Dense innervation in pseudocapsular tissue compared to aneural interface tissue in loose totally replaced hips

BACKGROUND: The function of many inflammatory cells is in part regulated by neuronal cells, which may lead to so-called neurogenic inflammation. Sensory nerves also mediate the pain sensation. METHODS: This immunohistochemical study focused on visualization of C-sensory and sympathetic innervation in the synovial membrane-like interface and pseudocapsular tissue around loosened total hip replacement. RESULTS: The synovial membrane-like interface did not contain C-sensory peptidergic or sympathetic neural structures. Only limited attempts to neural regeneration were detected. In contrast, pseudocapsule expressed dense innervation with strong CPON-ir sympathetic innervation and osteoarthritis also had C-sensory fibers. Intense neural regeneration was seen in these synovial membranes. Surprisingly, stellate and/or highly dendritic fibroblast-like cells in the fibrotic areas in the interface tissue expressed strong immunoreactivity to the neural marker PGP 9.5, ubiquitin carboxyterminal hydrolase. CONCLUSION: Pain related to aseptic loosening cannot arise in the aneural interface membrane. Inflammation in interface/aseptic loosening seems to be driven by non-neurogenic factors, such as foreign bodies and micromovement. Insufficient lysosomal degradation of denatured proteins causes accumulation of ubiquitinated conjugates and enzymes involved in the process. This leads to insufficient degradation of platelet derived growth factor (PDGF)-receptor complex and can contribute to the accumulation of connective tissue in the interface. Failure in ubiquitin mediated proteolysis might support overgrowth of interface tissue and aseptic loosening.     

MR perfusion, diffusion and BOLD imaging of methotrexate-exposed swine brain

PURPOSE: To evaluate the methotrexate (MTX)-exposed swine brain, functional magnetic resonance imaging (MRI), including perfusion, diffusion, and blood-oxygen-level-dependent (BOLD) contrast imaging, was used. MATERIAL AND METHODS: Juvenile pigs received either 2 x 5 g/m(2), or 5 x 2 g/m(2) MTX intravenously within one month. MRI was performed (sedative: propofol) before (14-17 kg, N = 6) and after (21-27 kg, N = 4) the MTX exposure. Also, age-matched controls (22-27 kg, N = 4) were imaged. RESULTS: After the MTX exposure, reduced (from 2%-4% to 0%-1%) or negative (-2% to -3%) BOLD responses were detected; apparent diffusion coefficient (ADC) or relative perfusion values did not change. CONCLUSION: This study suggests that MTX-related changes in the brain may be detected as changes in flow-metabolism coupling as reduced or negative response (for somatosensory activation) in the BOLD contrast MRI. The contrast agent perfusion MRI, without absolute quantification, may not show global damage in brain perfusion related to the MTX exposure in the swine model used. ADC (in one direction) may not indicate MTX-related changes in the brain.     

First report of saxitoxin in Finnish lakes and possible associated effects on human health

This study is the first report of saxitoxin in cyanobacterial blooms in Finland. Bloom samples (n = 50) were collected from Finnish freshwater sites during summer months of 2002 and 2003. These samples were screened for the presence of paralytic shellfish toxins (PSTs) using the Jellett rapid PSP screening test. Samples testing positive for PSTs (n = 7) were further analyzed with saxiphilin- and voltage-gated sodium channel [(3)H]-STX-binding radioreceptor assays and liquid chromatography using fluorescence and mass spectrometric analysis. The results indicated that saxitoxin (STX) was the only PST analogue in the samples and that it was present in high concentrations, as much as 1 mg L(-1). Microscopic analysis revealed that 95%-100% of the phytoplankton in the positive samples consisted of Anabaena lemmermannii. The trophic status of lakes in which STX-containing blooms were found varied from oligotrophic to hypertrophic. All the lakes had high nitrogen-to-phosphorus ratios. In some instances, samples had been collected from sites where swimmers had reported adverse health effects, and in three such cases, reported adverse health effects were associated with sites from which samples testing positive for STX had been received. Symptoms of fever, eye irritation, abdominal pains, and skin rash were reported in children aged 2-10 years after exposure to the water. These were not the adverse human symptoms typical of STX poisoning; rather, they represented acute effects often reported following recreational exposure to cyanobacterial blooms.     

Early intramedullary nailing of lower extremity fracture and respiratory function in polytraumatized patients with a chest injury: a retrospective study of 61 patients

BACKGROUND: The optimal treatment of diaphyseal fractures of the lower extremities in patients who also have serious chest injuries is not known. PATIENTS AND METHODS: We retrospectively evaluated the effect of an early intramedullary nailing (IMN) of femur or tibia fractures on respiratory function in 61 consecutive polytraumatized patients with unilateral or bilateral pulmonary contusion (thoracic AIS=3) admitted to our trauma intensive care unit between January 2000 and June 2001. 27 patients had a diaphyseal fracture of at least one long bone of the lower extremity, which was treated with IMN within 24 hours of admission. RESULTS: We found no difference between patients with or without a lower extremity fracture regarding the length of ventilator treatment, oxygenation ratio (PaO2/FiO2) or in the incidence of acute respiratory distress syndrome (ARDS), pneumonia, multi-organ failure or mortality. INTERPRETATION: In this retrospective study, IMN of a long bone fracture in a patient with multiple injuries and with a coexisting pulmonary contusion did not impair pulmonary function or outcome.     

Deletion of laminin-8 results in increased tumor neovascularization and metastasis in mice

Laminin-8 (alpha 4 beta 1 gamma 1) is one of the major laminin isoforms expressed in vascular endothelial basement membranes. Here we show that deletion of laminin-8 in mice affects angiogenesis under pathological conditions. Murine tumor models used in laminin alpha 4-deficient mice results in hyperneovascularization and significant promotion of tumor growth and metastasis. The higher tumor growth rates in mutant mice correlate with decreased tumor cell apoptosis. Depletion of laminin alpha 4 chain may alter the structure of vascular basement membranes, leading to increased angiogenesis. Our data suggest that the laminin-8 plays a critical role in the regulation of pathological angiogenesis.     

New prolyl oligopeptidase inhibitors developed from dicarboxylic acid bis(l-prolyl-pyrrolidine) amides

Isophthalic acid bis(l-prolyl-pyrrolidine) amide is a very potent prolyl oligopeptidase inhibitor, but it has a log P value of -0.2, which is very low for a compound targeted to the brain. Therefore, these types of compounds were further modified to improve the structure-activity relationships, with the focus on increasing the log P value. The inhibitory activity against prolyl oligopeptidase from pig brain was tested in vitro. The most promising compounds resulted from replacing the pyrrolidinyl group at the P5 site by cycloalkyl groups, such as cyclopentyl and cyclohexyl groups, and by a phenyl group. These compounds are slightly more potent, and they have a significantly higher log P value. The potency of these compounds was further increased by replacing the pyrrolidinyl group at the P1 site by 2(S)-cyanopyrrolidinyl and 2(S)-(hydroxyacetyl)pyrrolidinyl groups.     

Tracheobronchial stents in patients with malignant airway disease: Finnish tertiary care experience

Open in a separate window OBJECTIVESTracheobronchial stenting has an established role in the palliation of malignant central airway obstruction (CAO). The purpose of this study is to describe the experience with self-expanding metal airway stents in 2 tertiary referral centres, covering a third of the population of Finland.METHODSPatients referred to and treated with airway stenting for malignant CAO using self-expanding metal-stents were identified from electronic patient records, and data were collected using a structured Endoscopic Lower Airway Management instrument. Statistical analysis to reveal factors affecting patient benefit and survival was carried out.RESULTSA total of 101 patients (mean age 65.8) and 116 procedures were identified. Procedure-related mortality was rare (3/101 patients) and complications infrequent. The median survival was 2.3 months [95% confidence interval (CI): 1.4–3.1). Stent benefit was not significantly affected by clinical characteristics. Survival was impacted by the use of adjunct procedures [hazard ratio (HR) 0.36, 95% CI: 0.23–0.58, P < 0.001), procedural urgency (HR 0.40; 95% CI: 0.23–0.71, P = 0.002) and post-treatment chemoradiotherapy (HR 0.29, 95% CI: 0.15–0.56, P < 0.001).CONCLUSIONSThe beneficial impact observed supports the further use of tracheobronchial stenting in malignant CAO. The use of self-expanding metal stents is encouraged.     

Design, Synthesis and Brain Uptake of LAT1-Targeted Amino Acid Prodrugs of Dopamine

Purpose

Drug delivery to the brain is impeded by the blood-brain barrier (BBB). Here, we attempted to enhance the brain uptake of cationic dopamine by utilizing the large amino acid transporter 1 (LAT1) at the BBB by prodrug approach.

Methods

Three amino acid prodrugs of dopamine were synthesized and their prodrug properties were examined in vitro. Their LAT1-binding and BBB-permeation were studied using the in situ rat brain perfusion technique. The brain uptake after intravenous administration and the dopamine-releasing ability in the rat striatum after intraperitoneal administration were also determined for the most promising prodrug.

Results

All prodrugs underwent adequate cleavage in rat tissue homogenates. The prodrug with phenylalanine derivative as the promoiety had both higher affinity for LAT1 and better brain uptake properties than those with an alkyl amino acid -mimicking promoiety. The phenylalanine prodrug was taken up into the brain after intravenous injection but after intraperitoneal injection the prodrug did not elevate striatal dopamine concentrations above those achieved by corresponding L-dopa treatment.

Conclusions

These results indicate that attachment of phenylalanine to a cationic drug via an amide bond from the meta-position of its aromatic ring could be highly applicable in prodrug design for LAT1-mediated CNS-delivery of not only anionic but also cationic polar drugs.     

Three unrelated viruses occur in a single isolate of Gremmeniella abietina var. abietina type A

Five enclosed double-stranded RNA (dsRNA) bands in electrophoresis, probably of viral origin, were found from a single isolate (SurS4) of Gremmeniella abietina var. abietina type A. Analysis of the dsRNAs revealed that they represented three different viruses, named as Gremmeniella abietina mitochondrial RNA virus S2 (GaMRV-S2), Gremmeniella abietina RNA virus MS2 (GaRV-MS2) and Gremmeniella abietina RNA virus L2 (GaRV-L2). The genome of GaMRV-S2 was 2587 base pairs (bp) long and had a very low GC content (31%). Sequence variations occurred at both ends. The genome coded for a putative RNA-dependent RNA polymerase (RdRp) under a mitochondrial translation code. The GaRV-MS2 genome was composed of three dsRNA molecules (1781 bp, 1586 bp and 1186 bp). They coded for a putative RdRp, a coat protein (CP) and a protein with an unknown function, respectively. The GaRV-L2 genome was 5129 bp long and contained two ORFs. The 5′-proximal ORF coded for a putative CP, whereas the 3′-proximal ORF encoded for a putative RdRp. The buoyant density of GaRV-MS2 and GaRV-L2 were 1.37 and 1.42 g/ml, respectively. GaMRV-S2, GaRV-MS2 and GaRV-L2 were closely related to the previously described viruses GaMRV-S1, GaRV-MS1 and GaRV-L1, respectively, and are putative members of the genera Mitovirus, Partitivirus and Totivirus, respectively. This is the first report on the occurrence of viruses of all these different genera in a single fungal isolate.