Cortical reorganization after motor stroke: A pilot study on differences between the upper and lower limbs

Stroke patients suffering from hemiparesis may show substantial recovery in the first months poststroke due to neural reorganization. While reorganization driving improvement of upper hand motor function has been frequently investigated, much less is known about the changes underlying recovery of lower limb function. We, therefore, investigated neural network dynamics giving rise to movements of both the hands and feet in 12 well‐recovered left‐hemispheric chronic stroke patients and 12 healthy participants using a functional magnetic resonance imaging sparse sampling design and dynamic causal modeling (DCM). We found that the level of neural activity underlying movements of the affected right hand and foot positively correlated with residual motor impairment, in both ipsilesional and contralesional premotor as well as left primary motor (M1) regions. Furthermore, M1 representations of the affected limb showed significantly stronger increase in BOLD activity compared to healthy controls and compared to the respective other limb. DCM revealed reduced endogenous connectivity of M1 of both limbs in patients compared to controls. However, when testing for the specific effect of movement on interregional connectivity, interhemispheric inhibition of the contralesional M1 during movements of the affected hand was not detected in patients whereas no differences in condition‐dependent connectivity were found for foot movements compared to controls. In contrast, both groups featured positive interhemispheric M1 coupling, that is, facilitation of neural activity, mediating movements of the affected foot. These exploratory findings help to explain why functional recovery of the upper and lower limbs often develops differently after stroke, supporting limb‐specific rehabilitative strategies.     

Effects of diltiazem on serum lipids, exercise performance and blood pressure: randomized, double-blind, placebo-controlled evaluation for systemic hypertension

Treatment of hypertension with diuretics, beta blockers and alpha blockers may be associated with adverse effects on exercise performance, serum lipids and blood chemistries, as well as with orthostatic effects and fluid retention. A randomized, double-blind, placebo-controlled trial of a sustained-release preparation of diltiazem as sole therapy for moderate essential hypertension was conducted. Diltiazem was administered 2 times a day (360 mg/day) to 16 patients and placebo to 14 patients in a 12-week study. Average supine blood pressure with diltiazem therapy fell from 161/100 to 144/87 mm Hg without fluid retention or orthostatic effects. In an open-label study, patients from the placebo and diltiazem groups continued with diltiazem therapy. At an average of over 8 months, supine blood pressure on diltiazem was 147/88 mm Hg, and after withdrawal to single-blind placebo, average supine blood pressure increased to 173/104 mm Hg. All changes were significant compared with baseline and placebo (p less than 0.01). On diltiazem therapy, maximal treadmill exercise was increased by an average of 55 seconds (p less than 0.01), whereas heart rate, blood pressure and double product (heart rate X blood pressure) were reduced at submaximal exercise, and heart rate and double product were reduced at maximal exercise. No changes in serum glucose, potassium or uric acid were found. No adverse effects on serum lipids occurred. Diltiazem treatment was associated with an increase in high-density lipoprotein cholesterol (52 to 60 mg/dl, p less than 0.006) and a decrease in total cholesterol:high-density lipoprotein cholesterol ratio (4.7 to 4.2, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Activated natural killer cells and interleukin-2 promote granulocytic and megakaryocytic reconstitution after syngeneic bone marrow transplantation in mice

Purified populations of natural killer (NK) cells were obtained from mice with severe combined immune deficiency (SCID). SCID spleen cells were cultured and activated with recombinant human interleukin-2 (rhIL- 2) in vitro. The activated NK cells were then transferred with syngeneic BALB/c bone marrow cells (BMC) and rhIL-2 into lethally irradiated syngeneic recipients to determine their effect on long-term hematopoietic reconstitution. On analysis, the transfer of rhIL-2- activated NK cells along with BMC resulted in significant increases in splenic and BM hematopoietic progenitor cells when compared with those for mice not receiving NK cells. Histologic and flow cytometric analysis showed a marked increase in granulocytic and megakaryocytic lineage cells present in the spleens of the mice receiving activated NK cells. Analysis of the peripheral blood indicated that the transfer of activated NK cells with BMC also significantly improved platelet and total white blood cell counts, with increases in segmented neutrophils. Erythroid recovery was not affected. Finally, lethally irradiated mice receiving activated NK cells and rhIL-2 along with limiting numbers of syngeneic BMC showed a marked increase in survival rate. These results show that the use of populations enriched for activated NK cells after syngeneic BM transplantation (BMT) has a profound enhancing effect on engraftment primarily affecting megakaryocytic and granulocytic cell reconstitution. Therefore, the transfer of activated NK cells and rhIL- 2 may be of clinical use to promote hematopoietic reconstitution after BMT.     

Effectiveness of methyl-GAG (methylglyoxal-bis[guanylhydrazone]) in patients with advanced malignant lymphoma

We treated 51 patients with advanced malignant lymphoma refractory to conventional therapy with methyl-glyoxal-bis(guanylhydrazone) (methyl- GAG) at doses ranging from 400 to 800 mg/sq m. Therapy was started on a weekly schedule and was switched to every other week in responding patients at the onset of toxicity. Partial responses were observed in 6 of 13 evaluable patients with Hodgkin's disease (46%), 5 of 10 patients with diffuse poorly differentiated lymphocytic lymphoma (50%), 2 of 4 patients with nodular poorly differentiated lymphocytic lymphoma (50%), and 3 of 13 patients with diffuse histiocytic lymphoma (23%). Two of six patients with mycosis fungoides showed objective improvement in cutaneous disease. Toxicity was generally mild and included muscular weakness, myalgia, mucositis, and diarrhea; two patients developed bronchospasm following drug infusions. We conclude that methyl-GAG has major antitumor activity when administered on this schedule to patients with advanced malignant lymphoma. The low degree of toxicity, unique mechanism of action, and minimal myelosuppressive effects suggest that methyl-GAG will prove useful in future trials of combination chemotherapy regimens for the treatment of lymphoma.     

Lovastatin and coadministered antihypertensive/cardiovascular agents.

Hypertension and hypercholesterolemia frequently coexist and may require concomitant drug treatments. The efficacy and safety profile of lovastatin given in the presence of antihypertensive medication was evaluated using patient subgroups identified in the Expanded Clinical Evaluation of Lovastatin (EXCEL) Study. The EXCEL study examined 8,245 patients with moderate hypercholesterolemia randomly assigned either to a group treated with lovastatin (20-80 mg daily) or to a group given placebo for 48 weeks. After adjustment for patient characteristics, pairwise comparisons were made between patients taking no antihypertensive agents (n = 3,772) and those taking either calcium antagonists (n = 446), selective beta 1-adrenergic receptor blockers (n = 326), nonselective beta-adrenergic receptor blockers (n = 219), potassium-sparing diuretics (n = 187), thiazide diuretics (n = 126), or angiotensin converting enzyme inhibitors (n = 171). The placebo-corrected dose-dependent effect of lovastatin on the percent change from baseline in low-density lipoprotein cholesterol was not attenuated in any subgroup and was slightly enhanced in the calcium antagonist subgroup (-29% to -44%, p = 0.06) when compared with patients taking no antihypertensive agents (-24% to -40%); this difference, however, was only of borderline significance. Patterns of lovastatin-induced increase in high-density lipoprotein cholesterol and decrease in triglycerides were not consistently different among the subgroups. Examination of mean changes in serum transaminases, mean changes in creatine kinase, and the proportion of patients discontinuing therapy for clinical adverse experiences did not indicate the presence of an interaction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Transmaternal cell flow leads to antigen-experienced cord blood

Umbilical cord blood (UCB) is used for HSCT. It is known that UCB can comprise Ag-specific T cells. Here we question whether solely transmaternal cell flow may immunize UCB. Twenty-three female UCB samples were collected from healthy mothers and analyzed for minor histocompatibility Ag HY-specific responses. Forty-two of 104 tetramer(pos) T-cell clones, isolated from 16 of 17 UCB samples, showed male-specific lysis in vitro. Male microchimerism was present in 6 of 12 UCB samples analyzed. In conclusion, female UCB comprises HY-specific cytotoxic T cells. The immunization is presumably caused by transmaternal cell flow of male microchimerism present in the mother. The presence of immune cells in UCB that are not directed against maternal foreign Ags is remarkable and may explain the reported clinical observation of improved HSCT outcome with younger sibling donors.     

No Reduction in Circulating Preosteoclasts 18 Months after Treatment with Zoledronate: Analysis from a Randomized Placebo Controlled Trial

The conventional model that bisphosphonates bind to the bone surface and inhibit mature osteoclasts does not convincingly explain the prolonged duration of action of zoledronate. We hypothesized that zoledronate on the bone surface adjacent to marrow cells impairs osteoclastogenesis, contributing to sustained inhibition of resorption. In this case, numbers of circulating preosteoclasts may be reduced after zoledronate treatment. This study assessed this possibility in subjects from a clinical trial. Twenty-two osteopenic women participating in a randomized, controlled trial comparing zoledronate 5 mg with placebo were recruited, 18 months after administration of study drug. Peripheral blood mononuclear cells were analyzed for the presence of osteoclast precursors using flow cytometry for preosteoclast markers and the ability to form osteoclast-like cells in culture with RANKL and M-CSF. There was no difference in the percentage of CD14⁺/CD11b⁺ cells in peripheral blood between the two groups. The numbers of TRAP⁺ multinucleated cells in cultures in the absence of RANKL and M-CSF were very low in both groups, but a significantly higher number of these cells was observed in the zoledronate group compared with the placebo group (p = 0.01). The number of TRAP⁺ multinucleated cells and resorption pits following culture with RANKL and M-CSF did not differ between the two groups. Serum P1NP was reduced 53 % at 18 months in the zoledronate group but unchanged in the placebo group. These results do not support the hypothesis that the inhibitory action of zoledronate contributes to its prolonged action on preosteoclasts within bone marrow.     

EphB4 enhances the process of endochondral ossification and inhibits remodeling during bone fracture repair

Previous reports have identified a role for the tyrosine kinase receptor EphB4 and its ligand, ephrinB2, as potential mediators of both bone formation by osteoblasts and bone resorption by osteoclasts. In the present study, we examined the role of EphB4 during bone repair after traumatic injury. We performed femoral fractures with internal fixation in transgenic mice that overexpress EphB4 under the collagen type 1 promoter (Col1‐EphB4) and investigated the bone repair process up to 12 weeks postfracture. The data indicated that Col1‐EphB4 mice exhibited stiffer and stronger bones after fracture compared with wild‐type mice. The fractured bones of Col1‐EphB4 transgenic mice displayed significantly greater tissue and bone volume 2 weeks postfracture compared with that of wild‐type mice. These findings correlated with increased chondrogenesis and mineral formation within the callus site at 2 weeks postfracture, as demonstrated by increased safranin O and von Kossa staining, respectively. Interestingly, Col1‐EphB4 mice were found to possess significantly greater numbers of clonogenic mesenchymal stromal progenitor cells (CFU‐F), with an increased capacity to form mineralized nodules in vitro under osteogenic conditions, when compared with those of the wild‐type control mice. Furthermore, Col1‐EphB4 mice had significantly lower numbers of TRAP‐positive multinucleated osteoclasts within the callus site. Taken together, these observations suggest that EphB4 promotes endochondral ossification while inhibiting osteoclast development during callus formation and may represent a novel drug target for the repair of fractured bones. © 2013 American Society for Bone and Mineral Research.     

Waterproof cast liners in paediatric forearm fractures: a randomized trial

Purpose

Waterproof casts have been shown to provide adequate support and immobilization in fractures. This study evaluated two waterproof cast liners, namely, Wet or Dry^® and Delta Dry^®, in terms of ease of application/removal, durability, longevity, and patient satisfaction using patient- and technician-reported outcome measures.

Methods

A total of 105 children were enrolled in a randomized trial and received a below-elbow synthetic cast with either of the two cast liners.

Results

The two groups were comparable with regards to age, gender, side of cast, and hand dominance. Assessment was carried out at application and removal. In the patient-reported outcomes, the Wet or Dry^® group was rated significantly better in the odor and water resistance categories. In the technician-reported application and removal outcome measures, the Delta Dry^® group was rated significantly higher.

Conclusions

The use of waterproof cast liners appears to be safe in children with forearm fractures, with some differences in outcome between the two products trialed.