Associations among meniscal damage, meniscal symptoms and knee pain severity.

OBJECTIVE: Meniscal tears occur frequently in patients with knee osteoarthritis (OA). The aim of our study was to determine whether meniscal damage identified on magnetic resonance imaging (MRI) is associated with the severity of knee pain or the frequency of meniscal symptoms in patients with knee OA. METHODS: We performed a cross-sectional study using data from the Meniscal Tear in Osteoarthritis Research (MeTeOR) trial. We characterized meniscal damage hierarchically as: root tear; maceration; long and short complex or horizontal tears; and simple tears. Subjects completed the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Scale and a survey of frequency of meniscal symptoms. We used multivariable general linear models to assess the relationships between meniscal damage and 1) pain severity; and 2) meniscal symptoms, after adjusting for demographic and radiographic features. In further analysis root tear was considered as a binary variable. RESULTS: Analysis included 227 knees. Root tears were present in 19%, maceration in 14%, long complex or horizontal tears in 22%, short complex or horizontal tears in 30%, and simple tears in 14%. Root tears were associated with higher WOMAC pain scores. The adjusted mean WOMAC pain score was 45.2 (standard error (SE) 2.7) for those with root tear and 38.7 (SE 1.2) for subjects without root tear (P = 0.03). We did not find statistically significant associations between meniscal morphology and frequency of meniscal symptoms. CONCLUSION: Root tears were associated with greater pain than meniscal tears or maceration. We did not find a relationship between meniscal damage and meniscal symptoms.

The impact of forced joint exercise on lubricin biosynthesis from articular cartilage following ACL transection and intra-articular lubricin's effect in exercised joints following ACL transection.

OBJECTIVE: To evaluate the impact of forced joint exercise following acute knee injury on lubricin metabolism and its relationship to cartilage degeneration and to assess chondroprotection of a single-dose purified human lubricin injection in exercised injured joints. METHODS: Anterior cruciate ligament transection (ACLT) was performed in rats with six experimental groups; 3-week post-ACLT, 3-week post-ACLT + exercise, 5-week post-ACLT, 5-week post-ACLT + exercise, and 5-week post-ACLT + exercise treated with intra-articular phosphate buffered saline (PBS) or lubricin. Joint exercise was achieved using a rotating cylinder at a speed of 6 rpm for 30 min daily, 5 days a week starting 1 week following surgery. Cartilage lubricin expression in injured joints was determined. Histological analyses included Safranin O/Fast Green, activated caspase-3, and lubricin mRNA in-situ hybridization. Assessment of cartilage damage was performed by osteoarthritis research society international (OARSI) modified Mankin scoring and urinary CTXII (uCTXII) levels. RESULTS: At 3 weeks, lubricin expression in exercised ACLT joints was significantly (P < 0.001) lower compared to ACLT joints. The OARSI scores were significantly (P < 0.001) higher in the ACLT + exercise animals compared to ACLT animals at 5 weeks. Compared to 3-week ACLT, 3-week ACLT + exercise cartilage showed increased caspase-3 staining. Compared to ACLT + exercise and PBS-treated ACLT + exercise, lubricin intra-articular treatment resulted in a significant increase (P < 0.001) in cartilage lubricin gene expression and a reduction (P < 0.05) in uCTXII levels. CONCLUSION: Joint exercise resulted in decreased lubricin cartilage expression, increased cartilage degeneration and reduced superficial zone chondrocyte viability in the ACLT joint. Intra-articular lubricin administration ameliorated cartilage damage due to exercise and preserved superficial zone chondrocytes' viability.

Early metabolic improvement following bariatric surgery in morbidly obese adolescents.

Bariatric surgery results in durable weight loss and improved comorbidities. The objectives of this study were to examine the efficacy of gastric bypass in reducing comorbid burden and improving metabolic status among morbidly obese adolescents. The medical records of 15 gastric bypass patients were retrospectively reviewed. Changes in metabolic markers were determined at baseline, 1 and 2 years post-operatively. Comparative analysis demonstrated significant improvement in weight, BMI, insulin, HbA1C, C-peptide, %B, %S, IR, cholesterol, percentile cholesterol, TG, percentile TG, HDL, percentile HDL, LDL, percentile LDL, and VLDL. Results support bariatric surgery as a treatment for morbidly obese adolescents with comorbidities.

Assuming exponential decay by incorporating viscous damping improves the prediction of the coefficient of friction in pendulum tests of whole articular joints.

A pendulum test with a whole articular joint serving as the fulcrum is commonly used to measure the bulk coefficient of friction (COF). In such tests it is universally assumed that energy loss is due to frictional damping only, and accordingly the decay of pendulum amplitude is linear with time. The purpose of this work was to determine whether the measurement of the COF is improved when viscous damping and exponential decay of pendulum amplitude are incorporated into a lumped-parameter model. Various pendulum models with a range of values for COF and for viscous damping were constructed. The resulting decay was fitted with an exponential function (including both frictional and viscous damping) and with a linear decay function (frictional damping only). The values predicted from the fit of each function were then compared to the known values. It was found that the exponential decay function was able to predict the COF values within 2 per cent error. This error increased for models in which the damping coefficient was relatively small and the COF was relatively large. On the other hand, the linear decay function resulted in large errors in the prediction of the COF, even for small values of viscous damping. The exponential decay function including both frictional and constant viscous damping presented herein dramatically increased the accuracy of measuring the COF in a pendulum test of modelled whole articular joints.

Frictional properties of Hartley guinea pig knees with and without proteolytic disruption of the articular surfaces.

OBJECTIVE: To apply a pendulum technique to detect changes in the coefficient of friction of the articular cartilage of the intact guinea pig tibiofemoral joint after proteolytic disruption. DESIGN: Twenty-two hind limbs were obtained from 11 3-month old Hartley guinea pigs. Twenty knees were block-randomized to one of two treatment groups receiving injections of: (1) alpha-chymotrypsin (to disrupt the superficial layer of the articular surface) or (2) saline (sham; to control for the effects of the intra-articular injection). The legs were mounted in a pendulum where the knee served as the fulcrum. The decay in pendulum amplitude as a function of oscillation number was first recorded and the coefficient of friction of the joint was determined from these data before injection. Ten microliters of either isotonic saline or 1 Unit/microL alpha-chymotrypsin was then injected into the intra-articular joint space and incubated for 2h. The pendulum test was repeated. Changes in the coefficient of friction between the sham and alpha-chymotrypsin joints were compared. One additional pair of knees was used for histological study of the effects of the injections. RESULTS: Treatment with alpha-chymotrypsin significantly increased the coefficient of friction of the guinea pig knee by 74% while sham treatment decreased it by 8%. Histological sections using Gomori trichrome stain verified that the lamina splendens was damaged following treatment with alpha-chymotrypsin and not following saline treatment. CONCLUSIONS: Treatment with alpha-chymotrypsin induces mild cartilage surface damage and increases the coefficient of friction in the Hartley guinea pig knee.

Molecular population genetic analysis of Campylobacter jejuni HS:19 associated with Guillain-Barré syndrome and gastroenteritis.

Infection with Campylobacter jejuni serotype HS:19 is associated with the development of Guillain-Barré syndrome (GBS). To determine whether a particular HS:19 clone is associated with GBS, multilocus enzyme electrophoresis (MLEE) was used to analyze a worldwide collection of isolates. There were 34 electropherotypes (ETs) in 3 phylogenetic clusters among 83 C. jejuni isolates. Cluster I contained all HS:19 strains, and a single ET (ET4) accounted for most HS:19 strains. HS:19 strains did not occur in any of the other clusters. ET4 contained isolates from different geographic locations, indicating global spread of this clone. Furthermore, ET4 contained isolates from patients with uncomplicated enteritis and GBS, as well as isolates from animal sources. The results of this study show that HS:19 strains comprise a clonal, although not monomorphic, population, which is distinct from non-HS:19 strains within C. jejuni. A unique clone associated with GBS was not identified by use of MLEE.

A new solution for life without blood. Asanguineous low-flow perfusion of a whole-body perfusate during 3 hours of cardiac arrest and profound hypothermia.

BACKGROUND: The benefits of hypothermia for preventing ischemic injury are well known, but its application in surgery to protect the whole body during procedures requiring circulatory arrest is currently limited to < 1 hour at 15 degrees C using 50% hemodilution. In a significant departure from previous methods, we have developed a technique of asanguineous blood substitution with low-flow perfusion and cardiac arrest at < 10 degrees C in a canine model. Our approach has been to design a hypothermic blood substitute that would protect the brain and visceral organs during several hours of bloodless perfusion. Two different solutions have been designed to fulfill separate requirements in the procedure. METHODS AND RESULTS: With the use of extracorporeal cardiac bypass, 14 adult dogs were exsanguinated during cooling; 11 dogs were blood substituted using in combination the "purge" and "maintenance" solutions (group 1), and 3 dogs were perfused throughout with the "purge" solution alone as controls (group 2). After cardiac arrest, the solutions were continuously circulated for 3 1/2 hours by the extracorporeal pump (flow rate, 40 to 85 mL.kg-1.min-1; mean arterial blood pressure, 25 to 40 mm Hg). The temperature was maintained at < 10 degrees C (nadir, 6.6 +/- 0.1 degrees C) for 3 hours, and the hematocrit was kept at < 1% before controlled rewarming and autotransfusion. In the experimental group, the heart always started spontaneously in the temperature range of 11 degrees C to 27 degrees C, and 8 animals have survived long-term (current range, 14 to 110 weeks) without any detectable neurological deficit. In contrast, two control animals survived after extensive and aggressive cardiac resuscitation efforts; after surgery they exhibited transient motor and sensory deficits for approximately 1 week. Evaluation of biochemical and hematological parameters showed only a transient and inconsequential elevation in enzymes (eg, brain, liver, cardiac) in group 1 compared with the markedly greater elevations in group 2. For example, immediate postoperative values (mean +/- SEM) for lactate dehydrogenase were 114 +/- 10 for group 1 versus 490 +/- 210 for group 2 (P < .03); for SGOT, values were 93 +/- 18 for group 1 versus 734 +/- 540 for group 2 (P < .05). On day 1 for creatine kinase (CK), the group 1 value was 7841 +/- 2307 versus 71,550 +/- 2658 for group 2 (P = .03), and for CK-BB, the group 1 value was 108 +/- 22 versus 617 +/- 154 for group 2 (P = .03). Neurological evaluation using deficit scores (NDS) was based on a modification of the Glasgow Coma Scale score: 0, normal; 1, minimal abnormality; 2, weakness; 3, paralysis; 4, coma; and 5, death. At days 1 and 2 after surgery, NDS (mean +/- SEM) were 0 +/- 0 for the experimental group versus 1.5 +/- 0.5 for the control group. At days 3 and 7 after surgery, NDS were 0 +/- 0 for group 1 versus 1.0 +/- 1.0 for group 2. CONCLUSIONS: The faster neurological recovery of dogs treated with the "intracellular-type" maintenance solution supports the biochemical data showing the benefits of this type of blood substitute for extending the safe limits of hypothermic cardiac arrest procedures to > 3 hours.

Asanguineous whole body perfusion with a new intracellular acellular solution and ultraprofound hypothermia provides cellular protection during 3.5 hours of cardiac arrest in a canine model.

Temporary cessation of blood flow is a necessary aid for certain complex neurosurgical and cardiovascular procedures, and hypothermia is often used to help protect against the deleterious effects of ischemia and anoxia. In an attempt to protect cellular integrity during ultraprofound hypothermia (< 10 degrees C) and complete blood substitution, two new crystalloid-colloid blood substitutes (Hypothermosol-maintenance [HTS-M] and Hypothermosol-purge [HTS-P]) have been evaluated. Using extracorporeal bypass, 14 dogs were totally exsanguinated during cooling using the HTS-P solution, then perfused (40-85 ml/kg/min; mean arterial blood pressure = 25-40 mmHg) with either TS-M (Group I, n = 11), or with HTS-P as controls (Group II, n = 3) for 3 hr at 7 degrees C. During warming, the dogs were autotransfused and observed neurologically and biochemically during recovery. All dogs in Group I recovered and eight have survived long term (12-80 weeks) without apparent neurologic deficits. In contrast, dogs in Group II were more difficult to revive (cardiac resuscitation); two survived long term with delayed neurologic recovery. Evaluation of biochemical parameters showed only a transient and inconsequential elevation in enzymes (e.g., brain, liver, and heart) in Group I compared with the markedly greater elevations in Group II. The faster neurologic recovery of dogs treated with the "intracellular" maintenance solution supports the biochemical data showing the benefits of this type of blood substitute for extending the safe limits of hypothermic cardiac arrest to beyond 3 hr.

Effect of neuromuscular blockade on facial nerve monitoring.

Direct facial nerve stimulation and monitoring during cerebellopontine angle (CPA) tumor surgery are critical for identification and preservation of function. Electrically evoked facial nerve monitoring was compared with ulnar train-of-four monitoring under progressive neuromuscular blockade. Using a rabbit model, the facial nerve function of six controls was compared to that of six specimens with acute or chronic injuries. Eight of 18 patients who had undergone CPA tumor resection during one year were also studied. Regression analysis correlated between ulnar nerve monitoring and facial electromyographic (EMG) peak voltage in all groups. Facial EMG was measurable, even with 75 percent receptor blockade. The results of this study support the hypothesis that high degrees of neuromuscular blockade do not preclude satisfactory EMG monitoring of the facial nerve during CPA tumor surgery. This study did demonstrate that chronically injured facial nerves may show greater sensitivity to the effects of neuromuscular blockade. Lower levels or avoidance of neuromuscular blockade should be employed under these circumstances.

Combination of buspirone and other drugs with beta-CCE in monkeys: effects on respiration and behavior.

The respiratory and behavioral effects of the benzodiazepine receptor (BZR) inverse agonist ethyl-beta-carboline-3-carboxylate (beta-CCE) were determined alone and in combination with buspirone, lorazepam, flumazenil, and SR 95195 in rhesus monkeys. For the respiratory studies, one group of monkeys inhaled either air or 5% CO2 mixed in air according to a fixed alternating schedule; respiratory frequency and minute volume were monitored. For the behavioral studies, another group of monkeys responded under a fixed-ratio (FR 30) schedule of food presentation. The respiratory stimulant effects of beta-CCE in both air and 5% CO2 were enhanced by prior treatment with the 5-hydroxytryptamine1A (5-HT1A) partial agonist buspirone (0.03 and 0.3 mg/kg) and a weak BZR inverse agonist, SR 95195 (10.0 mg/kg). Coadministration of buspirone (0.1 and 0.3 mg/kg) also potentiated the rate-decreasing effects of beta-CCE under the FR schedule. The BZR agonist lorazepam (3.0 mg/kg) and BZR antagonist flumazenil (1.0 mg/kg) attenuated the effects of beta-CCE on respiratory frequency and minute volume particularly under the 5% CO2 condition, and lorazepam (0.1 and 0.3 mg/kg) and flumazenil (0.1 and 0.3 mg/kg) attenuated the effects of beta-CCE on FR responding. These latter results show that the respiratory and behavioral effects of beta-CCE in rhesus monkeys are at least in part due to effects at BZRs. Moreover, the findings suggest either that coactivation of benzodiazepine and 5-HT1A sites lead to a greater than additive effect or that beta-CCE and buspirone share a common mechanism of action that is unrelated to the receptor at which BZR inverse agonists act.

Rewarming, ultraprofound hypothermia and cardiopulmonary bypass.

Rewarming, a key event in resuscitation from accidental, experimental and clinical hypothermia, is sometimes followed by neurologic, cardiac, and respiratory sequelae and may lead to death. The rate of rewarming has been implicated but not quantified as etiologic in these sequelae. Under anesthesia fifteen dogs were cannulated and connected to an extracorporeal circuit for oxygenation, core cooling and rewarming. They were subjected to ultra-profound hypothermia with a core (esophageal) temperature as low as 1.3 degrees C, cardiac arrest, blood substitution, and continuous low flow perfusion. After 2-3 hours of cardiac arrest, rewarming began. Mechanical activity of the heart was seen between 10 degrees and 28 degrees C and respiration resumed at 29 degrees C. The rewarming rates of the 15 dogs were retrospectively studied. They were placed into three categories (G) based on the outcome. G-I (N=2):no neurological complications, G-II (N=8):transient neurological problems, and G-III (N=5):death, mainly from cardiovascular and respiratory complications confirmed at death by autopsy. Heat gain by each animal was recorded as a function of time for all experiments. The time it took each dog to reach 35 degrees C was determined and a mean was calculated (rewarming rate). Normal body temperature for a dog is 37.8 degrees C. Statistical analysis (ANOVA) was performed ex post facto to determine the relationship between rewarming rate and outcome. Our data contradicts the notion that slow core rewarming from nadir to normal temperature offers better outcome.(ABSTRACT TRUNCATED AT 250 WORDS)

Complete blood substitution during profound hypothermic cardiac arrest in dogs.

This study compared the effects of 3 hours of cardiac arrest performed at 2 different levels of profound hypothermia in totally exsanguinated, blood substituted dogs. Dogs (N = 10) were anesthetized and esophageal temperature was lowered to 24 degrees at which time exsanguination began. Once exsanguination was complete and the heart had arrested, continuous whole body perfusion of an oxygenated blood substitute solution was performed for 3 hours. Core temperature during this period remained below 10 degrees C and reached nadirs of 1.3 degrees C in Group 1 (N = 5) versus 7.3 degrees C in Group II (N = 5). Once the dog was allowed to rewarm to 10 degrees C replacement of the perfusate with blood was begun. All dogs survived the procedure but 2 dogs from each group died by 4 days following the experiment. The remaining 6 dogs were observed for between 10 and 85 days. The group perfused with blood substitute at the warmer nadir had a faster recovery of motor behavior and showed smaller changes from normal in several biochemical and hematological parameters. These findings indicate that profound hypothermia and total blood substitution can be successfully achieved at either temperature nadir, but the warmer level appears to be associated with a faster recovery.

Comparison of the effects of total blood substitution during two different levels of hypothermic cardiac arrest.

The effect of total blood replacement with a solution containing neither hemoglobin nor fluorocarbon was studied under two different levels of hypothermia. Ten dogs were anesthetized and esophageal temperature lowered to about 24 degrees at which time exsanguination began. Upon cardiac arrest and the completion of exsanguination, continuous whole body closed chest extracorporeal circulation of an oxygenated blood substitute was begun. Hematocrit was 1% while core temperature remained less than 10 degrees C for 3 hours of perfusion during which nadirs of 1.3 degrees C (Group I, N = 5) and 7.3 degrees (Group II, N = 5) were achieved. Replacement of the perfusate with whole blood began once the dog was rewarmed to approximately 10 degrees C. All dogs survived the procedure. Two dogs from each group died by the fourth post-operative day but the others survived long term. Group II showed a faster return to normal based on motor behavioral, biochemical and hematological changes. Thus the combination of profound hypothermia and complete blood substitution with a solution lacking any special oxygen carrying molecule, can be tolerated for 3 hours using both levels of hypothermia, however, the warmer one appears to be associated with faster recovery.

Blood substitution: an experimental study.

Priming fluids for cardiopulmonary bypass have been extremely varied, with resultant hemodilution. Furthermore, major surgeries utilizing cardiopulmonary bypass require multiple postoperative transfusions of blood and blood products. The appeal of having a readily available blood substitute for major cardiovascular and neurosurgical operations could prove to be a life saver, while also eliminating the risk of diseases transmitted by transfusion. Blood substitutes could also lessen the reported complications resulting from blood damage due to prolonged circulation of the blood by the extracorporeal pump. A technique was examined in 15 dogs using hypothermia for maximum metabolic suppression, incorporating an aqueous blood substitute (Cryomedical Sciences, Inc., Rockville, MD). The anesthetized animals were cannulated for extracorporeal pump oxygenation. As temperature was lowered the dogs were exsanguinated and volume replaced with blood substitute to lower the hematocrit to less than 1%. After 3 hours of cardiac arrest and continuous perfusion at a core temperature less than 10 degrees C, rewarming began. When temperature reached greater than or equal to 10 degrees C, the blood substitute was drained and the animals were autotransfused. The heart was started at 15 degrees C and spontaneous respiration resumed at 29 degrees C. Using the first generation blood substitute the survival rate was maximal (100%) at 2.5 hrs under 10 degrees C and 3 hours of cardiac arrest. Research is underway on a new blood substitute, which is to serve as a universal hypothermic preservation solution (in situ organ preservation).(ABSTRACT TRUNCATED AT 250 WORDS)

Ultraprofound hypothermia with complete blood substitution in a canine model.

The potential for hypothermia to prevent or ameliorate ischemic injury to the central nervous system is well known. To determine if a more prolonged period of metabolic suppression with blood substitution is possible, a method was developed to lower body temperature to near the freezing point. Eight adult mongrel dogs underwent closed-chest extracorporeal circulation with both external and internal body cooling. As they were cooled, progressive hemodilution was employed until complete exsanguination and blood substitution with an aqueous solution was accomplished. Continuous circulation and a core temperature at a mean of 1.7 degrees C were maintained from 2 1/2 to 3 hours. After rewarming to 20 degrees C, the animals were autotransfused and allowed to recover. Of the eight animals, two died due to technical factors related to cardiac defibrillation. Of the six surviving animals, five survived over a long period and one died on the 10th postoperative day with hepatorenal failure resulting from a presumed blood transfusion incompatability reaction. All six showed normal neurological function and kennel behavior, except one dog with mild weakness of a hindlimb. When the dogs were sacrificed 1 to 2 months postoperatively, all organs were histologically normal. Specifically, there was no gross or microscopic evidence of ischemic or hypoxic injury to any central nervous system structures. This pilot study demonstrates that it is possible to successfully achieve complete exsanguination, blood substitution, and ultraprofound body temperature, while continuous circulation of the blood substitute is maintained. With the capability of controlling and repeatedly performing washout of the extracellular environment and by reaching lower temperatures, it may be possible to attain greater cellular metabolic suppression. This perhaps will extend the allowable times for circulatory arrest procedures. In addition, "bloodless ischemia" may be beneficial in removing both blood substances and formed elements which may mediate organ ischemia. With replacement of blood at warm temperatures, coagulopathy is avoided. This preliminary evidence demonstrates potential in the combination of ultraprofound hypothermia and complete blood component substitution. However, further study is required to confirm the potential of achieving circulatory arrest of longer duration.

Respiratory effects of benzodiazepine-related drugs in awake rhesus monkeys.

The respiratory effects of several benzodiazepine (BZ) agonists and inverse agonists were compared with those of buspirone and pentobarbital in awake rhesus monkeys. Subjects, fitted with a helmet that served as a pressure displacement plethysmograph, were studied in a ventilated, sound-attenuating chamber; ventilatory frequency, tidal volume (VT) and minute volume (VE) were determined from the plethysmograph signal. During experimental sessions monkeys inhaled either 5% carbon dioxide (CO2) mixed in air or air alone according to a fixed alternating schedule. BZ agonists (alprazolam, 0.01-1.0 mg/kg; lorazepam, 0.3-10.0 mg/kg; quazepam, 1.0-5.6 mg/kg) decreased VT and VE during both 5% CO2 and air inhalation. Pentobarbital (3.0-30.0 mg/kg) also decreased VT and VE and additionally decreased respiratory frequency in monkeys breathing 5% CO2. Two BZ inverse agonists, the beta-carbolines beta-CCE and FG 7142 (0.3-5.6 or 10.00 mg/kg), increased frequency and had no effect on VT, resulting in an increase in VE in monkeys breathing either 5% CO2 or air. The weak BZ inverse agonist CGS 8216 (0.3-5.6 mg/kg) similarly increased ventilation only in monkeys breathing air. Buspirone (0.03-0.3 mg/kg), like the beta-carbolines, increased frequency and VE and, like the BZ agonists, decreased VT. The BZ antagonist Ro15-1788 (0.1-3.0 mg/kg) had little or no effect on ventilation, but Ro15-1788 and also CGS 8216 (both at 1.0 mg/kg) attenuated the respiratory depressant effects of lorazepam or alprazolam. In turn, alprazolam (0.03-0.3 mg/kg) and quazepam (1.0-3.0 mg/kg) attenuated the respiratory stimulant effects of FG 7142.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacology and physiology of narcotics.

Narcotics are explored in this section. Receptor theory is presented. Narcotics are broken into their specific groups (agonist, agonist-antagonist, and pure antagonist) and compared. Narcotic effects, desirable and undesirable, are related to organ systems and common problems found in ICU patients. Pharmacokinetics of classic methods of narcotic delivery are discussed and compared to newer technologies of delivery. Finally, a strategy for decision making in pain control, tying together all the concepts previously discussed, is given.