Potent inhibitory effect of the cyclolignan picropodophyllin (PPP) on human adrenocortical carcinoma cells proliferation

Adrenocortical carcinoma (ACC) is a very aggressive tumor with a poor prognosis. Available treatments for this type of cancer are far from being satisfactory. The IGF signalling pathway represents an important mechanism for ACT growth and constitutes a relevant therapeutic target. We investigated the effect of picropodophyllin (PPP), a member of the cyclolignan family and a new inhibitor of IGF-1R, on proliferation of human adrenocortical cell lines H295R and SW-13. PPP inhibits proliferation and induces an important accumulation in G2/M phase and apoptosis of H295R and SW-13 cells. Our data suggest that PPP may be a promising candidate for drug development for adrenocortical carcinoma.     

NMR reveals pathway for ferric mineral precursors to the central cavity of ferritin

Ferritin is a multimeric nanocage protein that directs the reversible biomineralization of iron. At the catalytic ferroxidase site two iron(II) ions react with dioxygen to form diferric species. In order to study the pathway of iron(III) from the ferroxidase site to the central cavity a new NMR strategy was developed to manage the investigation of a system composed of 24 monomers of 20 kDa each. The strategy is based on ¹³C-¹³C solution NOESY experiments combined with solid-state proton-driven ¹³C-¹³C spin diffusion and 3D coherence transfer experiments. In this way, 75% of amino acids were recognized and 35% sequence-specific assigned. Paramagnetic broadening, induced by iron(III) species in solution ¹³C-¹³C NOESY spectra, localized the iron within each subunit and traced the progression to the central cavity. Eight iron ions fill the 20-Å-long iron channel from the ferrous/dioxygen oxidoreductase site to the exit into the cavity, inside the four-helix bundle of each subunit, contrasting with short paths in models. Magnetic susceptibility data support the formation of ferric multimers in the iron channels. Multiple iron channel exits are near enough to facilitate high concentration of iron that can mineralize in the ferritin cavity, illustrating advantages of the multisubunit cage structure.     

Evaluation of Alloreactivity in Kidney Transplant Recipients Treated with Antithymocyte Globulin Versus IL‐2 Receptor Blocker

Induction therapy is used in kidney transplantation to inhibit the activation of donor‐reactive T cells which are detrimental to transplant outcomes. The choice of induction therapy is decided based on perceived immunological risk rather than by direct measurement of donor T‐cell reactivity. We hypothesized that immune cellular alloreactivity pretransplantation can be quantified and that blocking versus depleting therapies have differential effects on the level of donor and third‐party cellular alloreactivity. We studied 31 kidney transplant recipients treated with either antithymocyte globulin (ATG) or an IL‐2 receptor blocker. We tested pre‐ and posttransplant peripheral blood cells by flow cytometry to characterize T‐cell populations and by IFN‐γ ELISPOT assays to assess the level of cellular alloreactivity. CD8⁺ T cells were more resistant to depletion by ATG than CD4⁺ T cells. Posttransplantation, frequencies of donor‐reactive T cells were markedly decreased in the ATG‐treated group but not in the IL‐2 receptor blocker group, whereas the frequencies of third‐party alloreactivity remained nearly equivalent. In conclusion, when ATG is used, marked and prolonged donor hyporesponsiveness with minimal effects on nondonor responses is observed. In contrast, induction with the IL‐2 receptor blocker is less effective at diminishing donor T‐cell reactivity.     

Posttransplant diabetes mellitus: incidence and risk factors

Posttransplant diabetes mellitus (PTDM) is common post transplantation and is associated with tacrolimus (TAC) and steroid therapy. The aim of the present study was to analyze the incidences of PTDM and associated risk factors. METHODS: We selected renal transplant recipients treated with TAC, mycophenolate mofetil (MM), and steroids. Exclusion criteria were recipients <18 years old, history of diabetes, recipients of kidney/pancreas, and/or those receiving cyclosporine or sirolimus. PTDM was defined as glucose >126 mg/dL, with or without drug therapy. RESULTS: Among 67 patients who fulfilled the inclusion criteria, 18 (26.8%) developed PTDM within 2 months of transplantation. Compared with normal glucose patients, the PTDM group was older, male, received a kidney from deceased donors, and showed higher pretransplant glucose levels. No differences were noticed in renal function or daily dose of TAC or steroids. However, TAC trough levels in the first month were higher among the PTDM group, despite the lower dose per kilogram. After 1 year of follow-up, weight gain as well as daily TAC per kilogram dose was less among PTDM patients. Analysis of potential risk factors showed a higher incidence of hepatitis C virus infection in the PTDM group, as well as a higher frequency of HLA DR13. CONCLUSION: The incidence of PTDM diagnosed in the early posttransplant period in the present series was 26.8%. Risk factors included older age, male gender, recipients of kidneys from deceased donors, hepatitis C virus infection, higher pretransplant glucose levels, and higher TAC trough levels during the first month posttransplant.     

Rivastigmine in Parkinson's disease dementia

Dementia associated with Parkinson's disease (PD) ultimately develops in approximately 70% of patients with PD older than 80 years of age. The neuropathology of PD dementia (PDD) is likely multifactorial and affects several neuronal populations. There is evidence that PDD is associated with a cholinergic deficit, supporting the therapeutic role of cholinesterase inhibitors, which are already first-line agents in the treatment of Alzheimer's disease. Open-label and small controlled studies suggested a clinical efficacy of cholinesterase inhibitors in PDD. One large randomized placebo-controlled trial of 541 patients demonstrated that oral rivastigmine improved cognition, attention and executive functions, activities of daily living and behavioral symptoms after 6 months of treatment. Rivastigmine is a dual cholinesterase inhibitor, being effective on both acetylcholinesterase and butyrylcholinesterase. This paper reviews the pharmacokinetic and pharmacodynamic properties of rivastigmine (oral and transdermal administration). It also reviews evidence on clinical efficacy, safety and tolerability of the oral administration in PDD patients at doses of 3-12 mg/day.     

Response covariation. The relationship between correct academic responding and problem behavior.

This article examined the relationship between the accuracy of academic responding and aggression for two boys with mild mental retardation. Their teacher reported low rates of correct responding and high rates of aggressive behavior during spelling instruction. A functional analysis showed that aggression was escape maintained. Following the functional analysis, participants were tested on relations between printed, photographic, and dictated stimuli corresponding to their spelling words. On pretests, they were unable to match printed words to their photographs or to their dictated names; they could neither name the printed words nor spell the photographs or dictated words. High rates of aggression were observed during the pretests. The participants then were taught the letter-by-letter construction of the appropriate words when shown photographs. On posttests, the participants correctly matched printed words to their photographs and dictated names. In addition, they correctly named printed words and spelled dictated words orally. Data showed that rates of problem behavior negatively covaried with improvements in the participants' academic responding.     

Effects of Sucralfate and Sulglycotide Treatment on Active Gastritis and Helicobacter pylori Colonization of the Gastric Mucosa in Non-Ulcer Dyspepsia Patients

We conducted a double-blind randomized treatment study on patients affects by non-ulcer dyspepsia in whom multiple biopsy specimens showed active gastritis. Patients were given either 3 g/day of sucralfate (n = 39) or 600 mg/day of sulglycotide (n = 50) for 6 wk, a glycopeptide isolated from pig duodenum constituents. Endoscopy was carried out at baseline and at the end of treatment. We took biopsies from the gastric body (twice) and antrum (six times) at each endoscopy in order to determine grade and extent of gastritis and Helicobacter pylori colonization. Both treatments induced a marked regression of active gastritis (sucralfate group: p less than 0.05 and p less than 0.0001, respectively, in body and in antrum; sulglycotide group: p less than 0.01 and p less than 0.001, respectively). Conversely, Helicobacter pylori colonization remained unchanged at the end of the treatments. At baseline, a close relationship was found between grade of active inflammation in each biopsy and Helicobacter pylori density. After therapy, the association was lost in each treatment group. These results suggest that there can be a remission of active gastritis in patients with non-ulcer dyspepsia even without changes in Helicobacter pylori colonization. This result can be achieved by enhancing the protective properties of the gastric mucosa.