Allogeneic Mesenchymal Precursor Cells (MPC) in Diabetic Nephropathy: A Randomized, Placebo-controlled, Dose Escalation Study.

BACKGROUND: Diabetic nephropathy is the most common cause of end stage renal failure. We assessed the safety, tolerability, and explored therapeutic effects of adult allogeneic bone-marrow derived mesenchymal precursor cells (MPC) in patients with moderate to severe diabetic nephropathy. METHODS: Multicenter, randomized, double-blind, dose-escalating, sequential, placebo-controlled trial assessing a single intravenous (IV) infusion of allogeneic MPC (United States adopted name: rexlemestrocel-L) 150×106 (n=10), 300×106 (n=10) or placebo (n=10) in adults with diabetic nephropathy with an estimated glomerular filtration rate (eGFR) 20-50ml/min/1.73m2. Thirty patients at three Australian centers were enrolled between July 2013 and June 2014 and randomized 2:1, in two sequential dose cohorts, to receive rexlemestrocel-L or placebo. Study duration was 60weeks. Primary endpoint was safety and tolerability. Primary exploratory efficacy endpoint was change from baseline in eGFR and directly measured GFR by 99Tc-DTPA plasma clearance (mGFR) at 12weeks post-infusion. The trial was registered on ClinicalTrials.gov (NCT01843387). FINDINGS: All patients completed the study and were included in analyses applied to the intention to treat population. There were no acute adverse events (AEs) associated with infusion and no treatment-related AEs or serious AEs were deemed treatment-related by investigators. No patients developed persistent donor specific anti-HLA antibodies. Relative to placebo, a single IV rexlemestrocel-L infusion showed trends of stabilizing or improving eGFR and mGFR at week 12. The adjusted least squares mean (LSM±SE) differences from placebo in changes from baseline at 12weeks in the rexlemestrocel-L groups were 4.4±2.16 and 1.6±2.15ml/min/1.73m2 for eGFR and 4.1±2.75 and 3.9±2.75 for mGFR for the 150×106 and 300×106 cell groups, respectively. INTERPRETATION: This study demonstrates the safety of rexlemestrocel-L in diabetic nephropathy with suggestive effects on renal function to be confirmed in larger, appropriately powered trials.

Allogeneic Mesenchymal Precursor Cells in Type 2 Diabetes: A Randomized, Placebo-Controlled, Dose-Escalation Safety and Tolerability Pilot Study.

OBJECTIVE: To assess the safety, tolerability, and feasibility of adult allogeneic bone marrow-derived mesenchymal precursor cells (MPCs) in type 2 diabetes inadequately controlled with metformin either alone or with one additional oral antidiabetic agent. RESEARCH DESIGN AND METHODS: The study was a dose-escalating randomized placebo-controlled trial assessing one intravenous (IV) infusion of MPCs (rexlemestrocel-L; Mesoblast Inc.) 0.3 × 10(6)/kg (n = 15), 1.0 × 10(6)/kg (n = 15), or 2.0 × 10(6)/kg (n = 15) or placebo (n = 16). Study duration was 12 weeks. RESULTS: Subjects (21 women, 40 men) with a mean ± SD baseline HbA1c 8.3 ± 1.0% (67 ± 10.9 mmol/mol), BMI 33.5 ± 5.5 kg/m(2), and diabetes duration 10.1 ± 6.0 years were enrolled at 18 U.S. sites. No acute adverse events (AEs) were associated with infusion. No serious AEs, serious hypoglycemia AEs, or discontinuations due to AEs over 12 weeks were found. No subjects developed donor-specific anti-HLA antibodies or became sensitized. The safety profile was comparable among treatment groups. Compared with placebo, a single IV infusion of rexlemestrocel-L reduced HbA1c at all time points after week 1. The adjusted least squares mean ± SE dose-related differences in HbA1c from placebo in the rexlemestrocel-L groups ranged from -0.1 ± 0.2% (-1.1 ± 2.2 mmol/mol) to -0.4 ± 0.2% (4.4 ± 2.2 mmol/mol) at 8 weeks and from 0.0 ± 0.25% to -0.3 ± 0.25% (-3.3 ± -2.7 mmol/mol) at 12 weeks (P < 0.05 for 2.0 × 10(6)/kg dose at 8 weeks). The clinical target HbA1c <7% (53 mmol/mol) was achieved by 33% (5 of 15) of the subjects who received the 2.0 × 10(6)/kg dose vs. 0% of those who received placebo (P < 0.05). CONCLUSIONS: This short-term study demonstrates the safety and feasibility of up to 246 million MPCs in subjects with type 2 diabetes.

Evidence-based review and assessment of botulinum neurotoxin for the treatment of urologic conditions.

Botulinum neurotoxin (BoNT) can be injected to achieve therapeutic benefit across a large range of clinical conditions. To assess the efficacy and safety of BoNT injections for the treatment of certain urologic conditions, including detrusor sphincter dyssynergia (DSD), lower urinary tract symptoms due to benign prostatic hyperplasia (BPH), and detrusor overactivity (both neurogenic [NDO] and idiopathic [IDO]), an expert panel reviewed evidence from the published literature. Data sources included English-language studies identified via MEDLINE, EMBASE, CINAHL, Current Contents, and the Cochrane Central Register of Controlled Trials. Evidence tables generated in the 2008 Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology (AAN) review of the use of BoNT for autonomic disorders were also reviewed and updated. The panel evaluated evidence at several levels, supporting BoNT as a class, for the serotypes BoNT-A and BoNT-B, as well as for the four individual commercially available formulations: abobotulinumtoxinA (A/Abo), onabotulinumtoxinA (A/Ona), incobotulinumtoxinA (A/Inco), and rimabotulinumtoxinB (B/Rima). The panel ultimately made recommendations on the use of BoNT for the management of these urologic conditions based upon the strength of clinical evidence and following the AAN classification scale. For the treatment of DSD, the evidence supported a Level B recommendation for the use of A/Ona; A/Abo, A/Inco, and B/Rima received a Level U recommendation. For the treatment of NDO, there was sufficient clinical evidence to support a Level A recommendation for BoNT-A as well as for both A/Ona and A/Abo; no published data were identified for either A/Inco or B/Rima (Level U). For the treatment of IDO, the evidence supported a Level A recommendation for A/Ona; A/Inco, A/Abo, and B/Rima received a Level U recommendation. For the management of BPH, the evidence supported a Level B recommendation for BoNT and A/Ona; no published studies were identified for A/Abo, A/Inco, or B/Rima, warranting a Level U recommendation for these three formulations. Further studies are needed to evaluate the efficacy and safety of BoNT for the management of urologic conditions.

Evidence-based review and assessment of botulinum neurotoxin for the treatment of movement disorders.

Botulinum neurotoxin (BoNT) can be injected to achieve therapeutic benefit across a large range of clinical conditions. To assess the efficacy and safety of BoNT injections for the treatment of certain movement disorders, including blepharospasm, hemifacial spasm, oromandibular dystonia, cervical dystonia, focal limb dystonias, laryngeal dystonia, tics, and essential tremor, an expert panel reviewed evidence from the published literature. Data sources included English-language studies identified via MEDLINE, EMBASE, CINAHL, Current Contents, and the Cochrane Central Register of Controlled Trials. Evidence tables generated in the 2008 Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology (AAN) review of the use of BoNT for movement disorders were also reviewed and updated. The panel evaluated evidence at several levels, supporting BoNT as a class, the serotypes BoNT-A and BoNT-B, as well as the four individual commercially available formulations: abobotulinumtoxinA (A/Abo), onabotulinumtoxinA (A/Ona), incobotulinumtoxinA (A/Inco), and rimabotulinumtoxinB (B/Rima). The panel ultimately made recommendations for each therapeutic indication, based upon the strength of clinical evidence and following the AAN classification scale. For the treatment of blepharospasm, the evidence supported a Level A recommendation for BoNT-A, A/Inco, and A/Ona; a Level B recommendation for A/Abo; and a Level U recommendation for B/Rima. For hemifacial spasm, the evidence supported a Level B recommendation for BoNT-A and A/Ona, a Level C recommendation for A/Abo, and a Level U recommendation for A/Inco and B/Rima. For the treatment of oromandibular dystonia, the evidence supported a Level C recommendation for BoNT-A, A/Abo, and A/Ona, and a Level U recommendation for A/Inco and B/Rima. For the treatment of cervical dystonia, the published evidence supported a Level A recommendation for all four BoNT formulations. For limb dystonia, the available evidence supported a Level B recommendation for both A/Abo and A/Ona, but no published studies were identified for A/Inco or B/Rima, resulting in a Level U recommendation for these two formulations. For adductor laryngeal dystonia, evidence supported a Level C recommendation for the use of A/Ona, but a Level U recommendation was warranted for B/Rima, A/Abo, and A/Inco. For the treatment of focal tics, a Level U recommendation was warranted at this time for all four formulations. For the treatment of tremor, the published evidence supported a level B recommendation for A/Ona, but no published studies were identified for A/Abo, A/Inco, or B/Rima, warranting a Level U recommendation for these three formulations. Further research is needed to address evidence gaps and to evaluate BoNT formulations where currently there is insufficient or conflicting clinical data.

Evidence-based review and assessment of botulinum neurotoxin for the treatment of adult spasticity in the upper motor neuron syndrome.

Botulinum neurotoxin (BoNT) can be injected to achieve therapeutic benefit across a large range of clinical conditions. To assess the efficacy and safety of BoNT injections for the treatment of spasticity associated with the upper motor neuron syndrome (UMNS), an expert panel reviewed evidence from the published literature. Data sources included English-language studies identified via MEDLINE, EMBASE, CINAHL, Current Contents, and the Cochrane Central Register of Controlled Trials. Evidence tables generated in the 2008 Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology (AAN) review of the use of BoNT for autonomic disorders were also reviewed and updated. The panel evaluated evidence at several levels, supporting BoNT as a class, the serotypes BoNT-A and BoNT-B, as well as the four individual commercially available formulations: abobotulinumtoxinA (A/Abo), onabotulinumtoxinA (A/Ona), incobotulinumtoxinA (A/Inco), and rimabotulinumtoxinB (B/Rima). The panel ultimately made recommendations on the effectiveness of BoNT for the management of spasticity, based upon the strength of clinical evidence and following the AAN classification scale. While the prior report by the AAN provided recommendations for the use of BoNT as a class of drug, this report provides more detail and includes recommendations for the individual formulations. For the treatment of upper limb spasticity, the evidence supported a Level A recommendation for BoNT-A, A/Abo, and A/Ona, with a Level B recommendation for A/Inco; there was insufficient evidence to support a recommendation for B/Rima. For lower limb spasticity, there was sufficient clinical evidence to support a Level A recommendation for A/Ona individually and BoNT-A in aggregate; the clinical evidence for A/Abo supported a Level C recommendation; and there was insufficient information to recommend A/Inco and B/Rima (Level U). There is a need for further comparative effectiveness studies of the available BoNT formulations for the management of spasticity.

Evidence-based review and assessment of botulinum neurotoxin for the treatment of secretory disorders.

Botulinum neurotoxin (BoNT) can be injected to achieve therapeutic benefit across a large range of clinical conditions. To assess the efficacy and safety of BoNT injections for the treatment of certain hypersecretory disorders, including hyperhidrosis, sialorrhea, and chronic rhinorrhea, an expert panel reviewed evidence from the published literature. Data sources included English-language studies identified via MEDLINE, EMBASE, CINAHL, Current Contents, and the Cochrane Central Register of Controlled Trials. Evidence tables generated in the 2008 Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology (AAN) review of the use of BoNT for autonomic disorders were also reviewed and updated. The panel evaluated evidence at several levels, supporting BoNT as a class, the serotypes BoNT-A and BoNT-B, as well as the four individual commercially available formulations: abobotulinumtoxinA (A/Abo), onabotulinumtoxinA (A/Ona), incobotulinumtoxinA (A/Inco), and rimabotulinumtoxinB (B/Rima). The panel ultimately made recommendations for each therapeutic indication, based upon the strength of clinical evidence and following the AAN classification scale. For the treatment of axillary hyperhidrosis in a total of 923 patients, the evidence supported a Level A recommendation for BoNT-A, with a Level B recommendation for A/Abo and A/Ona and a Level U recommendation (insufficient data) for A/Inco and B/Rima. Five trials in 82 patients supported the use of BoNT in palmar hyperhidrosis, with a Level B recommendation for BoNT-A and a Level C recommendation for BoNT-B; individual formulations received a Level U rating due to insufficient data. BoNT (and all individual formulations) received a Level U recommendation for the treatment of gustatory sweating. Support for use of BoNT in sialorrhea was derived from eight trials in a total of 222 adults and children. Evidence supported a Level B recommendation for A/Abo, A/Ona, and B/Rima and a Level U recommendation for A/Inco. Evidence supported a Level B recommendation for A/Ona for the treatment of allergic rhinitis, based on two Class II studies in 73 patients. A lack of published studies for A/Abo, A/Inco, or B/Rima supported a Level U recommendation for those formulations. Further clarity on the optimal mode of administration and additional studies using other BoNT formulations are needed to fill current evidence gaps.

Type 2 diabetes and disease management: exploring the connections.

Type 2 diabetes is an enormous public health problem affecting an estimated 18.2 million Americans. The prevalence is increasing, particularly among youth and young adults, in parallel with the continuing rise in obesity. The cost of treating diabetes complications imposes a tremendous burden on healthcare resources, and there has been limited success in achieving the treatment targets which are clearly associated with reduced risks of complications and mortality. This paper reviews the relationship of obesity to the risk and health complications of diabetes, and the impact of weight loss in reducing the risk of developing diabetes and in reducing the severity of metabolic and cardiovascular consequences in individuals who have already developed diabetes.

Weight gain in the treatment of mood disorders.

Overweight and obesity have become an urgent public health problem in the United States: approximately 61% of the adult population (97 million adults) are overweight or obese, where overweight is defined as a body mass index (BMI) >/= 25 and obesity is defined as a BMI >/= 30. Overweight and obesity increase the risk for developing many serious chronic diseases such as cardiovascular disease, type 2 diabetes, hypertension, dyslipidemia, and certain cancers. Increased morbidity due to obesity-related disorders begins within the normal weight range. Weight gain in adulthood per se, even in individuals who are normal weight, has deleterious health effects. Medications, particularly those commonly used in psychiatry and neurology, are a significant iatrogenic source of overweight and obesity. The weight gain potential of prescription medications should be considered in order to enhance patient compliance and reduce the risk of metabolic sequelae of weight gain. This article provides an overview of the weight-gain potential of several classes of drugs commonly used in psychiatric practice and considerations for clinicians in prescribing these medications.

Effects of experimental weight perturbation on skeletal muscle work efficiency in human subjects.

Maintenance of reduced or elevated body weight results in respective decreases or increases in energy expended in physical activity, defined as 24-h energy expenditure excluding resting energy expenditure and the thermic effect of feeding, beyond those attributable to weight change. We examined skeletal muscle work efficiency by graded cycle ergometry and, in some subjects, rates of gastrocnemius muscle ATP flux during exercise by magnetic resonance spectroscopy (MRS), in 30 subjects (15 males, 15 females) at initial weight and 10% below initial weight and in 8 subjects (7 males, 1 female) at initial weight and 10% above initial weight to determine whether changes in skeletal muscle work efficiency at altered body weight were correlated with changes in the energy expended in physical activity. At reduced weight, muscle work efficiency was increased in both cycle ergometry [mean (SD) change = +26.5 (26.7)%, P < 0.001] and MRS [ATP flux change = -15.2 (23.2)%, P = 0.044] studies. Weight gain resulted in decreased muscle work efficiency by ergometry [mean (SD) change = -17.8 (20.5)%, P = 0.043]. Changes in muscle efficiency at altered body weight accounted for 35% of the change in daily energy expended in physical activity.

Nutritional assessment of hospital patients: New methods and new opportunities.

Recently, two new methods (total body electrical conductivity [TOBEC] and bioelectrical impedance analysis [BIA]) have become available for the rapid, safe, and convenient estimation of total body water in hospital patients. Despite these clear advantages, the clinical usefulness of the TOBEC and BIA methods in patient diagnosis and care is likely to be restricted by illness-related changes in the hydration of the lean body and in the distribution of water between the intracellular and extracellular water compartments. If these methods can be refined so as to permit their measurement of extracellular water as rapidly as they now measure total body water, the ability of clinicians to assess and monitor the nutritional and metabolic status of their hospital patients will be greatly enhanced.

Heart Rate Response to Ballet Stage Performance.

In brief The heart rate responses of 13 professional ballet dancers were monitored during stage performances. When performing allegro (fast tempo) dance variations, heart rates increased rapidly to near-maximal levels. Mean peak heart rate during these dances was 184 beats-min-1, or 94% of the maximum age-predicted heart rate; the highest recorded heart rate was 197 beats-min-1. Accordingly, ballet stage dancing may be categorized as high-intensity, brief-duration exercise.