Treatment of palmoplantar psoriasis with infliximab: a randomized,double‐blind placebo‐controlled study

Background Palmoplantar psoriasis is a difficult to treat variant of plaque psoriasis. Objective To study the safety and efficacy of infliximab in non‐pustular palmoplantar psoriasis. Methods Patients with non‐pustular palmoplantar psoriasis affecting at least 10% of their palms and soles and with a modified palmoplantar psoriasis area and severity index (m‐PPPASI) of at least eight were recruited. Patients were randomized (1:1) to receive infliximab 5 mg/kg or placebo at weeks 0, 2 and 6. Patients initially randomized to placebo received infliximab at weeks 14, 16 and 20 whereas patients randomized to infliximab received additional infliximab infusions every 8 weeks until week 22. Results Twenty four (24) patients were randomized in this study. At week 14, 33.3% and 66.7% of patients treated with infliximab achieved m‐PPPASI 75 and m‐PPPASI 50 respectively compared to 8.3% for both m‐PPPASI 75 (P = 0.317) and m‐PPPASI 50 (P = 0.009) for patients randomized to placebo. A reduction of 50.3% in the mean surface area of palms and soles affected with psoriasis was seen at week 14 in patients randomized to infliximab as compared to an increase of 14.9% in patients randomized to placebo (P = 0.009). Conclusions This pilot study did not reach its primary endpoint of m‐PPPASI 75 at week 14. However, infliximab was observed to be more efficacious than placebo in improving PPSA and with respect to the percentage of patients reaching m‐PPPASI 50 at week 14. Larger and longer term studies are needed for severe patients to better assess the efficacy of infliximab in palmoplantar psoriasis.     

Cerivastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme a reductase, inhibits endothelial cell proliferation induced by angiogenic factors in vitro and angiogenesis in in vivo models

Cerivastatin is an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase. It inhibits the biosynthesis of cholesterol and its precursors: farnesyl pyrophosphate and geranylgeranyl pyrophosphate (GGPP), which are involved in Ras and RhoA cell signaling, respectively. Statins induce greater protection against vascular risk than that expected by cholesterol reduction. Therefore, cerivastatin could protect plaque against rupture, an important cause of ischemic events. In this study, the effect of cerivastatin was tested on angiogenesis because it participates in plaque progression and plaque destabilization. Cerivastatin inhibits in vitro the microvascular endothelial cell proliferation induced by growth factors, whereas it has no effect on unstimulated cells. This growth arrest occurs at the G(1)/S phase and is related to the increase of the cyclin-dependent kinase inhibitor p21(Waf1/Cip1). These effects are reversed by GGPP, suggesting that the inhibitory effect of cerivastatin is related to RhoA inactivation. This mechanism was confirmed by RhoA delocalization from cell membrane to cytoplasm and actin fiber depolymerization, which are also prevented by GGPP. It was also shown that RhoA-dependent inhibition of cell proliferation is mediated by the inhibition of focal adhesion kinase and Akt activations. Moreover, cerivastatin inhibits in vivo angiogenesis in matrigel and chick chorioallantoic membrane models. These results demonstrate the antiangiogenic activity of statins and suggest that it may contribute to their therapeutic benefits in the progression and acute manifestations of atherosclerosis.     

Laparoscopic Resection for Colon Cancer: Would all Patients Benefit?

Purpose This study was designed to assess whether the exclusion criteria used in the Clinical Outcomes of Surgical Therapy and Colon Cancer Laparoscopic or Open Resection trials affected the generalizability of their findings. Methods A prospective database of consecutive laparoscopic resections performed for colon cancer was reviewed. Patients were categorized into two groups: inclusion group and exclusion group, based on the selection criteria used in the Clinical Outcomes of Surgical Therapy and Colon Cancer Laparoscopic or Open Resection trials. Baseline and perioperative data were analyzed by using t-tests, Wilcoxon’s rank-sum, chi-squared, and Fisher’s exact test. Kaplan-Meier survival curves, followed by adjustment for tumor nodes metastasis stage and age utilizing a Cox proportional hazard model, were performed. Results The inclusion group had 221 patients and the exclusion group had 166 (median age and gender distribution were similar). The exclusion group had a higher conversion rate (23 vs. 11.3 percent; P = 0.0023). There was no difference in intraoperative complications (9 percent for exclusion group vs. 8.6 percent for inclusion group; P = 0.8), operative time (180 minutes for exclusion group vs.172 minutes for inclusion group; P = 0.24), or postoperative complication rates (33.7 percent for exclusion group vs. 26 percent for inclusion group; P = 0.13). No difference was detected in perioperative mortality rates, length of stay, days to diet as tolerated, and adjusted two-year survival. Conclusions No differences were found in outcomes between the two groups in terms of operative/postoperative complications, length of stay, perioperative mortality, and two-year survival. It seems that all patients with colon cancer can potentially benefit from a laparoscopic approach. Read at the meeting of The American Society of Colon and Rectal Surgeons, St. Louis, Missouri, June 2 to 6, 2007.     

The effects of perinatal hypoxia on the behavioral,neurochemical, and neurohistological toxicity of the metabolic inhibitor 3-nitropropionic acid

3-nitropropionic acid (3-NPA) neurotoxicity and long-term effects of perinatal hypoxia were evaluated in 18 adult rats. Hypoxia-insulted (I) and noninsulted (NI) rats were delivered by cesarean section. Hypoxic insult was effected by submerging dissected uterine horns in warmed saline for 15 min. NI rats were delivered from the adjacent nonsubmerged horns. At postnatal day 90, I and NI rats were trained to perform tasks thought to measure behaviors dependent upon aspects of time estimation (TE), motivation, and learning. At 12 months of age, rats were injected i.p. with escalating doses of 3-NPA (5 mg/kg/day to a maximum of 30 mg/kg/day) immediately after each test session and sacrificed at the end of treatment. Additional male rats were used as untreated controls. Although 3-NPA produced a dose-dependent impairment of performance in each task, the effects were qualitatively similar for each group. A significant difference between I and NI rats was, however, observed in the TE task where NI rats completed less of the task at high doses of 3-NPA compared to I rats. Compared to untreated controls, dopamine concentrations were decreased in caudate nucleus of both I and NI rats after 3-NPA. Specific areas most frequently damaged included cerebral cortex, hippocampal subfield CA1, thalamus, caudate nucleus, and the cerebellum. Lesions usually were less extensive in the I rather than NI members of a littermate pair, suggesting a possible protective effect of perinatal hypoxia against subsequent 3-NPA neurotoxicity.     

Cyp7b, a novel brain cytochrome P450, catalyzes the synthesis of neurosteroids 7α-hydroxy dehydroepiandrosterone and 7α-hydroxy pregnenolone

Steroids produced locally in brain (neurosteroids), including dehydroepiandrosterone (DHEA), influence cognition and behavior. We previously described a novel cytochrome P450, Cyp7b, strongly expressed in rat and mouse brain, particularly in hippocampus. Cyp7b is most similar to steroidogenic P450s and potentially could play a role in neurosteroid metabolism. To examine the catalytic activity of the enzyme mouse Cyp7b cDNA was introduced into a vaccinia virus vector. Extracts from cells infected with the recombinant showed NADPH-dependent conversion of DHEA (K_m, 13.6 μM) and pregnenolone (K_m, 4.0 μM) to slower migrating forms on thin layer chromatography. The expressed enzyme was less active against 25-hydroxycholesterol, 17β-estradiol and 5α-androstane-3β,17β-diol, with low to undetectable activity against progesterone, corticosterone, and testosterone. On gas chromatography and mass spectrometry of the Cyp7b metabolite of DHEA the retention time and fragmentation patterns were identical to those obtained with authentic 7α-hydroxy DHEA. The reaction product also comigrated on thin layer chromatography with 7α-hydroxy DHEA but not with 7β-hydroxy DHEA; when [7α-³H]pregnenolone was incubated with Cyp7b extracts the extent of release of radioactivity into the medium suggested that hydroxylation was preferentially at the 7α position. Brain extracts also efficiently liberated tritium from [7α-³H]pregnenolone and converted DHEA to a product with a chromatographic mobility indistinguishable from 7α-hydroxy DHEA. We conclude that Cyp7b is a 7α-hydroxylase participating in the synthesis, in brain, of neurosteroids 7α-hydroxy DHEA, and 7α-hydroxy pregnenolone.     

Tau positron emission tomography,cerebrospinal fluid and plasma biomarkers of neurodegeneration,and neurocognitive testing: an exploratory study of participants with myotonic dystrophy type 1

Journal of Neurology - To investigate Tau pathology using multimodal biomarkers of neurodegeneration and neurocognition in participants with myotonic dystrophy type 1 (DM1). We recruited twelve...     

Immunohistochemical variability of epidermal growth factor receptor (EGFR) in liver metastases from colonic carcinomas

AIMS: To follow and compare immunohistochemical expression of epidermal growth factor receptor (EGFR) in tumour cells during the entire natural history of colonic carcinoma, from primary tumour to paired lymph node and sequentially resected liver metastases; and to test interobserver reproducibility of EGFR analysis. METHODS AND RESULTS: Forty patients had resection of colonic adenocarcinoma (27 with metastatic lymph nodes) and at least one partial hepatectomy (PH) for liver metastases; a second and a third PH were performed, respectively, in 14 and three patients; seven patients had tumour liver biopsy. EGFR immunohistochemistry (n = 130) was analysed independently by two pathologists. EGFR expression (membranous staining detected in > or = 1% of tumour cells) was detected in 38/40 colonic carcinomas, 23/26 lymph nodes and 51/64 liver metastases. Both primary tumours and related metastases were EGFR+ in 28 patients (73%). Discrepancies were found in EGFR status between liver and lymph node (23%) and among the different liver samples (31%). Interobserver agreement was very good (intraclass correlation coefficients of 0.81, 0.91 and 0.85, respectively, for interpretation of staining in colon, lymph node and liver metastases). CONCLUSIONS: Since immunohistochemical detection of EGFR remains a prerequisite for EGFR-targeted therapy eligibility, different tumour samples should be tested to allow every patient a chance to take advantage of this treatment.