Increased Parietal and Frontal Activation after Remission from Recurrent Major Depression: A Repeated fMRI Study

Nine patients with unipolar major depression were scanned with MRI twice over a 2-year period, and compared with 12 healthy control subjects. All patients fulfilled criteria for major depressive disorder, recurrent type, at first scanning. Level of depressive psychopathology was assessed by the Hamilton Depression Rating Scale. The participants had to work on a mental arithmetics/working memory task while in the MR scanner. The task consisted of single digits (1 to 9) that were shown to the participant, who had to add the numbers in successive pairs and press a response button when the sum was 10. Neuronal activation was recorded based on the BOLD contrast phenomenon in a functional MRI protocol. The results showed significant increase in activation for the patients in the inferior frontal gyrus and the superior and inferior parietal lobule at the second compared with the first MR scanning session. There were also significant correlations between the HDRS scores and neuronal activation which showed a negative correlation particularly in the inferior frontal and parietal lobe areas, which overlapped with similar areas activated in the healthy control participants. This may indicate normalization of brain activation in depressed patients as a function of time from an illness phase to a remission/recovery state.

The influence of CYP3A,PPARA, and POR genetic variants on the pharmacokinetics of tacrolimus and cyclosporine in renal transplant recipients

Purpose

Tacrolimus (Tac) and cyclosporine (CsA) are mainly metabolized by CYP3A4 and CYP3A5. Several studies have demonstrated an association between the CYP3A5 genotype and Tac dose requirements. Recently, CYP3A4, PPARA, and POR gene variants have been shown to influence CYP3A metabolism. The present study investigated potential associations between CYP3A5*3, CYP3A4*22, PPARA c.209-1003G>A and c.208?+?3819A>G, and POR*28 alleles and dose-adjusted concentrations (C/D) of Tac and CsA in 177 renal transplant patients early post-transplant.

Methods

All patients (n?=?177) were genotyped for CYP3A4*22, CYP3A5*3, POR*28, PPARA c.209-1003G>A, and PPARA c.208?+?3819A>G using real-time polymerase chain reaction (PCR) and melting curve analysis with allele-specific hybridization probes or PCR restriction fragment length polymorphisms (RFLP) methods. Drug concentrations and administered doses were retrospectively collected from patient charts at Oslo University Hospital, Rikshospitalet, Norway. One steady-state concentration was collected for each patient.

Results

We confirmed a significant impact of the CYP3A5*3 allele on Tac exposure. Patients with POR*28 and PPARA variant alleles demonstrated 15 % lower (P?=?0.04) and 19 % higher (P?=?0.01) Tac C₀/D respectively. CsA C₂/D was 53 % higher among CYP3A4*22 carriers (P?=?0.03).

Conclusion

The results support the use of pre-transplant CYP3A5 genotyping to improve initial dosing of Tac, and suggest that Tac dosing may be further individualized by additional POR and PPARA genotyping. Furthermore, initial CsA dosing may be improved by pre-transplant CYP3A4*22 determination.     

Case reports

The clinical presentation of lead intoxication may vary widely and in the absence of a high clinical index of suspicion, the diagnosis may be missed. The effects of lead on mitochondrial oxidative phosphorylation and its interaction with calcium-mediated processes explain the heterogenous presentation. In this case report, the diagnosis was finally made when bilateral wrist drop developed on top of abdominal cramps and anemia. Before, ascites raised the suspicion of a tumor. Therefore, each element of the triad of unexplained anemia, abdominal cramps, and bilateral wrist (or foot) drop should lead any physician to consider the diagnosis of lead intoxication. This case also illustrates the importance of a careful and meticulous social history in patient management.     

Cell-based resurfacing of large cartilage defects: long-term evaluation of grafts from autologous transgene-activated periosteal cells in a porcine model of osteoarthritis

OBJECTIVE: To investigate the potential of transgene-activated periosteal cells for permanently resurfacing large partial-thickness cartilage defects. METHODS: In miniature pigs, autologous periosteal cells stimulated ex vivo by bone morphogenetic protein 2 gene transfer, using liposomes or a combination of adeno-associated virus (AAV) and adenovirus (Ad) vectors, were applied on a bioresorbable scaffold to chondral lesions comprising the entire medial half of the patella. The resulting repair tissue was assessed, 6 and 26 weeks after transplantation, by histochemical and immunohistochemical methods. The biomechanical properties of the repair tissue were characterized by nanoindentation measurements. Implants of unstimulated cells and untreated lesions served as controls. RESULTS: All grafts showed satisfactory integration into the preexisting cartilage. Six weeks after transplantation, AAV/Ad-stimulated periosteal cells had adopted a chondrocyte-like phenotype in all layers; the newly formed matrix was rich in proteoglycans and type II collagen, and its contact stiffness was close to that of healthy hyaline cartilage. Unstimulated periosteal cells and cells activated by liposomal gene transfer formed only fibrocartilaginous repair tissue with minor contact stiffness. However, within 6 months following transplantation, the AAV/Ad-stimulated cells in the superficial zone tended to dedifferentiate, as indicated by a switch from type II to type I collagen synthesis and reduced contact stiffness. In deeper zones, these cells retained their chondrocytic phenotype, coinciding with positive staining for type II collagen in the matrix. CONCLUSION: Large partial-thickness cartilage defects can be resurfaced efficiently with hyaline-like cartilage formed by transgene-activated periosteal cells. The long-term stability of the cartilage seems to depend on physicobiochemical factors that are active only in deeper zones of the cartilaginous tissue.