Are low plasma levels of 25-(OH)vitamin D a major risk factor for hyperparathyroidism independent of calcitriol in renal transplant patients?

BACKGROUND: Recently, some studies have emphasized the role of plasma 25-(OH)vitamin D (25OHD) levels in mineral metabolism dysregulation in chronic kidney diseases (CKDs). However, to date little attention has been paid to 25OHD metabolism abnormalities after renal transplantation (Tx). This cross-sectional study aimed to focus on its role in mineral metabolism dysregulation in functioning Tx. METHODS: Twenty-eight out of 75 Caucasian Tx patients were selected following strict inclusion and exclusion criteria. Two blood samples were effected at the end of the winter for the measurements of plasma 25OHD and calcitriol levels. Serum creatinine (Cr), alkaline phosphatase (SAP), immunoreactive intact parathyroid hormone (PTH), electrolytes and 24-hr proteinuria were also determined. The Kolmogorov-Smirnov test was used to evaluate the data distribution: serum Cr, Cr clearance, dialysis duration and PTH levels were non-normally distributed and were log-transformed. Values of p<=0.01 were assumed as statistically significant. RESULTS: Median serum Cr and PTH levels were, respectively, 1.0 mg/dL and 90.0 pg/mL (range 27-420; normal range 10-65); most of our Tx patients (78.5%) had serum PTH levels above the upper limit of normal values. Mean plasma 25OHD concentration was 19.6 +/- 8.9 SD ng/mL (range: 6-36). None had levels <5 ng/mL (severe deficiency); 10 patients (35.7%) had mild deficiency (5-15 ng/mL); 14 patients (50%) had vitamin D insufficiency (16-30 ng/mL); and only four patients (14.3%) had target levels (>30 ng/mL). Mean plasma calcitriol levels were 69.7 +/- 19.0 pg/mL (range 47-105; normal range 35-85). They were not significantly correlated to plasma 25OHD levels. Proteinuria (292.6 +/- 147.0 mg/24 hr) inversely correlated to plasma 25OHD levels (r=-0.480; p<0.01). The bivariate correlation analysis between logPTH and the other parameters showed a significant correlation for SAP (r=0.494; p=0.008), plasma 25OHD levels (r=-0.442; p=0.01), proteinuria (r=0.452; p=0.01), log serum Cr (r=0.551; p=0.002) and log Cr clearance (r=-0.534; p=0.003). The other parameters did not correlate significantly with logPTH, notably plasma calcitriol and serum phosphate levels. Only the parameters significantly correlated to logPTH in the bivariate correlation analysis were included in the back stepwise multiple linear regression analysis as independent variables (model: p<0.0001; R2=0.54): among them, only plasma 25OHD levels (Beta=-0.486; p=0.001) and log serum Cr levels (Beta=0.589; p=0.0002) were the dependent variable logPTH predictors. CONCLUSIONS: This cross-sectional study demonstrated that plasma calcitriol levels in a highly selected group of Tx patients were normal and not significantly correlated to either plasma 25OHD or serum PTH levels. Most patients (85.7%) had plasma 25OHD levels below the target value of 30 ng/mL; the latter were inversely correlated with serum PTH levels. Therefore, our study strengthens the suggestion that low plasma 25OHD levels are a major risk factor for secondary hyperparathyroidism (sHPTH) in Tx patients and stresses the importance of monitoring these patients.     

Female hemodialysis patients have an increased risk of nodular hyperplasia of parathyroid glands

BACKGROUND: An association between female gender and more aggressive patterns of secondary hyper-parathyroidism (sHPTH) has been suggested: an increased incidence of refractory sHPTH seems evident in females; therefore, necessitating parathyroidectomy (PTx). METHODS: This study aimed to verify the existence of such an association and secondly to evaluate the impact of female gen-der on parathyroid gland histology. Therefore, a retrospective study was conducted on 67 patients who underwent first PTx (either total or subtotal) in our hospital from 1999-2003. Out of these patients, we selected 55 (28 males, 27 females, mean age 50.8 +/- 14.7 SD yrs, dialysis duration 109.2 +/- 62.4 months) in whom all four parathyroid glands were identified and removed. Serum levels of immunoreactive intact parathyroid hormone (iPTH), alkaline phosphatase, calcium and phosphate were determined at the PTx time point. The same pathologist performed the histological studies of the parathyroid glands on seven serial sections of the glands. Gland hyperplasia was classified as (1) exclusively diffuse (EDH) when only diffuse hyperplasia was found in the four glands; (2) exclusively nodular (ENH) when only nodular hyper-plasia was found in the four glands; (3) diffuse/nodular (D/NH), in which the four glands showed varying degrees of evolution towards both nodular and diffuse hyperplasia. RESULTS: EDH was found in 13 patients with a prevalence of males (11/13; 84.6%); ENH was found in 23 patients with a prevalence of females (15/23; 65.2%); D/NH was found in 19 patients with a similar prevalence between females and males (10 females and 9 males). The difference in the male/female prevalence among the three groups was statistically significant (chi2 test, p=0.015). Serum calcium was significantly higher in the ENH group (one-way analysis of variance, p=0.009). No difference was found among the three groups as far as age, dialysis duration, serum levels of iPTH, alkaline phosphatase and phosphate were concerned. CONCLUSIONS: Female gender is associated with more aggressive histological sHPTH patterns; this association seems to suggest that female gender predisposes to monoclonal proliferation of parathyroid glands in chronic uremia.     

Feasibility of sequential therapy with FOLFIRI followed by docetaxel/cisplatin in patients with radically resected gastric adenocarcinoma. A randomized phase III trial

OBJECTIVE: Combination therapies of fluorouracil (FU) with irinotecan (CPT-11) and docetaxel plus cisplatin have been proven to be active in metastatic gastric cancer. In this paper, we present the results of a phase III trial in which these two combinations given sequentially were compared to mitomycin C (MMC) monochemotherapy in an adjuvant setting. METHODS: 169 patients with radically resected gastric cancer were randomized to receive CPT-11 (180 mg/m2 day 1), leucovorin (100 mg/m2 days 1-2), FU (400-600 mg/m2 days 1-2, q 14; for four cycles; FOLFIRI regimen), followed by docetaxel (85 mg/m2 day 1), cisplatin (75 mg/m2 day 1, q 21; for three cycles; arm A), or MMC (8 mg/m2 days 1-2 as 2-hour infusion, q 42; for four cycles; arm B). All patients had histologically confirmed gastric carcinoma with nodal positivity or pT3/4. A total of 166 patients (85 in arm A and 81 in arm B) were treated. Adjuvant treatment was completed in 76% of the patients in arm A and in 70% of the patients in arm B. The main grade 3/4 side effects recorded were neutropenia in 35%, with only 1 febrile patient, and diarrhea in 11% in arm A, and thrombocytopenia in 10% and neutropenia in 7% in arm B. The FOLFIRI regimen and docetaxel/cisplatin given in sequence was well tolerated and feasible in adjuvant setting. This sequence treatment currently represents the experimental arm of an ongoing multicenter trial.     

Screening for mild cognitive impairment in elderly ambulatory patients with cognitive complaints

BACKGROUND AND AIMS: Identification of patients with Mild Cognitive Impairment (MCI) is strongly recommended because of their increased risk of dementia. Two brief global cognitive instruments, the Mini Mental State Examination (MMSE) and the Clock Drawing Test (CDT), were examined as useful screening methods for MCI. METHODS: The sensitivity and specificity of MMSE and CDT, scored using the Sunderland and Wolf-Klein methods, were evaluated in 113 elderly individuals with three different MCI subtypes: amnestic, multiple domain impairments, and single non-memory domain. Diagnoses were made on the basis of extensive clinical and neuropsychometric assessment. RESULTS: Used alone, MMSE and CDT at standard cut-offs were highly specific (about 0.80) but rather insensitive (less than 0.50) to all MCI subtypes. By contrast, when used in combination, an abnormal result on either MMSE or CDT scored by the Sunderland method had a specificity of 0.69 [0.57-0.81] and a sensitivity of 0.75 [0.64-0.87] for multiple domain impairments MCI. Results were similar for MMSE in combination with CDT scored by the Wolf-Klein method (specificity 0.71 [0.59-0.83]; sensitivity 0.68 [0.56-0.80]). CONCLUSIONS: MMSE and CDT alone are not valid screening methods for MCI detection. In combination, they reach fair sensitivity and specificity for the multiple domain impairment MCI subtype. However, some theoretical concerns relating to this subtype, together with the uncertainty that still lingers about its prognostic value, caution against routine use of MMSE and CDT as MCI screening instruments.     

High expression of ErbB family members and their ligands in lung adenocarcinomas that are sensitive to inhibition of epidermal growth factor receptor

Recent findings in tumor biopsies from lung adenocarcinoma patients suggest that somatic mutations in the genes encoding epidermal growth factor receptor (EGFR) and Kirsten ras (KRAS) confer sensitivity and resistance, respectively, to EGFR inhibition. Here, we provide evidence that these genetic mutations are not sufficient to modulate the biological response of lung adenocarcinoma cells to EGFR inhibition. We found high expression of ErbB family members, ErbB ligands, or both in three models that were sensitive to EGFR inhibition, including alveolar epithelial neoplastic lesions in mice that develop lung adenocarcinoma by oncogenic KRAS, human lung adenocarcinoma cell lines, and tumor biopsies from lung adenocarcinoma patients. Thus, lung adenocarcinoma cells that depend on EGFR for survival constitutively activate the receptor through a combination of genetic mutations and overexpression of EGFR dimeric partners and their ligands.     

Telomere length and telomerase activity: effect of ageing on human NK cells

Telomeres are repeats of TTAGGG sequences located at the end of eukaryotic chromosomes. They are essential for stabilisation and protection of chromosomal ends and for the regulation of cell replicative capacity. Due to the end-replication defect of DNA polymerase, telomeres shorten progressively with each cell division and telomere length may be an indicator of the replicative history of a cell. Compensatory mechanisms for the telomere loss have been identified. The most widely studied one is mediated by telomerase a ribonuclear protein-enzyme complex that synthesise telomeric repeats. In this study we have investigated whether NK cells, derived from a group of old healthy subjects, underwent the modifications of telomere length and telomerase activity observed in other sub-populations of lymphocytes with advancing age. We demonstrated that: (a) telomere shortening occurred and telomerase activity decreased in human NK cells with ageing; (b) the rate of telomere loss was different under and over 80 years of age; (c) similarly to telomere shortening, the modification of telomerase activity was particularly evident in octogenarians; (d) subjects with the most evident modifications of telomeres and telomerase were the oldest and those with increased NK cell numbers.     

Rhizomelic Chondrodysplasia Punctata Type 1 Caused by a Novel Mutation in the PEX7 Gene

Peroxisomes are involved in various metabolic reactions. Rhizomelic chondrodysplasia punctata (RCDP) type 1 is one of the peroxisomal biogenesis disorders caused by mutations in the PEX7 gene and is inherited in an autosomal recessive manner. We present a nine-year-old boy with skeletal abnormalities and dysmorphic facial appearance. The patient was born to parents who were first cousins. Very-long-chain fatty acids and pristanic acid levels were in the normal range, but an elevated phytanic acid level was detected by gas chromatography/mass spectrometry. The PEX7 gene was sequenced in the patient and his parents. A novel homozygous mutation, c.192delT (p.F64Lfs*10), was identified in the patient and was present in heterozygosity in both parents. In conclusion, the clinical presentation and peroxisome profile of the patient suggest that this novel mutation leads to RCDP type 1.     

Esophageal stenosis in epidermolysis bullosum: a challenge for the endoscopist

Background/Purpose

Esophageal stenosis is a severe complication in dystrophic epidermolysis bullosa (EB). Endoscopic dilations may cause mucosal injury with stricture recurrence. Our aim was to describe our referral EB-center experience on safety and long-term efficacy of fluoroscopically guided balloon dilation without endoscopy.

Methods

Over 14 years, 34 patients with EB, previously evaluated with barium esophagogram for dysphagia, underwent balloon esophageal dilation. Under fluoroscopy, a guide wire was introduced via a nostril into the stomach. A 12-mm pneumatic balloon, which passed over the wire, was filled using radio-opaque contrast, dilating the stricture. Orotracheal intubation was avoided. Antibiotics, dexamethasone, and proton-pump inhibitors were administered. Study approval was obtained from our ethical board.

Results

Ninety-three dilations were performed. Seventeen patients had a single stenosis. The mean age of onset was 18 years (range, 3-47 years). Thirteen patients underwent one dilation. In 6 cases, endoscopy was necessary to visualize the esophageal lumen. Complications included cervical esophageal perforation (2) and transitory dysphagia (10). Thirty patients were feeding within 24 hours. During the follow-up, 2 patients required a gastrostomy, and 2 patients underwent fundoplication for gastroesophageal reflux disease.

Conclusions

Fluoroscopically guided balloon dilation in EB is a safe and well-tolerated procedure. An experienced endoscopy team is necessary in certain cases.     

Microsatellite instability and compromised mismatch repair gene expression during in vitro passaging of monoclonal human T lymphocytes

An age-related accumulation of DNA damage caused by increased insult and/or decreased repair, could contribute to impaired cellular function. DNA mismatch repair (MMR), the main postreplicative correction pathway, can be monitored by assessing microsatellite instability and has been reported to decrease with age. Here, we analyzed the involvement of the MMR system in the accumulation of genetic damage in a cultured monoclonal human T lymphocyte model. We correlated microsatellite instability (MSI) and MMR gene expression, and replicative senescence of CD4+ clones derived from young, old and centenarian individuals or from CD34+ precursors. Cells were analyzed for MSI at five loci (CD4, VWA, Fes, D2S123, and BAT26), for the methylation status of MLH1 and MSH2 gene promoters, and for the expression of the MMR genes MSH2, MSH6, MSH3, MLH1, PMS2, and PMS1. MSI increased with increasing culture passages, particularly in the CD34+ progenitor-derived clones, but also in those from adult T cells. MSI and MMR gene expression were found to correlate, mostly due to a reduced expression of the components of MutL heterodimers, pointing to a role of MMR in the acquisition of DNA damage with in vitro aging.