This study investigates whether the type of corticospinal reorganization (identified by transcranial magnetic stimulation) influences the efficacy of constraint-induced movement therapy (CIMT). Nine patients (five males, four females; mean age 16y [SD 6y 5mo], range 11-30y) controlling their paretic hand via ipsilateral corticospinal projections from the contralesional hemisphere and seven patients (three males, four females; mean age 17y [SD 7y], range 10-30y) with preserved crossed corticospinal projections from the affected hemisphere to the paretic hand underwent 12 consecutive days of CIMT. A Wolf motor function test applied before and after CIMT revealed a significant improvement in the quality of upper extremity movements in both groups. Only in patients with preserved crossed projections, however, was this amelioration accompanied by a significant gain in speed, whereas patients with ipsilateral projections tended to show speed reduction. These data, although preliminary, suggest that patients with congenital hemiparesis and ipsilateral corticospinal projections respond differently to CIMT.Constraint-induced movement therapy (CIMT) is a relatively new therapeutic approach focused on ameliorating upper extremity function in hemiparetic patients. It consists of immobilization of the nonparetic hand combined with individualized, intensive repetitive training of the paretic hand. CIMT has its origins in earlier basic research with rhesus monkeys that underwent deafferentation (surgical abolition of sensation by dorsal rhizotomy) of a single forelimb, followed by intensive training of the deafferented limb combined with constraint of the other, intact limb.

ABBREVIATIONS CIMTprojections from the contralesional hemisphere, which can enable the contralesional hemisphere to exert motor control over the paretic hand. In contrast to the primary motor representation (M1), the primary somatosensory representation (S1) of the paretic hand always remains in the lesioned hemisphere. Here, we report on differences in exerciseinduced neuroplasticity between individuals with such ipsilateral motor projections (ipsi) and individuals with early unilateral lesions but 'healthy' contralateral motor projections (contra).METHOD Sixteen children and young adults with congenital hemiparesis participated in the study (contralateral [Contra] group: n=7, four females, three males; age range 10-30y, median age 16y; ipsilateral [Ipsi] group: n=9, four females, five males; age range 11-31y, median age 12y; Manual Ability Classification System levels I to II in all individuals in both groups). The participants underwent a 12-day intervention of constraint-induced movement therapy (CIMT), consisting of individual training (2h/d) and group training (8h/d). Before and after CIMT, hand function was tested using the Wolf Motor Function Test (WMFT) and diverging neuroplastic effects were observed by transcranial magnetic stimulation (TMS), functional magnetic resonance imaging (fMRI), and magnetoencephalography (MEG). Statistical analysis of TMS data was performed using the non-parametric Wilcoxon signed-rank test for pair-wise comparison; for fMRI standard statistical parametric and non-parametric mapping (SPM5, SnPM3) procedures (first level/second level) were carried out. Statistical analyses of MEG data involved analyses of variance (ANOVA) and t-tests.RESULTS While MEG demonstrated a significant increase in S1 activation in both groups (p=0.012), TMS showed a decrease in M1 excitability in the Ipsi group (p=0.036), but an increase in M1 excitability in the Contra group (p=0.043). Similarly, fMRI showed a decrease in M1 activation in the Ipsi group, but an increase in activation in the M1-S1 region in the Contra group (for both groups p<0.001 [SnPM3] within the search volume).INTERPRETATION Different patterns of sensorimotor (re)organization in individuals with early unilateral lesions show, on a cortical level, different patterns of exercise-induced neuroplasticity. The findings help to improve the understanding of the general principles of sensorimotor learning and will help to develop more specific therapies for different pathologies in congenital hemiparesis.Congenital hemiparesis is a unilateral movement disorder caused by a brain lesion acquired during the pre-, peri-, or neonatal period. Depending on the type, size, and time of appearance of the lesion, two types of corticospinal projections to the paretic hand can develop: (1) crossed projections from the affected hemisphere and (2)

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Abstract. Organic anion transport in intact renal proximal tubule cells in animal model systems is downregulated by treatments that activate protein kinase C (PKC). How this downregulation is achieved is not yet known. Stimulation of PKC with sn-1,2-dioctanoylglycerol resulted in strong inhibition of p-aminohippurate transport mediated by the cloned human organic anion transporter 1 (hOAT1) expressed in Xenopus oocytes and HEK293 cells, as well as hOAT1 internalization in both expression systems. The sn-1,2-dioctanoylglycerol-induced transport inhibition was partially prevented by staurosporine. It was independent of the conserved canonical PKC consensus sites in hOAT1, however, and was unaffected by agents that destabilize actin filaments or microtubules, which altered baseline hOAT1-mediated p-aminohippurate uptake activity in oocytes. It is concluded that PKC-induced hOAT1 downregulation is achieved through carrier retrieval from the cell membrane and does not involve phosphorylation of the predicted classic hOAT1 PKC consensus sites.The renal secretory organic anion transport pathway plays an important role in the elimination of a variety of potentially toxic environmental chemicals, such as phenoxyacetate herbicides and fungicides, as well as anionic drugs, including ␤-lactam antibiotics, cytostatic agents, diuretics, and antiviral drugs (1,2). The importance of this pathway is exemplified by the increased toxicity of methotrexate when it is coadministered with nonsteroidal anti-inflammatory drugs (3), which compete for the same elimination pathway (4) and thus lead to higher serum methotrexate concentrations (3). In a number of nonmammalian and mammalian renal proximal tubule model systems, peritubular uptake and/or transepithelial secretion of prototypical organic anions have been demonstrated to be inhibited by agents that stimulate protein kinase C (PKC) activity. The nonselective PKC activator phorbol-12-myristate-13-acetate (PMA) inhibited cellular and luminal fluorescein accumulation in isolated nonperfused killifish renal tubules (5), net secretion of 2,4-dichlorophenoxyacetic acid across winter flounder proximal tubule monolayer cultures (6), peritubular uptake and transepithelial fluorescein flux in isolated nonperfused (7) and perfused (8) rabbit proximal tubule S2 segments, respectively, and basolateral uptake and transcellular movement of p-aminohippurate (PAH) in opossum kidney cells (9,10).Because a number of agents, such as parathyroid hormone (PTH) (11), ␣ 1 -adrenergic agonists (12), angiotensin II (13), and bradykinin (14), modulate renal proximal tubule function via activation of PKC, these agents might be expected to impair renal elimination of organic anions. Indeed, bradykinin and phenylephrine were observed to inhibit basolateral uptake (7) and transepithelial secretion (8) of fluorescein in isolated rabbit proximal tubule S2 segments, and these effects were suppressed by the PKC inhibitor bisindolylmaleimide.On the basis of their localization, two of the cloned organic anion transpo...

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