Degradation, infection and heat effects on polypropylene mesh for pelvic implantation: what was known and when it was known

Many properties of polypropylene mesh that are causative in producing the complications that our patients are experiencing were published in the literature prior to the marketing of most currently used mesh configurations and mesh kits. These factors were not sufficiently taken into account prior to the sale of these products for use in patients. This report indicates when this information was available to both mesh kit manufacturers and the Food and Drug Administration

A One Base Pair Deletion in the Canine ATP13A2 Gene Causes Exon Skipping and Late-Onset Neuronal Ceroid Lipofuscinosis in the Tibetan Terrier

Neuronal ceroid lipofuscinosis (NCL) is a progressive neurodegenerative disease characterized by brain and retinal atrophy and the intracellular accumulation of autofluorescent lysosomal storage bodies resembling lipofuscin in neurons and other cells. Tibetan terriers show a late-onset lethal form of NCL manifesting first visible signs at 5–7 years of age. Genome-wide association analyses for 12 Tibetan-terrier-NCL-cases and 7 Tibetan-terrier controls using the 127K canine Affymetrix SNP chip and mixed model analysis mapped NCL to dog chromosome (CFA) 2 at 83.71–84.72 Mb. Multipoint linkage and association analyses in 376 Tibetan terriers confirmed this genomic region on CFA2. A mutation analysis for 14 positional candidate genes in two NCL-cases and one control revealed a strongly associated single nucleotide polymorphism (SNP) in the MAPK PM20/PM21 gene and a perfectly with NCL associated single base pair deletion (c.1620delG) within exon 16 of the ATP13A2 gene. The c.1620delG mutation in ATP13A2 causes skipping of exon 16 presumably due to a broken exonic splicing enhancer motif. As a result of this mutation, ATP13A2 lacks 69 amino acids. All known 24 NCL cases were homozygous for this deletion and all obligate 35 NCL-carriers were heterozygous. In a sample of 144 dogs from eleven other breeds, the c.1620delG mutation could not be found. Knowledge of the causative mutation for late-onset NCL in Tibetan terrier allows genetic testing of these dogs to avoid matings of carrier animals. ATP13A2 mutations have been described in familial Parkinson syndrome (PARK9). Tibetan terriers with these mutations provide a valuable model for a PARK9-linked disease and possibly for manganese toxicity in synucleinopathies

Phagocytosis of Cholesteryl Ester Is Amplified in Diabetic Mouse Macrophages and Is Largely Mediated by CD36 and SR-A

Type 2 diabetes (T2D) is associated with accelerated atherosclerosis, which accounts for approximately 75% of all diabetes-related deaths. Here we investigate the link between diabetes and macrophage cholesteryl ester accumulation. When diabetic (db/db) mice are given cholesteryl ester intraperitoneally (IP), peritoneal macrophages (PerMΦs) recovered from these animals showed a 58% increase in intracellular cholesteryl ester accumulation over PerMΦs from heterozygote control (db/+) mice. Notably, PerMΦ fluid-phase endocytosis and large particle phagocytosis was equivalent in db/+and db/db mice. However, IP administration of CD36 and SR-A blocking antibodies led to 37% and 25% reductions in cholesteryl ester accumulation in PerMΦ. Finally, in order to determine if these scavenger receptors (SRs) were part of the mechanism responsible for the increased accumulation of cholesteryl esters observed in the diabetic mouse macrophages, receptor expression was quantified by flow cytometry. Importantly, db/db PerMΦs showed a 43% increase in CD36 expression and an 80% increase in SR-A expression. Taken together, these data indicate that direct cholesteryl ester accumulation in mouse macrophages is mediated by CD36 and SR-A, and the magnitude of accumulation is increased in db/db macrophages due to increased scavenger receptor expression

Effect of Interlaminar Epidural Steroid Injection in Acute and Subacute Pain Due to Lumbar Disk Herniation: A Randomized Comparison of 2 Different Protocols

In order to assess the efficacy of epidural steroid injections (ESI) in acute and subacute pain due to lumbar spine disk herniation, we conducted a randomized trial, comparing 2 different protocols. Fourty patients with radicular pain due to L4-L5 and L5-S1 disc herniation were assigned to receive either 3 consecutive ESI every 24 hours through a spinal catheter (group A) or 3 consecutive ESI every 10 days with an epidural needle (group B). All patients had improved Oswestry Disabilty Index (ODI) and the Visual Analog Scale (VAS) for pain scores at 1 month of follow-up compared to baseline, while no significant differences were observed between the 2 groups. The scores for group B were statistically significant lower at 2 months of follow-up compared to those of group A. The improvement in the scores of group B was continuous since the mean scores at 2 months of follow up were lower compared to the respective scores at 1 month. Protocol B (3 consecutive ESI every 10 days) was found more effective in the treatment of subacute pain compared to Protocol A (3 consecutive ESI every 24 hours) with statistically significant differences in the ODI and VAS scores at 2 months of follow-up

Proximal major limb amputations – a retrospective analysis of 45 oncological cases

<p>Abstract</p> <p>Background</p> <p>Proximal major limb amputations due to malignant tumors have become rare but are still a valuable treatment option in palliation and in some cases can even cure. The aim of this retrospective study was to analyse outcome in those patients, including the postoperative course, survival, pain, quality of life, and prosthesis usage.</p> <p>Methods</p> <p>Data of 45 consecutive patients was acquired from patient's charts and contact to patients, and general practitioners. Patients with interscapulothoracic amputation (n = 14), shoulder disarticulation (n = 13), hemipelvectomy (n = 3) or hip disarticulation (n = 15) were included.</p> <p>Results</p> <p>The rate of proximal major limb amputations in patients treated for sarcoma was 2.3% (37 out of 1597). Survival for all patients was 42.9% after one year and 12.7% after five years. Survival was significantly better in patients with complete tumor resections. Postoperative chemotherapy and radiation did not prolong survival. Eighteen percent of the patients with malignant disease developed local recurrence. In 44%, postoperative complications were observed. Different modalities of postoperative pain management and the site of the amputation had no significant influence on long-term pain assessment and quality of life. Eighty-seven percent suffered from phantom pain, 15.6% considered their quality of life worse than before the operation. Thirty-two percent of the patients who received a prosthesis used it regularly.</p> <p>Conclusion</p> <p>Proximal major limb amputations severely interfere with patients' body function and are the last, albeit valuable, option within the treatment concept of extremity malignancies or severe infections. Besides short survival, high complication rates, and postoperative pain, patients' quality of life can be improved for the time they have remaining.</p

Mechanism of subunit interaction at ketosynthase-dehydratase junctions in trans-AT polyketide synthases

Modular polyketide synthases (PKSs) produce numerous structurally complex natural products with diverse applications in medicine and agriculture. They typically consist of several multienzyme subunits that utilize structurally-defined docking domains (DDs) at their N- and C-termini to ensure correct assembly into functional multi-protein complexes. Here we report a fundamentally different mechanism for subunit assembly in trans-AT modular PKSs at the junction between ketosynthase (KS) and dehydratase (DH) domains. This involves direct interaction of a largely unstructured docking domain (DD) at the C-terminus of the KS with the surface of the downstream DH. Acyl transfer assays and mechanism-based cross-linking established that the DD is required for the KS to communicate with the acyl carrier protein appended to the DH. Two distinct regions for binding of the DD to the DH were identified using NMR spectroscopy, carbene foot-printing and mutagenesis, providing a foundation for future elucidation of the molecular basis for interaction specificity

Torsional stability of interference screws derived from bovine bone - a biomechanical study

Introduction: It has been proposed that individual genetic variation contributes to the course of severe infections and sepsis. Recent studies of single nucleotide polymorphisms (SNPs) within the endotoxin receptor and its signaling system showed an association with the risk of disease development. This study aims to examine the response associated with genetic variations of TLR4, the receptor for bacterial LPS, and a central intracellular signal transducer (TIRAP/Mal) on cytokine release and for susceptibility and course of severe hospital acquired infections in distinct patient populations. Methods: Three intensive care units in tertiary care university hospitals in Greece and Germany participated. 375 and 415 postoperative patients and 159 patients with ventilator associated pneumonia (VAP) were included. TLR4 and TIRAP/Mal polymorphisms in 375 general surgical patients were associated with risk of infection, clinical course and outcome. In two prospective studies, 415 patients following cardiac surgery and 159 patients with newly diagnosed VAP predominantly caused by Gram-negative bacteria were studied for cytokine levels in-vivo and after ex-vivo monocyte stimulation and clinical course. Results: Patients simultaneously carrying polymorphisms in TIRAP/Mal and TLR4 and patients homozygous for the TIRAP/Mal SNP had a significantly higher risk of severe infections after surgery (odds ratio (OR) 5.5; confidence interval (CI): 1.34 - 22.64; P = 0.02 and OR: 7.3; CI: 1.89 - 28.50; P < 0.01 respectively). Additionally we found significantly lower circulating cytokine levels in double-mutant individuals with ventilator associated pneumonia and reduced cytokine production in an ex-vivo monocyte stimulation assay, but this difference was not apparent in TIRAP/Mal-homozygous patients. In cardiac surgery patients without infection, the cytokine release profiles were not changed when comparing different genotypes. Conclusions: Carriers of mutations in sequential components of the TLR signaling system may have an increased risk for severe infections. Patients with this genotype showed a decrease in cytokine release when infected which was not apparent in patients with sterile inflammation following cardiac surgery

Mechanical Strain Regulates Osteoblast Proliferation through Integrin-Mediated ERK Activation

Mechanical strain plays a critical role in the proliferation, differentiation and maturation of bone cells. As mechanical receptor cells, osteoblasts perceive and respond to stress force, such as those associated with compression, strain and shear stress. However, the underlying molecular mechanisms of this process remain unclear. Using a four-point bending device, mouse MC3T3-E1 cells was exposed to mechanical tensile strain. Cell proliferation was determined to be most efficient when stimulated once a day by mechanical strain at a frequency of 0.5 Hz and intensities of 2500 µε with once a day, and a periodicity of 1 h/day for 3 days. The applied mechanical strain resulted in the altered expression of 1992 genes, 41 of which are involved in the mitogen-activated protein kinase (MAPK) signaling pathway. Activation of ERK by mechanical strain promoted cell proliferation and inactivation of ERK by PD98059 suppressed proliferation, confirming that ERK plays an important role in the response to mechanical strain. Furthermore, the membrane-associated receptors integrin β1 and integrin β5 were determined to regulate ERK activity and the proliferation of mechanical strain-treated MC3T3-E1 cells in opposite ways. The knockdown of integrin β1 led to the inhibition of ERK activity and cell proliferation, whereas the knockdown of integrin β5 led to the enhancement of both processes. This study proposes a novel mechanism by which mechanical strain regulates bone growth and remodeling