Heterozygous variants in MYH10 associated with neurodevelopmental disorders and congenital anomalies with evidence for primary cilia-dependent defects in Hedgehog signaling.

PURPOSE: Nonmuscle myosin II complexes are master regulators of actin dynamics that play essential roles during embryogenesis with vertebrates possessing 3 nonmuscle myosin II heavy chain genes, MYH9, MYH10, and MYH14. As opposed to MYH9 and MYH14, no recognizable disorder has been associated with MYH10. We sought to define the clinical characteristics and molecular mechanism of a novel autosomal dominant disorder related to MYH10. METHODS: An international collaboration identified the patient cohort. CAS9-mediated knockout cell models were used to explore the mechanism of disease pathogenesis. RESULTS: We identified a cohort of 16 individuals with heterozygous MYH10 variants presenting with a broad spectrum of neurodevelopmental disorders and variable congenital anomalies that affect most organ systems and were recapitulated in animal models of altered MYH10 activity. Variants were typically de novo missense changes with clustering observed in the motor domain. MYH10 knockout cells showed defects in primary ciliogenesis and reduced ciliary length with impaired Hedgehog signaling. MYH10 variant overexpression produced a dominant-negative effect on ciliary length. CONCLUSION: These data presented a novel genetic cause of isolated and syndromic neurodevelopmental disorders related to heterozygous variants in the MYH10 gene with implications for disrupted primary cilia length control and altered Hedgehog signaling in disease pathogenesis.

Frailty and stroke thrombectomy outcomes-an observational cohort study.

INTRODUCTION: Mechanical thrombectomy (MT) can improve outcomes following ischaemic stroke. Patient selection for MT is predominantly based on physiological and imaging parameters. We assessed whether people living with pre-stroke frailty had differing outcomes following MT. METHODS: We included consecutive patients undergoing MT at a UK comprehensive stroke centre. We calculated a cumulative deficits frailty index to identify pre-stroke frailty in those patients presenting directly to the centre. Frailty was defined as an index score ≥ 0.24. We assessed univariable and multivariable association between pre-stroke frailty and stroke outcomes. Our primary outcomes were modified Rankin Scale (mRS) and mortality at 90 days. RESULTS: Of 175 patients who underwent MT (2014-2018), we identified frailty in 49 (28%). Frail and non-frail patients had similar rates of thrombolysis administration, successful recanalization and onset to recanalization times. Those with pre-stroke frailty had higher 24 hour National Institutes of Health Stroke Scale (12(IQR: 8-17) versus 3(IQR: 2-13); P = 0.001); were less likely to be independent (mRS 0-2: 18% versus 61%; P < 0.001) and more likely to die (47% versus 14%; P < 0.001) within 90 days. Adjusting for age, baseline NIHSS and thrombolysis, frailty remained a strong, independent predictor of poor clinical outcome at 90 days (Death OR: 3.12 (95% CI: 1.32-7.4); dependency OR: 3.04 (95%CI: 1.10-8.44). Age was no longer a predictor of outcome when adjusted for frailty. CONCLUSION: Pre-stroke frailty is prevalent in real-world patients eligible for MT and is an important predictor of poor outcomes. Routine assessment of pre-stroke frailty could help decision-making around patient selection for MT.

Newborn Screening for Pompe Disease: Pennsylvania Experience.

Pennsylvania started newborn screening for Pompe disease in February 2016. Between February 2016 and December 2019, 531,139 newborns were screened. Alpha-Glucosidase (GAA) enzyme activity is measured by flow-injection tandem mass spectrometry (FIA/MS/MS) and full sequencing of the GAA gene is performed as a second-tier test in all newborns with low GAA enzyme activity [<2.10 micromole/L/h]. A total of 115 newborns had low GAA enzyme activity and abnormal genetic testing and were referred to metabolic centers. Two newborns were diagnosed with Infantile Onset Pompe Disease (IOPD), and 31 newborns were confirmed to have Late Onset Pompe Disease (LOPD). The incidence of IOPD + LOPD was 1:16,095. A total of 30 patients were compound heterozygous for one pathogenic and one variant of unknown significance (VUS) mutation or two VUS mutations and were defined as suspected LOPD. The incidence of IOPD + LOPD + suspected LOPD was 1: 8431 in PA. We also found 35 carriers, 15 pseudodeficiency carriers, and 2 false positive newborns.

Outcomes after Thrombectomy in Belfast: Mothership and Drip-and-Ship in the Real World.

BACKGROUND: Mechanical thrombectomy has revolutionised the treatment of acute ischaemic stroke due to large vessel occlusion. It is well recognised that patients are more likely to benefit when reperfusion happens quickly, however, there is uncertainty as to how best to deliver this service. OBJECTIVES: To compare outcomes of patients in Northern -Ireland who underwent thrombectomy via direct admission to the single endovascular centre (mothership [MS]) with those transferred from primary stroke centres (drip-and-ship [DS]). METHODS: Analysis was conducted on the records of all patients who underwent thrombectomy from January 2014 to December 2017 inclusive. The primary outcome measure was 3 months functional independence (modified Rankin Score [mRS] 0-2). Secondary outcome measures were full recovery (mRS 0) at 3 months, symptomatic intracranial haemorrhage (sICH) rates and mortality rates. RESULTS: Two hundred fourteen patients underwent thrombectomy (MS 124, DS 90). Patients in the MS group were older (median 73 vs. 70 years, p = 0.026), but there was no significant difference in baseline National Institutes of Health Stroke Scale (median 15 MS vs. 16.5 DS, p = 0.162) or thrombolysis rates (41.9% MS vs. 54.4% DS, p = 0.070) between the groups. Time from stroke onset to arrival at thrombectomy centre was shorter in the MS group (median 71 vs. 218 min, p < 0.001) but door to groin puncture time was shorter in the DS group (median 30 vs. 60 min, p < 0.001). There was no significant difference in 3 months functional independence (51.6% MS vs. 62.2% DS, p = 0.123), or in the secondary outcome measures of full recovery (21.8% MS vs. 12.2% DS, p = 0.071), sICH (MS 0.8%, DS 4.4%, p = 0.082) and mortality (MS 24.2%, DS 20.0%, p = 0.468). CONCLUSIONS: Our analysis showed similar outcomes after thrombectomy in the MS and DS groups. For patients potentially eligible for thrombectomy, rapid access to the endovascular centre is essential to optimise both the number of patients treated and the outcomes achieved.

An interstitial deletion within 9p21.3 and extending beyond CDKN2A predisposes to melanoma, neural system tumours and possible haematological malignancies.

Familial atypical multiple mole melanoma syndrome (FAMMM) is characterised by dysplastic naevi, malignant melanoma and pancreatic cancer. Given that large deletions involving CDKN2A (cyclin-dependent kinase inhibitor 2A) account for only 2% of cases, we describe a family that highlights the co-occurrence of both melanoma and neural system tumours to aid clinical recognition and propose a management strategy. A patient with multiple neurofibromas was referred with a provisional diagnosis of neurofibromatosis type 1 (NF1). Prior molecular testing, though, had failed to identify an NF1 mutation by sequencing and multiplex ligation-dependent probe amplification. His family history was significant for multiple in situ/malignant melanomas at young ages and several different cancers reminiscent of an underlying syndrome. A search of the Familial Cancer Database, FaCD Online, highlighted several families with cutaneous melanoma and nervous system tumours who were subsequently identified to have large deletions spanning CDKN2A Although sequencing of CDKN2A and TP53 failed to identify a mutation, a heterozygous CDKN2A deletion was identified by targeted array comparative genomic hybridisation (CGH). Whole-genome oligonucleotide array CGH and SNP analysis identified an interstitial deletion of at least 1.5 Mb within 9p21.3 and spanning approximately 25 genes. Identification of the underlying molecular abnormality permits predictive testing for at-risk relatives. Given the young cancer diagnoses, a surveillance regimen was developed and a clinical team organised for ongoing management so that genetic testing could be offered to both adults and minor children. Surveillance recommendations addressed cancer risks associated with FAMMM, and other cancers exhibited by this family with a large contiguous gene deletion.

Transplanted bone marrow mononuclear cells and MSCs impart clinical benefit to children with osteogenesis imperfecta through different mechanisms.

Transplantation of whole bone marrow (BMT) as well as ex vivo-expanded mesenchymal stromal cells (MSCs) leads to striking clinical benefits in children with osteogenesis imperfecta (OI); however, the underlying mechanism of these cell therapies has not been elucidated. Here, we show that non-(plastic)-adherent bone marrow cells (NABMCs) are more potent osteoprogenitors than MSCs in mice. Translating these findings to the clinic, a T cell-depleted marrow mononuclear cell boost (> 99.99% NABMC) given to children with OI who had previously undergone BMT resulted in marked growth acceleration in a subset of patients, unambiguously indicating the therapeutic potential of bone marrow cells for these patients. Then, in a murine model of OI, we demonstrated that as the donor NABMCs differentiate to osteoblasts, they contribute normal collagen to the bone matrix. In contrast, MSCs do not substantially engraft in bone, but secrete a soluble mediator that indirectly stimulates growth, data which provide the underlying mechanism of our prior clinical trial of MSC therapy for children with OI. Collectively, our data indicate that both NABMCs and MSCs constitute effective cell therapy for OI, but exert their clinical impact by different, complementary mechanisms. The study is registered at www.clinicaltrials.gov as NCT00187018.

Association of 1,25-dihydroxyvitamin D levels with physical performance and thigh muscle cross-sectional area in chronic kidney disease stage 3 and 4.

BACKGROUND: Declines in 1,25-dihydroxyvitamin D (1,25(OH)2D) levels and physical functioning follow the course of chronic kidney disease (CKD). Although the molecular actions of vitamin D in skeletal muscle are well known, and muscle weakness and atrophy are observed in vitamin D-deficient states, there is little information regarding vitamin D and muscle function and size in CKD. OBJECTIVE: To examine associations of vitamin D with physical performance (PF) and muscle size. DESIGN: Cross-sectional. SETTING: CKD clinic. SUBJECTS: Twenty-six patients (61 ± 13 years, 92% men) with CKD stage 3 or 4. MAIN OUTCOME MEASURES: Gait speed, 6-minute walk, sit-to-stand time, 1-legged balance, and thigh muscle cross-sectional area (MCSA), measured by magnetic resonance imaging (MRI). RESULTS: Overall, 73% were 25-hydroxyvitamin D (25(OH)D) deficient (n = 10) or insufficient (n = 9) (Kidney Disease Outcomes Quality Initiative guidelines). 25(OH)D level was associated with normal gait speed only (r = 0.41, P = .04). Normal and fast gait speed, the distance walked in 6 minutes, and sit-to-stand time were best explained by 1,25(OH)2D and body mass index (P < .05 for all) and 1-legged stand by 1,25(OH)2D (r = 0.40, P < .05) only. There were no associations of age, estimated glomerular filtration rate (eGFR), intact parathyroid hormone (iPTH), or albumin with any PF measures. MCSA was associated with eGFR (r = 0.54, P < .01) only. Variance in MCSA was best explained by a model containing 1,25(OH)2D, plasma Ca²âº, and daily physical activity (by accelerometry) (P < .05 for all). Once these variables were in the model, there was no contribution of eGFR. CONCLUSION: These results suggest that 1,25(OH)2D is a determinant of PF and muscle size in patients with stage 3 and 4 CKD.

Management of osteoporosis in CKD Stages 3 to 5.

Osteoporosis and chronic kidney disease (CKD) are both common conditions of older adults and both may be associated with substantial morbidity. However, biochemical and histologic changes that occur with progressive kidney disease require specific interventions, some of which may be concordant with osteoporosis management in the general population, whereas others may be less relevant or perhaps even harmful. In this article, we review the diagnosis of and management strategies for osteoporosis in individuals with CKD, placing these into perspective with the recently published KDIGO (Kidney Disease: Improving Global Outcomes) guidelines for treatment of CKD-mineral and bone disorder (CKD-MBD). Specifically, we highlight osteoporosis treatment recommendations by CKD stage and discuss new avenues for osteoporosis treatment that may be useful in individuals with CKD.

Resistance training increases muscle mitochondrial biogenesis in patients with chronic kidney disease.

BACKGROUND AND OBJECTIVES: Muscle wasting, a common complication in chronic kidney disease (CKD), contributes to poor outcomes. Mitochondrial biogenesis is critical for the maintenance of skeletal muscle function and structural integrity. The present study--a secondary analysis from a published randomized controlled trial--examined the effect of resistance exercise training on skeletal muscle mitochondrial (mt)DNA copy number and determined its association with skeletal muscle phenotype (muscle mass and strength). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Twenty-three patients with moderate-to-severe CKD were randomized to resistance training (n = 13) or an attention-control (n = 10) group for 12 weeks. After a run-in period of a low-protein diet that continued during the intervention, mtDNA copy number in the vastus lateralis muscle was estimated by quantitative real-time PCR at baseline and 12 weeks. RESULTS: Participants mean age was 64 +/- 10 (SD) years and median (interquartile range, IQR) GFR 27.5 (37.0) ml/min. There were no differences between groups at baseline. Median (IQR) mtDNA copy number was 13,713 (10,618). There was a significant increase in muscle mtDNA with exercise compared with controls (1306 [13306] versus -3747 [15467], P = 0.01). The change in muscle mtDNA copy number was positively correlated with previously reported changes in types I and II muscle fiber cross-sectional area. CONCLUSIONS: In this pilot study, resistance training was highly effective in enhancing mitochondrial content in patients with moderate-to-severe CKD. This finding suggests that the mitochondrial dysfunction observed with chronic disease could potentially be restored with this exercise modality and should be investigated further.

Relationship between vitamin D and muscle size and strength in patients on hemodialysis.

OBJECTIVE: Vitamin D has various actions in skeletal muscle. The purpose of this study was to compare lower-limb muscle size and strength in hemodialysis (HD) patients being treated with 1,25-dihydroxyvitamin D (calcitriol) or a 1,25-dihydroxyvitamin D analogue (paricalcitol) with lower-limb muscle size and strength in HD patients who were receiving none. DESIGN: This was a retrospective, cross-sectional study. SETTING: This study was performed in outpatient HD centers. PATIENTS: Hemodialysis patients receiving calcitriol or paricalcitol (active vitamin D) for control of secondary hyperparathyroidism (VitD, n = 49) were compared with HD patients who were not (n = 30). MAIN OUTCOME MEASURES: The main outcome measures included the cross-sectional areas (CSAs) of the thigh and tibialis anterior muscles by magnetic resonance imaging, and three measures of strength: the three-repetition maximum (3RM) for knee extension (isotonic), the peak torque of knee extensors (isokinetic), and maximal voluntary contraction of the ankle dorsiflexor muscles (isometric). RESULTS: There were no differences in age, weight, dialysis vintage, or intact parathyroid hormone levels between groups, although serum albumin was higher in the VitD group (P < .05). Patients in the VitD group had a larger thigh-muscle CSA (P < .05) and were stronger across all strength measures (P < .05) after controlling for age and gender (by analysis of covariance). When all analyses were subsequently adjusted for serum albumin concentration, only the difference in 3RM knee-extension strength lost significance. There were no significant differences in any measurements between patients who received calcitriol or paricalcitol. CONCLUSION: Treatment with active vitamin D was associated with greater muscle size and strength in this cohort of HD patients.

Strength training improves muscle quality and insulin sensitivity in Hispanic older adults with type 2 diabetes.

Hispanics are at increased risk of morbidity and mortality due to their high prevalence of diabetes and poor glycemic control. Strength training is the most effective lifestyle intervention to increase muscle mass but limited data is available in older adults with diabetes. We determined the influence of strength training on muscle quality (strength per unit of muscle mass), skeletal muscle fiber hypertrophy, and metabolic control including insulin resistance (Homeostasis Model Assessment -HOMA-IR), C-Reactive Protein (CRP), adiponectin and Free Fatty Acid (FFA) levels in Hispanic older adults. Sixty-two community-dwelling Hispanics (>55 y) with type 2 diabetes were randomized to 16 weeks of strength training plus standard care (ST group) or standard care alone (CON group). Skeletal muscle biopsies and biochemical measures were taken at baseline and 16 weeks. The ST group show improved muscle quality (mean+/-SE: 28+/-3) vs CON (-4+/-2, p<0.001) and increased type I (860+/-252 microm(2)) and type II fiber cross-sectional area (720+/-285 microm(2)) compared to CON (type I: -164+/-290 microm(2), p=0.04; and type II: -130+/-336 microm(2), p=0.04). This was accompanied by reduced insulin resistance [ST: median (interquartile range) -0.7(3.6) vs CON: 0.8(3.8), p=0.05]; FFA (ST: -84+/-30 micromol/L vs CON: 149+/-48 micromol/L, p=0.02); and CRP [ST: -1.3(2.9) mg/L vs CON: 0.4(2.3) mg/L, p=0.05]. Serum adiponectin increased with ST [1.0(1.8) microg/mL] compared to CON [-1.2(2.2) microg/mL, p<0.001]. Strength training improved muscle quality and whole-body insulin sensitivity. Decreased inflammation and increased adiponectin levels were related with improved metabolic control. Further studies are needed to understand the mechanisms associated with these findings. However, these data show that strength training is an exercise modality to consider as an adjunct of standard of care in high risk populations with type 2 diabetes.

Unsafe and violent behavior in commercials aired during televised major sporting events.

OBJECTIVE: Injuries are the leading cause of death in children, and media exposure seems to increase children's risk-taking behavior. Televised sports are commonly viewed by children. The objective of this study was to determine the proportion of commercials that depict violence or other unsafe behavior during major televised sporting events that are aired before 9:00 pm. METHODS: We obtained a list of the 50 sports programs that were most highly rated by Nielsen Media Research and that were televised between September 1, 2001, and September 1, 2002. These 50 programs included Winter Olympics events (n = 15), National Football League (NFL) regular season games (n = 14), NFL playoff games (n = 10), Major League Baseball World Series and playoff games (n = 7), the NFL Super Bowl (n = 1), the National Basketball Association Western Conference Final Game (n = 1), the College Football Rose Bowl (n = 1), and the National Collegiate Athletic Association Basketball Championship game (n = 1). Two other events were reviewed as well: the final round of the Masters Golf Championship, because it was the only sporting event rated in the top 50 of the previous year that was not represented by a similar sporting event in the study year, and the Daytona 500 National Association for Stock Car Auto Racing race, because it was the only event rated among the top 75 of the study year that was not represented by a similar event (ie, there were no other golfing or auto racing events reviewed). These events were included because different sporting events may attract different viewers and different advertisements; thus, their inclusion provides a more comprehensive evaluation of the topic. For sporting events with >3 programs in the top 50 (NFL regular season games, NFL playoff games, Winter Olympic events, and Major League Baseball World Series), representative samples of events were assessed. Surrogate events were analyzed for programs that were aired after 9:00 PM (Eastern Time) to control for the reduced likelihood of viewing by children after 9:00 PM. For example, afternoon telecasts of the National Collegiate Athletic Association Regional Final and National Semifinal games were assessed in place of the Championship game, which started after 9:00 PM. Weekend afternoon telecasts of the Winter Olympics (3 successive weekends) were assessed as surrogates for all Olympics telecasts. For the World Series, the Super Bowl, and the National Basketball Association Conference Championship games, which began before 9:00 PM but ended after that time, we evaluated only commercials that aired before 9:00 PM. All commercials that were aired during these programs were reviewed at standard speed for unsafe behavior or violence. Commercials that were aired during pregame, postgame, or halftime periods were not assessed. Commercials were categorized according to the product being advertised. Unsafe behavior was simply defined as any action that could have harmful consequences or that contravened the injury prevention recommendations of national organizations. Violence was defined as any intentional physical contact by an aggressor that had the potential to inflict injury or harm or the legitimate threat of such action. All commercials were reviewed by at least 2 investigators; when the 2 could not agree on the findings, a third investigator was used to resolve differences. The percentage of commercials and of commercial breaks that portrayed violent or unsafe behavior was determined for each category of event and advertised product. A commercial break was defined as a series of commercials shown during a single break from the sporting event. chi2 analysis was used for all analyses, and relative risks with 95% confidence intervals were determined. The proportion of commercials that depicted unsafe behavior and/or violence during each sporting event was compared with the proportion of such commercials that were observed during the Masters Golf Tournament (which had the lowest proportion of commercials depicting such behavior). The proportion of commercials that contained violent/unsafe behavior for each advertised product was compared with the proportion of such commercials that advertised food or nonalcoholic beverages. Food and nonalcoholic beverage commercials were selected as the reference because they are a well-defined, common category of commercial. RESULTS: Of the 1185 commercials assessed, 14% (n = 165) displayed unsafe behavior and 6% (n = 66) depicted violence. Of the 322 commercial breaks, 158 (49%) contained at least 1 commercial showing unsafe behavior or violence. Sixty-three commercials required review by a third investigator to adjudicate violence or unsafe behavior; 20 of 52 were ultimately judged to portray unsafe behavior, and 4 of 11 were ultimately judged to portray violence. Sporting events differed in the proportion of commercials that showed violence or unsafe behavior. The Super Bowl had the highest proportion of such commercials, and the Masters Golf Tournament had the least (relative risk: 4.3; 95% confidence interval: 1.4-12.5). The Masters Golf Tournament was noteworthy for the complete absence of violent commercials. Only 18% of reviewed commercials advertised movies or television programs, yet these commercials accounted for 86% of all violent commercials. Forty-eight percent of commercials that contained violence were for movies, and an additional 38% were for television programs. Nearly two thirds of all commercials for movies contained violence, whereas 15% of all commercials for television programs contained violence, a rate that increased to 22% when commercials for other sporting events were excluded. Several categories of commercials portrayed unsafe behaviors; commercials for automobiles accounted for the most. In 8 different categories, 10% or more of the commercials depicted unsafe behavior, and 7 were significantly more likely to depict such behavior than a food or beverage commercial. CONCLUSIONS: Children who watch televised sports view a significant amount of violent and unsafe behavior. In accordance with American Academy of Pediatrics recommendations for television viewing, parents should both limit and directly supervise children's viewing of these events. Our findings suggest that parents should remain present during commercials or should consider implementing commercial-skipping technology. In addition, efforts should be made to regulate the content of commercials that promote television programs and movies on the basis of the hour at which the sporting event is aired. Moreover, the sports, movie, and television industries should be encouraged to adopt models of advertising that limit or eliminate such content. These efforts could help to ensure that the viewing of televised sporting events is a safe and positive experience for children.

Resistance training to reduce the malnutrition-inflammation complex syndrome of chronic kidney disease.

BACKGROUND: Systemic inflammation and protein-energy malnutrition may be associated with poor outcomes in kidney disease. METHODS: We studied 26 adults (age, 65 +/- 10 [SD] years) with chronic kidney disease, not on dialysis therapy. Subjects were randomly assigned to resistance training (n = 14) or a control group (n = 12) for 12 weeks, while counseled to consume a low-protein diet (protein, approximately 0.6 g/kg/d). We determined whether resistance training reduces levels of inflammatory mediators (serum C-reactive protein [CRP] and interleukin-6 [IL-6]), in addition to previously reported improvements in nutritional and functional status in this same subject population. RESULTS: Serum CRP levels were reduced in subjects undergoing resistance training (-1.7 mg/L) compared with controls (1.5 mg/L; P = 0.05). Similarly, IL-6 levels were reduced in the resistance-exercise group versus controls (-4.2 versus 2.3 pg/mL; P = 0.01). Resistance training lead to skeletal muscle hypertrophy, shown by increases in type I (24% +/- 31%) and type II (22% +/- 41%) muscle fiber cross-sectional areas, compared with control subjects (-14% +/- 34% and -13% +/- 18%, respectively; P < 0.05). Muscle strength also improved with resistance training (28% +/- 14%) compared with controls (-13% +/- 22%; P = 0.001). CONCLUSION: Resistance training reduced inflammation and improved nutritional status in individuals with moderate chronic kidney disease consuming a low-protein diet. These results need to be investigated further in larger cohorts of patients with varying stages of kidney disease to determine whether resistance training can improve disease outcomes long term.

A randomized controlled trial of resistance exercise training to improve glycemic control in older adults with type 2 diabetes.

OBJECTIVE: To determine the efficacy of high-intensity progressive resistance training (PRT) on glycemic control in older adults with type 2 diabetes. RESEARCH DESIGN AND METHODS: We performed a 16-week randomized controlled trial in 62 Latino older adults (40 women and 22 men; mean +/- SE age 66 +/- 8 years) with type 2 diabetes randomly assigned to supervised PRT or a control group. Glycemic control, metabolic syndrome abnormalities, body composition, and muscle glycogen stores were determined before and after the intervention. RESULTS: Sixteen weeks of PRT (three times per week) resulted in reduced plasma glycosylated hemoglobin levels (from 8.7 +/- 0.3 to 7.6 +/- 0.2%), increased muscle glycogen stores (from 60.3 +/- 3.9 to 79.1 +/- 5.0 mmol glucose/kg muscle), and reduced the dose of prescribed diabetes medication in 72% of exercisers compared with the control group, P = 0.004-0.05. Control subjects showed no change in glycosylated hemoglobin, a reduction in muscle glycogen (from 61.4 +/- 7.7 to 47.2 +/- 6.7 mmol glucose/kg muscle), and a 42% increase in diabetes medications. PRT subjects versus control subjects also increased lean mass (+1.2 +/- 0.2 vs. -0.1 +/- 0.1 kg), reduced systolic blood pressure (-9.7 +/- 1.6 vs. +7.7 +/- 1.9 mmHg), and decreased trunk fat mass (-0.7 +/- 0.1 vs. +0.8 +/- 0.1 kg; P = 0.01-0.05). CONCLUSIONS: PRT as an adjunct to standard of care is feasible and effective in improving glycemic control and some of the abnormalities associated with the metabolic syndrome among high-risk older adults with type 2 diabetes.

Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: Implications for cell therapy of bone.

Treatment with isolated allogeneic mesenchymal cells has the potential to enhance the therapeutic effects of conventional bone marrow transplantation in patients with genetic disorders affecting mesenchymal tissues, including bone, cartilage, and muscle. To demonstrate the feasibility of mesenchymal cell therapy and to gain insight into the transplant biology of these cells, we used gene-marked, donor marrow-derived mesenchymal cells to treat six children who had undergone standard bone marrow transplantation for severe osteogenesis imperfecta. Each child received two infusions of the allogeneic cells. Five of six patients showed engraftment in one or more sites, including bone, skin, and marrow stroma, and had an acceleration of growth velocity during the first 6 mo postinfusion. This improvement ranged from 60% to 94% (median, 70%) of the predicted median values for age- and sex-matched unaffected children, compared with 0% to 40% (median, 20%) over the 6 mo immediately preceding the infusions. There was no clinically significant toxicity except for an urticarial rash in one patient just after the second infusion. Failure to detect engraftment of cells expressing the neomycin phosphotransferase marker gene suggested the potential for immune attack against therapeutic cells expressing a foreign protein. Thus, allogeneic mesenchymal cells offer feasible posttransplantation therapy for osteogenesis imperfecta and likely other disorders originating in mesenchymal precursors.