Similar to p73, the tumor suppressor gene p53 is subject to alternative splicing. Besides p53DeltaE6 and p53beta, we identified p53zeta, p53delta and p53varepsilon, arising from alternative splicing of exon 6 and intron 9, respectively. p53 splice variants were present in 18 of 34 ovarian cancer cell lines (52.9%) and 134 of 245 primary ovarian cancers (54.7%). p53delta expression was associated with impaired response to primary platinum-based chemotherapy (P=0.032). Also, p53delta expression constituted an independent prognostic marker for recurrence-free and overall survival (hazard ratio 1.854, 95% confidence interval 1.121-3.065, P=0.016; and hazard ratio 1.937, 95% confidence interval 1.177-3.186, P=0.009, respectively). p53beta expression was associated with adverse clinicopathologic markers, that is, serous and poorly differentiated cancers (P=0.002 and P=0.008, respectively), and correlated with worse recurrence-free survival in patients exhibiting functionally active p53 (P=0.049). DeltaN'p73 constituted the main N-terminally truncated p73 isoform and was preferentially found in ovarian cancer cell lines showing functionally active p53, supporting our hypothesis that N-terminally truncated p73 isoforms can alleviate the selection pressure for p53 mutations by the inhibition of p53 protein function.Oncogene advance online publication, 18 January 2010; doi:10.1038/onc.2009.482.

HISTORY AND ADMISSION FINDINGS: A 27-year-old female presented with fever (40 C) and infection of the upper respiratory tract in an emergency room (ER) department of our university hospital. Within the last days, she worked as a nurse in that ER, responsible for taking care of patients with novel influenza and also executing screening-examinations of suspicious cases. INVESTIGATIONS: Patient in a reduced condition of health. C-reactive protein was significantly elevated (6.6 mg/dl - norm < 0.5). A PCR carried out on the admission day revealed a highly positive reaction (CT:19.29). DIAGNOSIS, TREATMENT AND COURSE: Due to positive PCR laboratory report for H1N1/2009 and multiple occupational contacts with H1N1/2009 patients, therapy with neuraminidase inhibitor was started. After a five-day antiviral therapy and clinical signs of recovery, PCR was negative on the sixth treatment day. CONCLUSION: Health care workers (HCWs) are at risk of occupational exposure to influenza. Against the backdrop of the spread of H1N1 (2009) appropriate protective measures should be implemented to reduce the risk for transmission in health-care settings. The acquisition of epidemiologic data of occupational infections in Germany ought to be optimized. Required protective measures should be evaluated with regard to practicability and effectiveness.

The world's largest brackish water sea area, the Baltic Sea, is considered to be one of the most polluted seas of the world. Many new pollutants are constantly entering the environment, such as brominated flame-retardants (BFRs). BFRs represent a group of compounds that structurally resemble hydrophobic organic contaminants, but only scarce data about their toxicity to marine organism exist. Thus, the purpose of this study was to analyze long-term in vivo cytotoxicity and genotoxicity of hexabromocyclodododecane (HBCDD) to exposed marine invertebrates using a suite of cytogenetic biomarkers. This included a set of nuclear and nucleolar characteristics and the micronucleus test. The use of those parameters reflects different mechanisms of nuclear activity regulation in cells (as a parameter of cytotoxicity) and measures subcellular processes. The induction of nuclear abnormalities (like the formation of micronuclei) was also employed here as a parameter of genotoxicity. In order to reflect the proliferative and metabolic activity of the cells the number of argylophillic nucleolar organiser regions (NORs) in interphase cells was scored. Over a period of 50 days an in vivo exposure experiment with a clam Macoma balthica and different concentrations of HBCDD (nominal concentrations of 0, 100 and 250mug/l) with three replicates each was performed. Gill cells were used as "sentinel systems" considering specificity in metabolism, repair mechanisms, adaptative response and cell proliferation. A significant increase in nuclear and nucleolar abnormalities and in the frequency of dead cells was observed during the duration of the experiment with the highest peak occurring 10 days after exposure for nuclear abnormalities and 20-30 days after exposure for malfunction of ribosomal genes (NORs)(GLM analyses and Spearman correlation, p<0.05). Thus, the induction of micronuclei and other nuclear abnormalities reflected the toxic potential of HBCDD to marine invertebrates while an increase in the number of NOR may also reflect adaptive responses of the system as enhanced induction of proliferative regeneration of the gill tissue.

AIMS: In this study, we examined whether hemokinin-1, the newest member of the tachykinin family and a close relative to substance P, has antimicrobial properties which have been attributed to other neuropeptides including substance P. MAIN METHODS: Top agar assays were performed to determine the antimicrobial activity of hemokinin-1 and substance P against various microorganisms. KEY FINDINGS: Here we provide evidence that hemokinin-1 peptide possesses antimicrobial properties against some strains of Pseudomonas aeruginosa, while substance P was only marginally effective. SIGNIFICANCE: Our study is the first to link hemokinin-1 to the essential role of defending the body against microbial challenges and adds hemokinin-1 to the list of potential drugs that could help in the fight against Pseudomonas aeruginosa, an opportunistic human pathogen.

Intravenous immunoglobulin (IVIG) is a therapeutic biologic agent that has been prescribed for over two decades to treat various neuromuscular conditions. Most of the treatments are given off-label, as little evidence from large randomized trials exists to support its use. Recently, IGIV-C has received an indication for the treatment of chronic inflammatory demyelinating polyneuropathy (CIDP). Because of the lack of evidence, an ad hoc committee of the AANEM was convened to draft a consensus statement on the rational use of IVIG for neuromuscular disorders. Recommendations were categorized as Class I-IV based on the strength of the medical literature. Class I evidence exists to support the prescription of IVIG to treat patients with Guillain-Barré syndrome (GBS), CIDP, multifocal motor neuropathy, refractory exacerbations of myasthenia gravis, Lambert-Eaton syndrome, dermatomyositis, and stiff person syndrome. Treatment of Fisher syndrome, polymyositis, and certain presumed autoimmune neuromuscular disorders is supported only by Class IV studies, whereas there is no convincing data to substantiate the treatment of inclusion body myopathy (IBM), idiopathic neuropathies, brachial plexopathy, or diabetic amyotrophy using IVIG. Treatment with IVIG must be administered in the context of its known adverse effects. There is little evidence to advise the clinician on the proper dosing of IVIG and duration of therapy. Muscle Nerve, 2009.

BACKGROUND: Pancreatic ductal adenocarcinoma is an aggressive disease. Surgical resection with negative margins (R0) offers the only opportunity for cure. Patients who have advanced disease that limits the chance for R0 surgical resection may undergo margin positive (MP) pancreaticoduodenectomy (PD), palliative surgical bypass (PB), celiac plexus neurolysis alone (PX), or neoadjuvant chemoradiation therapy in anticipation of future resection. OBJECTIVE: The aim of this study was to determine if there is a difference in the perioperative outcomes and survival patterns between patients who undergo MP PD and those who undergo PB for locally advanced disease in the treatment of pancreatic ductal adenocarcinoma. METHODS: We reviewed our pancreatic surgery database (January 2005-December 2007) to identify all patients who underwent exploration with curative intent of pancreatic ductal adenocarcinoma of the head/neck/uncinate process of the pancreas. Four groups of patients were identified, R0 PD, MP PD, PB, and PX. RESULTS: We identified 126 patients who underwent PD, PB, or PX. Fifty-six patients underwent R0 PD, 37 patients underwent MP PD, 24 patients underwent a PB procedure, and nine patients underwent PX. In the PB group, 58% underwent gastrojejunostomy (GJ) plus hepaticojejunostomy (HJ), 38% underwent GJ alone, and 4% underwent HJ alone. Of these PB patients, 25% had locally advanced disease and 75% had metastatic disease. All nine patients in the PX group had metastatic disease. The mean age, gender distribution, and preoperative comorbidities were similar between the groups. For the MP PD group, the distribution of positive margins on permanent section was 57% retroperitoneal soft tissue, 19% with more than one positive margin, 11% pancreatic neck, and 8% bile duct. The perioperative complication rates for the respective groups were R0 36%, MP 49%, PB 33%, and PX 22%. The 30-day perioperative mortality rate for the entire cohort was 2%, with all three of these deaths being in the R0 group. The median follow-up for the entire cohort was 14.4 months. Median survival for the respective groups was R0 27.2 months, MP 15.6 months, PB 6.5 months, and PX 5.4 months. CONCLUSIONS: Margin positive pancreaticoduodenectomy in highly selected patients can be performed safely, with low perioperative morbidity and mortality. Further investigation to determine the role of adjuvant treatment and longer-term follow-up are required to assess the durability of survival outcomes for patients undergoing MP PD resection.

Percutaneous closure of patent foramen ovale (PFO) has been proposed as the treatment of choice for young high-risk patients who suffered cryptogenic stroke and/or peripheral paradoxical embolism. We sought to compare prospectively two different devices used for percutaneous PFO closure.Prospective data were collected on 40 high risk patients (females: 38%, mean age : 44 +/- 11 years, interatrial septal aneurysm >10 mm: 68%) who underwent percutaneous PFO closure after cryptogenic stroke (n = 38) or peripheral paradoxical embolism (n = 2). Chronologically, 20 patients were first treated by a PFO-Star (Cardia, Burnsville, MI) device. Then, 20 other patients received a Starflex occluder (NMT, Boston, MA). The primary endpoint was complete PFO closure at 6 months as assessed by transthoracic contrast echocardiography. Secondary endpoints were major peri- or post procedural complications and clinical recurrence at 1 year follow-up.Baseline clinical and anatomical characteristics were comparable for both groups. Complete PFO closure was observed in 50%(PFO-Star) and 90%(Starflex) of patients (p=0.001) respectively. Major peri-procedural complications occurred in the PFO-star group only: right-sided device thrombus (1 patient) and aorto-right atrial fistula (1 patient). At 1 year follow-up, no clinical recurrence occurred.In conclusion, despite the absence of clinical recurrence in this high-risk population with presumed paradoxical embolism, complete PFO closure at 6 months follow-up was significantly related to the type of closure device used.

GMX1777 is a prodrug of the small molecule GMX1778, currently in phase I clinical trials for the treatment of cancer. We describe that GMX1778 is a potent and specific inhibitor of the nicotinamide adenine dinucleotide (NAD(+)) biosynthesis enzyme nicotinamide phosphoribosyltransferase (NAMPT). Cancer cells have a very high rate of NAD(+) turnover which makes NAD(+) modulation an attractive target for anticancer therapy. GMX1778 selectively inhibits NAMPT which blocks the production of NAD(+) and results in tumor cell death. Furthermore, GMX1778 is phosphoribosylated by NAMPT, which increases its cellular retention. The cytotoxicity of GMX1778 can be bypassed with exogenous nicotinic acid (NA) which permits NAD(+) repletion via nicotinic acid phosphoribosyltransferase 1 (NAPRT1). The cytotoxicity of GMX1778 in cells with NAPRT1 deficiency, however, cannot be rescued by NA. Analyses of NAPRT1 mRNA and protein levels in cell lines and primary tumor tissue indicate that a high frequency of glioblastomas, neuroblastomas and sarcomas are deficient in NAPRT1 and not susceptible to rescue with NA. As a result, the therapeutic index of GMX1777 can be extended in animals bearing NAPRT1-deficient tumors by co-administration with NA. This provides the rationale for a novel therapeutic approach for the use of GMX1777 in the treatment of human cancers.

OBJECTIVE: Reconstruction of powerful active elbow flexion. Reconstruction of missing muscle unit by neurovascular pedicled functional muscle transplantation. INDICATIONS: Treatment of last choice for --secondary reconstruction of active elbow flexion in case of complete lesion of the brachial plexus or musculocutaneous nerve (M0 muscle function = replacement indication), partial but incomplete lesion of the brachial plexus or musculocutaneous nerve (M1-(3) muscle function = augmentation indication);--replacement of the elbow flexor muscles in case of primary muscle loss (tumor, trauma). CONTRAINDICATIONS: Concomitant lesions of the axillary artery. No adequate donor nerve. Relative: no sensibility at all at the forearm and hand. SURGICAL TECHNIQUE: Free functional biarticular myocutaneous transplantation of gracilis muscle. A myocutaneous gracilis flap is raised at the thigh. At the upper arm the flap is fixed proximally to the coracoid process or the lateral clavicle. The distal insertion is sutured to the distal biceps tendon. Vascular anastomoses are carried out in end-to-side fashion with the brachial artery and vein. Nerval coaptation is done in end-to-end technique using the muculocutaneous nerve. POSTOPERATIVE MANAGEMENT: Complete immobilization for 6 weeks. Dorsal upper arm splint until sufficient muscle power (M(4)). Progressive increase of active range of motion for another 6 weeks. Continuation of physiotherapy for 12-18 months. Postoperative standardized compression therapy, combined with scar therapy (silicone sheet). RESULTS: Functionally useful results can be expected in 60-75% of patients, especially if there is some residual function (M1 or M2) left ("augmentation indication"). Early free functional muscle transplantation shows best results in patients with direct muscle defect, because all vascular and neuronal structures are still available, and no secondary changes such as fibrosis or joint stiffness are present yet. There are inconsistent results for patients with neurologic insufficiency (i.e., total brachial plexus palsy) or mixed neuromuscular insufficiency, such as compartment syndrome. Especially in complete brachial plexus lesion, free functional muscle transfer is often the only treatment option. Provided there is a good patient selection, satisfactory results can be achieved for elbow flexion. Whether a higher number of axons, as provided by the contralateral C7 transfer, will lead to better results is the topic of an ongoing study.

OBJECTIVE: Active elbow flexion is necessary for bimanual tasks. Reconstruction of powerful active elbow flexion. Reconstruction of missing muscle unit by neurovascular pedicled functional muscle transposition. INDICATIONS: Treatment of second choice (first choice bipolar latissimus dorsi transfer according to Zancolli & Mitre, transfer of the flexor/pronator muscle onto the distal humerus, or transposition of the triceps onto the biceps):--(Secondary) reconstruction of active elbow flexion in case of lesion of the brachial plexus or musculocutaneous nerve.--Replacement of the elbow flexor muscles in case of primary muscle loss (tumor, trauma). CONTRAINDICATIONS: Ongoing spontaneous or postoperative nerve regeneration. Ankylosis of the elbow joint (in case of good shoulder and hand function, one should consider arthrolysis or even total joint replacement). Insufficient power of the pectoralis major muscle (< M(4)). Lesion of the axillary artery involving the thoracoacromial artery. Relative: concomitant lesion of the latissimus dorsi and teres major muscles (loss of glenohumeral adduction [thoracohumeral pinch]. SURGICAL TECHNIQUE: Distal muscle transposition: transposition of the origin--pars abdominalis, pars sternocostalis, pars clavicularis (unipolar or bipolar, partial or complete distal transfer):--Unipolar partial pectoralis major muscle transposition according to Clark.--Bipolar partial pectoralis major muscle transposition according to Schottstaedt et al.--Bipolar complete pectoralis major muscle transposition according to Dautry et al. and Carroll & Kleinmann, respectively, possibly in combination with transfer of the pectoralis minor muscle.--Myocutaneous flap in case of concomitant skin defect at the upper arm level. Proximal tendon transfer: transposition of the tendinous insertion at the humerus of the pectoralis major muscle. POSTOPERATIVE MANAGEMENT : Immobilization for 6 weeks in a dorsal upper arm splint, a Gilchrist bandage or a thorax-arm abduction orthesis with the elbow in 90 degrees flexion and supination. Early passive motion depending on pain within the sector 90-140 degrees. Progressive increase of active range of motion after 6 weeks. Protected exercise from "out of the splint" with increasing elbow extension of 10 degrees per week. It is important, that there is still an extension lag of 30-40 degrees at 3 months after transfer, in order to protect the reinnervated muscle and avoid overstretching. Although complete elbow extension should be the aim after 1 year, most patients will keep an extension lag of 20-30 degrees. Physiotherapy must continue for 12-18 months. Postoperative standardized compression therapy, combined with scar therapy (silicone sheet). RESULTS: Meta-analysis of the literature and personal results show functional (very good and good) results in 54-86% of patients. There are only few complications.