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1.  Clinical Presentation and Self-Reported Patterns of Pain and Function in Patients with Plantar Heel Pain 
Background
Plantar heel pain is a common disorder of the foot for which patients seek medical treatment. The purpose of this study is to explore the relationship between duration of symptoms in plantar fasciitis patients and demographic factors, the intensity and location of pain, extent of previous treatment and self reported pain and function.
Methods
The charts of patients presenting with plantar heel pain between June 2008 and October 2010 were reviewed retrospectively and 182 patients with a primary diagnosis of plantar fasciitis were identified. Patients with symptoms less than 6 months were identified as acute and patients with symptoms greater than or equal to six months were defined as having chronic symptoms. Comparisons based on duration of symptoms were performed for age, gender, BMI, comorbidities, pain location and intensity, and a functional score measured by the Foot and Ankle Ability Measure (FAAM).
Results
The two groups were similar in age, BMI, gender, and comorbidities. Pain severity, as measured by a VAS, was not statistically significant between the two groups (6.6 and 6.2). The acute and chronic groups of patients reported similar levels of function on both the activity of daily living (62 and 65) and sports (47 and 45) subscales of the FAAM. Patients in the chronic group were more likely to have seen more providers and tried more treatment options for this condition.
Conclusion
As plantar fasciitis symptoms extend beyond 6 months, patients do not experience increasing pain intensity or functional limitation. No specific risk factors have been identified to indicate a risk of developing chronic symptoms.
PMCID: PMC4083061  PMID: 22995253
plantar fasciitis; heel pain; functional limitation
2.  Kinetics and Kinematics after the Bridle Procedure for Treatment of Traumatic Foot Drop 
Background
The Bridle procedure restores active ankle dorsiflexion through a tri-tendon anastamosis of the tibialis posterior, transferred to the dorsum of the foot, with the peroneus longus and tibialis anterior tendon. Inter-segmental foot motion after the Bridle procedure has not been measured. The purpose of this study is to report kinetic and kinematic variables during walking and heel rise in patients after the Bridle procedure.
Methods
18 Bridle and 10 control participants were studied. Walking and heel rise kinetic and kinematic variables were collected and compared using an ANOVA.
Findings
During walking the Bridle group, compared with controls, had reduced ankle power at push off [2.3 (SD 0.7) W/kg, 3.4 (SD 0.6) W/kg, respectively, P<.01], less hallux extension during swing [−13 (SD 7)°, 15 (SD6)°, respectively, P<.01] and slightly less ankle dorsiflexion during swing [6 (SD4)°, 9 (SD 2)°, respectively, P=.03]. During heel rise the Bridle group had 4 (SD 6)° of forefoot on hindfoot dorsiflexion compared to 8 (SD 3)° of plantarflexion in the controls (P<.01).
Interpretation
This study provides evidence that the Bridle procedure restores the majority of dorsiflexion motion during swing. However, plantarflexor function during push off and hallux extension during swing were reduced during walking in the Bridle group. Abnormal mid-tarsal joint motion, forefoot on hindfoot dorsiflexion instead of plantarflexion, was identified in the Bridle group during the more challenging heel rise task. Intervention after the Bridle procedure must maximize ankle plantarflexor function and midfoot motion should be examined during challenging tasks.
doi:10.1016/j.clinbiomech.2013.04.008
PMCID: PMC3934630  PMID: 23684087
3.  An Automated System for Monitoring and Regulating the pH of Bicarbonate Buffers 
AAPS PharmSciTech  2013;14(2):517-522.
The bicarbonate buffer is considered as the most biorelevant buffer system for the simulation of intestinal conditions. However, its use in dissolution testing of solid oral dosage forms is very limited. The reason for this is the thermodynamic instability of the solution containing hydrogen carbonate ions and carbonic acid. The spontaneous loss of carbon dioxide (CO2) from the solution results in an uncontrolled increase of the pH. In order to maintain the pH on the desired level, either a CO2 loss must be completely avoided or the escaped CO2 has to be replaced by quantitative substitution, i.e. feeding the solution with the respective amount of gas, which re-acidifies the buffer after dissociation. The present work aimed at the development of a device enabling an automatic pH monitoring and regulation of hydrogen carbonate buffers during dissolution tests.
doi:10.1208/s12249-013-9933-5
PMCID: PMC3666009  PMID: 23468339
bicarbonate media; hydrogen carbonate buffer; modified release; physiological buffers; biorelevant dissolution
4.  Miniaturized Transfer Models to Predict the Precipitation of Poorly Soluble Weak Bases upon Entry into the Small Intestine 
AAPS PharmSciTech  2012;13(4):1230-1235.
For poorly soluble weak bases, the possibility of drug precipitation upon entry into the small intestine may affect the amount of drug available for uptake through the intestinal mucosa. A few years ago, a transfer model was introduced which has been developed to simulate the transfer of a dissolved drug out of the stomach into the small intestine. However, this setup requires the use of clinically relevant doses of the drug, which are typically not available in the early stages of formulation development. The present series of tests was performed to check whether it is possible to create a miniaturized but physiologically relevant transfer model that can be applied in the early formulation development. Experiments were performed with two miniaturized setups: a 96-well plate model and a mini-paddle transfer system. Itraconazole and tamoxifen were used as model drugs. An appropriate amount of each drug formulation was dissolved in simulated gastric fluid and then transferred into an acceptor phase consisting of fasted/fed state simulated small intestinal fluid. The amount of drug dissolved in the acceptor phase was monitored over a period of 4 h. Results from both setups were very similar. The tamoxifen preformulation did not precipitate, whereas the itraconazole formulation precipitated to the same extent in both setups. Due to the possibility of generating physiologically relevant results but using smaller sample sizes and smaller volumes of media, both miniaturized transfer systems offer various advantages in terms of substance and analytical and material cost savings when evaluating the precipitation potential of poorly soluble weakly basic drug candidates.
doi:10.1208/s12249-012-9851-y
PMCID: PMC3513478  PMID: 22968547
96-well plate; biorelevant media; drug precipitation; gastric emptying; transfer model
5.  An Oral-Controlled Release Drug Delivery System for Liquid and Semisolid Drug Formulations 
AAPS PharmSciTech  2011;12(4):1183-1185.
A novel oral drug delivery system for the controlled release of liquid drugs, drug solutions, and semisolid drug preparations is presented that is utilizing the constant vapor pressure of liquefied gas. The system is equipped with a capillary as an element determining the drug delivery rate and contains a liquefied propellant with a suitable boiling point below human body temperature. In the dissolution studies, polyacrylate gels of different viscosities containing paracetamol as model drug were used. Zero-order release kinetics was obtained. The release rates were dependent on the gel viscosity. Besides, by gel viscosity, the drug release rates could also be modified by changing the propellant type and the capillary parameters such as length or diameter. Accordingly, the new system enables a wide range of drug delivery kinetics which can be modified in a case-by-case basis in order to match the desired drug delivery characteristics.
doi:10.1208/s12249-011-9689-8
PMCID: PMC3225522  PMID: 21918919
controlled delivery of liquids; controlled release; extended release; oral drug delivery system
6.  The Use of Biorelevant Dissolution Media to Forecast the In Vivo Performance of a Drug 
The AAPS Journal  2010;12(3):397-406.
Simulation of gastrointestinal conditions is essential to adequately predict the in vivo behavior of drug formulations. To reduce the size and number of human studies required to identify a drug product with appropriate performance in both the fed and fasted states, it is advantageous to be able to pre-screen formulations in vitro. The choice of appropriate media for such in vitro tests is crucial to their ability to correctly forecast the food effect in pharmacokinetic studies. The present paper gives an overview of the development and composition of biorelevant dissolution media that can be used for the in vitro simulation of different dosing conditions (fasted and fed states). In addition, the application of these media to predicting food effects is described in several case examples.
doi:10.1208/s12248-010-9203-3
PMCID: PMC2895438  PMID: 20458565
BA; biorelevant media; dissolution; fasted state; fed state; food effects
7.  Acute glial activation by stab injuries does not lead to overt damage or motor neuron degeneration in the G93A mutant SOD1 rat model of Amyotrophic Lateral Sclerosis 
Experimental neurology  2009;221(2):346-352.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease where motor neurons within the brain and spinal cord are lost, leading to paralysis and death. Recently, a correlation has been reported between head trauma and the incidence of ALS. Furthermore, new invasive neurosurgical studies are being planned which involve inserting needles directly to the spinal cord. We therefore tested whether acute trauma to the spinal cord via a knife wound injury would lead to accelerated disease progression in rodent models of ALS (SOD1G93A rats). A longitudinal stab injury using a small knife was performed within the lumbar spinal cord region of presymptomatic SOD1G93A rats. Host glial activation was detected in the lumbar area surrounding a micro-knife lesion at 2 weeks post-surgery in both wild type and SOD1G93A animals. However, there was no sign of motor neuron loss in the injured spinal cord of any animal and normal motor function was maintained in the ipsilateral limb. These results indicate that motor neurons in pre-symptomatic G93A animals are not affected by an invasive puncture wound injury involving reactive astrocytes. Furthermore, acute trauma alone does not accelerate disease onset or progression in this ALS model which is important for future strategies of gene and cell therapies directly targeting the spinal cord of ALS patients.
doi:10.1016/j.expneurol.2009.12.004
PMCID: PMC2839070  PMID: 20005223
Amyotrophic lateral sclerosis (ALS); SOD1G93A rats; acute trauma; stab injury; astrocyte activation; motor neuron; spinal cord
8.  No Evidence for XMRV in German CFS and MS Patients with Fatigue Despite the Ability of the Virus to Infect Human Blood Cells In Vitro 
PLoS ONE  2010;5(12):e15632.
Background
Xenotropic murine leukemia virus-related virus (XMRV), a novel human retrovirus originally identified in prostate cancer tissues, has recently been associated with chronic fatigue syndrome (CFS), a disabling disease of unknown etiology affecting millions of people worldwide. However, several subsequent studies failed to detect the virus in patients suffering from these illnesses or in healthy subjects. Here we report the results of efforts to detect antibody responses and viral sequences in samples from a cohort of German CFS and relapsing remitting multiple sclerosis (MS) patients with fatigue symptoms.
Methodology
Blood samples were taken from a cohort of 39 patients fulfilling the Fukuda/CDC criteria (CFS), from 112 patients with an established MS diagnosis and from 40 healthy donors. Fatigue severity in MS patients was assessed using the Fatigue Severity Scale (FSS). Validated Gag- and Env-ELISA assays were used to screen sera for XMRV antibodies. PHA-activated PBMC were cultured for seven days in the presence of IL-2 and DNA isolated from these cultures as well as from co-cultures of PBMC and highly permissive LNCaP cells was analyzed by nested PCR for the presence of the XMRV gag gene. In addition, PBMC cultures were exposed to 22Rv1-derived XMRV to assess infectivity and virus production.
Conclusion
None of the screened sera from CFS and MS patients or healthy blood donors tested positive for XMRV specific antibodies and all PBMC (and PBMC plus LNCaP) cultures remained negative for XMRV sequences by nested PCR. These results argue against an association between XMRV infection and CFS and MS in Germany. However, we could confirm that PBMC cultures from healthy donors and from CFS patients can be experimentally infected by XMRV, resulting in the release of low levels of transmittable virus.
doi:10.1371/journal.pone.0015632
PMCID: PMC3008728  PMID: 21203514
9.  A Standardized Mini Paddle Apparatus as an Alternative to the Standard Paddle 
AAPS PharmSciTech  2008;9(4):1179-1184.
doi:10.1208/s12249-008-9161-6
PMCID: PMC2628255  PMID: 19034672
dissolution; hydrodynamics; mini paddle; miniaturization; paddle
10.  Lesion-induced increase in survival and migration of human neural progenitor cells releasing GDNF 
Cell transplantation  2008;17(7):753-762.
The use of human neural progenitor cells (hNPC) has been proposed to provide neuronal replacement or astrocytes delivering growth factors for brain disorders such as Parkinson’s and Huntington’s disease. Success in such studies likely requires migration from the site of transplantation and integration into host tissue in the face of ongoing damage. In the current study, hNPC modified to release glial cell line derived neurotrophic factor (hNPCGDNF) were transplanted into either intact or lesioned animals. GDNF release itself had no effect on the survival, migration or differentiation of the cells. The most robust migration and survival was found using a direct lesion of striatum (Huntington’s model) with indirect lesions of the dopamine system (Parkinson’s model) or intact animals showing successively less migration and survival. No lesion affected differentiation patterns. We conclude that the type of brain injury dictates migration and integration of hNPC which has important consequences when considering transplantation of these cells as a therapy for neurodegenerative diseases.
PMCID: PMC2650839  PMID: 19044202
Parkinson’s disease; Huntington’s disease; striatum; stem cell transplants
11.  GDNF Secreting Human Neural Progenitor Cells Protect Dying Motor Neurons, but Not Their Projection to Muscle, in a Rat Model of Familial ALS 
PLoS ONE  2007;2(8):e689.
Background
Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease characterized by rapid loss of muscle control and eventual paralysis due to the death of large motor neurons in the brain and spinal cord. Growth factors such as glial cell line derived neurotrophic factor (GDNF) are known to protect motor neurons from damage in a range of models. However, penetrance through the blood brain barrier and delivery to the spinal cord remains a serious challenge. Although there may be a primary dysfunction in the motor neuron itself, there is also increasing evidence that excitotoxicity due to glial dysfunction plays a crucial role in disease progression. Clearly it would be of great interest if wild type glial cells could ameliorate motor neuron loss in these models, perhaps in combination with the release of growth factors such as GDNF.
Methodology/Principal Findings
Human neural progenitor cells can be expanded in culture for long periods and survive transplantation into the adult rodent central nervous system, in some cases making large numbers of GFAP positive astrocytes. They can also be genetically modified to release GDNF (hNPCGDNF) and thus act as long-term ‘mini pumps’ in specific regions of the rodent and primate brain. In the current study we genetically modified human neural stem cells to release GDNF and transplanted them into the spinal cord of rats over-expressing mutant SOD1 (SOD1G93A). Following unilateral transplantation into the spinal cord of SOD1G93A rats there was robust cellular migration into degenerating areas, efficient delivery of GDNF and remarkable preservation of motor neurons at early and end stages of the disease within chimeric regions. The progenitors retained immature markers, and those not secreting GDNF had no effect on motor neuron survival. Interestingly, this robust motor neuron survival was not accompanied by continued innervation of muscle end plates and thus resulted in no improvement in ipsilateral limb use.
Conclusions/Significance
The potential to maintain dying motor neurons by delivering GDNF using neural progenitor cells represents a novel and powerful treatment strategy for ALS. While this approach represents a unique way to prevent motor neuron loss, our data also suggest that additional strategies may also be required for maintenance of neuromuscular connections and full functional recovery. However, simply maintaining motor neurons in patients would be the first step of a therapeutic advance for this devastating and incurable disease, while future strategies focus on the maintenance of the neuromuscular junction.
doi:10.1371/journal.pone.0000689
PMCID: PMC1925150  PMID: 17668067
12.  Persistence of acquired behavioral control in the context of imprinting1 
Newly hatched Khaki Campbell ducklings (Anas platyrhynchos domesticus) were exposed to a moving object that immediately suppressed distress vocalizations occurring in a novel environment. The static visual and auditory features of this object acquired the ability to suppress distress vocalizations after eight 20-min sessions of exposure to the object in motion. The acquired suppressive properties of these features were found to persist throughout thirty 20-min sessions given over 10 days. During these sessions, the ducklings were continually exposed to the static features in the absence of visual movement. In a second experiment, the ability of these features in the absence of visual movement. In a second experiment, the ability of these features to serve as reinforcement for a pecking response was shown to persist for up to 56 hr. In one duckling, presentations of the static visual features did not maintain pecking behavior. However, it was shown that pecking responses could be re-instated in this duckling by introducing novel stimuli to the environment.
doi:10.1901/jeab.1975.24-255
PMCID: PMC1333427  PMID: 16811877
imprinting; novel stimuli; extinction; conditioned reinforcement; conditioned suppression; pecking; duckling

Results 1-12 (12)