Haploinsufficiency of Pkd2 is associated with increased tubular cell proliferation and interstitial fibrosis in two murine Pkd2 models.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited human kidney disease and is caused by germline mutations in PKD1 (85%) or PKD2 (15%). It has been estimated that around 1% of tubular cells give rise to cysts, and cell hyperproliferation has been noted to be a cardinal feature of cystic epithelium. Nevertheless, it is uncertain whether the increase in proliferative index observed is an early or late feature of the cystic ADPKD kidney. METHODS: Two Pkd2 mouse mutants (WS25 and WS183) have been recently generated as orthologous models of PKD2. To determine the effect of Pkd2 dosage on cell proliferation, cyst formation and renal fibrosis, we studied renal tissue from Pkd2(WS25/WS25) and Pkd2(+/-) mice by histological analysis. We also examined the proliferative index in archival nephrectomy tissue obtained from patients with ADPKD and normal controls. RESULTS: The proliferative index of non-cystic tubules in Pkd2 mutant mice as assessed by proliferating cell nuclear antigen and Ki67-positive nuclei was between 1-2%, values 5-10 times higher than control tissue. Similarly, the proliferative index of non-cystic tubules in human ADPKD kidneys was 40 times higher than corresponding controls. In Pkd2 mutant mice, significant correlations were found between the fibrosis score and the mean cyst area as well as with the proliferative index. Of significance, proliferating tubular cells were uniformly positive for polycystin-2 expression in Pkd2(+/-) kidney. CONCLUSION: These results suggest that an increase in cell proliferation is an early event preceding cyst formation and can result from haploinsufficiency at Pkd2. The possible pathogenic link between tubular cell proliferation, interstitial fibrosis and cyst formation is discussed.     

L'atteinte du pied au cours du rhumatisme psoriasique. À propos de 26 cas

Objective. – To describe the clinical and radiological features of foot involvement in patients with psoriatic arthritis.Methods. – We retrospectively reviewed the medical records of patients admitted between 1972 and 1999 for psoriatic arthritis with involvement of the foot. We included all patients who had peripheral and/or axial, asymmetric, chronic inflammatory joint disease meeting or not Avila's radiological criteria for psoriatic arthritis, with or without other imaging findings suggestive of psoriatic arthritis and with or without psoriasis.Results. – Twenty-six patients were included. Inflammatory heel pain was reported by 14 patients, whereas forefoot involvement was found in only seven patients. Sausage toe was present in two patients. None of the patients had Bauer's toe (combining arthritis and psoriatic skin and/or nail changes) or psoriatic onychopachydermoperiostitis of the great toe. Radiological abnormalities were found in 20 patients. Half the patients had calcaneal changes. Osteoperiostitis of the great toe was noted in two patients and mushrooming in five.Discussion. – The features of psoriatic arthritis in Morocco seem similar to those in other countries. Hindfoot involvement was present in 53% of patients. Involvement of the forefoot was rarely recorded in the charts, suggesting missed cases because of insufficient attention to the forefoot during the physical examination and availability of anteroposterior radiographs only. Oblique views (Hirtz and Chaumet) should be obtained because they give a clearer image of the distal part of the toes, which is often difficult to analyze on anteroposterior films.     

Glatiramer acetate in the treatment of multiple sclerosis

Glatiramer acetate is an immunomodulating drug used in the treatment of multiple sclerosis. It consists of a copolymer of amino acid residues in the same stoichiometric proportions as in myelin basic protein. Its mechanism of action is not entirely known and is probably multifaceted, with deletion of some immune cell populations and stimulation of others in these patients. Some mechanisms involve neuroprotectant effects. There is ample evidence of its efficacy in relapsing-remitting disease, using both clinical and imaging measures of disease activity, and in this paper we review the clinical and basic studies of this drug. Finally we discuss how some of its neuroprotectant effects may be useful in neurodegeneration such as is seen in more advanced cases of multiple sclerosis and other diseases such as amyotrophic lateral sclerosis and Parkinson’s disease.     

Séquelles fonctionnelles de la chirurgie carcinologique du rectum

The development of therapeutic options for rectal cancer strives to reach the ultimate goals of improved local control and overall survival. However, preserving continence, as well as genitourinary and sexual function, remains elusive in some patients. Loss of bowel control may be the most unsettling factor in terms of quality of life. Patients must be accurately informed about the surgery’s possible adverse effects, and surgeons must offer the best options (e.g. colostomy bag or sphincteroplasty) in order to minimize these complaints.     

Synthesis and antimalarial activity of new atovaquone derivatives

In this paper we describe the design and synthesis of 18 derivatives of the antimicrobial atovaquone which were substituted at the 3-hydroxy group by ester and ether functions. The compounds were evaluated in vitro for their activity against the growth of Plasmodium falciparum, the malaria causing parasite. All the compounds showed potent activity, with IC₅₀ values in the range of 1.25–50 nM, comparable to those of atovaquone and much higher than chloroquine or quinine.     

Improvement in quality of life after initiation of lamotrigine therapy in patients with epilepsy in a naturalistic treatment setting.

Quality of life is impaired in patients with epilepsy and can be improved by effective therapy. Randomised clinical trials have shown that lamotrigine treatment is associated with improved quality of life. However, little information is available on quality of life or treatment effects in patients with epilepsy in the general population. The objective of this study was to estimate the impact of lamotrigine on quality of life in a naturalistic treatment setting. The study included adult patients with epilepsy in whom lamotrigine therapy was initiated. Each subject completed the Quality of Life in Epilepsy Inventory (QOLIE)-31 quality of life questionnaire at inclusion and at a follow-up visit in the next 4 months. Demographic information and medical history were provided by the investigator. These were evaluated as potential determinants of change in quality of life using logistic regression. Three hundred and forty-one patients were evaluated, 192 starting lamotrigine in combination with another drug, 90 as a first-line monotherapy, 45 as a switch from another drug and 14 as a reduction to monotherapy from a previous combination. Baseline scores on the QOLIE-31 ranged from 53.8 in the combination group to 69.5 in the first-line group. 34.6% of patients were considered to be responders, with no significant differences between treatment regimen. Most improvement was seen for the energy-fatigue and medication effects subscales and, for the first-line group, seizure worry. Seizure type was the only determinant of improvement of quality of life identified. In conclusion, lamotrigine treatment is associated with improved quality of life, regardless of treatment regimen.     

Antimutagenic properties of bell and black peppers.

The wing Somatic Mutation And Recombination Test (SMART) in Drosophila melanogaster was used to study the modulating action of bell pepper (Capsicum annuum) and black pepper (Piper nigrum) in combination with the alkylating agent methyl methanesulfonate (MMS) and the promutagen agent ethyl carbamate (EC). Larvae trans-heterozygous for the third chromosome recessive markers multiple wing hairs (mwh) and flare-3 [flr(3)] were fed genotoxins alone or in combination with each of the two spices. Genetic changes induced in somatic cells of the wing's imaginal discs lead to the formation of mutant clones on the wing blade. Our results showed that bell pepper was effective in reducing the mutational events induced by EC and MMS and black pepper was only effective against EC. Pretreatment of 2-day-old larvae with the spices for 24 h followed by a treatment with EC and MMS was only effective in reducing mutations induced by EC. Suppression of metabolic activation or interaction with the active groups of mutagens could be mechanisms by which the spices exert their antimutagenic action.