Implant retention and high rate of treatment failure in hematogenous acute knee and hip prosthetic joint infections.

OBJECTIVES: Only few studies evaluated hematogenous prosthetic joint infections. We aimed to describe the characteristics of these infections and factors associated with management failure. METHODS: We selected hematogenously-acquired infections, defined by the occurrence of infectious symptoms more than a year after implantation among records of patients treated for hip and knee prosthetic joint infections at Montpellier University Hospital between January 2004 and May 2015. Failure was defined by death due to prosthesis-related infection, need for prosthesis removal in case of conservative treatment, or recurrence of infectious signs on a new prosthesis. RESULTS: Forty-seven patients with hematogenous prosthetic joint infection were included (33 knee infections and 14 hip infections). Infectious agents were streptococci (43%), Staphylococcus aureus (43%), Gram-negative bacilli (13%), and Listeria monocytogenes (2%). Thirty-one patients were initially treated with debridement and implant retention and 15 with prosthesis removal (three with one-stage surgery, 10 with two-stage surgery). The median duration of antibiotic therapy was 66.5 days. The overall failure rate was 52% (24/48), 71% (22/31) with implant retention strategy, 13% (2/15) with prosthesis removal, and 63% (12/19) in case of Staphylococcus aureus infection. Conservative treatment was appropriate (arthrotomy on a well-implanted prosthesis without sinus tract and symptom onset <21 days) in 13/31 patients (42%) with a failure rate still high at 69% (9/13). The only factor associated with failure was conservative surgical treatment. CONCLUSION: The high risk of failure of conservative treatment for hematogenous prosthetic joint infections should lead to considering prosthesis replacement as the optimal strategy, particularly with Staphylococcus aureus.

Five-century record of climate and groundwater recharge variability in southern California.

Modifications to the rates of water flowing from the surface to groundwater (groundwater recharge) due to climate variability are the most difficult to assess because of the lack of direct long-term observations. Here, we analyze the chloride salt distribution below the surface soil on a plateau near Los Angeles to reconstruct the amount of recharge that occurred in the last five centuries. Over this time interval, periods of major high and low recharge with different duration follow each other and this cyclicity is consistent with long-term atmospheric forcing patterns, such as the Pacific Decadal Oscillation. This study determines the range and the natural variability of recharge to groundwater, which sustains local freshwater flow system, and helps forecast future availability of groundwater resource in southern California, where water scarcity is critical to both local and global populations.

Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation.

BACKGROUND: Data on dermatological manifestations of Noonan syndrome (NS) remain heterogeneous and are based on limited dermatological expertise. OBJECTIVES: To describe the dermatological manifestations of NS, compare them with the literature findings, and test for dermatological phenotype-genotype correlations with or without the presence of PTPN11 mutations. METHODS: We performed a large 4-year, prospective, multicentric, collaborative dermatological and genetic study. RESULTS: Overall, 129 patients with NS were enrolled, including 65 patients with PTPN11-NS, 34 patients with PTPN11-NS with multiple lentigines (NSML), and 30 patients with NS who had a mutation other than PTPN11. Easy bruising was the most frequent dermatological finding in PTPN11-NS, present in 53·8% of patients. Multiple lentigines and café-au-lait macules (n ≥ 3) were present in 94% and 80% of cases of NSML linked to specific mutations of PTPN11, respectively. Atypical forms of NSML could be associated with NS with RAF1 or NRAS mutations. In univariate analysis, patients without a PTPN11 mutation showed (i) a significantly higher frequency of keratinization disorders (P = 0·001), including keratosis pilaris (P = 0·005), ulerythema ophryogenes (P = 0·0001) and palmar and/or plantar hyperkeratosis (P = 0·06, trend association), and (ii) a significantly higher frequency of scarce scalp hair (P = 0·035) and scarce or absent eyelashes (P = 0·06, trend association) than those with PTPN11 mutations. CONCLUSIONS: The cutaneous phenotype of NS with a PTPN11 mutation is generally mild and nonspecific, whereas the absence of a PTPN11 mutation is associated with a high frequency of keratinization disorders and hair abnormalities.

Distinctive cutaneous and systemic features associated with specific antimyositis antibodies in adults with dermatomyositis: a prospective multicentric study of 117 patients.

BACKGROUND: Identification of myositis-specific autoantibodies (MSAs) for dermatomyositis (DM) could allow the characterization of an antibody-associated clinical phenotype. OBJECTIVE: We sought to define the clinical phenotype of DM and the risk of cancer, interstitial lung disease (ILD) and calcinosis based on MSA. METHODS: A 3.5-year multicentre prospective study of adult DM patients was conducted to determine the clinical phenotype associated with MSAs and the presence of cancer, ILD and calcinosis. RESULTS: MSAs were detected in 47.1% of 117 included patients. Patients with antimelanoma differentiation-associated protein-5 antibodies (13.7%) had significantly more palmar violaceous macules/papules [odds ratio (OR) 9.9], mechanic's hands (OR 8), cutaneous necrosis (OR 3.2), articular involvement (OR 15.2) and a higher risk of ILD (OR 25.3). Patients with antitranscriptional intermediary factor-1 antibodies (11.1%), antinuclear matrix protein-2 antibodies (6.8%) and antiaminoacyl-transfer RNA synthetase (5.1%) had, respectively, significantly more poikiloderma (OR 5.9), calcinosis (OR 9.8) and articular involvement (OR 15.2). Cutaneous necrosis was the only clinical manifestation significantly associated with cancer (OR 3.1). CONCLUSION: Recognition of the adult DM phenotype associated with MSAs would allow more accurate appraisal of the risk of cancer, ILD and calcinosis.

Disentangling the role of seed bank and dispersal in plant metapopulation dynamics using patch occupancy surveys.

In plants, the presence of a seed bank challenges the application of classical metapopulation models to aboveground presence surveys; ignoring seed bank leads to overestimated extinction and colonization rates. In this article, we explore the possibility to detect seed bank using hidden Markov models in the analysis of aboveground patch occupancy surveys of an annual plant with limited dispersal. Patch occupancy data were generated by simulation under two metapopulation sizes (N = 200 and N = 1,000 patches) and different metapopulation scenarios, each scenario being a combination of the presence/absence of a 1-yr seed bank and the presence/absence of limited dispersal in a circular 1-dimension configuration of patches. In addition, because local conditions often vary among patches in natural metapopulations, we simulated patch occupancy data with heterogeneous germination rate and patch disturbance. Seed bank is not observable from aboveground patch occupancy surveys, hence hidden Markov models were designed to account for uncertainty in patch occupancy. We explored their ability to retrieve the correct scenario. For 10 yr surveys and metapopulation sizes of N = 200 or 1,000 patches, the correct metapopulation scenario was detected at a rate close to 100%, whatever the underlying scenario considered. For smaller, more realistic, survey duration, the length for a reliable detection of the correct scenario depends on the metapopulation size: 3 yr for N = 1,000 and 6 yr for N = 200 are enough. Our method remained powerful to disentangle seed bank from dispersal in the presence of patch heterogeneity affecting either seed germination or patch extinction. Our work shows that seed bank and limited dispersal generate different signatures on aboveground patch occupancy surveys. Therefore, our method provides a powerful tool to infer metapopulation dynamics in a wide range of species with an undetectable life form.

CRIPTO and its signaling partner GRP78 drive the metastatic phenotype in human osteotropic prostate cancer.

CRIPTO (CR-1, TDGF1) is a cell surface/secreted oncoprotein actively involved in development and cancer. Here, we report that high expression of CRIPTO correlates with poor survival in stratified risk groups of prostate cancer (PCa) patients. CRIPTO and its signaling partner glucose-regulated protein 78 (GRP78) are highly expressed in PCa metastases and display higher levels in the metastatic ALDHhigh sub-population of PC-3M-Pro4Luc2 PCa cells compared with non-metastatic ALDHlow. Coculture of the osteotropic PC-3M-Pro4Luc2 PCa cells with differentiated primary human osteoblasts induced CRIPTO and GRP78 expression in cancer cells and increases the size of the ALDHhigh sub-population. Additionally, CRIPTO or GRP78 knockdown decreases proliferation, migration, clonogenicity and the size of the metastasis-initiating ALDHhigh sub-population. CRIPTO knockdown reduces the invasion of PC-3M-Pro4Luc2 cells in zebrafish and inhibits bone metastasis in a preclinical mouse model. These results highlight a functional role for CRIPTO and GRP78 in PCa metastasis and suggest that targeting CRIPTO/GRP78 signaling may have significant therapeutic potential.

Sensitive analysis of α-synuclein by nonlinear laser wave mixing coupled with capillary electrophoresis.

Multi-photon nonlinear laser wave-mixing spectroscopy is a novel absorption-based technique that offers excellent detection sensitivity for biomedical applications, including early diagnosis and investigation of neurodegenerative diseases. α-Synuclein is linked to Parkinson's disease (PD), and characterization of its oligomers and quantification of the protein may contribute to understanding PD. The laser wave-mixing signal has a quadratic dependence on analyte concentration, and hence the technique is effective in monitoring small changes in concentration within biofluids. A wide variety of labels can be employed for laser wave-mixing detection due to its ability to detect both chromophores and fluorophores. In this investigation, two fluorophores and a chromophore are studied and used as labels for the detection of α-synuclein. Wave-mixing detection limits of PD-related protein conjugated with fluorescein isothiocyanate, QSY 35 acetic acid, succinimidyl ester, and Chromeo P503 were determined to be 1.4 × 10(-13) M, 1.4 × 10(-10) M, and 1.9 × 10(-13) M, respectively. Based on the laser probe volume used, the corresponding mass detection limits were determined to be 1.1 × 10(-23) mol, 1.1 × 10(-20) mol, and 1.5 × 10(-23) mol. This study also presents molecular-based separation and quantification of α-synuclein by laser wave mixing coupled with capillary electrophoresis.

Study on Association of Maternal Serum Triglyceride with Pre-eclampsia.

Till now pre-eclampsia is a disease of multiple theories. This case control study was carried out in the department of Obstetrics and Gynaecology of Bangabandhu Sheikh Mujib Medical University Hospital and Dhaka Medical College Hospital, from January 2006 to December 2007 to determine the association of maternal serum triglyceride with pre-eclampsia. Ninety pregnant women were studied, among them 45 patients were pre-eclamptic and served as case and 45 normal healthy pregnant women served as control. Estimation of serum triglyceride levels of all study patients was done with the help of enzymatic method. The mean (± SD) systolic blood pressure was 152.4 ± 19.8 mmHg in study group and 112.0 ± 8.9 mmHg in control group (p<0.05). Similarly the mean (± SD) diastolic blood pressure was 103.1 ± 12.2 mmHg in case group and 75.5 ± 6.6 mmHg in control group (p<0.05). Serum triglyceride level was more than the normal reference value in pre-eclamptic group. The mean (± SD) serum triglyceride level was 242.9 ± 36.8 mg/dl in case group and 184.6 ± 12.5mg/dl in control group. Statistically the difference was significant (p<0.05). The level of serum triglyceride positively correlated with the rise of blood pressure and degree of albuminuria. Thus serum triglyceride level increase in pre-eclampsia and the level correlate with the severity of the disease.

The high-throughput yeast deletion fitness data and the theories of dominance.

The development of high-throughput fitness measurement methods provides unprecedented power to test evolutionary theories. However, with this comes new challenges regarding data quality and data analysis. We illustrate this by reanalysing the fitness distribution in several environments of yeast mutants (homo- and heterozygous) from the yeast deletion project. Originally created to study functional properties of genes, evolutionary biologists took advantage of this database to study evolutionary questions, such as dominance for fitness of mutations. We uncover several problems in this data set strongly affecting these questions that have remained unnoticed despite the numerous studies based on it. High-throughput methodologies are necessarily challenging, both experimentally and for data analysis: our point is not to criticize these approaches, but to pinpoint these challenges and to propose several improvements that may help avoid several shortcomings. Further, in the light of this finding, we question the conclusions regarding theories of dominance that have been made using this data set. We show that the data on deletion of small effects are not sufficiently reliable to be informative on this question. On the other hand, deletions of large effect exhibit no correlation between homo- and heterozygous fitness effects, a pattern that sheds new light on the h-s correlation issue, with several consequences for the debate over the different theories of dominance.

A comparison of two techniques for the removal of calcium hydroxide from root canals.

AIM: To compare the ability of two irrigant regimens to remove calcium hydroxide (CH) mixed with different vehicles from root canal walls. METHODOLOGY: The root canals of 92 freshly extracted bovine incisor teeth were prepared with a step-back technique and randomly assigned into two experimental groups (n = 40), whilst the remaining teeth (n = 12) served as positive and negative controls. In each experimental group, ten teeth were assigned to each CH preparation: G1 - CH powder; G2 - CH + saline solution; G3 - CH + polyethylene glycol (PEG); G4 - CH + PEG + camphorated paramonochlorophenol (CPMC). The negative control did not receive CH placement, and the positive control received the intracanal dressing, but no subsequent removal. After 7 days, the CH was retrieved using manual or passive ultrasonic irrigation (PUI). The roots were grooved longitudinally and split into halves. Images of each half of the canal were acquired by a digital camera, and the percentage of CH coated surface area in relation to the surface area of each third of the canal was calculated. The results were statistically analysed with anova with post hoc Tukey test with the null hypothesis set as 5%. RESULTS: Remnants of medicament were found in all experimental groups. The positive control group had complete coverage of the canal walls with CH in contrast to the negative control (P < 0.001). Considering the cervical and middle thirds, the percentage of CH retention in G1 was significantly lower using PUI (26.6% and 32.2%, respectively) than the manual (38.7% and 46.1%, respectively) technique (P < 0.05). No significant differences were observed between G2, G3 and G4 in all thirds and the experimental groups at the apical third (P > 0.05). CONCLUSIONS: Neither syringe injection nor PUI methods were efficient in removing the inter-appointment root canal medicaments. Remnants of medicament were found in all experimental groups regardless of the vehicle used.

Management of full-thickness skin defects in the hand and wrist region: first long-term experiences with the dermal matrix Matriderm.

The gold standard for the coverage of full-thickness skin defects is autologous skin grafts. However, poor skin quality and scar contracture are well-known problems in functional, highly strained regions. The use of dermal substitutes is an appropriate way to minimise scar contraction and, thereby, to optimise the quality of the reconstructed skin. The aim of this study was to evaluate the impact of the collagen-elastin matrix, Matriderm, for the single-step reconstruction of joint-associated defects of the upper extremity. Seventeen patients with full-thickness skin defects of the upper extremity were treated with the dermal substitute, Matriderm, and unmeshed skin graft in the functional critical region of the distal upper extremity in a single-step procedure. The take rate of the matrix-and-skin graft was 96%. Long-term follow-up revealed an overall Vancouver scar scale of 1.7. No limitation concerning hand function was observed; DASH-score analysis revealed excellent hand function in patients with burn injury and patients with a defect due to the harvest of a radial forearm flap achieved satisfying hand function. This matrix represents a viable alternative to other types of defect coverage and should therefore be considered in the treatment of skin injuries, especially in very delicate regions such as the joint regions. The possibility of performing a one-stage procedure is supposed to be a major advantage in comparison to a two-stage procedure.

Screwlike order, macroscopic chirality, and elastic distortions in high-density DNA mesophases.

We investigate a new screwlike liquid-crystalline ordering in solutions of helical biopolymers and its influence on the state of individual molecules. In the resulting mesophase translational and rotational motions of molecules are coupled in screw fluctuations. We show that in contrast to the case of conventional chiral liquid crystals the elastic distortion does not twist the screw order but leads to overwinding of individual helical molecules. This explains the peculiarities of high-density DNA mesophases.

Synthesis and in vitro selective anti-Helicobacter pylori activity of pyrazoline derivatives.

In order to develop new anti-Helicobacter pylori agents, a series of N1-substituted 3,5-diphenyl pyrazolines P1-P13 was prepared and evaluated for their antibacterial activity. All synthesized compounds showed little or no activity against different species of Gram-positive and Gram-negative bacteria of clinical relevance and against various strains of pathogenic fungi. The same derivatives exhibited a significant degree of activity against a range of H. pylori strains, including those resistant to the reference compound metronidazole. Among the prepared compounds those with an N1-acetyl group and a 4-methoxy substituent in the 5-phenyl ring showed the best activity against H. pylori metronidazole resistant strains in the 1-4 microg/mL MIC range.

Synthesis of a carbocyclic sialic acid analogue for the inhibition of influenza virus neuraminidase.

The influenza virus neuraminidase (NA) is essential for viral infection and offers a potential target for antiviral drug development. We prepared a carbocyclic sialic acid analogue, potentially able to inhibit NA. Its structure is an analogue of the transition-state of the reaction catalysed by NA. As starting material, quinic acid was selected owing to its ready availability and its stereochemical feature suitable for the target structure. The quinic acid was first converted in the shikimic acid; then two of the three hydroxyl functions of this product were selectively functionalised to obtain the target molecule (3R,4S,5R)-4-acetamido-3-guanidino-5-hydroxycyclohex-1-ene-1-carboxylic acid.

Synthesis and preliminary biological evaluation of 4,6-disubstituted 3-cyanopyridin-2(1H)-ones, a new class of calcium entry blockers.

The preparation of 3-cyano-4,6-diaryl-pyridin-2(1H)-ones 4a-h, calcium entry blockers related to diltiazem, is described starting from 1,3-diaryl-2-propen-1-ones 5. On preliminary pharmacological tests all compounds are active and some of them show calcium antagonistic activity superior or comparable to diltiazem.

Comparative chemical evaluation of two commercially available derivatives of hyaluronic acid (hylaform from rooster combs and restylane from streptococcus) used for soft tissue augmentation.

Hyaluronic acid (HA) derivatives have been developed to try to enhance rheological properties of this molecule to make it suitable for various medical applications. The main dermatological application of HA derivatives is the augmentation of soft tissues, via injection into the dermis. HA derivatives are indicated for the correction of cutaneous contour deficiencies of the skin, particularly in cases of ageing or degenerative lesions or to increase lips. Two HA derivatives have been evaluated: Hylaform Viscoelastic Gel (Hylan B), derived from rooster combs and subjected to cross-linking, and Restylane, produced through bacterial fermentation (streptococci) and stabilized, as declared by the producer. In both cases the purpose is to improve HA theological characteristics and slow down its degradation once it is in contact with biological structures. Distribution of particle dimensions, pH, protein concentration and rheological properties have been investigated in order to evaluate their reliability as fillers for soft tissue augmentation. The results of the analyses showed that there are differences between Restylane and Hylaform. Especially as far as rheological characteristics are concerned, the results outline different structures of the products: Hylaform behaves as a strong hydrogel, Restylane as a weak hydrogel; rheologically Hylaform is clearly superior to Restylane. Hylaform contains a definitely minor quantity (about a quarter) of cross-linked hyaluronic acid than Restylane. Furthermore, although not declared by the manufacturer, Restylane contains protein, resulting from bacterial fermentation or added to enable cross-linking reaction; the quantity of proteins contained by Restylane can be as much as four times the quantity contained by Hylaform, for the same volume (1 ml). It is evident that Hylaform offers higher safety margin than Restylane. Furthermore, wide literature and 20 years of clinical experience on hyaluronan derived from rooster combs confirm the reliability of this derivative while we did not find evidence regarding about the safety of HA obtained from streptococcus.

Synthesis and antimicrobial activity of coumarin 7-substituted cephalosporins and sulfones.

Some coumarin 7-substituted cephalosporins and related sulfones were prepared and an antimicrobial assay was performed. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) carried out on cephalosporins showed a potential activity of some of the synthesized compounds against Gram-positive microorganisms. The tests performed on the corresponding sulfones showed no significant activity, neither as antimicrobial agents nor as inhibitors of beta-lactamase. An association of sulfone 6a with ampicillin was observed to inhibit Gram-positive microorganisms with a lower MIC than for ampicillin alone.

Analysis of lung damage induced by trichloroethylene inhalation in mice fed diets with low, normal, and high copper content.

Copper is both an essential nutrient required for the activity of several enzymes and a toxic element able to catalyze free radical formation. Trichloroethylene (TCE) is a xenobiotic that generates epoxidic intermediates by bioactivation through the cytochrome P-450 system. In this study, the influence of a dietary copper imbalance on the TCE-induced lung damage was investigated. Weaning mice were fed copper-deficient, copper-sufficient, and copper-excessive diets. After 4 wk, mice were exposed for 30 min to 6,500 ppm of TCE and euthanatized 48 hr later. Lung damage in the TCE-treated mice consisted of vacuolations of Clara cells and was quantitatively evaluated by counting the vacuolated cells per micrometer of basal lamina. At the ultrastructural level, vacuolations appeared as the result of hydropic swelling of the endoplasmic reticulum cisternae. The copper-deficient mice presented the highest number of vacuolated Clara cells. These mice also showed alteration of the capillary endothelium and interstitium and decreased pulmonary copper-zinc-superoxide dismutase activity. Occurrence of oxidative stress in lungs of both copper-sufficient and copper-deficient mice following TCE treatment was indicated by a decrease in reduced glutathione and an increase in its oxidized form.

Inhibitory effect of 1,3,5-triphenyl-4,5-dihydro-(1H)-pyrazole derivatives on activity of amine oxidases.

A new series of 1,3,5-triphenyl-4,5-dihydro-(1H)-pyrazole derivatives was synthesized to ascertain the contribution of substituted phenyl rings present on the 4,5-dihydro-(1H)-pyrazole nucleus to the monoamine oxidases inhibition and bovine serum amine oxidase inhibition. All compounds were tested on bovine brain mitochondria preparation containing flavin-monoamine oxidases and on purified bovine serum amine oxidases, taken as a model of trihydroxyphenylalanine quinone-copper-containing amine oxidases. The 1,3,5-triphenyl-4,5-dihydro-(1H)-pyrazole derivatives showed a good inhibitory activity and belonged to the third generation of monoamine oxidase inhibitors and bovine serum amine oxidase inhibitors which have the advantage of acting through a reversible mode. Furthermore, their activity showed a good degree of selectivity towards the bovine serum amine oxidase inhibition dependent on the substituents present on the phenyl ring at position 5 of the 4,5-dihydro-(1H)-pyrazole.