Conjunctival provocation tests in suspected allergic conjunctivitis: a clinical study

We examined 57 patients who showed conjunctivitis suspected of allergic pathogenesis with skin radioallergosorbent (RAST) and conjunctival provocation tests (CPT). Our aim was to define statistical correlations between those tests and their exact values for the right diagnosis. Our data show that CPT is more sensitive than skin tests or RAST to ascertain the origin of conjunctivitis.     

Inactivation of the peroxisomal ABCD2 transporter in the mouse leads to late-onset ataxia involving mitochondria, Golgi and endoplasmic reticulum damage

ATP-binding cassette (ABC) transporters facilitate unidirectional translocation of chemically diverse substances, ranging from peptides to lipids, across cell or organelle membranes. In peroxisomes, a subfamily of four ABC transporters (ABCD1 to ABCD4) has been related to fatty acid transport, because patients with mutations in ABCD1 (ALD gene) suffer from X-linked adrenoleukodystrophy (X-ALD), a disease characterized by an accumulation of very-long-chain fatty acids (VLCFAs). Inactivation in the mouse of the abcd1 gene leads to a late-onset neurodegenerative condition, comparable to the late-onset form of X-ALD [Pujol, A., Hindelang, C., Callizot, N., Bartsch, U., Schachner, M. and Mandel, J.L. (2002) Late onset neurological phenotype of the X-ALD gene inactivation in mice: a mouse model for adrenomyeloneuropathy. Hum. Mol. Genet., 11, 499-505.]. In the present work, we have generated and characterized a mouse deficient for abcd2, the closest paralog to abcd1. The main pathological feature in abcd2-/- mice is a late-onset cerebellar and sensory ataxia, with loss of cerebellar Purkinje cells and dorsal root ganglia cell degeneration, correlating with accumulation of VLCFAs in the latter cellular population. Axonal degeneration was present in dorsal and ventral columns in spinal cord. We have identified mitochondrial, Golgi and endoplasmic reticulum damage as the underlying pathological mechanism, thus providing evidence of a disturbed organelle cross-talk, which may be at the origin of the pathological cascade.     

The use of the peripheral leukocyte count and chest X-rays in early assessment of the severity of acute pancreatitis in comparison with the Ranson score system

BACKGROUND: To evaluate the efficacy of the peripheral leukocyte count and chest X-rays as an index which could be used in the early assessment of the severity of acute pancreatitis in an Emergency Room. METHODS: We prospectively evaluated the peripheral leukocyte count and the findings of chest X-rays in 181 consecutive patients (102 males, 79 females, mean age 61 years, range 16-97) who were admitted to our Emergency Department with acute pancreatitis. One hundred twenty six patients had mild pancreatitis and 55 had severe pancreatitis. The peripheral leukocyte count and the chest X-rays were evaluated in all patients upon admission. The Ranson criteria were also assessed. RESULTS: Using a cut off value of 13,000/mm3, 45% of the patients with severe pancreatitis and 17% of those with mild acute pancreatitis had a peripheral leukocyte count greater than 13,000/mm3. Pleural or pulmonary alterations observed on chest X-ray were found in 66% of patients with severe pancreatitis and in 2% of those with mild acute pancreatitis. A peripheral leukocyte count greater than 13,000/mm3 and/or pleural or pulmonary alterations present on chest X-ray were found in 78% of the patients with severe pancreatitis and in 19% of those with mild pancreatitis. The Ranson criteria greater than or equal to three were found in 45% of the patients with severe acute pancreatitis and in 16% of those with the mild form of the disease. The positive predictive value was 92% for the presence of alterations on the chest X-rays, 64% for the alteration of at least one of the abnormal findings on the chest X-ray and a peripheral leukocyte count greater than 13,000/mm3, 56% for a peripheral leukocyte count greater than 13,000/mm3, and 54% for the presence of Ranson criteria greater than or equal to three. The negative predictive values were similar. CONCLUSIONS: The presence of pleural or pulmonary alterations on chest X-rays may be useful in the Emergency Room for the early identification of patients with severe acute pancreatitis.     

Telomerase is frequently activated in tumors with microsatellite instability

Telomeres are specialized structures at the ends of eukaryotic chromosomes that are required for the complete replication and stability of naturally occurring chromosome ends. Telomere stabilization is critical for the unlimited cellular proliferation that is necessary for tumor formation. While most tumors achieve telomere stabilization through activation of telomerase, a subset of tumors utilize a recombination-based mechanism termed Alternative Lengthening of Telomeres (ALT) to maintain chromosome termini. Tumors utilizing ALT for telomere preservation will likely be refractory to treatment with telomerase inhibitors. Furthermore, tumors carrying mutations that predispose a cell to utilize ALT may activate this pathway when challenged by telomerase inhibition. Mutation of the mismatch repair (MMR) pathway enhances telomerase independent survival in yeast, with the survivors using recombination-based pathways for telomere maintenance. One possibility is that mutation of the MMR pathways alleviates suppression of recombination, thereby abrogating the need for telomerase activation. If true, one might predict an increased frequency of tumors harboring MMR mutation to use ALT for telomere maintenance. Here we characterized tumors with and without MMR mutation for the presence of telomerase activity versus ALT. We found similarly frequent activation of telomerase in tumors with and without MMR mutation, suggesting that human tumors with MMR mutation may respond favorably to treatment with telomerase inhibitors.     

CYP superfamily perturbation by diflubenzuron or acephate in different tissues of CD1 mice.

This work aimed to investigate whether the insecticide acephate (125 or 250 mg/kg b.w.) or diflubenzuron (752 or 1075 mg/kg b.w.), two of the most widely used pesticides worldwide, impairs CYP-linked murine metabolism in liver, kidney and lung microsomes after repeated (daily, for three consecutive days) i.p. administration. The regio- and stereo-selective hydroxylation of testosterone was used as multibiomarker of different CYP isoforms. Both gender and tissue specific effects were observed. Lung was the most responsive tissue to induction by lower diflubenzuron dose, as exemplified by the marked increase of testosterone 7alpha-hydroxylation (CYP2A) (up to 13-fold) in males. Higher dose produced a generalized inactivation. At the lower dose acephate induced 6beta- (CYP3A1/2, liver) as well as 2beta- (CYP2B1/2, kidney) hydroxylase activities ( approximately 5 and approximately 4-fold increase, respectively) in males. In females, a marked suppression of the various hydroxylations was observed. At 250 mg/kg of acephate, animals did not survive. Induction of the most affected isoforms was sustained by immunoblotting analysis. Corresponding human CYP modulations might disrupt normal physiological functions related to these enzymes. Furthermore, the co-mutagenic and promoting potential of these pesticides, phenomena linked to CYP upregulation (e.g. increased bioactivation of ubiquitous pollutants and generation of oxygen free radicals) are of concern for a more complete definition of their overall toxicological potential.