Degradation of cytoplasmic substrates by FtsH,a membrane-anchored protease with many talents

Control of cellular processes by regulated proteolysis is conserved among all organisms. FtsH, the only membrane-anchored AAA protease in bacteria, fulfills a variety of regulatory functions. This review focuses on soluble FtsH substrates in Escherichia coli and in other bacteria and outlines emerging substrate recognition principles.     

Melatonin protects kidney grafts from ischemia/reperfusion injury through inhibition of NF-kB and apoptosis after experimental kidney transplantation

Abstract:  Free radicals are involved in pathophysiology of ischemia/reperfusion injury (IRI). Melatonin is a potent scavenger of reactive oxygen and nitrogen species. Thus, this study was designed to elucidate its effects in a model of rat kidney transplantation. Twenty Lewis rats were randomly divided into 2 groups (n = 10 animals each). Melatonin (50 mg/kg BW) dissolved in 5 mL milk was given to one group via gavage 2 hr before left donor nephrectomy. Controls were given the same volume of milk only. Kidney grafts were then transplanted into bilaterally nephrectomized syngeneic recipients after 24 hr of cold storage in Histidine–Tryptophan–Ketoglutarate solution. Both graft function and injury were assessed after transplantation through serum levels of blood urea nitrogen (BUN), creatinine, transaminases, and lactate dehydrogenase (LDH). Biopsies were taken to evaluate tubular damage, the enzymatic activity of superoxide dismutase (SOD) and lipid hydroperoxide (LPO), and the expression of NF-kBp65, inducible nitric oxide synthase (iNOS), caspase-3 as indices of oxidative stress, necrosis, and apoptosis, respectively. Melatonin improved survival ( P  < 0.01) while decreasing BUN, creatinine, transaminases, and LDH values up to 39–71% ( P  < 0.05). Melatonin significantly reduced the histological index for tubular damage, induced tissue enzymatic activity of SOD while reducing LPO. At the same time, melatonin down-regulated the expression of NF-kBp65, iNOS, and caspase-3. In conclusion, donor preconditioning with melatonin protected kidney donor grafts from IRI-induced renal dysfunction and tubular injury most likely through its anti-oxidative, anti-apoptotic and NF-kB inhibitory capacity.     

Combined 1p/19q loss in oligodendroglial tumors: predictive or prognostic biomarker?

PURPOSE: The combined loss of genetic material on chromosomes 1p and 19q is strongly associated with favorable outcome in patients with WHO grade 3 anaplastic oligodendroglial tumors. The prognostic value of 1p/19q loss in WHO grade 2 oligodendroglial tumors is less well defined. Importantly, the possible effect of combined 1p/19q loss has not been studied in patients who were not treated with radiotherapy or chemotherapy. EXPERIMENTAL DESIGN: Seventy-six patients with oligodendroglioma (n = 33), oligoastrocytoma (n = 30), anaplastic oligodendroglioma (n = 6), or anaplastic oligoastrocytoma (n = 7) were identified who had not received radiotherapy or chemotherapy after their first operation until the end of follow-up or until the first progression and had tissue for 1p/19q status available. 1p/19q status was assessed by multiplex ligation-dependent probe amplification. RESULTS: After a median follow-up of 3.8 years, progressive disease was documented in 34 patients. The estimated median progression-free survival was 4.6 years. Fifty-eight of the 76 patients had a combined loss of 1p and 19q. The absence or presence of combined 1p/19q loss was not prognostic for progression-free survival using multivariate adjustment for histology, extent of resection, and gender. CONCLUSIONS: Combined 1p/19q loss is not a sensitive prognostic biomarker in patients with oligodendroglial tumors who do not receive radiotherapy or chemotherapy. The gene products lost as a consequence of this codeletion may include mediators of resistance to genotoxic therapies. Alternatively, 1p/19q loss might be an early oncogenic lesion promoting the formation of glial neoplasms, which retain high sensitivity to genotoxic stress.     

Deep brain stimulation to reward circuitry alleviates anhedonia in refractory major depression.

Deep brain stimulation (DBS) to different sites allows interfering with dysfunctional network function implicated in major depression. Because a prominent clinical feature of depression is anhedonia--the inability to experience pleasure from previously pleasurable activities--and because there is clear evidence of dysfunctions of the reward system in depression, DBS to the nucleus accumbens might offer a new possibility to target depressive symptomatology in otherwise treatment-resistant depression. Three patients suffering from extremely resistant forms of depression, who did not respond to pharmacotherapy, psychotherapy, and electroconvulsive therapy, were implanted with bilateral DBS electrodes in the nucleus accumbens. Stimulation parameters were modified in a double-blind manner, and clinical ratings were assessed at each modification. Additionally, brain metabolism was assessed 1 week before and 1 week after stimulation onset. Clinical ratings improved in all three patients when the stimulator was on, and worsened in all three patients when the stimulator was turned off. Effects were observable immediately, and no side effects occurred in any of the patients. Using FDG-PET, significant changes in brain metabolism as a function of the stimulation in fronto-striatal networks were observed. No unwanted effects of DBS other than those directly related to the surgical procedure (eg pain at sites of implantation) were observed. Dysfunctions of the reward system--in which the nucleus accumbens is a key structure--are implicated in the neurobiology of major depression and might be responsible for impaired reward processing, as evidenced by the symptom of anhedonia. These preliminary findings suggest that DBS to the nucleus accumbens might be a hypothesis-guided approach for refractory major depression.     

Cogrinding enhances the oral bioavailability of EMD 57033, a poorly water soluble drug, in dogs.

The oral bioavailability of EMD 57033, a calcium sensitizing agent with poor solubility, was compared in dogs using four solid dosage form formulation approaches: a physical blend of the drug with excipients, micronization of the drug, preparation of coground mixtures and spray-drying of the drug from a nanocrystalline suspension. The formulations contained generally accepted excipients such as lactose, hydroxypropylmethyl cellulose and sodium lauryl sulphate in usual quantities. Drug micronization and cogrinding was realized by a jet-milling technique. Nanoparticles were created by media milling using a bead mill. All formulations were administered orally as dry powders in hard gelatine capsules. While micronization increased the absolute bioavailability of the solid drug significantly compared to crude material (from nondetectable to 20%), cogrinding with specific excipients was able to almost double this improvement (up to 39%). With an absolute bioavailability of 26%, spray-dried nanoparticular EMD 57033 failed to show the superior bioavailability that had been anticipated from in vitro data. The control solution prepared with cyclodextrin was shown to have an absolute bioavailability of 57% (vs. i.v. infusion). It was concluded that cogrinding can be a useful tool to improve the bioavailability of poorly soluble drugs from a solid dosage form format.     

Propensity score matching without conditional independence assumption—with an application to the gender wage gap in the United Kingdom

Summary Propensity score matching is frequently used for estimating average treatment effects. Its applicability, however, is not confined to treatment evaluation. In this paper, it is shown that propensity score matching does not hinge on a selection on observables assumption and can be used to estimate not only adjusted means but also their distributions, even with non‐i.i.d. sampling. Propensity score matching is used to analyze the gender wage gap among graduates in the UK. It is found that subject of degree contributes substantially to explaining the gender wage gap, particularly at higher quantiles of the wage distribution.     

The consequences of delayed intervention when treating chemical eye burns

Background Immediate rescue intervention for chemical and thermal eye burns can save the victim’s sight. We studied the anterior chamber pH changes immediately after ex vivo eye burn to investigate the effects of immediate and delayed intervention. Methods Twenty three enucleated pigs eyes were burnt with 500 μl 2 mol NaOH for 20 s using a cylinder with a diameter of 10 mm. The corneas were rinsed in groups with 1015 ml ordinary tap water at a flow rate of 1.125 ml/s for 15 minutes immediately after burning (n = 6), and after a delay of 20, 40, and 60 s (n = 5, 3 and 4 respectively). One group of eyes was not rinsed (n = 5). The intraocular pH was defined at the start as ‘min pH’ and the end as ‘max pH’(ΔpH = max pH-min pH). Results The intraocular pH increased sharply in the untreated eyes from a min pH of 6.76 ± 0.55 to a max pH of 11.85 ± 0.24, yielding a ΔpH of 5.08. The difference between the timepoint at which the pH began to increase and the speed of change was significantly different between the unrinsed and rinsed eyes, and there was an inverse correlation between this and the time at which rinsing started (p < 0.001). The best results were achieved in eyes rinsed immediately after burning (p < 0.001). The pH in the eyes not rinsed immediately increased rapidly, and in all groups in which rinsing was delayed the max pH was markedly higher (p = 0.093). Conclusions Immediate emergency rinsing is essential in eye burn victims. Appropriate rinsing solutions and treatment facilities in the form of rinsing stations where chemical burns may occur must be available at the workplace. Tap water is also effective as a rinsing solution. Presentation The results were the subject of a short oral presentation at the 104th DOG Annual Meeting 2006 in Berlin.     

Pseudarthrosis in fibrous dysplasia treated with bone morphogenetic protein

We present a case of pseudarthrosis in a patient suffering from polyostotic fibrous dysplasia of the right part of the body that was successfully treated with bone morphogenetic protein. Pseudarthrosis occurred after proximal femoral shaft fracture due to a motorcycle accident initially treated by intramedullary nailing. After revision, the patient was treated by pseudarthrosis debridement and grafting of bone morphogenetic protein-7/osteogenic protein-1, resulting in callus formation that allowed indolent full weight-bearing after 6 weeks. The underlying disease as well as the described treatment is discussed.