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2.  Does the Diabetic Foot Have a Significant Impact on Selected Psychological or Social Characteristics of Patients with Diabetes Mellitus? 
Journal of Diabetes Research  2014;2014:371938.
The aim of our case-control study was to compare selected psychological and social characteristics between diabetic patients with and without the DF (controls). Methods. 104 patients with and 48 without DF were included into our study. Both study groups were compared in terms of selected psychosocial characteristics. Results. Compared to controls, patients with DF had a significantly worse quality of life in the area of health and standard of living as shown by lower physical health domain (12.7 ± 2.8 versus 14.7 ± 2.5; P < 0.001) and environment domain (14.1 ± 2.2 versus 15 ± 1.8; P < 0.01) that negatively correlated with diabetes duration (r = −0.061; P = 0.003). Patients with DF subjectively felt more depressed in contrast to controls (24.5 versus 7.3%; P < 0.05); however, the depressive tuning was objectively proven in higher percentage in both study groups (83.2 versus 89.6; NS). We observed a significantly lower level of achieved education (P < 0.01), more patients with disability pensions (P < 0.01), and low self-support (P < 0.001) in patients with the DF compared to controls. In the subgroup of patients with a previous major amputation and DF (n = 6), there were significantly worse outcomes as in the environment domain (P < 0.01), employment status, and stress readaptation (P < 0.01) in contrast to the main study groups. Conclusions. Patients with DF had a predominantly worse standard of living. In contrast to our expectations, patients with DF appeared to have good stress tolerability and mental health (with the exception of patients with previous major amputation) and did not reveal severe forms of depression or any associated consequences.
PMCID: PMC3984852  PMID: 24791012
3.  Behavioral and Histopathological Assessment of Adult Ischemic Rat Brains after Intracerebral Transplantation of NSI-566RSC Cell Lines 
PLoS ONE  2014;9(3):e91408.
Stroke is a major cause of death and disability, with very limited treatment option. Cell-based therapies have emerged as potential treatments for stroke. Indeed, studies have shown that transplantation of neural stem cells (NSCs) exerts functional benefits in stroke models. However, graft survival and integration with the host remain pressing concerns with cell-based treatments. The current study set out to investigate those very issues using a human NSC line, NSI-566RSC, in a rat model of ischemic stroke induced by transient occlusion of the middle cerebral artery. Seven days after stroke surgery, those animals that showed significant motor and neurological impairments were randomly assigned to receive NSI-566RSC intracerebral transplants at two sites within the striatum at three different doses: group A (0 cells/µl), group B (5,000 cells/µl), group C (10,000 cells/µl), and group D (20,000 cells/µl). Weekly behavioral tests, starting at seven days and continued up to 8 weeks after transplantation, revealed dose-dependent recovery from both motor and neurological deficits in transplanted stroke animals. Eight weeks after cell transplantation, immunohistochemical investigations via hematoxylin and eosin staining revealed infarct size was similar across all groups. To identify the cell graft, and estimate volume, immunohistochemistry was performed using two human-specific antibodies: one to detect all human nuclei (HuNu), and another to detect human neuron-specific enolase (hNSE). Surviving cell grafts were confirmed in 10/10 animals of group B, 9/10 group C, and 9/10 in group D. hNSE and HuNu staining revealed similar graft volume estimates in transplanted stroke animals. hNSE-immunoreactive fibers were also present within the corpus callosum, coursing in parallel with host tracts, suggesting a propensity to follow established neuroanatomical features. Despite absence of reduction in infarct volume, NSI-566RSC transplantation produced behavioral improvements possibly via robust engraftment and neuronal differentiation, supporting the use of this NSC line for stroke therapy.
PMCID: PMC3948841  PMID: 24614895
4.  Depressive Symptoms in Mild Cognitive Impairment Predict Greater Atrophy in Alzheimer’s Disease-Related Regions 
Biological Psychiatry  2012;71(9):814-821.
Depression has been associated with higher conversion rates from mild cognitive impairment (MCI) to Alzheimer’s disease (AD) and may be a potential clinical marker of prodromal AD that can be used to identify individuals with MCI who are most likely to progress to AD. Using tensor-based morphometry (TBM), we examined the longitudinal neuroanatomical changes associated with depressive symptoms in MCI.
243 MCI subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) who had brain MRI scans at baseline and 2-year follow-up were classified into depressed (DEP, n=44), non-depressed with other neuropsychiatric symptoms (OTHER, n=93), and no-symptom (NOSYMP, n=106) groups based on the Neuropsychiatric Inventory Questionnaire (NPI-Q). TBM was used to create individual 3D-maps of 2-year brain changes that were compared between groups.
DEP subjects had more frontal (p=0.024), parietal (p=0.030), and temporal (p=0.038) white matter atrophy than NOSYMP subjects. A subset of DEP subjects whose depressive symptoms persisted over 2-years also had higher conversion to AD and more decline on measures of global cognition, language abilities, and executive functioning compared to stable NOSYMP subjects. OTHER and NOSYMP groups exhibited no differences in rates of atrophy.
Depressive symptoms in MCI subjects were associated with greater atrophy in AD-affected regions, increased cognitive decline, and higher rates of conversion to AD. Depression in individuals with MCI may be associated with underlying neuropathological changes including prodromal AD. Thus, assessment of depressive symptoms may be a potentially useful clinical marker in identifying MCI patients who are most likely to progress to AD.
PMCID: PMC3322258  PMID: 22322105
Depression; Mild Cognitive Impairment; Alzheimer’s Disease; Neuropsychiatric Symptoms; Tensor-Based Morphometry; White Matter
5.  Safety and Efficacy of Mild Compression (18–25 mm Hg) Therapy in Patients with Diabetes and Lower Extremity Edema 
Patients with diabetes often present with lower extremity (LE) edema; however, because of concomitant peripheral arterial disease, compression therapy is generally avoided by providers in fear of compromising arterial circulation. This pilot study sought to assess whether diabetic socks with mild compression (18–25 mm Hg) can reduce LE edema in patients with diabetes without negatively impacting vascularity.
Eighteen subjects (9 males, 9 females) aged 61 ± 11 years with diabetes, LE edema, and a mean ankle–brachial index (ABI) of 1.10 ± 0.21 successfully completed this uncontrolled study. At baseline, subjects were fitted and instructed to wear the socks during all waking hours. Follow-up visits occurred weekly for four consecutive weeks. Edema was quantified through midfoot, ankle, and calf circumferences and cutaneous fluid measurements. Vascular status was tracked via ABI.
Repeated measures analysis of variance and least significant difference post hoc analyses were used for data analyses. Calf circumferences showed a statistically significant (p < .05) decrease of 1.3 ± 0.28 cm after just one week and remained significantly smaller than baseline throughout the study. Foot circumferences were significantly reduced at week 2 (−0.98 ± 0.35 cm) and remained significantly below baseline for the remainder of the study. The ankle also demonstrated a trend of circumference reduction but was not statistically significant. Cutaneous edema significantly reduced by week 3 (−3.1 ± 1.3 U) and remained so at week 4. Ankle–brachial index significantly increased (0.14 ± 0.049) at week 2 but was not significantly higher at weeks 3 or 4. No adverse events occurred during the study.
Mild compression therapy (18–25 mm Hg) decreased swelling in diabetes patients with LE edema without compromising vascularity.
PMCID: PMC3440039  PMID: 22768895
compression; diabetes; edema; lower extremity
6.  A Growing Troubling Triad: Diabetes, Aging, and Falls 
Journal of Aging Research  2013;2013:342650.
There is a significant and troubling link between diabetes (DM) and falls in the elderly. Individuals with DM are prone to fall for reasons such as decreased sensorimotor function, musculoskeletal/neuromuscular deficits, foot and body pain, pharmacological complications, and specialty (offloading) footwear devices. Additionally, there is some concern that DM patients are prone to have more severe problems with falls than non-DM individuals. Fractures, poorer rehabilitation, and increased number of falls are all concerns. Fortunately, efforts to mitigate falls by DM patients show promise. A number of studies have shown that balance, strength, and gait training may be utilized to successfully reduce fall risk in this population. Furthermore, new technologies such as virtual reality proprioceptive training may be able to provide this reduced risk within a safe training environment.
PMCID: PMC3586503  PMID: 23476773
7.  Familial Aggregation of Autoimmune Disease in Juvenile Dermatomyositis 
Pediatrics  2011;127(5):e1239-e1246.
Familial aggregation of autoimmune diseases likely reflects shared pathogenic factors between different diseases. Familial aggregation of autoimmunity has not been examined in juvenile dermatomyositis. Interferon-α is thought to be a pathogenic factor in both systemic lupus erythematosus and juvenile dermatomyositis, and we have previously demonstrated familial aggregation of serum interferon-α.
Family histories were obtained from 304 families of children with juvenile dermatomyositis via 3-generation structured interviews performed by the same person. Rates of autoimmune disease in families of children with juvenile dermatomyositis were compared with published population rates. Serum interferon-α, tumor necrosis factor-α, and neopterin were measured using standard techniques.
A total of 51% of families of children with juvenile dermatomyositis reported at least 1 additional member affected by an autoimmune disease. In particular, both type 1 diabetes and systemic lupus erythematosus were significantly more common than would be expected (odds ratio >5, P ≤ 1 × 10−7 for both). Pedigree analysis showed particularly strong familial clustering of systemic lupus erythematosus with little decrease in incidence across generations, suggesting the possibility of rare causal genes with large effect. Untreated subjects with juvenile dermatomyositis with a family history of systemic lupus erythematosus had higher serum interferon-α than those who did not (P = .047).
We find strong familial aggregation of specific autoimmune diseases in families of children with juvenile dermatomyositis, suggesting that these conditions share pathogenic factors. Higher serum interferon-α in juvenile dermatomyositis patients with a family history of systemic lupus erythematosus suggesting that interferon-α is one such shared factor.
PMCID: PMC3081190  PMID: 21502224
juvenile dermatomyositis; systemic lupus erythematosus; diabetes mellitus type I; psoriasis; celiac disease; interferons
8.  Assessing Postural Control and Postural Control Strategy in Diabetes Patients Using Innovative and Wearable Technology 
Currently, diagnosis of patients with postural instability relies on a rudimentary clinical examination. This article suggests an innovative, portable, and cost-effective prototype to evaluate balance control objectively.
The proposed system uses low-cost, microelectromechanical sensor, body-worn sensors (BalanSens™) to measure the motion of ankle and hip joints in three dimensions. We also integrated resulting data into a two-link biomechanical model of the human body for estimating the two-dimensional sway of the center of mass (COM) in anterior–posterior (AP) and medial–lateral (ML) directions. A new reciprocal compensatory index (RCI) was defined to quantify postural compensatory strategy (PCS) performance. To validate the accuracy of our algorithms in assessing balance, we investigated the two-dimensional sway of COM and RCI in 21 healthy subjects and 17 patients with diabetic peripheral neuropathic (DPN) complications using the system just explained. Two different conditions were examined: eyes open (EO) and eyes closed (EC) for duration of at least 30 seconds. Results were compared with center of pressure sway (COP) as measured by a pressure platform (Emed-x system, Novel Inc., Germany). To further investigate the contribution of the somatosensory (SOM) feedback to balance control, healthy subjects performed EO and EC trials while standing on both a rigid and a foam surface.
A relatively high correlation was observed between COM measured using BalanSens and COP measured using the pressure platform (r = 0.92). Results demonstrated that DPN patients exhibit significantly greater COM sway than healthy subjects for both EO and EC conditions (p < 0.005). The difference becomes highly pronounced while eyes are closed (197 ± 44 cm2 vs 68 ± 56 cm2). Furthermore, results showed that PCS assessed using RCI is significantly better in healthy subjects compared to DPN subjects for both EO and EC conditions, as well as in both ML and AP directions (p < 0.05). Alteration in SOM feedback in healthy subjects resulted in diminished RCI values that were similar to those seen in DPN subjects (p > 0.05).
This study suggested an innovative system that enables the investigation of COM as well as postural control compensatory strategy in humans. Results suggest that neuropathy significantly impacts PCS.
PMCID: PMC2909506  PMID: 20663438
balance; body-worn sensor; diabetic peripheral neuropathy; postural compensatory strategy; sensory feedback
9.  Liquid Silicone to Mitigate Plantar Pedal Pressure: A Literature Review 
Disruption of the body’s plantar fat pad can occur as a result of one of three mechanisms: simple fat pad atrophy associated with age-related degeneration, steroid use, or collagen vascular disease. Actual or relative displacement in to the underlying osseous prominences may be seen in association with structural deformity of the foot. Disease states such as diabetes may alter the normal structural integrity of soft tissues through nonenzymatic glycation leading to increased stiffness and thus reduced attenuating capacity. Fat pad atrophy, regardless of the cause, is often associated with substantial emotional, physical, productivity, and financial losses. In situations where the patient is sensate, the resultant skin on bone situation is extremely painful, especially when walking.
PMCID: PMC2909515  PMID: 20663447
atrophy; augmentation; pressure; silicone
10.  Apolipoprotein E Genotype is Associated with Temporal and Hippocampal Atrophy Rates in Healthy Elderly Adults: A Tensor-Based Morphometry Study1 
Apolipoprotein E (ApoE) ε4 genotype is a strong risk factor for developing Alzheimer’s disease (AD). Conversely, the presence of the ε2 allele has been shown to mitigate cognitive decline. Tensor-based morphometry (TBM), a novel computational approach for visualizing longitudinal progression of brain atrophy, was used to determine whether cognitively intact elderly participants with the ε4 allele demonstrate greater volume reduction than those with the ε2 allele. Healthy “younger elderly” volunteers, aged 55–75, were recruited from the community and hospital staff. They were evaluated with a baseline and follow-up MRI scan (mean scan interval = 4.72 years, s.d. = 0.55) and completed ApoE genotyping. Twenty-seven participants were included in the study of which 16 had the ε4 allele (all heterozygous ε3ε4 genotype) and 11 had the ε2ε3 genotype. The two groups did not differ significantly on any demographic characteristics and all subjects were cognitively “normal” at both baseline and follow-up time points. TBM was used to create 3D maps of local brain tissue atrophy rates for individual participants; these spatially detailed 3D maps were compared between the two ApoE groups. Regional analyses were performed and the ε4 group demonstrated significantly greater annual atrophy rates in the temporal lobes (p = 0.048) and hippocampus (p = 0.016); greater volume loss was observed in the right hippocampus than the left. TBM appears to be useful in tracking longitudinal progression of brain atrophy in cognitively asymptomatic adults. Possession of the ε4 allele is associated with greater temporal and hippocampal volume reduction well before the onset of cognitive deficits.
PMCID: PMC3107252  PMID: 21098974
Aging; Alzheimer’s disease; Apolipoprotein E; asymmetry; healthy elderly; hippocampus; magnetic resonance imaging; tensor-based morphometry; temporal lobe; white matter
11.  Three-Dimensional Reconstruction of Serial Mouse Brain Sections: Solution for Flattening High-Resolution Large-Scale Mosaics 
Recent advances in high-throughput technology facilitate massive data collection and sharing, enabling neuroscientists to explore the brain across a large range of spatial scales. One such form of high-throughput data collection is the construction of large-scale mosaic volumes using light microscopy (Chow et al., 2006; Price et al., 2006). With this technology, researchers can collect and analyze high-resolution digitized volumes of whole brain sections down to 0.2 μm. However, until recently, scientists lacked the tools to easily handle these large high-resolution datasets. Furthermore, artifacts resulting from specimen preparation limited volume reconstruction using this technique to only a single tissue section. In this paper, we carefully describe the steps we used to digitally reconstruct a series of consecutive mouse brain sections labeled with three stains, a stain for blood vessels (DiI), a nuclear stain (TO-PRO-3), and a myelin stain (FluoroMyelin). These stains label important neuroanatomical landmarks that are used for stacking the serial sections during reconstruction. In addition, we show that the use of two software applications, ir-Tweak and Mogrifier, in conjunction with a volume flattening procedure enable scientists to adeptly work with digitized volumes despite tears and thickness variations within tissue sections. These applications make processing large-scale brain mosaics more efficient. When used in combination with new database resources, these brain maps should allow researchers to extend the lifetime of their specimens indefinitely by preserving them in digital form, making them available for future analyses as our knowledge in the field of neuroscience continues to expand.
PMCID: PMC3096995  PMID: 21629828
connectivity; myelin; confocal microscopy; serial sections; warping correction; whole brain catalog; cell centered database; neuroinformatics
12.  Use of Pressure Offloading Devices in Diabetic Foot Ulcers 
Diabetes Care  2008;31(11):2118-2119.
OBJECTIVE—Pressure mitigation is crucial for the healing of plantar diabetic foot ulcers. We therefore discuss characteristics and considerations associated with the use of offloading devices.
RESEARCH DESIGN AND METHODS—A diabetic foot ulcer management survey was sent to foot clinics in all 50 states and the District of Columbia in 2005. A total of 901 geographically diverse centers responded. The survey recorded information regarding usage frequency and characteristics of assessment and treatment of diabetic foot ulcers in each center.
RESULTS—Of the 895 respondents who treat diabetic foot ulcers, shoe modifications (41.2%, P < 0.03) were the most common form of pressure mitigation, whereas total contact casts were used by only 1.7% of the centers.
CONCLUSIONS—This study reports the usage and characteristics of offloading devices in the care of diabetic foot ulcers in a broadly distributed geographic sample. Less than 2% of specialists use what has been termed the “gold standard” (total contact cast) for treating the majority of diabetic foot ulcers.
PMCID: PMC2571059  PMID: 18694976
13.  Foot ulcers in the diabetic patient, prevention and treatment 
Lower extremity complications in persons with diabetes have become an increasingly significant public health concern in both the developed and developing world. These complications, beginning with neuropathy and subsequent diabetic foot wounds frequently lead to infection and lower extremity amputation even in the absence of critical limb ischemia. In order to diminish the detrimental consequences associated with diabetic foot ulcers, a com-mon-sense-based treatment approach must be implemented. Many of the etiological factors contributing to the formation of diabetic foot ulceration may be identified using simple, inexpensive equipment in a clinical setting. Prevention of diabetic foot ulcers can be accomplished in a primary care setting with a brief history and screening for loss of protective sensation via the Semmes-Weinstein monofilament. Specialist clinics may quantify neuropathy, plantar foot pressure, and assess vascular status with Doppler ultrasound and ankle-brachial blood pressure indices. These measurements, in conjunction with other findings from the history and physical examination, may enable clinicians to stratify patients based on risk and help determine the type of intervention. Other effective clinical interventions may include patient education, optimizing glycemic control, smoking cessation, and diligent foot care. Recent technological advanced combined with better understanding of the wound healing process have resulted in a myriad of advanced wound healing modalities in the treatment of diabetic foot ulcers. However, it is imperative to remember the fundamental basics in the healing of diabetic foot ulcers: adequate perfusion, debridement, infection control, and pressure mitigation. Early recognition of the etiological factors along with prompt management of diabetic foot ulcers is essential for successful outcome.
PMCID: PMC1994045  PMID: 17583176
diabetes; ulcer; prevention; infection; amputation

Results 1-13 (13)