Polymeric Microspheres Prepared by Spraying into Compressed Carbon Dioxide

Purpose. The objective was to prepare polymeric microparticles by atomizing organic polymer solutions into a spray chamber containing compressed CO₂ (PCA-process) and to study the influence of various process parameters on their morphological characteristics. Methods. The swelling of various pharmaceutically acceptable polymers [ethyl cellulose, poly(methyl methacrylate), poly(-caprolactone), poly(dl-lactide), poly(l-lactide) and poly(dl-lactide-glycolide) copolymers] in CO₂ was investigated in order to find polymers which did not agglomerate during the spraying process. Poly(l-lactide) (L-PLA) microparticles were prepared by spraying the organic polymer solution into CO₂ in a specially designed spraying apparatus. The effect of various process (pressure and temperature of the CO₂ phase, flow rate) and formulation (polymer concentration) variables on the morphology and particle size of L-PLA-microparticles was investigated. Results. Polymers with low glass transition temperatures agglomerated even at low temperatures. The formation of microparticles was favored at moderate temperatures, low polymer concentrations, high pressures and high flow rates of CO₂. High polymer concentrations and low flow rates resulted in the formation of polymeric fibers. Colloidal L-PLA particles could also be prepared with this technique in a surfactant-free environment. Initial studies on the microencapsulation of drugs resulted in low encapsulation efficiencies. Conclusions. The PCA method is a promising technique for the preparation of drug-containing microparticles. Potential advantages of this method include the flexibility of preparing microparticles of different size and morphology, the elimination of surfactants, the minimization of residual organic solvents, low to moderate processing temperatures and the potential for scale-up.     

Effect of cold exposure, exercise and high altitude on plasma endothelin-1 and endothelial cell markers in man

The aims were to examine the effect of cold exposure, exercise and high altitude on plasma concentrations of big endothelin-1, endothelin-1, von Willebrand factor and serum e-selectin in twenty five healthy male volunteers. Clinical evaluation and venesection were performed before and after 24 hours of low altitude mountaineering, exposure to temperatures of -18 degrees C and +4 degrees C and whilst ascending from sea level to an altitude of 5000 m in the Karakoram. Plasma big endothelin-1, plasma endothelin-1 and serum soluble e-selectin concentrations were significantly elevated after two hours at -18 degrees C (p < 0.05, p < 0.05 and p < 0.01 respectively). At +4 degrees C, plasma big endothelin-1 and endothelin-1 concentrations rose significantly after 5 hours (p < 0.005 for both) but not after 2.5 hours. Low altitude mountaineering did not alter circulating marker concentrations. At high altitude, big endothelin-1 and endothelin-1 (p < 0.01 for both) rose significantly at 2500 m and initially at 5000 m but returned to sea level values after prolonged exposure to 5000 m. Serum e-selectin rose at all altitudes greater than sea level (p < 0.05). In conclusion, exposure to high altitude, moderate cold or freezing temperatures, but not exercise, selectively activates endothelial cells increasing endothelin-1 production. Cold exposure may contribute to the observed increase in plasma endothelin-1 in mountaineers at high altitude.     

Surgeons' assessment of symptoms suggesting extrathoracic metastases in patients with lung cancer. Canadian Lung Oncology Group.

BACKGROUND: In patients with apparently operable non-small cell lung cancer (NSCLC), clinicians often omit investigation for M disease in asymptomatic patients. Previous investigations have not specified in detail what is meant by "symptomatic," and this could differ between surgeons. We have investigated the extent to which surgeons' criteria differ for presence of symptoms. METHODS: Participating surgeons from seven centers, enrolled patients they judged "asymptomatic" in a randomized trial of investigational strategies for NSCLC. Patients completed a structured questionnaire describing symptoms of the central nervous system (CNS). In 685 patients, we documented CNS symptom recurrence after resectional surgery over 1 year of follow-up. RESULTS: Two centers enrolled only patients without even the mildest symptoms. Three centers took an intermediate approach, occasionally classifying patients with mild symptoms as "asymptomatic" and thus enrolling them in the trial. Two centers classified an appreciable number of patients with minimal symptoms, and occasionally with more than minimal symptoms, as "asymptomatic." Patients with even mild CNS symptoms were more likely to subsequently present with CNS metastases. CONCLUSIONS: Thoracic surgeons differ in their ideas of what may constitute the symptoms of M disease. Patients with structured questionnaire results that suggest symptoms of CNS disease are more likely to have CNS symptom recurrence after resectional surgery.     

Increased intracerebral excitatory amino acids and nitric oxide after hypothermic circulatory arrest

BACKGROUND: Prolonged hypothermic circulatory arrest (HCA) results in neurologic injury, but the mechanism of this injury is unknown. This study was undertaken to measure quantitatively intracerebral excitatory amino acids and citrulline, an equal coproduct of nitric oxide, during HCA. We hypothesized that HCA resulted in higher levels of glutamate, aspartate, glycine, causing increased intracellular calcium, and therefore, nitric oxide and citrulline. METHODS: Ten dogs underwent intracerebral microdialysis and 2 hours of HCA at 18 degrees C. Effluent was analyzed by high performance liquid chromatography with electrochemical detection. Five dogs each were sacrificed at 8 and 20 hours after HCA. Neuronal apoptosis was scored from 0 (no injury) to 100 (severe injury). RESULTS: Time course of HCA was divided into six periods. Peak levels of amino acids in each period were compared with those at baseline. Glutamate, coagonist glycine, and citrulline, an equal coproduct of nitric oxide, increased significantly over baseline during HCA, cardiopulmonary bypass, and 2 to 8 hours after HCA. Aspartate increased significantly during HCA and 8 to 20 hours after HCA. Apoptosis score was 65.56 +/- 5.67 at 8 hours and 30.63 +/- 14.96 at 20 hours after HCA. CONCLUSIONS: Our results provide direct evidence that HCA causes increased intracerebral glutamate and aspartate, along with coagonist glycine. We conclude that HCA causes glutamate excitotoxicity with subsequent nitric oxide production resulting in neurologic injury, which begins during arrest and continues until 20 hours after hypothermic circulation arrest. To provide effective cerebral protection, pharmacologic strategies to reduce glutamate excitotoxicity require intervention beyond the initial ischemic insult.     

The John Charnley Award. Practice surveillance: a practical method to assess outcome and to perform clinical research

The senior author systematically began collecting preoperative and postoperative data on all the total hip arthroplasties he performed starting in July 1970. The data collected represent a 26-year experience using practice surveillance (preoperative and regular interval postoperative collection and analysis of outcomes) as a method to document the outcome of the total hip arthroplasty procedure and as a method to evaluate the need for changes in the procedure. As the senior author made few selected changes in the operative procedure during the followup period, the primary author has been able to evaluate the change in outcome based on these changes. The six studies reported in the current study show the durability of the long-term results of cemented total hip arthroplasty, the improvement in radiographic reproducibility obtained on the femoral side of the construct with improved cementing techniques, the deleterious effects of using cable to reattach the greater trochanter, the deleterious effects of changing femoral component design that included a change in surface finish, the improvement in acetabular fixation using cementless fixation, and the optimization of bearing surface wear using smaller diameter femoral heads. All of these findings have been incorporated into the primary surgeon's practice based on this practice surveillance. As shown, practice surveillance also has provided a tool for performing clinical research. Although practice surveillance of controlled cohorts never will supplant prospective randomized clinical trials in evidence based medicine, it should help each surgeon with his or her own practice and can be used as an important research tool to study the optimization of outcomes of a surgical procedure.     

The effects of surface roughness and polymethylmethacrylate precoating on the radiographic and clinical results of the Iowa hip prosthesis. A study of patients less than fifty years old

BACKGROUND: The purpose of the present study was to compare the results associated with two different surface finishes (bead-blasted and grit-blasted) for Iowa femoral components used in total hip arthroplasties performed between January 1979 and June 1991 in patients who were less than fifty years old. METHODS: Between January 1979 and December 1985, thirty-six primary total hip replacements were performed in twenty-five patients with insertion of a bead-blasted Iowa femoral component (average surface roughness, 0.8 micrometer) with cement and insertion of a titanium-backed acetabular component (thirty-five hips) or non-metal-backed acetabular component (one hip) with cement. Between January 1986 and June 1991, forty-five primary total hip replacements were performed in thirty-seven patients with use of a precoated grit-blasted Iowa femoral component (average surface roughness, 2.1 micrometers) and a Harris-Galante-I porous ingrowth acetabular component (forty-one hips) or an Osteonics component (four hips). The only change in the design of the femoral component (other than the surface finish) between the two consecutive series was the addition of polymethylmethacrylate precoating to the proximal third of all forty-five grit-blasted stems and modularity of the femoral head of the last eight grit-blasted stems. RESULTS: No hip was lost to follow-up. The duration of radiographic follow-up of the hips treated with the bead-blasted component averaged 11.3 years (range, ten to sixteen years) postoperatively, whereas that of the hips treated with the precoated grit-blasted component averaged 8.2 years (range, five to eleven years). Two (6 percent) of the bead-blasted femoral components were revised because of aseptic loosening compared with eight (18 percent) of the precoated grit-blasted components. Four bead-blasted components (11 percent) were either radiographically loose or were revised because of loosening compared with eleven precoated grit-blasted components (24 percent). Kaplan-Meier survivorship curves evaluated with log-rank analysis revealed that the bead-blasted Iowa femoral components were revised because of aseptic loosening (p = 0.0184) and were radiographically loose (p = 0.0068) less often than the precoated grit-blasted Iowa femoral components. CONCLUSIONS: The findings of the present study have led the senior ones of us to resume using femoral components with a polished surface and fixed with cement.     

Correlates of suffering in amyotrophic lateral sclerosis

OBJECTIVES: 1) To determine the prevalence of pain, suffering, poor quality of life, depression, and hopelessness in people with ALS, and the correlates of suffering and poor quality of life; 2) to analyze the relationship between pain, suffering, quality of life, and attitudes toward life-sustaining medical treatment and physician-assisted suicide; and 3) to determine concordance between patients with ALS and their caregivers in rating the patients' pain, quality of life, and suffering. METHODS: Subjects completed a single interview. We measured the subject's pain, quality of life, suffering, hopelessness, depression, social support, perception of burden to others, level of disability, desire for life-sustaining medical treatment, and interest in assisted suicide. Caregivers also rated the patient's quality of life, pain, and suffering. RESULTS: A total of 100 subjects with ALS and 91 caregivers participated. Suffering was rated as 4 or greater on a six-point scale by 20% of subjects with ALS, and 19% rated their pain as 4 or greater on a six-point scale. Eleven percent had clinical depression. Physicians frequently failed to recognize and treat pain and depression. The correlates of suffering were increasing pain, hopelessness, and level of disability. The correlates of poor quality of life were poor social support and increasing hopelessness. The correlation between subjects' and caregivers' rating of the patient's suffering was r = 0.47. There was no relationship between subjects' ratings of pain, suffering, and quality of life, and their interest in life-sustaining treatment or physician-assisted suicide. CONCLUSION: Many patients with ALS suffer, and their suffering is correlated to pain and hopelessness. Physicians caring for patients with ALS frequently fail to recognize and treat their patients' pain and depression.     

Behavioral changes associated with grafts of embryonic ventral mesencephalon tissue into the striatum and/or substantia nigra in a rat model of Parkinson's Disease

Unilateral 6-hydroxydopamine lesion of the ascending nigrostriatal pathway in rats is a commonly used model of Parkinson's Disease. Transplantation of embryonic ventral mesencephalon (VM) into the striatum of such rats reduces drug-induced turning and ameliorates some simple behavioral deficits. While considerably less research has been conducted on the topic, VM grafts into the lesioned substantia nigra (SN) may induce recovery on more complex and/or spontaneous tasks. The present series of experiments was conducted to explicitly compare the behavioral efficacy of intrastriatal and intranigral VM grafts with the effects of grafts into both of these sites. Animals receiving control grafts were also tested. Following transplantation of VM or control tissue derived from E14 rat embryos, changes in drug-induced and spontaneous turning, as well as spontaneous paw use when rearing, were assessed each month for 5 months post-graft. Intrastriatal VM grafts were associated with decreases in drug-induced and spontaneous turning asymmetry but no change in paw use. Intranigral VM grafts did not affect drug-induced turning but decreased the asymmetry in spontaneous turning and spontaneous paw use. Following simultaneous VM grafts into the striatum and SN there was a decrease in drug-induced turning and an increase in the spontaneous use of the contralateral paw and both paws simultaneously. These results may have important implications for our understanding of the mechanisms mediating graft-induced behavioral recovery, both in the rat model of, and human Parkinson's Disease.