Antibodies against copper-oxidised and malondialdehyde-modified low density lipoproteins in pre-eclamptic pregnancies

Objective To measure auto-antibodies against oxidatively modified low density lipoprotein (LDL) in pre-eclamptic pregnancies using two different techniques.
Design Clinical study comparing pre-eclamptic and normal pregnancies.
Setting Tampere University Hospital, Finland.
Population Twenty-one primigravidae with pre-eclampsia and 13 healthy, normotensive primigravidae as controls.
Methods The serum titers of antibodies against both malondialdehyde-modified and copper-oxidised LDL (MDA-LDL and copper-ox LDL) were analysed and related to parameters reflecting the severity of pre-eclampsia.
Results There was a positive correlation (   r = 0.58  ) between antibodies against MDA-LDL and copper-ox LDL in women with pre-eclampsia but not in healthy pregnant controls. The antibody levels against copper-ox LDL, but not against MDA-LDL, were higher in women with pre-eclampsia than in women with a normal pregnancy (   P < 0.01  ). While the antibody titers against copper-ox LDL did not correlate with any parameter reflecting the severity of pre-eclampsia, those against MDA-LDL showed a positive correlation with the level of diastolic blood pressure (   r = 0.54  ) and a negative correlation with platelet count (   r = 461  ) in women with pre-eclampsia.
Conclusions There are increased titers of serum autoantibodies against copper-oxidised LDL in pre-eclampsia, which may reflect enhanced lipid peroxidation involving circulating lipoproteins.     

Sacral Neuromodulation for the Treatment of Chronic Functional Anorectal Pain: A Single Center Experience

Introduction:   Treatment of functional anorectal pain disorders remains a challenge. The purpose of this study is to describe a single center experience with sacral neuromodulation for the treatment of chronic functional anorectal pain.
Methods:   This is a retrospective study based on prospectively collected data of patients treated with sacral neuromodulation for functional anorectal pain from April 2005 to August 2008. Symptoms were analyzed using a visual analog scale pain score (0 to 10). A 7-point Likert scale was used to rate global perceived effect. All patients had a percutaneous nerve evaluation and subsequent test stimulation to assess sacral neuromodulation outcome prior to permanent implantation. Patients were eligible for permanent sacral neuromodulation in case of a pain score <3 during test stimulation and/or >50% decrease in the pain score compared to baseline.
Results:   Nine patients (2 males) were included in this study. Mean age was 53.8 years (27.6 to 74.0). Four patients (1 male) had successful test stimulation and were eligible for permanent implantation. Median pain score decreased from 8.0 (6.0 to 9.0) to 1.0 (0 to 2.0). All patients experienced a lasting improvement during the follow-up till 24 months. Global perceived effect in successful patient was 1 (completely recovered) in one patient and 2 (much improved) in three patients.
Conclusion:   This study showed that sacral neuromodulation can be a successful treatment for functional anorectal pain not responding to other treatments. Improvement obtained during test stimulation is a good predictor (diagnostic) for sustained success of permanent sacral neuromodulation.     

Concentrations of metronidazole and tinidazole in female reproductive organs after a single intravenous infusion and after repeated oral administration

Summary Concentrations of metronidazole and tinidazole in serum and gynecological organs were analyzed after a single 500 mg intravenous infusion and after three days of treatment with 400 mg t.i.d. of metronidazole or 500 mg b.i.d. of tinidazole. The studies were performed in 67 patients subjected to hysterectomy and/or oophorectomy because of myomatosis uteri, carcinoma uteri or endometriosis. At the time of organ removal (about 30 min after infusion), metronidazole and tinidazole levels in serum were 14.5 ± 0.45 mg/l and 12.3 ± 0.38 mg/l, respectively. Concentrations of both drugs in the uterus and Fallopian tube were about the same as the simultaneous serum levels and concentrations in the ovaries about 55% thereof. At steady-state, the concentrations of tinidazole in serum (23.5 ± 1.0 mg/l) were remarkably higher than those of metronidazole (13.5 ± 0.84 mg/l) about three hours after the last oral dose. Drug concentrations in organs of the female reproductive tract were 70 to 100% those of the simultaneous serum levels.

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Konzentrationen von Metronidazol und Tinidazol in weiblichen Genitalorganen nach intravenöser Einzelinfusion und wiederholter oraler Gabe

Zusammenfassung Die Konzentrationen von Metronidazol und Tinidazol in Serum und Genitalorganen wurden nach einer intravenösen Einzelinfusion von 500 mg sowie nach dreitägiger oraler Behandlung mit 400 mg Metronidazol dreimal täglich oder 500 mg Tinidazol, zweimal täglich, bestimmt. Die Untersuchungen wurden bei 67 Patientinnen durchgeführt, bei denen eine Hysterektomie und/oder Oophorektomie wegen Myomatosis uteri, Uteruskarzinom oder Endometriose vorgenommen wurde. Zum Zeitpunkt der Organentnahme (etwa 30 min nach Infusion) betrugen die Metronidazol-und Tinidazolspiegel im Serum 14,5 ± 0,45 mg/l bzw. 12,3 ± 0,38 mg/l. Die Konzentrationen der beiden Medikamente im Uterus und in der Tube entsprachen den gleichzeitig bestimmten Serumspiegeln; die Konzentrationen in den Ovarien lagen bei etwa 55% der Serumspiegel. Im Steady state, etwa drei Stunden nach der letzten oralen Dosis, waren die Serumkonzentrationen von Tinidazol mit 23,5 ± 1,0 mg/l erheblich höher als die Metronidazolserumspiegel (13,5 ± 0,84 mg/l). Die Konzentrationen der Medikamente in den weiblichen Genitalorganen lagen bei 70 bis 100% der simultanen Serumspiegel.

     

Human articular cartilage proteoglycans are not undersulfated in osteoarthritis

Chondroitin sulfate is the major constituent of cartilage. Inadequate sulfate availability results in the production of undersulfated proteoglycans. In osteoarthritis, there is a net loss of articular cartilage proteoglycans. Theoretically, it is possible that during the progress of disease undersulfated glycosaminoglycans are synthesized producing proteoglycans with poorer biological properties. In this study, we tested whether in early human osteoarthritic articular cartilage (Mankin's score of 2 and 3) or more advanced disease (Mankin's score over 3), there are proteoglycans that contain a higher relative amount of nonsulfated chondroitin disaccharide isomer in their chondroitin sulfate chains by analyzing the molar ratios of chondroitin sulfate disaccharide isoforms with fluorophore-assisted carbohydrate electrophoresis. Our results indicated that the nonsulfated disaccharide of chondroitin sulfate formed in average only 1-2% of the total chondroitin sulfate. More important, the molar ratio of nonsulfated disaccharide did not appear to be increased in the osteoarthritic articular cartilage. We conclude that undersulfation of articular cartilage proteoglycans is not present in the human osteoarthritic joint.     

Computerized tomography imaging of round atelectasis. Study of a series of 21 patients

AIM: To show and compare to literature CT findings in round atelectasis. MATERIAL AND METHODS: It is a retrospective review of the clinical and radiological files of 21 patients (17 men; 4 women; Mean age: 62), having asbestos exposure (6/21) or pleural history (13/21) and in whom the diagnosis of round atelectasis was performed from 1988 to 1998. This diagnosis was based on the presence of the classical radiological triad: round mass abutting to pleurae, converging bronchovascular markings and pleural thickening adjacent to the mass associated at a one year follow up or three years radiological and clinical follow up or the association with three minors radiological signs. RESULTS: The 25 round atelectasis, 4 bilateral, were localized in the lower lobes (22/25) or upper lobes (3/25) at right (17/25) or left (8/25) side. Minor signs were found as in literature as followed: air bronchograms and centrally indistinct margin (25/25, diffused pleural thickening or pleural plaques (19/25), acute angles with the pleura (18/25), fissures displacement (18/25), main stem bronchus displacement (13/25), calcifications within the plaque (10/25), calcifications within the mass (10/25). A mean of 6.7 signs was found for each lesion. CONCLUSION: More than the major signs of round atelectasis the air bronchogram, the centrally indistinct margin and the presence of one sign of retraction were very frequent. The mean number of signs was 6.7 for every lesion.     

The impact of nanoparticles on the mucosal translocation and transport of GLP-1 across the intestinal epithelium

Glucagon like peptide-1 (GLP-1) is an incretin hormone that is in the pipeline for type 2 diabetes mellitus (T2DM) therapy. However, oral administration of GLP-1 is hindered by the harsh conditions of the gastrointestinal tract and poor bioavailability. In this study, three nanosystems composed by three different biomaterials (poly(lactide-co-glycolide) polymer (PLGA), Witepsol E85 lipid (solid lipid nanoparticles, SLN) and porous silicon (PSi) were developed and loaded with GLP-1 to study their permeability in vitro. All the nanoparticles presented a size of approximately 200 nm. The nanoparticles' interaction with the mucus and the intestinal cells were enhanced after coating with chitosan (CS). PSi nanosystems presented the best association efficiency (AE) and loading degree (LD), even though a high AE was also observed for PLGA nanoparticles and SLN. Among all the nanosystems, PLGA and PSi were the only nanoparticles able to sustain the release of GLP-1 in biological fluids when coated with CS. This characteristic was also maintained when the nanosystems were in contact with the intestinal Caco-2 and HT29-MTX cell monolayers. The CS-coated PSi nanoparticles showed the highest GLP-1 permeation across the intestinal in vitro models. In conclusion, PLGA + CS and PSi + CS are promising nanocarriers for the oral delivery of GLP-1.     

Augmented cellular trafficking and endosomal escape of porous silicon nanoparticles via zwitterionic bilayer polymer surface engineering

The development of a stable vehicle with low toxicity, high cellular internalization, efficient endosomal escape, and optimal drug release profile is a key bottleneck in nanomedicine. To overcome all these problems, we have developed a successful layer-by-layer method to covalently conjugate polyethyleneimine (PEI) and poly(methyl vinyl ether-co-maleic acid) (PMVE-MA) copolymer on the surface of undecylenic acid functionalized thermally hydrocarbonized porous silicon nanoparticles (UnTHCPSi NPs), forming a bilayer zwitterionic nanocomposite containing free positive charge groups of hyper-branched PEI disguised by the PMVE-MA polymer. The surface smoothness, charge and hydrophilicity of the developed NPs considerably improved the colloidal and plasma stabilities via enhanced suspensibility and charge repulsion. Furthermore, despite the surface negative charge of the bilayer polymer-conjugated NPs, the cellular trafficking and endosomal escape were significantly increased in both MDA-MB-231 and MCF-7 breast cancer cells. Remarkably, we also showed that the conjugation of surface free amine groups of the highly toxic UnTHCPSi-PEI (Un-P) NPs to the carboxylic groups of PMVE-MA renders acceptable safety features to the system and preserves the endosomal escape properties via proton sponge mechanism of the free available amine groups located inside the hyper-branched PEI layer. Moreover, the double layer protection not only controlled the aggregation of the NPs and reduced the toxicity, but also sustained the drug release of an anticancer drug, methotrexate, with further improved cytotoxicity profile of the drug-loaded particles. These results provide a proof-of-concept evidence that such zwitterionic polymer-based PSi nanocomposites can be extensively used as a promising candidate for cytosolic drug delivery.     

In vivo biocompatibility of porous silicon biomaterials for drug delivery to the heart

Myocardial infarction (MI), commonly known as a heart attack, is the irreversible necrosis of heart muscle secondary to prolonged ischemia, which is an increasing problem in terms of morbidity, mortality and healthcare costs worldwide. Along with the idea to develop nanocarriers that efficiently deliver therapeutic agents to target the heart, in this study, we aimed to test the in vivo biocompatibility of different sizes of thermally hydrocarbonized porous silicon (THCPSi) microparticles and thermally oxidized porous silicon (TOPSi) micro and nanoparticles in the heart tissue. Despite the absence or low cytotoxicity, both particle types showed good in vivo biocompatibility, with no influence on hematological parameters and no considerable changes in cardiac function before and after MI. The local injection of THCPSi microparticles into the myocardium led to significant higher activation of inflammatory cytokine and fibrosis promoting genes compared to TOPSi micro and nanoparticles; however, both particles showed no significant effect on myocardial fibrosis at one week post-injection. Our results suggest that THCPSi and TOPSi micro and nanoparticles could be applied for cardiac delivery of therapeutic agents in the future, and the PSi biomaterials might serve as a promising platform for the specific treatment of heart diseases.