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1.  A longitudinal study of the durability of long-lasting insecticidal nets in Zambia 
Malaria Journal  2016;15:106.
A key goal of malaria control is to achieve universal access to, and use of, long-lasting insecticidal nets (LLINs) among people at risk for malaria. Quantifying the number of LLINs needed to achieve and maintain universal coverage requires knowing when nets need replacement. Longitudinal studies have observed physical deterioration in LLINs well before the assumed net lifespan of 3 years. The objective of this study was to describe attrition, physical integrity and insecticide persistence of LLINs over time to assist with better quantification of nets needing replacement.
999 LLINs distributed in 2011 in two highly endemic provinces in Zambia were randomly selected, and were enrolled at 12 months old. LLINs were followed every 6 months up to 30 months of age. Holes were counted and measured (finger, fist, and head method) and a proportional hole index (pHI) was calculated. Households were surveyed about net care and repair and if applicable, reasons for attrition. Functional survival was defined as nets with a pHI <643 and present for follow-up. At 12 and 24 months of age, 74 LLINs were randomly selected for examination of insecticidal activity and content using bioassay and chemical analysis methods previously described by the World Health Organization (WHO).
A total of 999 LLINs were enrolled; 505 deltamethrin-treated polyester nets and 494 permethrin-treated polyethylene nets. With 74 used to examine insecticide activity, 925 were available for full follow-up. At 30 months, 325 (33 %) LLINs remained. Net attrition was primarily due to disposal (29 %). Presence of repairs and use over a reed mat were significantly associated with larger pHIs. By 30 months, only 56 % of remaining nets met criteria for functional survival. A shorter functional survival was associated with having been washed. At 24 months, nets had reduced insecticidal activity (57 % met WHO minimal criteria) and content (5 % met WHO target insecticide content).
The median functional survival time for LLINs observed the study was 2.5–3 years and insecticide activity and content were markedly decreased by 2 years. A better measure of net survival incorporating insecticidal field effectiveness, net physical integrity, and attrition is needed.
PMCID: PMC4759777  PMID: 26891696
Long-lasting insecticidal nets; Durability; Attrition
2.  Myocardin-related transcription factor A regulates conversion of progenitors to beige adipocytes 
Cell  2015;160(0):105-118.
Adipose tissue is an essential regulator of metabolic homeostasis. In contrast with white adipose tissue, which stores excess energy in the form of triglycerides, brown adipose tissue is thermogenic, dissipating energy as heat via the unique expression of the mitochondrial uncoupling protein UCP1. A subset of UCP1+ adipocytes develop within white adipose tissue in response to physiological stimuli, however, the developmental origin of these “brite” or “beige” adipocytes is unclear. Here, we report the identification of a BMP7-ROCK signaling axis regulating beige adipocyte formation via control of the G-actin-regulated transcriptional coactivator myocardin related transcription factor A, MRTFA. White adipose tissue from MRTFA–/– mice contains more multilocular adipocytes and expresses enhanced levels of brown-selective proteins, including UCP1. MRTFA–/– mice also show improved metabolic profiles and protection from diet-induced obesity and insulin resistance. Our study hence unravels a central pathway driving the development of physiologically functional beige adipocytes.
PMCID: PMC4384505  PMID: 25579684
Bone Morphogenetic Protein 7; RhoA kinase; actin; Myocardin-related transcription factor A (MRTFA); Serum response factor (SRF); Beige adipocytes; Uncoupling protein 1 (UCP1)
Shoulder pain is common in competitive young swimmers. A relationship between shoulder strength and shoulder soreness in competitive young swimmers may indicate need for strengthening.
To determine if a shoulder exercise program will improve shoulder strength and decrease pain in competitive young swimmers.
Study Design
Randomized control
Participants (10 control, 11 experimental), randomly assigned to a control or experiment group, completed the 12 week program. Strength was measured prior to the study for shoulder flexion, abduction, external rotation, internal rotation, and extension on the dominant arm using handheld dynamometry. The experimental group was then assigned exercises to be performed three times per week. The control group was instructed not to perform the exercises. All participants were re‐tested at six and twelve weeks following initiation of the study.
The changes in strength for each muscle group and pain were compared between groups using a mixed design two‐way ANOVA. The experimental group significantly increased external rotation strength compared to the control group. Shoulder soreness was not significantly different between groups.
Adolescents who perform shoulder strengthening significantly increased their external rotation strength compared to adolescents who only participated in a regular swimming regimen.
PMCID: PMC4637920  PMID: 26618065
Competitive swimmer; rotator cuff strength; soreness; adolescent; external rotation. Randomized controlled trial
5.  Muscle pathology, limb strength, walking gait, respiratory function and neurological impairment establish disease progression in the p.N155K canine model of X-linked myotubular myopathy 
Loss-of-function mutations in the myotubularin (MTM1) gene cause X-linked myotubular myopathy (XLMTM), a fatal, inherited pediatric disease that affects the entire skeletal musculature. Labrador retriever dogs carrying an MTM1 missense mutation exhibit strongly reduced synthesis of myotubularin, the founder member of a lipid phosphatase required for normal skeletal muscle function. The resulting canine phenotype resembles that of human patients with comparably severe mutations, and survival does not normally exceed 4 months.
We studied MTM1 mutant dogs (n=7) and their age-matched control littermates (n=6) between the ages of 10 and 25 weeks. Investigators blinded to the animal identities sequentially measured limb muscle pathology, fore- and hind limb strength, walking gait, respiratory function and neurological impairment.
MTM1-mutant puppies display centrally-nucleated myofibers of reduced size and disrupted sarcotubular architecture progressing until the end of life, an average of 17 weeks. In-life measures of fore- and hind limb strength establish the rate at which XLMTM muscles weaken, and their corresponding decrease in gait velocity and stride length. Pulmonary function tests in affected dogs reveal a right-shifted relationship between peak inspiratory flow (PIF) and inspiratory time (TI); neurological assessments indicate that affected puppies as young as 10 weeks show early signs of neurological impairment (neurological severity score, NSS =8.6±0.9) with progressive decline (NSS =5.6±1.7 at 17 weeks-of-age).
Our findings document the rate of disease progression in a large animal model of XLMTM and lay a foundation for preclinical studies.
PMCID: PMC4630545  PMID: 26605308
Animal models; muscle disease; myopathy; muscular dystrophy; myotubular myopathy; dog
6.  Randomized Clinical Trial of 3 Types of Physical Exercise for Patients With Parkinson Disease 
JAMA neurology  2013;70(2):183-190.
To compare the efficacy of treadmill exercises and stretching and resistance exercises in improving gait speed, strength, and fitness for patients with Parkinson disease.
A comparative, prospective, randomized, single-blinded clinical trial of 3 types of physical exercise.
The Parkinson's Disease and Movement Disorders Center at the University of Maryland and the Baltimore Veterans Affairs Medical Center, Geriatric Research Education and Clinical Center.
A total of 67 patients with Parkinson disease who had gait impairment were randomly assigned to 1 of 3 arms of the trial.
(1) A higher-intensity treadmill exercise (30 minutes at 70%-80% of heart rate reserve), (2) a lower-intensity treadmill exercise (50 minutes at 40%-50% of heart rate reserve), and (3) stretching and resistance exercises (2 sets of 10 repetitions on each leg on 3 resistance machines [leg press, leg extension, and curl]). These exercises were performed 3 times a week for 3 months.
Main Outcome Measures
The primary outcome measures were gait speed (6-minute walk), cardiovascular fitness (peak oxygen consumption per unit time [V̇O2], and muscle strength (1-repetition maximum strength).
All 3 types of physical exercise improved distance on the 6-minute walk: lower-intensity treadmill exercise (12% increase; P=.001), stretching and resistance exercises (9% increase; P<.02), and higher-intensity treadmill exercise (6% increase; P=.07), with no between-group differences. Both treadmill exercises improved peak V̇O2 (7%-8% increase; P< .05) more than did the stretching and resistance exercises. Only stretching and resistance improved muscle strength (16% increase; P< .001).
The effects of exercise were seen across all 3 exercise groups. The lower-intensity treadmill exercise resulted in the greatest improvement in gait speed. Both the higher- and lower-intensity treadmill exercises improved cardiovascular fitness. Only the stretching and resistance exercises improved muscle strength. Therefore, exercise can improve gait speed, muscle strength, and fitness for patients with Parkinson disease. The combination of treadmill and resistance exercises may result in greater benefit and requires further investigation.
PMCID: PMC4574905  PMID: 23128427
7.  Imaging transplanted stem cells in real time using an MRI dual-contrast method 
Scientific Reports  2015;5:13628.
Stem cell therapies are currently being investigated for the repair of brain injuries. Although exogenous stem cell labelling with superparamagnetic iron oxide nanoparticles (SPIONs) prior to transplantation provides a means to noninvasively monitor stem cell transplantation by magnetic resonance imaging (MRI), monitoring cell death is still a challenge. Here, we investigate the feasibility of using an MRI dual-contrast technique to detect cell delivery, cell migration and cell death after stem cell transplantation. Human mesenchymal stem cells were dual labelled with SPIONs and gadolinium-based chelates (GdDTPA). The viability, proliferation rate, and differentiation potential of the labelled cells were then evaluated. The feasibility of this MRI technique to distinguish between live and dead cells was next evaluated using MRI phantoms, and in vivo using both immune-competent and immune-deficient mice, following the induction of brain injury in the mice. All results were validated with bioluminescence imaging. In live cells, a negative (T2/T2*) MRI contrast predominates, and is used to track cell delivery and cell migration. Upon cell death, a diffused positive (T1) MRI contrast is generated in the vicinity of the dead cells, and serves as an imaging marker for cell death. Ultimately, this technique could be used to manage stem cell therapies.
PMCID: PMC4556978  PMID: 26330231
8.  Mitochondrial Respiration and Passive Stretch of the Diaphragm During Unilateral Phrenic Nerve Stimulation: Authors' Response 
Critical care medicine  2014;42(9):e634.
PMCID: PMC4262149  PMID: 25126819
mechanical ventilation; phrenic nerve stimulation; diaphragm muscle; mitochondrial respiration
9.  Respiratory assessment in centronuclear myopathies 
Muscle & nerve  2014;50(3):315-326.
The centronuclear myopathies (CNMs) are a group of inherited neuromuscular disorders classified as congenital myopathies. While several causative genes have been identified, some patients do not harbor any of the currently known mutations. These diverse disorders have common histological features, which include a high proportion of centrally-nucleated muscle fibers, and clinical attributes of muscle weakness and respiratory insufficiency. Respiratory problems in CNMs may manifest initially during sleep, but daytime symptoms, ineffective airway clearance, and hypoventilation predominate as more severe respiratory muscle dysfunction evolves. Respiratory muscle capacity can be evaluated using a variety of clinical tests selected with consideration for the age and baseline motor function of the patient. Similar clinical tests of respiratory function can also be incorporated into preclinical CNM canine models to offer insight for clinical trials. Since respiratory problems account for significant morbidity in patients, routine assessments of respiratory muscle function are discussed.
PMCID: PMC4140950  PMID: 24668768
myopathy; respiratory assessment; canine; muscle disease; genetics
10.  Altered Activation of the Tibialis Anterior in Individuals with Pompe Disease: Implications for Motor Unit Dysfunction 
Muscle & nerve  2015;51(6):877-883.
Pompe disease is a progressive disease that affects skeletal muscles and leads to loss of ambulation. We investigated the activation of the tibialis anterior (TA) in late onset Pompe disease (LOPD) individuals during maximal voluntary contraction (MVC) and evoked involuntary responses.
Four LOPD patients and matched control subjects performed MVC of the TA using dorsiflexion and TA evoked responses. Activation of the TA was recorded with surface EMG.
The Pompe patients exhibited greater power at frequencies below 60 Hz and reduced power above 100 Hz. They exhibited reduced increase in M-wave and prolonged M-wave latency and duration in response to stimulation.
These results provide evidence that LOPD individuals have an altered activation pattern of the TA during maximal contractions. The observed activation pattern may reflect impairments in voluntary command, neuromuscular junction pathology, or compensatory drive due to a reduced number of functional motoneurons.
PMCID: PMC4348349  PMID: 25186912
Pompe disease; Glycogen Storage disease; Skeletal Muscle; Modulation; Motoneuron
11.  Combined effects of aging and inflammation on renin-angiotensin system mediate mitochondrial dysfunction and phenotypic changes in cardiomyopathies 
Oncotarget  2015;6(14):11979-11993.
Although the effects of aging and inflammation on the health of the cardiac muscle are well documented, the combined effects of aging and chronic inflammation on cardiac muscle are largely unknown. The renin-angiotensin system (RAS) has been linked independently to both aging and inflammation, but is understudied in the context of their collective effect. Thus, we investigated localized cardiac angiotensin II type I and type II receptors (AT1R, AT2R), downstream effectors, and phenotypic outcomes using mouse models of the combination of aging and inflammation and compared it to a model of aging and a model of inflammation. We show molecular distinction in the combined effect of aging and inflammation as compared to each independently. The combination maintained an increased AT1R:AT2R and expression of Nox2 and exhibited the lowest activity of antioxidants. Despite signaling pathway differences, the combined effect shared phenotypic similarities with aging including oxidative damage, fibrosis, and hypertrophy. These phenotypic similarities have dubbed inflammatory conditions as premature aging, but they are, in fact, molecularly distinct. Moreover, treatment with an AT1R blocker, losartan, selectively reversed the signaling changes and ameliorated adverse phenotypic effects in the combination of aging and inflammation as well as each independently.
PMCID: PMC4494917  PMID: 26019138
aging; mitochondria; AT1R; inflammation; heart
12.  A Role of Myocardin Related Transcription Factor-A (MRTF-A) in Scleroderma Related Fibrosis 
PLoS ONE  2015;10(5):e0126015.
In scleroderma (systemic sclerosis, SSc), persistent activation of myofibroblast leads to severe skin and organ fibrosis resistant to therapy. Increased mechanical stiffness in the involved fibrotic tissues is a hallmark clinical feature and a cause of disabling symptoms. Myocardin Related Transcription Factor-A (MRTF-A) is a transcriptional co-activator that is sequestered in the cytoplasm and translocates to the nucleus under mechanical stress or growth factor stimulation. Our objective was to determine if MRTF-A is activated in the disease microenvironment to produce more extracellular matrix in progressive SSc. Immunohistochemistry studies demonstrate that nuclear translocation of MRTF-A in scleroderma tissues occurs in keratinocytes, endothelial cells, infiltrating inflammatory cells, and dermal fibroblasts, consistent with enhanced signaling in multiple cell lineages exposed to the stiff extracellular matrix. Inhibition of MRTF-A nuclear translocation or knockdown of MRTF-A synthesis abolishes the SSc myofibroblast enhanced basal contractility and synthesis of type I collagen and inhibits the matricellular profibrotic protein, connective tissue growth factor (CCN2/CTGF). In MRTF-A null mice, basal skin and lung stiffness was abnormally reduced and associated with altered fibrillar collagen. MRTF-A has a role in SSc fibrosis acting as a central regulator linking mechanical cues to adverse remodeling of the extracellular matrix.
PMCID: PMC4425676  PMID: 25955164
13.  Risk of lymphedema after mastectomy – potential benefit of applying ACOSOG Z0011 protocol to mastectomy patients 
Axillary lymph node dissection (ALND) and radiation therapy (RT) are commonly recommended for mastectomy patients with positive sentinel lymph node biopsy (SLNB). Effective alternatives to ALND that reduce lymphedema risk are needed. We evaluated rates of lymphedema in mastectomy patients who received SLNB with RT, compared to ALND with or without RT.
627 breast cancer patients who underwent 664 mastectomies between 2005–2013 were prospectively screened for lymphedema, median 22.8 months follow-up (range 3.0–86.9). Each mastectomy was categorized as: SLNB-no RT, SLNB+RT, ALND-no RT, or ALND+RT. RT included chest wall +/− nodal radiation. Perometer arm volume measurements were obtained pre- and post-operatively. Lymphedema was defined as ≥10% arm volume increase. Kaplan-Meier and Cox regression analyses were performed to determine lymphedema rates and risk factors.
Of 664 mastectomies, 52% (343/664) were SLNB-no RT, 5% (34/664) SLNB+RT, 9% (58/664) ALND-no RT, and 34% (229/664) ALND+RT. The two-year cumulative lymphedema incidence was 10.0% (95% CI: 2.6–34.4%) for SLNB+RT compared with 19.3% (95% CI: 10.8–33.1%) for ALND-no RT, and 30.1% (95% CI: 23.7–37.8%) for ALND+RT. The lowest cumulative incidence was 2.19% (95% CI: 0.88%–5.40%) for SLNB-no RT. By multivariate analysis, factors significantly associated with increased lymphedema risk included RT (p=0.0017), ALND (p=0.0001), greater number of lymph nodes removed (p=0.0006), no reconstruction (p=0.0418), higher BMI (p<0.0001) and older age (p=0.0021).
Avoiding completion ALND and instead receiving SLNB with RT may decrease lymphedema risk in patients requiring mastectomy. Future trials should investigate the safety of applying the ACOSOG Z0011 protocol to mastectomy patients.
PMCID: PMC4011490  PMID: 24500108
Mastectomy; Lymphedema; Quality of Life; Radiation Therapy; Sentinel Lymph Node Biopsy
Almost all research using participants wearing barefoot‐style shoes study elite runners or have participants with a history of barefoot style shoe training run on a treadmill when shod or barefoot. Wearing barefoot‐style shoes is suggested as a method of transition between shod and barefoot running. Static and dynamic balance exercises also are recommended. However, little information is available on the effects five‐toed barefoot style shoes have on static balance. The purpose of this study was to examine balance of subjects barefoot, wearing Vibram FiveFingers™ barefoot‐style shoes, and regular athletic shoes with eyes closed when using the Biodex Balance System‐SD™.
Study Design
This was a repeated measures study.
Forty nine participants aged 18‐30 years without lower extremity injury or experience wearing barefoot‐style shoes were tested for static balance on the Biodex Stability System™ with their eyes closed while wearing Vibram FiveFingers™, athletic shoes, or barefoot. Three trials of 10 seconds for each footwear type were completed. Repeated measures analysis of variance with Bonferroni's correction was used to analyze the degrees of sway in the anterior‐posterior and medial lateral directions. An overall stability index was also calculated by the Biodex.
For anterior‐posterior and overall indices, differences were found between all conditions. Participants wearing athletic shoes demonstrated the smallest anterior‐posterior stability index (least sway) and spent the most time in the innermost concentric circular zone. Medial‐lateral indices were not different for any condition.
Wearing Vibram FiveFingers™ provided better overall and anterior‐posterior static balance than going barefoot. While differences between Vibram FiveFingers™ and barefoot are significant, results may reflect statistical significance rather than any clinical difference in young, uninjured individuals.
Clinical relevance
It would appear that Vibram FiveFingers™ mimic going barefoot and may be a bridge for exercising in preparation for barefoot exercise.
Level of Evidence
PMCID: PMC4325290  PMID: 25709865
static balance; Biodex; postural control; postural index; Vibram FiveFingers
15.  Effect of Training on Inspiratory Load Compensation in Weaned and Unweaned Mechanically Ventilated ICU Patients 
Respiratory care  2013;59(1):22-31.
While inspiratory muscle weakness is common in prolonged mechanical ventilation, inspiratory muscle strength training (IMST) can facilitate strengthening and ventilator weaning. However, the inspiratory load compensation (ILC) responses to threshold loads are not well characterized in patients. We retrospectively compared ILC responses according to the clinical outcomes of IMST (ie, maximum inspiratory pressure [PImax], weaning outcome), in difficult-to-wean ICU patients.
Sixteen tracheostomized subjects (10 weaned, 6 unweaned) from a previous clinical trial underwent IMST 5 days/week, at the highest tolerated load, in conjunction with daily, progressive spontaneous breathing trials. PImax and ILC with a 10 cm H2O load were compared in the subjects before and after IMST. Changes in ILC performance were further characterized (5, 10, 15 cm H2O loads) in the trained subjects who weaned.
Demographics, respiratory mechanics, and initial PImax (52 ± 26 cm H2O vs 42 ± 13 cm H2O) did not significantly differ between the groups. Upon enrollment, PImax significantly correlated with flow ILC responses with the 10 cm H2O load (r = 0.64, P = .008). After IMST, PImax significantly increased in the entire sample (P = .03). Both before and after IMST, subjects who weaned generated greater flow and volume ILC than subjects who failed to wean. Additionally, ILC flow, tidal volume, and duty cycle increased upon ventilator weaning, at loads of 5, 10, and 15 cm H2O.
Flow ILC at a threshold load of 10 cm H2O in ventilated, tracheostomized subjects positively correlated with PImax. Although PImax improved in both groups, the flow and volume ILC responses of the weaned subjects were more robust, both before and after IMST. The results suggest that ILC response is different in weaned and unweaned subjects, reflecting dynamic inspiratory muscular efforts that could be influential in weaning.
PMCID: PMC4157996  PMID: 23764858
respiratory failure; respiratory muscle training; respiratory muscles; ventilator weaning
16.  Intrinsic Transient Tracheal Occlusion Training and Myogenic Remodeling of Rodent Parasternal Intercostal Fibers 
It is recognized that diaphragm muscle plasticity occurs with mechanical overloads, yet less is known regarding synergistic parasternal intercostal muscle fiber remodeling. We conducted overload training with intrinsic transient tracheal occlusion (ITTO) exercises in conscious animals. We hypothesized ITTO would yield significant fiber hypertrophy and myogenic activation that would parallel diaphragm fiber remodeling. Sprague-Dawley rats underwent placement of a tracheal cuff and were randomly assigned to receive daily ten-minute sessions of conscious ITTO or observation (SHAM) over two weeks. After training, fiber morphology, myosin heavy chain isoform composition, cross-sectional area, proportion of Pax7-positive nuclei, and presence of embryonic myosin (eMHC) were quantified. Type IIx/b fibers were 20% larger after ITTO training than with SHAM training (ITTO: 4431±676 μm2, SHAM: 3689±400 μm2, p<0.05), and type I fibers were more prevalent after ITTO (p<0.01). Expression of Pax7 was increased in ITTO parasternals and diaphragm (p<0.05). In contrast, the proportion of eMHC-positive fibers was increased only in ITTO parasternals (1.2 (3.4-0.6)%, SHAM: 0 (0.6-0%, p<0.05). Although diaphragm and parasternal type II fibers hypertrophy to a similar degree, myogenic remodeling appears to differ between the two muscles.
PMCID: PMC4269303  PMID: 25509059
17.  Prediction of primary breast cancer size and T-stage using micro-computed tomography in lumpectomy specimens 
Histopathology is the only accepted method to measure and stage the breast tumor size. However, there is a need to find another method to measure and stage the tumor size when the pathological assessment is not available. Micro-computed tomography. (micro-CT) has the ability to measure tumor in three dimensions in an intact lumpectomy specimen. In this study, we aimed to determine the accuracy of micro-CT to measure and stage the primary tumor size in breast lumpectomy specimens, as compared to the histopathology.
Materials and Methods:
Seventy-two women who underwent lumpectomy surgery at the Massachusetts General Hospital Department of Surgery from June 2011 to September 2011, and from August 2013 to December 2013 participated in this study. The lumpectomy specimens were scanned using micro-CT followed by routine pathological processing. The maximum dimension of the invasive breast tumor was obtained from the micro-CT image and was compared to the corresponding pathology report for each subject.
The invasive tumor size measurement by micro-CT was underestimated in 24 cases. (33%), overestimated in 37 cases. (51%), and matched it exactly in 11 cases. (15%) compared to the histopathology measurement for all the cases. However, micro-CT T-stage classification differed from histopathology in only 11. (15.2%) with 6 cases. (8.3%) classified as a higher stage by micro-CT, and 5 cases. (6.9%) classified as lower compared to histopathology. In addition, micro-CT demonstrated a statically significant strong agreement (κ =0.6, P < 0.05) with pathological tumor size and staging for invasive ductal carcinoma. (IDC) group. In contrast, there was no agreement. (κ = −2, P = 0.67) between micro-CT and pathology in estimating and staging tumor size for invasive lobular carcinoma. (ILC) group. This could be explained by a small sample size. (7) for ILC group.
Micro-CT is a promising modality for measuring and staging the IDC.
PMCID: PMC4687161  PMID: 26730350
Breast cancer; breast imaging; gross pathology; micro-computed tomography; tumor size
19.  Mechanical ventilation, diaphragm weakness and weaning: A rehabilitation perspective 
Respiratory physiology & neurobiology  2013;189(2):10.1016/j.resp.2013.05.012.
Most patients are easily liberated from mechanical ventilation (MV) following resolution of respiratory failure and a successful trial of spontaneous breathing, but about 25% of patients experience difficult weaning. MV use leads to cellular changes and weakness, which has been linked to weaning difficulties and has been labeled ventilator induced diaphragm dysfunction (VIDD). Aggravating factors in human studies with prolonged weaning include malnutrition, chronic electrolyte abnormalities, hyperglycemia, excessive resistive and elastic loads, corticosteroids, muscle relaxant exposure, sepsis and compromised cardiac function. Numerous animal studies have investigated the effects of MV on diaphragm function. Virtually all of these studies have concluded that MV use rapidly leads to VIDD and have identified cellular and molecular mechanisms of VIDD. Molecular and functional studies on the effects of MV on the human diaphragm have largely confirmed the animal results and identified potential treatment strategies. Only recently have potential VIDD treatments been tested in humans, including pharmacologic interventions and diaphragm “training”. A limited number of human studies have found that specific diaphragm training can increase respiratory muscle strength in FTW patients and facilitate weaning, but larger, multicenter trials are needed.
PMCID: PMC3808482  PMID: 23692928
ventilator weaning; ventilator induced diaphragm dysfunction; diaphragm strength training
20.  Adeno-Associated Virus–Mediated Gene Therapy for Metabolic Myopathy 
Human Gene Therapy  2013;24(11):928-936.
Metabolic myopathies are a diverse group of rare diseases in which impaired breakdown of stored energy leads to profound muscle dysfunction ranging from exercise intolerance to severe muscle wasting. Metabolic myopathies are largely caused by functional deficiency of a single gene and are generally subcategorized into three major types of metabolic disease: mitochondrial, lipid, or glycogen. Treatment varies greatly depending on the biochemical nature of the disease, and unfortunately no definitive treatments exist for metabolic myopathy. Since this group of diseases is inherited, gene therapy is being explored as an approach to personalized medical treatment. Adeno-associated virus–based vectors in particular have shown to be promising in the treatment of several forms of metabolic myopathy. This review will discuss the most recent advances in gene therapy efforts for the treatment of metabolic myopathies.
PMCID: PMC3814817  PMID: 24164240
21.  The respiratory neuromuscular system in Pompe disease☆ 
Pompe disease is due to mutations in the gene encoding the lysosomal enzyme acid α-glucosidase (GAA). Absence of functional GAA typically results in cardiorespiratory failure in the first year; reduced GAA activity is associated with progressive respiratory failure later in life. While skeletal muscle pathology contributes to respiratory insufficiency in Pompe disease, emerging evidence indicates that respiratory neuron dysfunction is also a significant part of dysfunction in motor units. Animal models show profound glycogen accumulation in spinal and medullary respiratory neurons and altered neural activity. Tissues from Pompe patients show central nervous system glycogen accumulation and motoneuron pathology. A neural mechanism raises considerations about the current clinical approach of enzyme replacement since the recombinant protein does not cross the blood-brain-barrier. Indeed, clinical data suggest that enzyme replacement therapy delays symptom progression, but many patients eventually require ventilatory assistance, especially during sleep. We propose that treatments which restore GAA activity to respiratory muscles, neurons and networks will be required to fully correct ventilatory insufficiency in Pompe disease.
PMCID: PMC4083814  PMID: 23797185
Pompe; Respiratory; Motoneurons; Plasticity; Therapy; Pathology
22.  Hemocompatibility of Polymeric Nanostructured Surfaces 
Tissue integration is an important property when inducing transplant tolerance, however, the hemocompatibility of the biomaterial surface also plays an important role in the ultimate success of the implant. Therefore, in order to induce transplant tolerance, it is critical to understand the interaction of blood components with the material surfaces. In this study, we have investigated the adsorption of key blood serum proteins, in vitro adhesion and activation of platelets and clotting kinetics of whole blood on flat polycaprolactone (PCL) surfaces, nanowire (NW) surfaces and nanofiber (NF) surfaces. Previous studies have shown that polymeric nanostructured surfaces improve cell adhesion, proliferation and viability; however it is unclear how these polymeric nanostructured surfaces interact with the blood and its components. Protein adsorption results indicate that while there were no significant differences in total albumin adsorption on PCL, NW and NF surfaces, NW surfaces had higher total fibrinogen and immunoglobulin-G adsorption compared to NF and PCL surfaces. In contrast, NF surfaces had higher surface FIB and IgG adsorption compared to PCL and NW surfaces. Platelet adhesion and viability studies show more adhesion and clustering of platelets on the NF surfaces as compared to PCL and NW surfaces. Platelet activation studies reveal that NW surfaces have the highest percentage of unactivated platelets, whereas NF surfaces have the highest percentage of fully activated platelets. Whole blood clotting results indicate that NW surfaces maintain an increased amount of free hemoglobin during the clotting process compared to PCL and NF surface, indicating less clotting and slower rate of clotting on their surfaces.
PMCID: PMC3713522  PMID: 23848447
Hemocompatibility; nanowire surfaces; nanofiber surfaces; platelets
Psycho-oncology  2008;17(8):831-843.
Prophylactic mastectomy (PM) offers 90% or greater reduction in risk of breast cancer to women at increased hereditary risk. Nonetheless, acceptance in North America has been low (0–36%). Most women report reduced cancer worry post-operatively, but up to 25–50% of women electing surgery also report psychological distress and/or difficulty adapting following PM. Psychological consultation to aid decision-making and improve post-surgical coping isn’t routinely offered. This retrospective, cross-sectional study explored, quantitatively and qualitatively, interest in and acceptability of psychological consultation for issues related to PM among 108 women who had undergone or were considering surgery. Of the 71 women who had undergone PM, more than half felt pre-surgical psychological consultation was advisable and nearly 2/3 felt post-surgical psychological consultation would be helpful. All 37 women (100%) currently considering PM believed psychological consultation would aid decision-making and preparation for surgery.
Narratives from the interviews illustrate the nature and intensity of the need for psychological support and describe preferences for the role of the psychologist. Suggestions are offered for the integration of psychological services for women deciding about or adapting to PM.
PMCID: PMC4133134  PMID: 18636423
24.  Defining a threshold for intervention in breast cancer-related lymphedema: What level of arm volume increase predicts progression? 
Evaluate arm volume measurements and clinico-pathologic characteristics of breast cancer patients to define a threshold for intervention in breast cancer-related lymphedema.
We prospectively performed arm volume measurements on breast cancer patients using a Perometer. Arm measurements were performed pre- and post-operatively, and change in arm volume was quantified using a relative volume change (RVC) equation. Patient and treatment risk factors were evaluated. Cox proportional hazards models with time-dependent covariates for RVC were used to evaluate whether RVC elevations of ≥3%-<5% or ≥5%-<10% occurring ≤3 months or >3 months after surgery were associated with progression to ≥10% RVC.
1173 patients met eligibility criteria with a median of 27 months post-operative follow-up.The cumulative incidence of ≥10% RVC at 24 months was 5.26% (95% CI: 4.01% – 6.88%). By multivariable analysis, a measurement of ≥5-<10% RVC occurring >3 months after surgery was significantly associated with an increased risk of progression to ≥10% RVC (HR: 2.97, p<0.0001), but a measurement of ≥3-<5% RVC during the same time period was not statistically significantly associated (HR: 1.55, p=0.10). Other significant risk factors included a measurement ≤3 months after surgery with RVC of ≥3–<5% (p=0.007), ≥5–<10% (p<0.0001), or ≥10% (p=0.023), axillary lymph node dissection (ALND) (p<0.0001), and higher BMI at diagnosis (p=0.0028). Type of breast surgery, age, number of positive or number of lymph nodes removed, nodal radiation, chemotherapy, and hormonal therapy were not significant (p>0.05).
Breast cancer patients who experience a relative arm volume increase of ≥3%-<5% occurring >3 months after surgery do not have a statistically significant increase in risk of progression to ≥10%, a common lymphedema criterion . Our data supports utilization of a ≥5-<10% threshold for close monitoring or intervention, warranting further assessment. Additional risk factors for progression to ≥10% include ALND, higher BMI, and post-operative arm volume elevation.
PMCID: PMC3788652  PMID: 23912961
Lymphedema; Quality of Life; Compression Therapy; Threshold; Early Intervention
25.  Lumpectomy Plus Tamoxifen With or Without Irradiation in Women Age 70 Years or Older With Early Breast Cancer: Long-Term Follow-Up of CALGB 9343 
Journal of Clinical Oncology  2013;31(19):2382-2387.
To determine whether there is a benefit to adjuvant radiation therapy after breast-conserving surgery and tamoxifen in women age ≥ 70 years with early-stage breast cancer.
Patients and Methods
Between July 1994 and February 1999, 636 women (age ≥ 70 years) who had clinical stage I (T1N0M0 according to TNM classification) estrogen receptor (ER) –positive breast carcinoma treated by lumpectomy were randomly assigned to receive tamoxifen plus radiation therapy (TamRT; 317 women) or tamoxifen alone (Tam; 319 women). Primary end points were time to local or regional recurrence, frequency of mastectomy, breast cancer–specific survival, time to distant metastasis, and overall survival (OS).
Median follow-up for treated patients is now 12.6 years. At 10 years, 98% of patients receiving TamRT (95% CI, 96% to 99%) compared with 90% of those receiving Tam (95% CI, 85% to 93%) were free from local and regional recurrences. There were no significant differences in time to mastectomy, time to distant metastasis, breast cancer–specific survival, or OS between the two groups. Ten-year OS was 67% (95% CI, 62% to 72%) and 66% (95% CI, 61% to 71%) in the TamRT and Tam groups, respectively.
With long-term follow-up, the previously observed small improvement in locoregional recurrence with the addition of radiation therapy remains. However, this does not translate into an advantage in OS, distant disease-free survival, or breast preservation. Depending on the value placed on local recurrence, Tam remains a reasonable option for women age ≥ 70 years with ER-positive early-stage breast cancer.
PMCID: PMC3691356  PMID: 23690420

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