University of South Alabama Medical Center

BACKGROUND: Preconditioning (5 minutes of ischemia followed by 10 minutes of recovery) renders the heart very resistant to infarction from subsequent ischemia. This study tests whether adenosine receptors might mediate preconditioning protection. METHODS AND RESULTS: We examined the effect on infarct size of pretreatment with either of two adenosine receptor antagonists in both control and preconditioned in situ rabbit hearts. Hearts underwent 30 minutes of regional ischemia plus 3 hours of reperfusion, and infarct size was measured with tetrazolium. Infarct size averaged 39% of the zone at risk in controls but only 8% in preconditioned hearts. Preconditioned and nonpreconditioned hearts receiving either blocker had infarcts not different in size from the controls. A 5-minute intracoronary infusion of adenosine was as effective as 5 minutes of ischemia in protecting parabiotically perfused isolated hearts against infarction from a 45-minute ischemic insult. Similarly, intracoronary infusion of N6-1-(phenyl-2R-isopropyl)adenosine, an A1-selective adenosine receptor agonist, at a dose that delayed conduction but did not dilate the coronary vessels, also limited infarct size. The protection disappeared when we reduced the coronary concentration of drug by intravenous infusion of adenosine, indicating that cardiac rather than peripheral receptors were involved in the protection. CONCLUSIONS: We conclude that adenosine released during the preconditioning occlusion stimulates cardiac A1 receptors, which leaves the heart protected against infarction even after the adenosine has been withdrawn.

The distribution of catalase and superoxide dismutase has been examined in various micro-organisms. Strict anaerobes exhibited no superoxide dismutase and, generally, no catalase activity. All aerobic organisms containing cytochrome systems were found to contain both superoxide dismutase and catalase. Aerotolerant anaerobes, which survive exposure to air and metabolize oxygen to a limited extent but do not contain cytochrome systems, were found to be devoid of catalase activity but did exhibit superoxide dismutase activity. This distribution is consistent with the proposal that the prime physiological function of superoxide dismutase is protection of oxygen-metabolizing organisms against the potentially detrimental effects of the superoxide free radical, a biologically produced intermediate resulting from the univalent reduction of molecular oxygen.

Midazolam is an imidazobenzodiazepine with unique properties when compared with other benzodiazepines. It is water soluble in its acid formulation but is highly lipid soluble in vivo. Midazolam also has a relatively rapid onset of action and high metabolic clearance when compared with other benzodiazepines. The drug produces reliable hypnosis, amnesia, and antianxiety effects when administered orally, intramuscularly, or intravenously. There are many uses for midazolam in the perioperative period including premedication, anesthesia induction and maintenance, and sedation for diagnostic and therapeutic procedures. Midazolam is preferable to diazepam in many clinical situations because of its rapid, nonpainful induction and lack of venous irritation. Compared with thiopental, midazolam is not as rapid acting nor predictable in hypnotic effect. It will not replace thiopental as an induction agent. Advantages of midazolam over thiopental are those of the more versatile pharmacologic properties of a benzodiazepine compared with a barbiturate such as amnestic and anxiolytic properties. Midazolam should be a useful addition to the formulary.

Myocardial protection in the rabbit induced by ischemic preconditioning is thought to be adenosine receptor linked, but the signaling pathway responsible for the protection has yet to be identified. This study tests whether protein kinase C could be involved. Either of two inhibitors of protein kinase C, staurosporine (50 micrograms/kg) or polymyxin B (24 mg/kg), were administered to rabbits subjected to 30 min regional myocardial ischemia followed by 180 min reperfusion. Half of the rabbits were preconditioned while the other half served as nonpreconditioned controls. Nonpreconditioned hearts without drug or treated with staurosporine or polymyxin B resulted in 37.8 +/- 3.1, 40.5 +/- 2.8, and 42.0 +/- 7.0% infarction of the risk zone, respectively. Preconditioning limited infarct size to 7.3 +/- 2.7%. Both inhibitors blocked protection in preconditioned hearts with 36.2 +/- 2.7 and 40.9 +/- 2.5% of the risk zone infarcted, respectively. Activation of protein kinase C with 4 beta-phorbol 12-myristate 13-acetate (PMA) or with 1-oleyl-2-acetyl glycerol (OAG) mimicked preconditioning in buffer-perfused hearts. PMA (0.01 nmol/min) or OAG (10 nmol/min) for 5 min was followed by 10 min of washout. Infarct size after 30 min regional ischemia was limited in the PMA and OAG groups (6.4 +/- 1.4 and 11.7 +/- 3.3 vs. 28.0 +/- 4.5% in untreated controls) and was equipotent with ischemic preconditioning (11.8 +/- 2.2%). Polymyxin B also blocked protection from ischemic preconditioning in the isolated heart (33.0 +/- 5.0%).(ABSTRACT TRUNCATED AT 250 WORDS)

Echocardiographic measurements of minor axis and wall thickness and calculations from these two measurements of left ventricular end-diastolic volume and mass were performed in 24 patients and compared with angiocardiographic measurements of the same variables in corresponding patients. The echo-measured left ventricular end-diastolic chamber dimension (D d ) correlated closely with the angiographic minor axis in the AP plane (correlation coefficient 0.87 and se ± 0.45 cm) and with the minor axis from the lateral film (r = 0.91, se ±0.39 cm). Similar correlations were found between measurements by these methods of wall thickness (r = 0.89, se ±1.3 mm), of end-diastolic volume (r = 0.94, se ±30.6 cc), and of left ventricular mass (r = 0.88, se ±49.19 g). The reproducibility of this method was established by independent recordings and measurements of echo Polaroid films by two observers. The percent systolic wall thickening, as determined by echocardiography, identified subjects with ejection fractions greater or less than 0.50. Echocardiography offers a reliable and reproducible method for measuring left ventricular wall thickness and mass. Finally, ultrasound may provide an accurate method for measuring systolic wall thickening in man.

In a study of genetic variation in the AIDS virus, HTLV-III/LAV, sequential virus isolates from persistently infected individuals were examined by Southern blot genomic analysis, molecular cloning, and nucleotide sequencing. Four to six virus isolates were obtained from each of three individuals over a 1-year or 2-year period. Changes were detected throughout the viral genomes and consisted of isolated and clustered nucleotide point mutations as well as short deletions or insertions. Results from genomic restriction mapping and nucleotide sequence comparisons indicated that viruses isolated sequentially had evolved in parallel from a common progenitor virus. The rate of evolution of HTLV-III/LAV was estimated to be at least 10(-3) nucleotide substitutions per site per year for the env gene and 10(-4) for the gag gene, values a millionfold greater than for most DNA genomes. Despite this relatively rapid rate of sequence divergence, virus isolates from any one patient were all much more related to each other than to viruses from other individuals. In view of the substantial heterogeneity among most independent HTLV-III/LAV isolates, the repeated isolation from a given individual of only highly related viruses raises the possibility that some type of interference mechanism may prevent simultaneous infection by more than one major genotypic form of the virus.

Collagen moleculess with the chain comizposition [alpha1(III)](3), have been isolated from pepsin-solubilized collagen of dermis, aorta, and leiomlyoma of the uterus by differential salt precipitation. On denaturation, approximately 90 percent of this collagen is recovered as a gamma component (300,000 daltons). Reduction and alkylation of the high-molecular-weight component yields alpha1(III) chains (95,000 daltons). In addition to containing cysteine, alpha1(III) chains exhibit several other compositional differences when compared to alpha1(I), alpha1(II), or alpha2 chains from human tissues.

OBJECTIVES: The aim of this study was to evaluate the safety and effectiveness of percutaneous mechanical thrombectomy using the FlowTriever System (Inari Medical, Irvine, California) in a prospective trial of patients with acute intermediate-risk pulmonary embolism (PE). BACKGROUND: Catheter-directed thrombolysis has been shown to improve right ventricular (RV) function in patients with PE. However, catheter-directed thrombolysis increases bleeding risk and many patients with PE have relative and absolute contraindications to thrombolysis. METHODS: Patients with symptomatic, computed tomography-documented PE and RV/left ventricular (LV) ratios ≥0.9 were eligible for enrollment. The primary effectiveness endpoint was core laboratory-assessed change in RV/LV ratio. The primary safety endpoint comprised device-related death, major bleeding, treatment-related clinical deterioration, pulmonary vascular injury, or cardiac injury within 48 h of thrombectomy. RESULTS: From April 2016 to October 2017, 106 patients were treated with the FlowTriever System at 18 U.S. sites. Two patients (1.9%) received adjunctive thrombolytics and were analyzed separately. Mean procedural time was 94 min; mean intensive care unit stay was 1.5 days. Forty-three patients (41.3%) did not require any intensive care unit stay. At 48 h post-procedure, average RV/LV ratio reduction was 0.38 (25.1%; p < 0.0001). Four patients (3.8%) experienced 6 major adverse events, with 1 patient (1.0%) experiencing major bleeding. One patient (1.0%) died, of undiagnosed breast cancer, through 30-day follow-up. CONCLUSIONS: Percutaneous mechanical thrombectomy with the FlowTriever System appears safe and effective in patients with acute intermediate-risk PE, with significant improvement in RV/LV ratio and minimal major bleeding. Potential advantages include immediate thrombus removal, absence of thrombolytic complications, and reduced need for post-procedural critical care.

A multicenter clinical study assessed the ability of an acellular allograft dermal matrix to function as a permanent dermal transplant in full-thickness and deep partial-thickness burns. The study consisted of a pilot phase (24 patients) to identify the optimum protocol and a study phase (43 patients) to evaluate graft performance. Each patient had both a test and a mirror-image or contiguous control site. At the test site, the dermal matrix was grafted to the excised wound base and a split-thickness autograft was simultaneously applied over it. The control site was grafted with a split-thickness autograft alone. Fourteen-day take rates of the dermal matrix were statistically equivalent to the control autografts. Histology of the dermal matrix showed fibroblast infiltration, neovascularization, and neoepithelialization without evidence of rejection. Wound assessment over time showed that thin split-thickness autografts plus allograft dermal matrix were equivalent to thicker split-thickness autografts.

OBJECTIVE: To determine if regional cerebral blood flow (rCBF) in the left and right hemithalami or the left and right heads of the caudate nucleus is abnormal in women with fibromyalgia (FM). METHODS: Resting-state rCBF in the hemithalami and left and right heads of the caudate nucleus of 10 untreated women with FM and 7 normal control women was measured by single-photon-emission computed tomography. Pain threshold levels at tender and control points also were assessed in both the women with FM and the controls. RESULTS: The rCBF in the left and right hemithalami and the left and right heads of the caudate nucleus was significantly lower in women with FM than in normal controls (P = 0.01, P = 0.003, P = 0.01, and P = 0.02, respectively). Compared with controls, the women with FM also were characterized by significantly lower cortical rCBF (P = 0.001) and lower pain threshold levels at both tender points (P = 0.0001) and control points (P = 0.0001). CONCLUSION: The findings of low rCBF and generalized low pain thresholds support the hypothesis that abnormal pain perception in women with FM may result from a functional abnormality within the central nervous system.

Endogenous circadian and exogenously driven daily rhythms of antioxidative enzyme activities and of low molecular weight antioxidants (LMWAs) are described in various phylogenetically distant organisms. Substantial amplitudes are detected in several cases, suggesting the significance of rhythmicity in avoiding excessive oxidative stress. Mammalian and/or avian glutathione peroxidase and, as a consequence, glutathione reductase activities follow the rhythm of melatonin. Another hint for an involvement of melatonin in the control of redox processes is seen in its high-affinity binding to cytosolic quinone reductase 2, previously believed to be a melatonin receptor. Although antioxidative protection by pharmacological doses of melatonin is repeatedly reported, explanations of these findings are still insufficient and their physiological and chronobiological relevance is not yet settled. Recent data indicate a role of melatonin in the avoidance of mitochondrial radical formation, a function which may prevail over direct scavenging. Rhythmic changes in oxidative damage of protein and lipid molecules are also reported. Enhanced oxidative protein modification accompanied by a marked increase in the circadian amplitude of this parameter is detected in the Drosophila mutant rosy, which is deficient in the LMWA urate. Preliminary evidence for the significance of circadian rhythmicity in diminishing oxidative stress comes from clock mutants. In Drosophila, moderately enhanced protein damage is described for the arrhythmic and melatonin null mutant per0, but even more elevated, periodic damage is found in the short-period mutant per(s), synchronized to LD 12:12. Remarkably large increases in oxidative protein damage, along with impairment of tissue integrity and--obviously insufficient--compensatory elevations in protective enzymes are observed in a particularly vulnerable organ, the Harderian gland, of another short-period mutant tau, in the Syrian hamster. Mice deficient in the per2 gene homolog are reported to be cancer-prone, a finding which might also relate to oxidative stress. In the dinoflagellate Lingulodinium polyedrum [Gonyaulax polyedra], various treatments that cause oxidative stress result in strong suppressions of melatonin and its metabolite 5-methoxytryptamine (5-MT) and to secondary effects on overt rhythmicity. The glow maximum, depending on the presence of elevated 5-MT at the end of subjective night, decreases in a dose-dependent manner already under moderate, non-lethal oxidative stress, but is restored by replenishing melatonin. Therefore, a general effect of oxidative stress may consist in declines of easily oxidizable signaling molecules such as melatonin, and this can have consequences on the circadian intraorganismal organization and expression of overt rhythms. Recent findings on a redox-sensitive input into the core oscillator via modulation of NPAS2/BMAL1 or CLK/BMAL1 heterodimer binding to DNA indicate a direct influence of cellular redox balance, including oxidative stress, on the circadian clock.

Scapular fractures have been the subject of study since Desault's treatise of 1805, but few large-scale studies have been completed with long-term follow-up evaluation of displaced scapular neck and spine fractures. This series of 148 fractures in 116 scapulae (113 patients) appears to be the largest ever reported and the only one with a follow-up study of a significant group (24 patients). Significant disability was found in patients with displaced scapular spine and neck fractures: (1) pain at rest in 50%-100%, (2) weakness with exertion in 40%-60%, and (3) pain with exertion in 20%-66%. Based on these findings, the indications for operative management should be expanded to include displaced scapular neck and spine fractures. Using extensile exposure through a posterior Judet incision, rigid internal fixation, and early motion, results in eight cases were excellent. All patients recovered at least 85 degrees of glenohumeral abduction, normal scapulothoracic motion, and none had resting pain, night pain, or pain with abduction. The minimum follow-up study period was 15 months.

The presence of amyloid-beta (Abeta) plaques in the brain is a hallmark pathological feature of Alzheimer's disease (AD). Transgenic mice overexpressing mutant amyloid precursor protein (APP), or both mutant APP and presenilin-1 (APP/PS1), develop Abeta plaques similar to those in AD patients, and have been proposed as animal models in which to test experimental therapeutic approaches for the clearance of Abeta. However, at present there is no in vivo whole-brain imaging method to detect Abeta plaques in mice or men. A novel method is presented to detect Abeta plaques in the brains of transgenic mice by magnetic resonance microimaging (muMRI). This method uses Abeta1-40 peptide, known for its high binding affinity to Abeta, magnetically labeled with either gadolinium (Gd) or monocrystalline iron oxide nanoparticles (MION). Intraarterial injection of magnetically labeled Abeta1-40, with mannitol to transiently open the blood-brain barrier (BBB), enabled the detection of many Abeta plaques. Furthermore, the numerical density of Abeta plaques detected by muMRI and by immunohistochemistry showed excellent correlation. This approach provides an in vivo method to detect Abeta in AD transgenic mice, and suggests that diagnostic MRI methods to detect Abeta in AD patients may ultimately be feasible.

Enhancement of phagocytosis by serum from patients with sickle-cell disease was studied in an attempt to define further the opsonin deficiency present in the disorder and its role in the increased susceptibility of these patients to infection. Serums from 28 patients promoted phagocytosis of pneumococci normally if the bacteria had previously been sensitized with an excess of antibody, but a deficiency emerged when the amount of antibody added to the system was decreased. The abnormality could not be attributed to a deficiency of antibody or complement components. However, under conditions that prevented activation of C1 and the classic complement sequence, the serums did not fully activate and fix the essential opsonin C3 to the micro-organism by the alternate pathway. When specific antibody is deficient, such patients may be unable to phagocytize invading pneumococci normally because of an inability to utilize fully the alternate pathway as a mediator of natural immunity. (N Engl J Med 288:803–808, 1973)

Deferasirox is a once-daily, oral iron chelator developed for treating transfusional iron overload. Preclinical studies indicated that the kidney was a potential target organ of toxicity. As patients with sickle cell disease often have abnormal baseline renal function, the primary objective of this randomised, open-label, phase II trial was to evaluate the safety and tolerability of deferasirox in comparison with deferoxamine in this population. Assessment of efficacy, as measured by change in liver iron concentration (LIC) using biosusceptometry, was a secondary objective. A total of 195 adult and paediatric patients received deferasirox (n = 132) or deferoxamine (n = 63). Adverse events most commonly associated with deferasirox were mild, including transient nausea, vomiting, diarrhoea, abdominal pain and skin rash. Abnormal laboratory studies with deferasirox were occasionally associated with mild non-progressive increases in serum creatinine and reversible elevations in liver function tests. Discontinuation rates from deferasirox (11.4%) and deferoxamine (11.1%) were similar. Over 1 year, similar dose-dependent LIC reductions were observed with deferasirox and deferoxamine. Once-daily oral deferasirox has acceptable tolerability and appears to have similar efficacy to deferoxamine in reducing iron burden in transfused patients with sickle cell disease.

The relationship of abnormal regional myocardial performance to left ventricular (LV) function 2-12 months following transmural myocardial infarction was investigated in 25 patients by quantitative biplane angiocardiography. Abnormally contracting segments (ACS) (akinetic or dyskinetic) of the LV were identified in 24 patients. Their sites correlated with the electrocardiographic locations of infarction. ACS were expressed as a percentage (ACS%) of the end-diastolic ventricular circumference, and the percentages obtained correlated with ejection fraction (EF) (r = —0.838, P = 0.0001) using a quadratic regression equation. The group of patients (N = 8) with heart failure (paroxysmal nocturnal dyspnea and/or ventricular gallop sound) demonstrated a significantly lower mean value for EF ( P = 0.0003) and a significantly larger mean value for ACS% ( P = 0.0041) than the group of patients (N = 16) without heart failure. EF sharply separated the two groups. ACS% was a poor separator because in the majority of patients in both groups it was between 14 and 38%. Since EF sharply separated the heart failure and non-heart failure groups but ACS% did not, a theoretic model was developed to assess the contribution of the remaining myocardium to LV function. The curve described by the model did not differ significantly from the curve derived from the quadratic regression equation. Data from heart failure and non-heart failure patients were generally separated by a point (EF = 0.30, ACS = 23%) on the theoretic curve. Abnormal function of the nonakinetic myocardium was considered to be present when observed EF was lower than predicted EF for the observed ACS%. Thus, within the year following transmural myocardial infarction, the relative size of an abnormally contracting region of the ventricle was quantitatively related to impairment of LV function. The spherical model not only provided a framework for relating the clinical status of a patient to both ventricular function and size of the ACS, but also offered a means of estimating the function of the myocardium that appeared angiographically to be nonakinetic.

Today's nursing programs are struggling to accommodate the changing needs of the health care environment and need to make changes in how students are taught. Using constructivism theory, whereby learning is an active process in which learners construct new ideas or concepts based upon their current or past knowledge, leaders in nursing education can make a paradigm shift toward concept-based curricula. This article presents a summary and analysis of constructivism and an innovative application of its active-learning principles to curriculum development, specifically for the education of nursing students.

BACKGROUND: Several mechanisms have been proposed to explain toxicity of local anesthetics to chondrocytes, including the blockade of potassium channels and mitochondrial injury. The purposes of this investigation were to study the effects of lidocaine, bupivacaine, and ropivacaine on human chondrocyte viability and mitochondrial function in vitro and to characterize the type of cell death elicited following exposure. METHODS: Primary chondrocyte cultures from patients with osteoarthritis undergoing knee replacement were treated with saline solution and the following concentrations of local anesthetics: 2%, 1%, and 0.5% lidocaine, 0.5% and 0.25% bupivacaine, and 0.5% and 0.2% ropivacaine for one hour. Cell viability and apoptosis were measured by flow cytometry at twenty-four hours and 120 hours after treatment. Nuclear staining and caspase 3 and 9 cleavage assays (Western blot) were used to further establish the induction of apoptosis. Mitochondrial dysfunction was evaluated by the accumulation of mitochondrial DNA damage (quantitative Southern blot), changes in adenosine triphosphate production (bioluminescence kit), and mitochondrial protein levels (Western blot analysis). RESULTS: Exposure of primary human chondrocytes to a 2% concentration of lidocaine caused massive necrosis of chondrocytes after twenty-four hours, 1% lidocaine and 0.5% bupivacaine caused a detectable, but not significant, decrease in viability after twenty-four hours, while 0.5% lidocaine, 0.25% bupivacaine, and both concentrations of ropivacaine (0.5% and 0.2%) did not affect chondrocyte viability. Flow cytometry analysis of chondrocytes 120 hours after drug treatment revealed a significant decrease in viability (p < 0.05) with a concomitant increase in the number of apoptotic cells at all concentrations of lidocaine, bupivacaine, and ropivacaine analyzed, except 0.2% ropivacaine. Apoptosis was verified by observation of condensed and fragmented nuclei and a decrease in procaspase 3 and 9 levels. Local anesthetics induced mitochondrial DNA damage and a decrease in adenosine triphosphate and mitochondrial protein levels. CONCLUSIONS: Lidocaine, bupivacaine, and ropivacaine cause delayed mitochondrial dysfunction and apoptosis in cultured human chondrocytes.

Laryngotracheal trauma is rare and complications are frequent. Twelve major series totalling 392 cases have been published over the past decade, with complication rates as high as 40%. We have treated over 30,000 trauma victims at our Level I Trauma Center over the past 5 years, of which 109 had neck injuries, but only 12 suffered cervical laryngotracheal trauma. The mechanism of injury was penetrating in eight and blunt trauma in four. The time to tracheostomy decannulation varied from 7 to 60 days. Airway patency was assured without stenosis or significant granulation tissue in 10 of the 12 patients. Three patients suffered permanent voice changes. Based on review of the 392 previously reported cases and a critical analysis of our 12 cases, a detailed management algorithm is proposed.

Thirty cases of posterior ankle impingement in 28 patients were treated over a 10-year period (1982-1992). All conditions were caused by forced plantar flexion. An os trigonum or posterior process fracture was demonstrated radiographically in 63% of these cases, and an intact posterior process was demonstrated in 33%. Ten cases were lost to follow-up. Of the remaining 20 cases, in 18 patients 12 (60%) improved with nonoperative treatment; 8 (40%) required operative excision. The results were good to excellent in 7 patients and fair in 1 patient. Operative excision for the treatment of recalcitrant posterior ankle impingement can relieve symptoms and allow a return to full preinjury activities.