Which dyskinesia scale best detects treatment response?

Numerous scales assess dyskinesia in Parkinson's disease (PD), variably focusing on anatomical distribution, phenomenology, time, severity, and disability. No study has compared these scales and their relative ability to detect change related to an established treatment. We conducted a randomized placebo‐controlled trial of amantadine, assessing dyskinesia at baseline and at 4 and 8 weeks using the following scales: Unified Dyskinesia Rating Scale (UDysRS), Lang‐Fahn Activities of Daily Living Dyskinesia Rating Scale (LF), 26‐Item Parkinson's Disease Dyskinesia scale (PDD‐26), patient diaries, modified Abnormal Involuntary Movements Scale (AIMS), Rush Dyskinesia Rating Scale (RDRS), dyskinesia items from the Movement Disorder Society–sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS‐UPDRS), and Clinical Global Impression (severity and change: CGI‐S, CGI‐C). Scale order was randomized at each visit, but raters were aware of each scale as it was administered. Sensitivity to treatment was assessed using effect size. Sixty‐one randomized dyskinetic PD subjects (31 amantadine, 30 placebo) completed the study. Four of the 8 scales (CGI‐C, LF, PDD‐26, and UDysRS) detected a significant treatment. The UDysRS Total Score showed the highest effect size (η² = 0.138) for detecting treatment‐related change, with all other scales having effect sizes < 0.1. No scale was resistant to placebo effects. This study resolves 2 major issues useful for future testing of new antidyskinesia treatments: among tested scales, the UDysRS, having both subjective and objective dyskinesia ratings, is superior for detecting treatment effects; and the magnitude of the UDysRS effect size from amantadine sets a clear standard for comparison for new agents. © 2012 Movement Disorder Society     

Changes in Energy Intake and Diet Quality during an 18-Month Weight-Management Randomized Controlled Trial in Adults with Intellectual and Developmental Disabilities

Background

Previous research indicates that individuals with intellectual and developmental disabilities (IDDs) are at risk for poor diet quality.

Prostate cancer risk after anti-androgen treatment for priapism

Background

Patients with recurrent ischemic priapism have historically been treated with anti-androgen therapy due to the limited available evidence for more targeted therapies to treat the underlying pathophysiologic mechanisms of this condition. We report a case in which anti-androgen therapy caused significant adverse side effects and likely masked this patient’s elevated prostate-specific antigen (PSA) levels, which adversely impacted the timely diagnosis and treatment of his prostate cancer.

Case report

A 69-year-old man treated with anti-androgens for priapism initially developed unwanted anti-androgenic side effects such as gynecomastia, erectile dysfunction, and decreased libido. After decreasing his anti-androgen dosage and starting a specified regimen of phosphodiesterase type 5 inhibitor therapy, his serum PSA levels were found to be elevated. He was subsequently diagnosed with adenocarcinoma of the prostate and underwent a radical prostatectomy with the pathologic finding of high-grade, locally progressive disease.

Conclusion

Anti-androgen therapy carries significant complication risks, including the potential to alter the diagnosis and treatment of prostate cancer. Clinicians administering this therapy for priapism management should be aware of these possible risks.     

The past,present, and future of telemedicine for Parkinson's disease

Travel distance, growing disability, and uneven distribution of doctors limit access to care for most Parkinson's disease (PD) patients worldwide. Telemedicine, the use of telecommunications technology to deliver care at a distance, can help overcome these barriers. In this report, we describe the past, present, and likely future applications of telemedicine to PD. Historically, telemedicine has relied on expensive equipment to connect single patients to a specialist in pilot programs in wealthy nations. As the cost of video conferencing has plummeted, these efforts have expanded in scale and scope, now reaching larger parts of the world and extending the focus from care to training of remote providers. Policy, especially limited reimbursement, currently hinders the growth and adoption of these new care models. As these policies change and technology advances and spreads, the following will likely develop: integrated care networks that connect patients to a wide range of providers; education programs that support patients and health care providers; and new research applications that include remote monitoring and remote visits. Together, these developments will enable more individuals with PD to connect to care, increase access to expertise for patients and providers, and allow more‐extensive, less‐expensive participation in research. © 2014 International Parkinson and Movement Disorder Society     

Cytokine activation during attacks of the hyperimmunoglobulinemia D and periodic fever syndrome

The hyperimmunoglobulinemia D and periodic fever (hyper-IgD) syndrome is typified by recurrent febrile attacks with abdominal distress, joint involvement (arthralgias/arthritis), headache, skin lesions, and an elevated serum IgD level (> 100 U/mL). This familial disorder has been diagnosed in 59 patients, mainly from Europe. The pathogenesis of this febrile disorder is unknown, but attacks are joined by an acute-phase response. Because this response is considered to be mediated by cytokines, we measured the acute-phase proteins C-reactive protein (CRP) and soluble type-II phospholipase A2 (PLA2) together with circulating concentrations and ex vivo production of the proinflammatory cytokines interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-6, and tumor necrosis factor alpha (TNF alpha) and the inhibitory compounds IL-1 receptor antagonist (IL-1ra), IL-10, and the soluble TNF receptors p55 (sTNFr p55) and p75 (sTNFr p75) in 22 patients with the hyper-IgD syndrome during attacks and remission. Serum CRP and PLA2 concentrations were elevated during attacks (mean, 213 mg/L and 1,452 ng/mL, respectively) and decreased between attacks. Plasma concentrations of IL-1 alpha, IL-1 beta, or IL-10 were not increased during attacks. TNF alpha concentrations were slightly, but significantly, higher with attacks (104 v 117 pg/mL). Circulating IL-6 values increased with attacks (19.7 v 147.9 pg/mL) and correlated with CRP and PLA2 values during the febrile attacks. The values of the antiinflammatory compounds IL-1ra, sTNFr p55, and sTNFr p75 were significantly higher with attacks than between attacks, and there was a significant positive correlation between each. The ex-vivo production of TNF alpha, IL-1 beta, and IL-1ra was significantly higher with attacks, suggesting that the monocytes/macrophages were already primed in vivo to produce increased amounts of these cytokines. These findings point to an activation of the cytokine network, and this suggests that these inflammatory mediators may contribute to the symptoms of the hyper-IgD syndrome.     

Serotoninergic activation and inhibition: effects on carbohydrate tolerance and plasma insulin and glucagon.

Glucose and arginine infusion tests were performed on 12 healthy volunteers (8 males, 4 females) before and after serotoninergic activation [oral administration of L-5-hydroxytryptophan (5-HTP-) for 6 days] and serotoninergic inhibition (oral treatment with D,L-p-chloropenylalanine for 6 days). 5-HTP treatment markedly increased urinary 5-hydroxyindoleacetic acid excretion, increased the mild hyperglycemic effect of arginine infusion, and lowered the glucose disposal rate constant. The adverse effect of serotoninergic activation on glucose tolerance is not sufficiently explained by the observed changes in insulin and glucagon secretion during the fasting state and after intravenous glucose and arginine infusions. Serotoninergic inhibition did not affect the carbohydrate tolerance of normal individuals. The results of this work supports the idea that excessive indoleamine production is probably the main cause for carbohydrate intolerance in carcinoid tumors.     

Support of human cord blood progenitor cells on human stromal cell lines transformed by SV40 large T antigen under the influence of an inducible (metallothionein) promoter

We describe the development of a human bone marrow (BM) culture system which allows study of the interaction of stromal cell lines (SCL) and highly purified hematopoietic progenitor cells. Normal BM stromal cells were electroporated with a plasmid containing the simian virus 40 (SV40) large T antigen (SV40 T Ag) under the control of a synthetic metallothionein promoter (MT4); this construct is designated MT4 SV40 T Ag. SCL in which the rate of proliferation could be controlled by altering the zinc (Zn) concentration were characterized, demonstrating that the SCL were heterogeneous with respect to G-CSF and GM-CSF production. Suppression of SCL proliferation on removal of Zn made it possible to use these lines in coculture with purified CD34+ progenitor cells from umbilical cord blood. The ability to control proliferation of SCL has allowed us to maintain the survival and expansion of colony- forming cells in culture for up to 2 months. These lines have enabled us to test for stromal cell characteristics at a clonal level and provided us with a tool to analyze the events leading to lineage commitment and hematopoietic differentiation, as demonstrated by suppression of hematopoiesis by an antibody directed against the c-kit molecule.     

A descending dopamine pathway conserved from basal vertebrates to mammals

Dopamine neurons are classically known to modulate locomotion indirectly through ascending projections to the basal ganglia that project down to brainstem locomotor networks. Their loss in Parkinson’s disease is devastating. In lampreys, we recently showed that brainstem networks also receive direct descending dopaminergic inputs that potentiate locomotor output. Here, we provide evidence that this descending dopaminergic pathway is conserved to higher vertebrates, including mammals. In salamanders, dopamine neurons projecting to the striatum or brainstem locomotor networks were partly intermingled. Stimulation of the dopaminergic region evoked dopamine release in brainstem locomotor networks and concurrent reticulospinal activity. In rats, some dopamine neurons projecting to the striatum also innervated the pedunculopontine nucleus, a known locomotor center, and stimulation of the dopaminergic region evoked pedunculopontine dopamine release in vivo. Finally, we found dopaminergic fibers in the human pedunculopontine nucleus. The conservation of a descending dopaminergic pathway across vertebrates warrants re-evaluating dopamine’s role in locomotion.Dopaminergic neurons represent a vital neuromodulatory component essential for vertebrate motor control, and their loss in neurodegenerative disease is devastating. The meso-diencephalic dopamine (DA) neurons are known to provide ascending projections to the basal ganglia, which, in turn, provide input to cortical structure in mammals but also project caudally to the mesencephalic locomotor region (MLR), a highly conserved structure that controls locomotion in all vertebrates investigated to date (1–7; for review, see ref. 8). A growing body of evidence supports the view that basal ganglia connectivity is highly conserved among vertebrates, from lampreys to mammals (9–11; for review, see ref. 12), with some interspecies differences recently highlighted (13). As such, the homology between DA cell populations remains to be resolved in vertebrates. As a general rule, DA neurons from the meso-diencephalon send projections to the striatum in all vertebrates. In lampreys and teleosts, those neurons are located only in the diencephalon (posterior tuberculum), but in tetrapods and cartilaginous fishes (14) they are located in both the diencephalon and the mesencephalon. An increasing number of authors seem to agree with the hypothesis that at least some of the meso-diencephalic DA neurons located in the diencephalon are homologous in all vertebrates, and thus, homologous to at least a portion of the mammalian substantia nigra pars compacta (SNc)/ventral tegmental area (VTA) (13, 15–19; for review, see ref. 20). Alternatively, it was suggested that the posterior tuberculum DA neurons projecting to the striatum in zebrafish are homologs of the mammalian DA neurons of the A11 group (21). This will be discussed below in light of the results of the present study.In lampreys, only a few meso-diencephalic DA neurons send ascending projections to the striatum (9, 22); the majority of DA neurons send a direct descending projection to the MLR (22, 23), where DA is released and increases locomotor output through D1 receptors (22). These results demonstrate that the descending dopaminergic pathway to the MLR is an important modulator of locomotor output, but it remains to be determined whether this pathway is conserved in higher vertebrates.The existence of a descending dopaminergic pathway that powerfully increases locomotor output has important implications for Parkinson’s disease, which involves the meso-diencephalic DA neurons. A loss of descending dopaminergic projections could play a role in the locomotor deficits systematically observed in that disease. Because of the highly conserved nature of both the dopaminergic system and brainstem locomotor circuitry in vertebrates, we hypothesized that a direct descending dopaminergic pathway to the MLR also exists in higher vertebrates. Previous anatomical (24, 25) and electrophysiological (26) studies in rats support the idea of a descending connection from the SNc to the pedunculopontine nucleus [PPN, considered part of the MLR (2)]. Moreover, dopaminergic terminals were found in the PPN of monkeys (27), but the origin of this projection is still unknown in mammals.Here, we investigated whether the direct descending projection from meso-diencephalic DA neurons to the MLR is present in two tetrapods, the salamander and the rat. Moreover, we supplement our analyses with anatomical data from human brain tissue. Using traditional and virogenetic axonal tracing, immunofluorescence, in vivo voltammetry, and calcium imaging of reticulospinal neurons, we provide anatomical and functional evidence strongly supporting a conserved role for the descending projections of meso-diencephalic DA neurons in the regulation of brainstem locomotor networks across the vertebrate subphylum.     

Administration of pegylated recombinant human megakaryocyte growth and development factor to humans stimulates the production of functional platelets that show no evidence of in vivo activation

This report describes the effect of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) on platelet production and platelet function in humans. Subjects with advanced solid tumors received PEG-rHuMGDF daily for up to 10 days. There was no increase in circulating platelet count at doses of 0.03 or 0.1 microgram/kg/d by day 12 of study. At doses of 0.3 and 1.0 microgram/kg/d there was a threefold median increase (maximum 10-fold) in platelet count by day 16. The platelets produced in vivo in response to PEG-rHuMGDF showed unchanged aggregation and adenosine triphosphate (ATP)-release responses in in vitro assays. Tests included aggregation and release of ATP in response to adenosine diphosphate (ADP) (10, 5, 2.5, and 1.25 mumol/L), collagen (2 micrograms/mL), thrombin-receptor agonist peptide (TRAP, 10 mumol/L) and ristocetin (1.5 mg/mL). Administration of aspirin to an individual with platelet count of 1,771 x 10(3)/L resulted in the typical aspirin-induced ablation of the normal aggregation and ATP-release response to stimulation with arachidonic acid (0.5 mg/mL), collagen, and ADP (2.5 and 1.25 mumol/L). There was no change in the expression of the platelet-surface activation marker CD62P (P-selectin) nor induction of the fibrinogen binding site on glycoprotein IIb/IIIa as reported by the monoclonal antibody, D3GP3. An elevation of reticulated platelets was evident after 3 days of treatment with PEG-rHuMGDF and preceded the increase in circulating platelet count by 5 to 8 days; this reflected the production of new platelets in response to PEG-rHuMGDF. At later time points, the mean platelet volume (MPV) decreased in a manner inversely proportional to the platelet count. Levels of plasma glycocalicin, a measure of platelet turnover, rose 3 days after the initial increase in the peripheral platelet count. The level of plasma glycocalicin was proportional to the total platelet mass, suggesting that platelets generated in response to PEG-rHuMGDF were not more actively destroyed. Thus, the administration of PEG-rHuMGDF, to humans, increased the circulating platelet count and resulted in fully functional platelets, which showed no detectable increase in reactivity nor alteration in activation status.     

Inefficacy of infliximab in primary Sjögren's syndrome: results of the randomized, controlled Trial of Remicade in Primary Sjögren's Syndrome (TRIPSS)

OBJECTIVE: There is no effective treatment for patients with primary Sj?gren's syndrome (SS). Since tumor necrosis factor alpha (TNF alpha) could be a key element in the pathogenesis of primary SS, we conducted a multicenter, randomized, double-blind, placebo-controlled trial to evaluate the effect of infliximab in primary SS. METHODS: A total of 103 patients with primary SS were randomly assigned to receive infliximab infusions (5 mg/kg) or placebo at weeks 0, 2, and 6 and were followed up for 22 weeks. All patients fulfilled the new American-European Consensus Group criteria for SS and had active disease as assessed by values >50 mm on 2 of 3 visual analog scales (VAS) (0-100 mm) that evaluated joint pain, fatigue, and buccal, ocular, skin, vaginal, or bronchial dryness. A favorable overall response was defined as the patient having > or =30% improvement between weeks 0 and 10 in the values on 2 of the 3 VAS. Secondary end points were values on each VAS separately, the number of tender and swollen joints, the basal salivary flow rate, results of the Schirmer test for lacrimal gland function, the focus score on labial salivary gland biopsy, the level of C-reactive protein, and the erythrocyte sedimentation rate evaluated at weeks 0, 10, and 22, as well as quality of life evaluated by use of the generic Short Form 36 questionnaire administered at weeks 0, 10, and 22. RESULTS: At week 10, 26.5% of patients receiving placebo and 27.8% of patients treated with infliximab had a favorable overall response (P = 0.89), and at week 22, 20.4% of the placebo group and 16.7% of the infliximab group had a favorable response (P = 0.62). In addition, the 2 groups did not differ in any of the secondary end points over the 22 weeks of the trial. Severe adverse events reported in the infliximab group did not differ from those observed in previous studies. CONCLUSION: This randomized, double-blind, placebo-controlled study of an anti-TNF agent did not show any evidence of efficacy of infliximab in primary SS.