of various cytotoxic agents used in the treatment of cancer. Objective: To evaluate the predictive value of acute toxicity of methylenetetrahydrofolate reductase 677T polymorphism, glutathione S-transferase P1 (GSTP1) substitution of isoleucine with valine at codon 105 (Ile105Val) polymorphism and the tandem repeat polymorphism in the thymidylate synthase gene promoter in elderly patients with rectal cancer receiving preoperative chemoradiotherapy (CRT). Method: From 1994 to 2002, 166 Caucasian patients underwent surgery following CRT for mid-low rectal cancer at a single institution, 42 (male-to-female ratio, 25:17) of whom were aged ≥65 years (median age 70 years, range 65–79). The pre-treatment clinical stage was tumour (T) stage 3–4 in 38 patients and node (N)-positive in 29 patients. Patients received external-beam radiotherapy with conventional fractionation and fluorouracil-based chemotherapy. Blood samples were used to extract and amplify DNA. Gene polymorphisms were determined by polymerase chain reaction and restriction enzyme digestion. Acute toxicity to preoperative therapy was reported according to the National Cancer Institute Common Toxicity Criteria, version 2. Univariate and multivariate analyses were performed using one-way analysis of variance and linear regression, respectively. Results: Haematological toxicity (grade 1–2) was observed in 15 of 40 patients for whom toxicity data were available and gastrointestinal toxicity (grade 1–4) in 24 of these same 40 patients. At univariate analysis, female sex (p = 0.036) and GSTP1 Ile105Val (p = 0.0376) were associated with haematological toxicity. At multivariate analysis, GSTP1 Ile105Val polymorphism (p = 0.041) was the only factor found to be associated with haematological toxicity. Patients carrying the Val/Val genotype in the GSTP1 gene had a lower risk of haematological toxicity (odds ratio = 0.322, 95% CI 0.101, 0.957) than patients with the Ile/Ile genotype. Conclusion: GSTP1 Ile105Val polymorphism is a promising marker of potential haematological toxicity in elderly patients with rectal cancer receiving preoperative CRT.

Occult macular dystrophy in an Italian family carrying a mutation in the RP1L1 gene.

Occult macular dystrophy (OMD) is an inherited macular disease characterized by progressive visual decline with the absence of visible retinal abnormalities. Typical alterations of the retinal structure are detectable by spectral domain optical coherence tomography (SD‑OCT). Mutations in the RP1L1 gene have been identified to be responsible for the disease in Asian subjects. The present study assessed the role of mutations in the RP1L1 gene in an Italian family with OMD. One patient with OMD and five related subjects (two male offspring affected by progressive visual decline and three asymptomatic siblings of the patient) were subjected to complete ophthalmological examination. SD‑OCT was also performed. All subjects were screened for OMD‑associated genetic mutations in the RP1L1 gene. The OMD patient and the two symptomatic offspring presented with a reduced best‑corrected visual acuity. Although no fundus abnormalities were observed, SD‑OCT examination showed that the external limiting membrane and the inner segment/outer segment band were not clearly identifiable and a focal disruption of the photoreceptor layer was present. The degree of photoreceptor alterations was correlated with the severity of visual impairment. Clinical and tomographic results in the three asymptomatic relatives were normal. A p.Arg45Trp mutation in the RP1L1 gene was identified in the OMD patient, in the two symptomatic offspring and also in two of the asymptomatic siblings of the patient. The identification of RP1L1 mutations in subjects with OMD may improve the accuracy of diagnosis of this rare condition and may aid in enhancing the efficacy of genetic counseling.