Amiodarone-Induced Lung Injury With Bilateral Lung Pneumonitis and Peripheral Eosinophilia.

Amiodarone is a widely used antiarrhythmic that is used in the management of a variety of atrial and ventricular arrhythmias. Amiodarone-induced lung injury is an adverse effect in 5% of patients taking amiodarone, usually within 12 months of commencing therapy. Different mechanisms of injury and histopathological changes have been proposed and described. Eosinophilic pneumonia is one uncommon presentation of amiodarone-induced lung injury. The following is a case report of a 62-year-old woman who, after taking 400 mg of amiodarone twice daily for 8 months, developed bilateral interstitial pneumonitis with peripheral eosinophilia. After cessation of amiodarone, she had significant improvement in terms of her clinical symptoms and partial regression of pulmonary infiltrates on radiological imaging. The case underlies the importance of vigilance monitoring patients who are taking potentially pneumotoxic drugs as well as describing a classic example of drug-induced pneumonitis.

Lower body predictors of glenohumeral compressive force in high school baseball pitchers.

The purpose of this study was to better understand how lower body kinematics relate to peak glenohumeral compressive force and develop a regression model accounting for variability in peak glenohumeral compressive force. Data were collected for 34 pitchers. Average peak glenohumeral compressive force was 1.72% ± 33% body weight (1334.9 N ± 257.5). Correlation coefficients revealed 5 kinematic variables correlated to peak glenohumeral compressive force (P < .01, α = .025). Regression models indicated 78.5% of the variance in peak glenohumeral compressive force (R2 = .785, P < .01) was explained by stride length, lateral pelvis flexion at maximum external rotation, and axial pelvis rotation velocity at release. These results indicate peak glenohumeral compressive force increases with a combination of decreased stride length, increased pelvic tilt at maximum external rotation toward the throwing arm side, and increased pelvis axial rotation velocity at release. Thus, it may be possible to decrease peak glenohumeral compressive force by optimizing the movements of the lower body while pitching. Focus should be on both training and conditioning the lower extremity in an effort to increase stride length, increase pelvis tilt toward the glove hand side at maximum external rotation, and decrease pelvis axial rotation at release.

Cost-effectiveness in orthopedics: providing essential information to both physicians and health care policy makers for appropriate allocation of medical resources.

Cost-effective analysis has become an important tool in helping determine what procedures are both cost-effective and appropriate in today's cost control health care. The quality-adjusted life-year (QALY) is a standard measure for health-related quality-of-life in medical cost-effectiveness research. It can be used to compare different interventions to determine the cost-effectiveness of each procedure. Use of QALY to compare health care interventions has become the new gold standard. The key words arthroscopy, cost-effectiveness analysis, QALY, shoulder, hip, knee, ankle, elbow, wrist, and pubic symphysis were searched utilizing PubMed and an internet search engine. Cost/QALY ratios were determined and compared with other surgical procedures using techniques other than arthroscopy. Cost/QALYs were found for the shoulder, hip, knee, and elbow. The QALY for the shoulder was $13,092, for a simple knee was $5783, for a hip $21,700, and for an elbow $2031. General costs were found for the ankle, wrist, and pubic symphysis, that could be used to estimate QALYs without the complex formal calculation. On the basis of our findings, arthroscopy is an extremely cost-effective allocation of health care resources.

PPD-QALY-an index for cost-effectiveness in orthopedics: providing essential information to both physicians and health care policy makers for appropriate allocation of medical resources.

Because of the increasing health care costs and the need for proper allocation of resources, it is important to ensure the best use of health benefits for sick and injured people of the population. An index or indicator is needed to help us quantify what is being spent so that comparisons with other options can be implemented. Cost-effective analysis seems to be well suited to provide this essential information to health care policy makers and those charged with distributing disability funds so that the proper allocation of resources can be achieved. There is currently no such index to show whether the benefits paid out are the most cost-effective. By comparing the quality-adjusted life year (QALY) of a treatment method to the disability an individual would experience, on the basis of lost wages as measure of disability, we provide decision makers more information for the basis of cost allocation in health care. To accomplish this, we describe a new term, the PPD-QALY (permanent partial disability-quality of life year). This term was developed to establish an index to which musculoskeletal care can be compared, to evaluate the cost-effectiveness of a treatment on the basis of the monetary value of the disability. This term serves to standardize the monetary value of an injury. Cost-effective analysis in arthroscopic surgery may prove to be a valuable asset in this role and to provide decision makers the information needed to determine the societal benefit from new arthroscopic procedures as they are developed and implemented.

Shoulder kinematics during pitching: comparing the slide step and traditional stretch deliveries.

Although studies have investigated the traditional stretch delivery, there is little biomechanical data describing the slide step delivery in baseball pitchers. Thus, the purpose of this study was to compare shoulder kinematics across the traditional stretch and slide step deliveries. To collect kinematic data from thirty-seven high school baseball pitchers, electromagnetic sensors recording at 140 Hz were affixed to various body segments. The average of those data from the three fastest pitches passing through the strike-zone were analyzed for each delivery. At the instances of front foot contact and ball release, no differences were observed between the two deliveries. At the instant of maximum shoulder external rotation, differences were observed between the two deliveries with regard to plane of elevation (t(72)=4.19, p<.001), elevation (t(72)=-3.38, p<.001), and axial rotation (t(72)=2.49, p=.015). The mechanical differences observed between the two delivery styles may have the potential to impact both performance and injury. Also, based on these results there may be a tradeoff between injury risk and performance. Thus, further study is warranted in an effort to identify the interrelationships between injury risk, performance, and pitching kinematics when throwing from the stretch position.

A biomechanical model correlating shoulder kinetics to pain in young baseball pitchers.

Previous work has postulated that shoulder pain may be associated with increases in both peak shoulder anterior force and peak shoulder proximal force. Unfortunately these relationships have yet to be quantified. Thus, the purpose of this study was to associate these kinetic values with reported shoulder pain in youth baseball pitchers. Nineteen healthy baseball pitchers participated in this study. Segment based reference systems and established calculations were utilized to identify peak shoulder anterior force and peak shoulder proximal force. A medical history questionnaire was utilized to identify shoulder pain. Following collection of these data, the strength of the relationships between both peak shoulder anterior force and peak shoulder proximal force and shoulder pain were analyzed. Although peak anterior force was not significantly correlated to shoulder pain, peak proximal force was. These results lead to the development of a single variable logistic regression model able to accurately predict 84.2% of all cases and 71.4% of shoulder pain cases. This model indicated that for every 1 N increase in peak proximal force, there was a corresponding 4.6% increase in the likelihood of shoulder pain. The magnitude of peak proximal force is both correlated to reported shoulder pain and capable of being used to accurately predict the likelihood of experiencing shoulder pain. It appears that those pitchers exhibiting high magnitudes of peak proximal force are significantly more likely to report experiencing shoulder pain than those who generate lower magnitudes of peak proximal force.

Effective virus inactivation and removal by steps of Biotest Pharmaceuticals IGIV production process.

The virus validation of three steps of Biotest Pharmaceuticals IGIV production process is described here. The steps validated are precipitation and removal of fraction III of the cold ethanol fractionation process, solvent/detergent treatment and 35 nm virus filtration. Virus validation was performed considering combined worst case conditions. By these validated steps sufficient virus inactivation/removal is achieved, resulting in a virus safe product.

c-Jun N-terminal kinase (JNK-1) confers protection against brief but not extended ischemia during acute myocardial infarction.

Brief periods of ischemia do not damage the heart and can actually protect against reperfusion injury caused by extended ischemia. It is not known what causes the transition from protection to irreversible damage as ischemia progresses. c-Jun N-terminal kinase-1 (JNK-1) is a stress-regulated kinase that is activated by reactive oxygen and thought to promote injury during severe acute myocardial infarction. Because some reports suggest that JNK-1 can also be protective, we hypothesized that the function of JNK-1 depends on the metabolic state of the heart at the time of reperfusion, a condition that changes progressively with duration of ischemia. Mice treated with JNK-1 inhibitors or transgenic mice wherein the JNK-1 gene was ablated were subjected to 5 or 20 min of ischemia followed by reperfusion. When JNK-1 was inactive, ischemia of only 5 min duration caused massive apoptosis, infarction, and negative remodeling that was equivalent to or greater than extended ischemia. Conversely, when ischemia was extended JNK-1 inactivation was protective. Mechanisms of the JNK-1 switch in function were investigated in vivo and in cultured cardiac myocytes. In vitro there was a comparable switch in the function of JNK-1 from protective when ATP levels were maintained during hypoxia to injurious when reoxygenation followed glucose and ATP depletion. Both apoptotic and necrotic death pathways were affected and responded reciprocally to JNK-1 inhibitors. JNK-1 differentially regulated Akt phosphorylation of the regulatory sites Ser-473 and Thr-450 and the catalytic Thr-308 site in vivo. The studies define a novel role for JNK-1 as a conditional survival kinase that protects the heart against brief but not protracted ischemia.

Muscle activation of the uninjured leg during an acute Achilles tendon rupture.

The purpose of this study was to describe muscle activation of the uninjured leg during an acute Achilles tendon rupture. Electromyographic (EMG) data were collected on the following muscles: medial hamstring, biceps femoris, gluteus medius, gluteus maximus, and the gastrocnemius while the participant was performing a round-off dismount type of maneuver in which she sustained an Achilles tendon rupture. Electromyographic data analysis suggested that the participant fell into a knee valgus flexed hip position on the uninjured leg immediately after the injury. Vastus medialis obliqueous activity indicated a position of knee valgus, whereas the shutdown of the gluteus medius and gluteus maximus indicated the patient's hip was falling into hip collapse. The lateral hamstring activity indicated an attempt to catch the falling pelvis and that the medial hamstrings were most likely caught in the reflex arc of the gluteals. If the decreased EMG activity in the uninjured limb occurred subsequently to the rupture, the resultant kinetic chain activity displays the way the body adapts because of a traumatic injury of the lower extremity. Reproduction of the muscular pattern of activity in landing maneuvers and subsequent training intervention may reveal targeting muscle groups that have been shown to fail early. Targeting the muscle groups through training interventions may have an impact on injury reduction patterns.

Comparison of hamstring and gluteus muscles electromyographic activity while performing the razor curl vs. the traditional prone hamstring curl.

This study examined the muscle activation of the razor curl functional hamstring exercise (the razor curl has the total body extended and then requires the hips and knees to flex to 90 degrees simultaneously with full contraction of the hamstrings to further the knee flexion) to the traditional prone hamstring curl. Eight healthy, female intercollegiate athletes participated (mean age 20.8 +/- 3.9 y; mean height, 177.8 +/- 10.9 cm; mean weight, 67.3 +/- 9.9 kg). Electromyographic (EMG) data were collected on the following muscles: medial hamstring (semimembranosus and semitendinosus), biceps femoris, gluteus medius, and gluteus maximus while participants performed the 2 exercises: razor curl and the traditional prone curl. Results revealed no significant differences between muscle activations during the 2 exercises (p

The razor curl: a functional approach to hamstring training.

This study examined the effectiveness of a functional hamstring training exercise, the razor curl on conditioning the hamstring and gluteal musculature. Eight healthy, female intercollegiate athletes participated (mean age 20.8 +/- 3.9 years; mean height, 177.8 +/- 10.9 cm; mean weight, 67.3 +/- 9.9 kg). Electromyographic (EMG) data were collected on the following muscles: medial hamstring (semimembranosus and semitendinosus), biceps femoris, gluteus medius, and gluteus maximus while participants performed the razor curl. The functional positioning of the razor curl showed maximum activation of the medial hamstring muscle group of up to 220% of its maximum voluntary isometric contraction (MVIC), just as the biceps femoris displayed a max of up to 140% of MVIC. Maximum activation of the hamstrings and gluteals were observed from the point of 90 degrees of hip flexion to the point of knee flexion beyond 90 degrees . These data reveal that the razor curl does indeed activate the hamstring musculature and based on the mechanics of the razor curl one can train in a more functional position. It is known biomechanically that flexing the hip allows for a lengthening contraction of the hamstring at the hip, thus allowing for a more optimal forceful contraction of the hamstrings at the knee. In conclusion, the razor curl hamstring exercise is designed to increase hamstring contractibility by placing the hip into flexion. By including strengthening the hamstring in a functional position one accentuates other land based training methods such as jump landing training in efforts to ultimately decrease the susceptibility of anterior cruciate ligament injury.

Selective degeneration of central photoreceptors after hyperbaric oxygen in normal and metallothionein-knockout mice.

PURPOSE: Metallothioneins (MTs) in the brain and retina are believed to bind metals and reduce free radicals, thereby protecting neurons from oxidative damage. This study was undertaken to investigate whether retinal photoreceptor (PR) cells lacking MTs are more susceptible to hyperbaric oxygen (HBO)-induced cell death in vivo. METHODS: Wild-type (WT) and MT-knockout (MT-KO) mice lacking metallothionein (MT)-1 and MT-2 were exposed to three atmospheres of 100% oxygen for 3 hours, 3 times per week for 1, 3, or 5 weeks. The control animals were not exposed. Histologic analysis of PR viability was performed by counting rows of nuclei in the outer nuclear layer (ONL). Ultrastructure studies verified PR damage. RESULTS: HBO exposure produced a major loss of PR cells in the central retinas of WT and MT-KO mice, with no effect on the peripheral retina even at the longest (5 weeks) exposures. The degree of PR damage and cell death increased with duration of HBO exposure. One week of HBO exposure was insufficient to cause PR death, but tissue damage was observed in the inner and outer segments. At 3 weeks, the rows of PR nuclei in the central retina were significantly reduced by 38% in WT and 28% in MT-KO animals. At 5 weeks, PR loss was identical in WT (34%) and MT-KO (34%) animals and was comparable to that in WT at 3 weeks. CONCLUSIONS: The data suggest that MT-1 and -2 alone are not sufficient for protecting PRs against HBO-induced cell death. The selective degeneration of central PRs may provide clues to mechanisms of oxidative damage in retinal disease.

Selective apoptosis of breast cancer cells by siRNA targeting of BORIS.

Brother of the regulator of imprinted sites (BORIS) is an epigenetically acting transcription factor which represses the tumor inhibitor functions of the tumor suppressor protein CTCF. BORIS expression has not been documented in adult females, making it an exciting molecular target for drug development in breast cancer. Previously, we demonstrated that vaccination of mice with zing-finger (ZF)-deleted non-functional BORIS results in regression of breast cancer and generation of potent anti-tumor immune responses. RNAi induction can be used as an alternative approach for selective tumor cell killing. Short interfering RNA (siRNA) molecules targeting BORIS were generated and their efficacy was tested in MDA-MB-231 breast cancer and non-malignant epithelial cell lines. Treatment with BORIS-specific siRNA, but not control siRNA led to a concentration-dependent reduction in BORIS expression and proportional apoptotic death of the cancer but not control cells. To our knowledge this is first report demonstrating a critical role of BORIS in maintaining tumor cell viability.

Robust hypoxia-selective regulation of a retinal pigment epithelium-specific adeno-associated virus vector.

PURPOSE: To develop an hypoxia-regulated retinal pigment epithelium (RPE)-specific adeno-associated virus (AAV) gene transfer platform that exploits hypoxia as a physiologic trigger for an early antiangiogenic treatment strategy directed at arresting neovascularization in the eye. METHODS: Tissue-specific and hypoxia-regulated expression vectors were constructed with tandem combinations of hypoxia responsive elements and aerobically silenced elements (HRSE) that together induce gene expression in hypoxia and suppress it in normoxia. For RPE-specific expression, the HRSE and a (6x) HRE (hypoxia responsive element) oligomer were ligated upstream of the Rpe65 promoter in a pGL3 firefly luciferase plasmid (pGL3-HRSE-6xHRE-Rpe65). The cell specificity of this novel hybrid promoter was tested in human RPE (ARPE-19), human glioblastoma, rat C6 glioma, mouse hippocampal neurons, and human embryonic kidney cell lines. Expression of all cell types in normoxia, and following 40 h hypoxia, was analyzed by dual luciferase assay. After confirmation of its tissue-specificity and hypoxia-inducibility, the hybrid promoter construct was integrated into a replication-deficient AAV delivery system and tested for cell-selectivity and hypoxia-inducible green fluorescent protein (GFP) reporter expression. RESULTS: The HRSE-6xHRE-Rpe65 promoter was highly selective for RPE cells, strongly induced in hypoxia, and similar in activation strength to the cytomegalovirus (CMV) promoter. The AAV.HRSE.6xHRE.Rpe65 vector induced robust GFP expression in hypoxic ARPE-19 cells, but elicited no GFP expression in hypoxia in other cell types or in normoxic ARPE-19 cells. CONCLUSIONS: The hypoxia-regulated, aerobically-silenced RPE-targeting vector forms a platform for focal autoregulated delivery of antiangiogenic agents in hypoxic regions of the RPE. Such autoinitiated therapy provides a means for early intervention in choroidal neovascularization, when it is most sensitive to inhibition.

PKC-alpha and TAK-1 are intermediates in the activation of c-Jun NH2-terminal kinase by hypoxia-reoxygenation.

c-Jun NH(2)-terminal kinase (JNK), a member of the MAPK family of protein kinases, is a stress-response kinase that is activated by proinflammatory cytokines and growth factors coupled to membrane receptors or through nonreceptor pathways by stimuli such as heat shock, UV irradiation, protein synthesis inhibitors, and conditions that elevate the levels of reactive oxygen intermediates (ROI). Ischemia followed by reperfusion or hypoxia with reoxygenation represents a condition of high oxidative stress where JNK activation is associated with elevated ROI. We recently demonstrated that the activation of JNK by this condition is initiated by ROI generated by mitochondrial electron transport and involves sequential activation of the proline-rich kinase 2 and the small GTP-binding factors Rac-1 and Cdc42. Here we present evidence that protein kinase C (PKC) and transforming growth factor-beta-activated kinase-1 (TAK-1) are also components of this pathway. Inhibition of PKC with the broad-range inhibitor calphostin C, the PKC-alpha/beta-selective inhibitor Go9367, or adenovirus-expressing dominant-negative PKC-alpha blocked the phosphorylation of proline-rich kinase 2 and JNK. Reoxygenation activated the mitogen-activated protein kinase kinase kinase, TAK-1, and promoted the formation of a complex containing Rac-1, TAK-1, and JNK but not apoptosis-stimulating kinase-1 or p21-activated kinase-1, which was detected within the first 10 min of reoxygenation. These results identify two new components, PKC and TAK-1, that have not been previously described in this signaling pathway.

Core stability and its relationship to lower extremity function and injury.

Core stability may provide several benefits to the musculoskeletal system, from maintaining low back health to preventing knee ligament injury. As a result, the acquisition and maintenance of core stability is of great interest to physical therapists, athletic trainers, and musculoskeletal researchers. Core stability is the ability of the lumbopelvic hip complex to prevent buckling and to return to equilibrium after perturbation. Although static elements (bone and soft tissue) contribute to some degree, core stability is predominantly maintained by the dynamic function of muscular elements. There is a clear relationship between trunk muscle activity and lower extremity movement. Current evidence suggests that decreased core stability may predispose to injury and that appropriate training may reduce injury. Core stability can be tested using isometric, isokinetic, and isoinertial methods. Appropriate intervention may result in decreased rates of back and lower extremity injury.

Mitochondrial signals initiate the activation of c-Jun N-terminal kinase (JNK) by hypoxia-reoxygenation.

C-Jun N-terminal kinase (JNK) is part of the mitogen-activated protein kinase (MAPK) family of signaling pathways that are induced in response to extracellular stimuli. JNK is primarily a stress-response pathway and can be activated by proinflammatory cytokines and growth factors coupled to membrane receptors or through non-receptor pathways by stimuli such as heat shock, UV irradiation, protein synthesis inhibitors, and conditions that elevate the levels of reactive oxygen intermediates (ROI). The molecular initiators of MAPKs by non-receptor stimuli have not been described. Ischemia followed by reperfusion or hypoxia with reoxygenation represents a condition of high oxidative stress where JNK activation is associated with elevated ROI. We show here that the activation of JNK by this condition is initiated in the mitochondria and requires coupled electron transport, ROI generation, and calcium flux. These signals cause the selective, sequential activation of the calcium-dependent, proline-rich kinase Pyk2 and the small GTP binding factors Rac-1 and Cdc42. Interruption of these interactions with inactivated dominant negative mutant proteins, blocking calcium flux, or inhibiting electron transport through mitochondrial complexes II, III, or IV prevents JNK activation and results in a proapoptotic phenotype that is characteristic of JNK inhibition in this model of ischemia-reperfusion. The signaling pathway is unique for the reoxygenation stimulus and provides a framework for other non-receptor-mediated pathways of MAPK activation.

Lateral subtalar dislocation in a 19-month-old female.

We report a lateral subtalar dislocation in a female 19-month-old after a minor fall. Review of the literature reveals no prior report of this injury in a patient of this age. This case illustrates the importance of thoroughly examining the pediatric patient. When fracture is not diagnosed and a child refuses to use the affected extremity, examination to rule out occult fracture or dislocation must be included.

Activation of c-Jun N-terminal kinase promotes survival of cardiac myocytes after oxidative stress.

Reperfusion injury occurs when ischaemic tissue is reperfused. It involves the generation and release of reactive oxygen that activates numerous signalling pathways and initiates cell death. Exposure of isolated cardiac myocytes to chronic hypoxia followed by reoxygenation results in the early activation of c-Jun N-terminal kinase (JNK) and death by apoptosis of approx. 30% of the myocytes. Although JNK activation has been described in a number of models of ischaemia/reperfusion, the contribution of JNK activation to cell fate has not been established. Here we report that the activation of JNK by reoxygenation correlates with myocyte survival. Transfection of myocytes with JNK pathway interfering plasmid vectors or infection with adenoviral vectors support the hypothesis that JNK is protective. Transfection or infection with JNK inhibitory mutants increased the rates of apoptosis by almost 2-fold compared with control cultures grown aerobically or subjected to hypoxia and reoxygenation. Caspase 9 activity, measured by LEHD cleavage, increased >3-fold during reoxygenation and this activity was enhanced significantly at all times in cultures infected with dominant negative JNK adenovirus. Hypoxia-reoxygenation mediated a biphasic (2.6- and 2.9-fold) activation of p38 mitogen-activated protein kinase, as well as a small increase of tumour necrosis factor alpha (TNFalpha) secretion, but treatments with the p38 MAPK-specific inhibitor SB203580 or saturating levels of a TNFalpha-1 blocking antibody provided only partial protection against apoptosis. The results suggest that JNK activation is protective and that the pathway is largely independent of p38 MAPK or secreted TNFalpha.