Comparison of amounts and properties of collagen and proteoglycans in condylar, costal and nasal cartilages

In this study we compared the compositions of extracellular matrices of condylar, costal and nasal cartilages to characterize differences in growth patterns in relation to matrix composition. Condylar, costal and nasal cartilages of 25- and 35-day-old rabbits were extracted and subjected to bio- and histochemical analysis to determine total amounts of collagen and amounts and aggregating properties of proteoglycans. We found that proteoglycan content and aggregate formation were greatest in nasal cartilage, and lower in costal and markedly lower in condylar cartilage. The amount of proteoglycans increased by varying amounts in all samples with age. Collagen content was highest in costal cartilage. In 25-day-old rabbits the quantity of collagen in condylar cartilage exceeded that in nasal cartilage. In 35-day-old rabbits the quantities were nearly the same. It is suggested that collagen does not only provide tensile strength, but counteracts forces responsible for interstitial growth such as osmotic pressure. Based on the results, it seems that the amount of proteoglycans is greater in cartilages, which have greater independent growth potential. Variations in increase in amount of proteoglycans with age could reflect differences in the timing of growth of such cartilages.     

Acute hormonal responses to heavy resistance exercise in strength athletes versus nonathletes.

The aim of the present study was to investigate acute hormonal and neuromuscular responses and recovery in strength athletes versus nonathletes during heavy resistance exercise performed with the forced and maximum repetitions training protocol. Eight male strength athletes (SA) with several years of continuous resistance training experience and 8 physically active but non-strength athletes (NA) volunteered as subjects. The experimental design comprised two loading sessions: maximum repetitions (MR) and forced repetitions (FR). MR included 12-RM squats for 4 sets with a 2-min recovery between sets. In FR the initial load was higher than in MR so that the subject could lift approximately 8 repetitions by himself and 4 additional repetitions with assistance. Before and after the loading protocols, blood samples were drawn to determine serum testosterone, free testosterone, cortisol and growth hormone concentrations, and blood lactate. Maximal voluntary isometric force and EMG activity of the leg extensors was measured before and after the loading as well as 24 and 48 hrs after the loading. The concentrations of the hormones measured increased significantly (p < .01-.001) after both loadings in both groups. The responses tended to be higher in FR than the MR loading and the increases of testosterone concentrations were significantly (p < .01) greater in both loadings in SA than in NA. Both loading protocols in both groups also led to neuromuscular fatigue observable with significant acute decreases in isometric strength by 32-52% (p < .001) and in maximal iEMG (p < .05-01) associated with large increases in blood lactate. These data suggest that, at least in experienced strength athletes, the forced-repetition protocol is a viable alternative to the more traditional maximum-repetition protocol and may even be a superior approach.     

Inhomogeneous exercise uptake and accelerated washout of a radioiodinated fatty acid analogue in syndromeX A SPECT study of the left ventricle

Myocardial metabolism in exercise was determined by studying 21 syndromeX patients and 14 healthy volunteers with an aromatic fatty acid analogue IPPA and a gamma camera. We developed criteria for visual semiquantitative assessment of relative segmental radiotracer uptake and washout, and tested a new computer program for quantitative evaluation. One volunteer (7%) and 12 patients (57%) showed visually inhomogeneous uptake (p=0.006, ²-test) in SPECT polar tomograms after a maximal ergometry test. Images in none of the volunteers and seven patients (33%) gave the impression of a slowed regional washout (p=0.057). Only six patients (29%) had a normal radial polarogram. Patients with irregular coronary angiograms (showing slow flow or minor sclerosis) and those with chest pain during the IPPA exercise test had a very low frequency of normalcy, but this was not significant.Total washout was higher in patients than in the reference population, as the exercise to rest activity ratio was 1.36 SD 0.13 versus 1.25 SD 0.11 in computerized quantitation (p=0.015, t-test). Washout did not correlate with age, sex or exercise heart rate. Regarding computerized analysis of uptake and slow washout, the number of deviant segments was not significantly higher in patients than in reference population. Semiquantitative and quantitative analysis correlated in the assessment of uptake, but not in the assessment of washout. Possible reasons for the discrepancy are discussed.Conclusions of this study are not straightforward. SyndromeX was associated with inhomogeneous IPPA uptake, which is not at variance with the theory of microvascular dysfunction. On the other hand, the analysis of washout presumably implies higher fatty acid utilization in patients than in normal controls, which is not a characteristic phenomenon in myocardial ischemia.     

Hydroxypropyl-β-Cyclodextrin Increases the Aqueous Solubility and Stability of Pilocarpine Prodrugs

Purpose. The effects of 2-hydroxypropyl--cyclodextrin (HP--CD) on the aqueous solubility and stability of two lipophilic bispilocarpine prodrugs were investigated at pH 7.4. Methods. The solubility of prodrugs was studied by phase-solubility method (0–72.5 mM HP--CD). The stability of one of the prodrugs was investigated as a function of temperature (40°C–70°C) and HP--CD concentration (0–72.5 mM). The apparent rate constants (k ₁, k ₂) for degradation of prodrug in 1:1 and 1:2 inclusion complexes and apparent stability constants (K _1:1, K _l:2) were calculated by the curve-fitting method. Results. The phase-solubility diagrams were classified as A_p-type and the apparent stability constants (K _l:l, K _l:2) for 1:1- and 1:2-inclusion complexes were calculated to be 143–815 M^–l and 29–825 M^–1, respectively. The stability of prodrug increased as a function of HP--CD concentration over the studied temperature range. The shelf-life (t _90%, calculated by the Arrhenius equation) of the prodrug in 72.5 mM HP--CD solution increased 5.1-fold and 6.1-fold at 25°C and 4°C, respectively. Conclusions. The solubility of the prodrugs was shown to increase markedly in phase-solubility studies. The degradation rate of prodrug in stability studies was shown to be slower in the l:2-complex than in the l:l-complex and the relative amounts of complex species were found to be dependent on CD concentration.     

Effect of Liposomal and Free Bisphosphonates on the IL-1β, IL-6 and TNFα Secretion from RAW 264 Cells in Vitro

Purpose. In order to evaluate the possible antiinflammatory action of bisphosphonates, the effect of the drugs on the secretion of proinflammatory cytokines (IL-l, IL-6 and TNF) from macrophages was studied. Liposomes or high concentration of extracellular calcium was used to enhance the intracellular delivery of bisphosphonates. Methods. RAW 264 cells were used as macrophage model, and they were induced with lipopolysaccharide to produce the cytokines. The cytokine concentrations in the culture supernatants were measured with time-resolved fluoroimmunoassay. Results. As a free drug, clodronate and pamidronate, but not etidronate, inhibited LPS-stimulated secretion of the cytokines from macrophage-like RAW 264 cells. Low concentrations of pamidronate, however, induced the IL-6 secretion, and the cytokine inhibitory action at the higher concentrations of pamidronate was attributed to cytotoxicity of the compound. The cytokine induction or toxic effects were not observed with clodronate or etidronate. When the drugs were encapsulated in negatively charged unilamellar liposomes, the inhibitory potency of both clodronate and etidronate enhanced by a factor of 10-20, while that of pamidronate was not increased. The complex formation of bisphosphonates with extracellular calcium, although enhancing the uptake of the compounds by macrophages, did not considerably increase their cytokine inhibitory potency. Conclusions. Bisphosphonates have inhibitory action on cytokine secretion by macrophages. The non-cytotoxic cytokine inhibition by liposome encapsulated clodronate could be beneficial in local inflammatory diseases, where the inflammation is sustained by the excessive amounts of inflammatory cytokines produced by activated macrophages.     

Demonstration of Cerebral Plasticity by Intra-Operative Neurophysiological Monitoring: Report of an Uncommon Case

Summary  It has been postulated long ago that “eloquent” areas shift their location in patients with arteriovenous malformations (AVM). Obviously the “motor region” in not located in the precentral gyrus in a patient with an AVM in the “motor region”.  We report on the case of a 15-year old boy with an AVM in the left sensorimotor cortex, in whom intra-operative mapping showed an inexcitability of the precentral gyrus, while stimulation of the cortex anterior to the primary motor cortex elicited motor responses. This indicates that motor function was translocated from the primary to the supplementary motor cortex. Surgery was performed under general anaesthesia. Neurophysiological monitoring was performed throughout surgery. The central sulcus was identified by phase reversal of the somatosensory evoked potentials. The motor cortex was mapped by direct high-frequency (500 Hz) monopolar anodal stimulation.  In the patient herein reported, stimulation of the “anatomically” defined primary motor cortex induced no motor response, as expected. Motor response was elicited only by stimulation of the cortex anterior to the precentral gyrus. There was no postoperative deterioration of motor function. These observations indicate that the precentral gyrus was functionally “useless”. The motor region was relocated into more rostral areas in the supplementary motor cortex. This translocation of function in the presence of an AVM indicates cerebral plasticity.     

Improved Corneal Pilocarpine Permeability with O,O′-(l,4-Xylylene) Bispilocarpic Acid Ester Double Prodrugs

0,0-(l,4-Xylylene) bispilocarpic acid esters are pilocarpine pro-drugs containing two pilocarpic acid monoesters linked with one pro-moiety. Each mole of prodrug forms two pilocarpine moles in the presence of esterases. Corneal uptake and permeability of various bispilocarpic acid diesters were investigated in vitro using isolated albino rabbit corneas. The permeability coefficient of pilocarpine was 2.8 × 10 ^–6 cm/sec, whereas for bispilocarpic acid diesters, despite their large molecular weights (between 638 and 722), permeability coefficients were 6.5–20.2 × 10 ^–6 cm/sec. Only pilocarpine, and no intact prodrug, was observed at the endothelial side. Corneal uptake was increased with increasing lipophilicity, but a parabolic relationship between the logarithm of the apparent partition coefficient (1-octanol–pH 7.4 phosphate buffer) (log PC) and the corneal permeability was noticed. Corneal permeability and the rate of enzymatic hydrolysis of the compounds correlated well. The corneal permeability of pilocarpine given as lipophilic bispilocarpic acid diester (log PC 3) prodrugs seems to be controlled by the formation of pilocarpine in the corneal epithelium rather than by the absorption of prodrugs into the epithelium or their epithelium–stroma transport rate.     

Pre-operative serum level of tumour-associated trypsin inhibitor and residual turnour size as prognostic indicators in Stage III epithelial ovarian cancer

Objective To evaluate the use of the pre-operative tumour-associated trypsin inhibitor (TATI) level and residual tumour size at primary surgery as a prognostic indicators for patients with Stage III epithelial ovarian cancer.
Design Retrospective cohort study.
Setting Department of Obstetrics and Gynaecology, University Hospital, Helsinki, Finland.
Participants Ninety-eight women with Stage III ovarian cancer.
Methods TATI was measured by radioimmunoassay from serum samples obtained within one week before surgery. A cutoff value of 22 μg/L was used. Multivariate analysis included pre-operative TATI level, age, histologic grade and histologic type. Mantel-Cox test was used for calculating statistical significance of differences in survival between groups.
Main outcome measures Cumulative five-year survival, pre-operative serum TATI level and residual tumour size.
Results Surgery was optimal (residual tumour size ≤ 2 cm) in 55 patients and suboptimal (residual tumour size > 2 cm) in 43. Pre-operative TATI level ≤ 22 μg/L predicted better prognosis both in patients with optimal and suboptimal surgery compared with patients with pre-operative TATI level > 22 μ/L. Patients with optimal surgery and a pre-operative TATI > 22 μg/L had a twofold relative risk of death compared with those with a pre-operative TATI ≤ 22 μg/L. The cumulative survival was less than three years for patients with suboptimal surgery and pre-operative TATI > 22 μg/L.
Conclusions Pre-operative serum TATI in combination with residual tumour size may be useful in stratifying patients with Stage III ovarian cancer into different categories in randomised treatment trials.     

Balance board training: prevention of traumatic injuries of the lower extremities in female soccer players?

This prospective randomized intervention investigated whether training on a balance board could reduce the amount of traumatic injuries of the lower extremities in female soccer players. A total of 221 female soccer players from 13 different teams playing in the second and third Swedish divisions volunteered to participate in the study. Seven teams (n = 121) were randomized to an intervention group and six teams (n = 100) to a control group and were followed during one outdoor season (April-October). Before and after the season muscle flexibility and balance/postural sway of the lower extremities were measured in the players. There were no significant differences in age, height, weight, muscle flexibility and balance/postural sway of the lower extremities between the intervention and the control group. During the season the players in the intervention group performed a special training program consisting of 10-15 min of balance board training in addition to their standard soccer practice and games. After a 37% drop-out the intervention group consisted of 62 players and the control group of 78 players. The results showed no significant differences between the groups with respect either to the number, incidence, or type of traumatic injuries of the lower extremities. The incidence rate of "major" injuries was higher in the intervention group than in the control group. Four of five anterior cruciate ligament injuries occurred in the intervention group, which means that we could not prevent severe knee injuries in female soccer players with balance board training. However, among the players who had been injured during the 3-month period prior to this investigation there were significantly more players from the control group than from the intervention group who sustained new injuries during the study period.     

Surgical Treatment of Spinal Hemangioblastomas

Summary  Background. The routine use of magnetic resonance imaging (MRI) in recent years for the diagnostic assessment of the spinal column and especially for screening patients with von Hippel-Lindau (vHL) disease has shown that spinal hemangioblastomas (sHBs) are more common than assumed so far. Since most sHBs are thus discovered while they are still asymptomatic, especially in vHL disease, the question arises whether and when these tumors should be treated. The present article reports the results of the surgical treatment of sHBs using the protocol described below and compares them to the course in a control group of patients with conservatively treated sHBs.  Patients and Methods. A total of 30 sHBs were treated microsurgically in 15 patients. Hemangioblastoma-associated cysts were merely opened in 14 cases, drained with the help of Teflon cotton in 2 of these cases, and not opened in 4 instances. Laminoplasties were performed with insertion of absorbable, MRI-compatible micro-osteosynthesis plates. Perioperatively, all patients were administered methylprednisolone according to the NASCIS (National Acute Spinal Cord Injury Study) scheme, and sensory evoked potentials were monitored intra-operatively in all cases. Nine patients in whom the course of primarily conservative treatment of a total of 17 asymptomatic sHBs was documented served as controls. The follow-up time was 7 to 51 months (mean 20) after surgery and 10 to 51 months (mean 21) in the control group.  Findings. Preoperative HB-associated pareses showed transient postoperative deterioration (n=5). The other accompanying neurological deficits improved in 6 HBs and remained unchanged in all other HBs (n=19), of which 16 had been asymptomatic before surgery. In the control group, 6 HBs (in 6 different patients) became permanently symptomatic despite subsequent surgical treatment according to the study protocol.  Interpretations. With the new diagnostic tools now available, microsurgical removal of spinal hemangioblastomas has a low morbidity rate, suggesting that surgical treatment should be considered even for asymptomatic sHBs in certain circumstances.