Opposing cartilages in the patellofemoral joint adapt differently to long-term cruciate deficiency: chondrocyte deformation and reorientation with compression

OBJECTIVE: The purposes of this study were to quantify patellofemoral histology in the feline knee 67 months post-anterior cruciate ligament transection (ACL-T) and to apply an in situ static load of physiological magnitude to the articular cartilage and evaluate the resulting cartilage and chondrocyte deformation. DESIGN: Six cats were sacrificed 67+/-6 months post-unilateral ACL-T. Static compression was applied to the cartilage surfaces of the patellofemoral joint using a cylindrical metal indentor. After fixation, full thickness osteochondral blocks were harvested and sections cut from not-indented and indented areas. Chondrocyte shape, orientation and volumetric fraction as well as cartilage thickness were evaluated. RESULTS: Experimental and contralateral patellae were histologically different compared to normal with thickened cartilage, rounded superficial chondrocytes, and uneven proteoglycan staining throughout. In contrast, no differences were apparent in 10 of the 12 femoral groove samples. The structural reorganisation of the experimental patellae cartilage that occurred with load was also different compared to normal. Specifically, the indentation shape was deeper and had steeper sides and the realignment of deep zone cells at angles of 45 degrees and 135 degrees observed in normal cartilage was no longer apparent in the experimental tissue. CONCLUSIONS: Two directly articulating cartilage surfaces of the feline patellofemoral joint have completely contrasting responses to long-term ACL-T. We speculate that this could be a result of the different nature of the loads experienced by the two surfaces (intermittent vs constant) and/or the differences in the histology and material properties of the two tissues in their normal state, and/or an inherent difference in the biological response capabilities of the articular cartilages.     

Reflux-free cannula for convection-enhanced high-speed delivery of therapeutic agents

OBJECT: Clinical application of the convection-enhanced delivery (CED) technique is currently limited by low infusion speed and reflux of the delivered agent. The authors developed and evaluated a new step-design cannula to overcome present limitations and to introduce a rapid, reflux-free CED method for future clinical trials. METHODS: The CED of 0.4% trypan blue dye was performed in agarose gel to test cannula needles for distribution and reflux. Infusion rates ranging from 0.5 to 50 microl/minute were used. Agarose gel findings were translated into a study in rats and then in cynomolgus monkeys (Macacafascicularis) by using trypan blue and liposomes to confirm the efficacy of the reflux-free step-design cannula in vivo. Results of agarose gel studies showed reflux-free infusion with high flow rates using the step-design cannula. Data from the study in rats confirmed the agarose gel findings and also revealed increasing tissue damage at a flow rate above 5-microl/minute. Robust reflux-free delivery and distribution of liposomes was achieved using the step-design cannula in brains in both rats and nonhuman primates. CONCLUSIONS: The authors developed a new step-design cannula for CED that effectively prevents reflux in vivo and maximizes the distribution of agents delivered in the brain. Data in the present study show reflux-free infusion with a constant volume of distribution in the rat brain over a broad range of flow rates. Reflux-free delivery of liposomes into nonhuman primate brain was also established using the cannula. This step-design cannula may allow reflux-free distribution and shorten the duration of infusion in future clinical applications of CED in humans.     

Static compressive loading reduces the mRNA expression of type II and X collagen in rat growth-plate chondrocytes during postnatal growth

The mechanisms by which chondrocytes modulate longitudinal bone growth are not well understood. This in vitro study investigated the effects of loading on the mRNA expression pattern of key molecular components of the growth-plate related to the extracellular matrix (type II and type X collagen) and the PTH-PTHrP feedback loop. Short-term static compressive loading was applied to rat proximal tibial growth-plate explants. Four age groups at specific developmental stages were investigated. The spatial variation in the mRNA expression was compared among loaded explants, their contralateral sham controls, and uncultured growth plates from normal animals. Basic cell metabolism (18S rRNA) was unaffected by load. Results indicated a narrower spatial distribution of mRNA expression of type II collagen throughout the growth plate; similarly, a narrowed distribution of expression of type X collagen was noted in the lower hypertrophic zone of the growth-plate. This suggests that mechanical compression influences chondrocytes of the hypertrophic zone to alter their expression of specific genes encoding proteins of the extracellular matrix, while PTH-PTHrP receptor mRNA, a regulatory protein, remained unaffected by loading. The effects of compression were similar at the different stages of growth, suggesting that additional factors may be involved in the clinical progression of skeletal deformities observed during growth spurts. Although this study was done in vitro and limited to static loading, it furthers our understanding of growth-plate mechanobiology as a first step toward providing a scientific rationale for treating progressive musculoskeletal deformities.     

Indirect injury stimulates scar formation-adaptation or pathology?

In several animal models of osteoarthritis induced by cruciate ligament transection, a dense, scar-like tissue mass forms rapidly on the medial side of the knee joint. This mass mimics clinical fibrosis that sometimes occurs after joint surgery. It is unknown exactly why this medial tissue mass forms and what cells are involved in its formation. This study characterizes this medial mass by histology, biochemistry, and the expression of types I and III collagen mRNA. The medial mass is compared with the medial collateral ligament (MCL) and the MCL epiligament in anterior cruciate-transected and unoperated joints, and to normal skin and skin scar. The morphology of the medial mass resembled the epiligament and skin scar more than the MCL. The concentration of DNA and RNA and the RNA-DNA ratio were elevated dramatically in the medial mass compared with all other tissues including skin scar. However, the mRNA copy number and ratio of collagen types I and III mRNAs did not differ significantly among the medial mass, MCL, epiligament, and skin in either the control or the operated joints. The response of the medial mass, MCL, and MCL epiligament to cruciate transaction involves both hyperplasia and hypertrophy, but without a dramatic shift in cell phenotype. The medial mass may be a useful mimic or model of intraarticular adhesions, hypertrophic scars, ligament sprains, and arthrofibrosis.     

Tularemia on Martha's Vineyard: seroprevalence and occupational risk

We conducted a serosurvey of landscapers to determine if they were at increased risk for exposure to Francisella tularensis and to determine risk factors for infection. In Martha's Vineyard, Massachusetts, landscapers (n=132) were tested for anti-F. tularensis antibody and completed a questionnaire. For comparison, serum samples from three groups of nonlandscaper Martha's Vineyard residents (n=103, 99, and 108) were tested. Twelve landscapers (9.1%) were seropositive, compared with one person total from the comparison groups (prevalence ratio 9.0; 95% confidence interval 1.2 to 68.1; p=0.02). Of landscapers who used a power blower, 15% were seropositive, compared to 2% who did not use a power blower (prevalence ratio 9.2; 95% confidence interval 1.2 to 69.0; p=0.02). Seropositive landscapers worked more hours per week mowing and weed-whacking and mowed more lawns per week than their seronegative counterparts. Health-care workers in tularemia-endemic areas should consider tularemia as a diagnosis for landscapers with a febrile illness.     

Association of tumor necrosis factor alpha gene -G308A polymorphism with schizophrenia

BACKGROUND: Tumor necrosis factor alpha (TNFalpha), a cytokine involved in inflammatory processes, has been implicated in the pathophysiology of schizophrenia. The chromosomal location in the major histocompatibility complex (MHC) region on 6p21.1-21.3, a region with evidence for linkage, suggests a role in susceptibility to schizophrenia. Association of the minor (A) allele of the -G308A TNFalpha gene polymorphism with schizophrenia has been reported [Mol. Psychiatry 6 (2001) 79]. METHODS: Association of the -G308A TNFalpha gene and the lymphotoxin alpha (LTalpha)+A252G gene polymorphisms with schizophrenia was studied in 79 sib pair families with linkage in the MHC region and in 128 trio families using the transmission disequilibrium test (TDT). RESULTS: Weak association of the common G allele was detected for TNFalpha -G308A in both samples independently with borderline significance in the sib pair families (0.064) and with a nominally significant value of P=0.022 in the trio families. Combining both samples produced P=0.003, while LTalpha+A252G, located approximately 2-3 kb distally, revealed P=0.03 and the two locus haplotype yielded a P value of 0.001. CONCLUSION: Our data suggests association of the common G allele of the -G308A TNFalpha gene polymorphism with schizophrenia in a sample of 207 families. However, linkage disequilibrium with a different allele of the TNFalpha gene or another gene in the MHC region cannot be excluded.     

Objective measurement of binocular fixation misalignment

The amount of deviation from central fixation during binocular fusion of a vertical border was compared with conventional fixation disparity measured at the same time, forced convergence serving as the independent variable. Fixation eccentricity was measured objectively by monitoring a scleral blood vessel with a video camera and by analyzing the movement, greatly magnified, on a video screen. Fixation disparity was measured conventionally by interocular nonius alignment of vertically dissociated line segments. The results agree well with previous comparisons of these responses, in which the fixation eccentricity was measured by using a technique based on the effect of retinal stimulus location on border enhancement. As in the previous experiment, the fixation misalignment was found to be many times larger than the corresponding disparity for most forced convergence values. The large discrepancy between actual fixation misalignment and fixation disparity has thus been documented objectively as well as subjectively.     

Association of DNA polymorphisms in the synaptic vesicular amine transporter gene (SLC18A2) with alcohol and nicotine dependence.

The brain synaptic vesicular amine transporter SLCA18A2 is a key component for the uptake of monoamines like dopamine or serotonin into vesicles. We have analyzed seven DNA polymorphisms located in the genomic region of SLC18A2 for association with alcohol- and nicotine dependence, using a family-based design. Our sample comprised 131 families with alcohol-dependent offspring and 96 families with at least one nicotine-dependent offspring. For the alcohol-dependent sample, we found statistical significant association for two single markers (rs363387, P=0.03; rs363333, P=0.0066) as well as for several haplotypes (minimal P=0.0038). When the sample with alcohol dependence was stratified according to gender, we observed increased association for the male subgroup (rs363387, P=0.0011). None of the markers showed association in the sample of families with nicotine dependence. However, analysis of a combined sample of alcohol and nicotine-dependent families resulted in single markers as well as several haplotypes showing statistical significant association with substance dependence (minimal P=0.0044). We conclude that DNA polymorphisms located in SLC18A2 might contribute to the development of substance dependence.     

Comparison of spiramycin and clarithromycin for community-acquired lower respiratory tract infections

This open multicentre study compared the efficacy and tolerability of clarithromycin and spiramycin in the treatment of lower respiratory tract infections in Brazil and Colombia. A total of 125 patients with a clinical and radiological diagnosis of pneumonia, acute bronchitis or exacerbation of chronic bronchitis were randomised to receive oral doses of either clarithromycin (500 mg) or spiramycin (3 MIU) every 12 hours for courses of 5-10 days. Patients were assessed before the start of treatment, and at days 3-4 and days 9-17. Twenty-six (26) patients (16 in the spiramycin group and 10 in the clarithromycin group) reported adverse events, seven of whom withdrew from the trial. Statistical analysis detected no significant differences between efficacy (p = 0.768) or tolerability (p = 0.236) for the two treatment groups. Spiramycin therefore has similar efficacy to clarithromycin in the treatment of community-acquired lower respiratory tract infections.