Advances in spinal cord stimulation - enhancement of efficacy, improved surgical technique and a new indication

Introduction and aim: Spinal cord stimulation (SCS) has been used for treatment of otherwise therapy-resistant chronic neuropathic pain for about four decades. However, 30-40 % of the patients do not benefit from SCS, despite careful case selection and technical advances. In search of ways to improve the outcome mechanisms underlying the pain relieving effect of SCS have been extensively explored. Experimental findings suggest a possibility to enhance the effect of SCS by concomitant intrathecal (i.t.) administration of pharmaceuticals, such as baclofen, clonidine and adenosine. Animal research has indicated that hypersensitivity to colonic dilatation can be attenuated by SCS. This finding, as well as related clinical observations, forms a basis for the possibility of treating irritable bowel syndrome (IBS) with SCS. Implantation of an SCS system with a plate electrode requires extensive surgery. This can be painful and cumbersome for the patient, since finding an optimal electrode position demands patient cooperation with reporting of stimulation evoked sensations. Aims of the thesis were to study: 1) if co-administration of baclofen (Study I and III), clonidine (Study III) or adenosine (Study I) can enhance the effect of SCS, 2) if long-term i.t. administration of a drug will continue to support the effect of SCS over time (Study II), 3) if implantation of plate electrodes can be performed in spinal anesthesia, retaining the possibility for the patient to feel and report stimulation evoked paresthesias and 4) if SCS can be used as a treatment option for IBS, otherwise resistant to therapy. Methods: In Study I, 43 patients with neuropathic pain either experiencing diminished effect of previously efficacious SCS or with insufficient initial effect of SCS were recruited for trials of bolus i.t. injections of baclofen. Patients responding to the addition of baclofen were offered continued administration either i.t., via an implanted pump, or orally. Seven patients were also tested with i.t. adenosine. In Study II, the patients who continued with i.t. baclofen via a pump were assessed for long-term results. In Study III, 10 neuropathic pain patients with insufficient effect of SCS were recruited for a randomized double-blind trial, with i.t. injections of baclofen, clonidine and placebo. In Study IV, results from 20 implantations of plate electrodes in spinal anesthesia are reported. In Study V, 10 patients with IBS participated in a study of SCS, comparing randomly assigned periods of active stimulation versus a period without stimulation. Results: In Study I, 20 patients responded to i.t. baclofen, with or without SCS. Three patients tested oral baclofen as an adjunct to SCS, but terminated treatment due to side effects. Eleven patients had pumps implanted, two of which were explanted during the trial period. Two patients opted for i.t. adenosine delivery via a pump, but discontinued due to side effects. In Study II, it was confirmed that all 9 patients with remaining working pumps continued to benefit from the therapy, albeit with a dose increase. In Study III, 5 patients responded to either baclofen or clonidine and 4 received pumps for i.t. delivery (2 baclofen, 2 clonidine). In Study IV, it was demonstrated that in all 20 implantations it was possible to perform successful intraoperative testing in spinal anesthesia. In Study V, 6 out of 9 patients responded beneficially to SCS as a treatment for IBS (1 patient left the study). Conclusions: I.t. medication with baclofen or clonidine can enhance the effect of SCS. This enhancement remains over a long-term follow up. Implantations of plate electrodes can be performed with intra-operative testing in spinal anesthesia. SCS may alleviate pain in IBS, but studies in larger patient materials are needed to investigate effects on other IBS symptoms

Categories of Public e-Services -an Inquiry Based on the e-Diamond Model

Abstract: Today there exist a lot of public e-services. An unsolved quest still however is how to categorize such e-services. Stage-models are today dominating for pinpointing high-range characteristics of e-services. There relies however confusion in whether these stage models are prescriptions of desired e-services. A need for classifying middle-range categories of e-services as a support for guiding development and refinement of e-services as well as a support for citizens to select and find e-services. In this paper such classification of middle-range categories of eservices, based on foundational action-theoretic categories founded in the e-diamond model, is made. Based on a categorization of 335 public e-services in Sweden four classes of middle-range categories are identified; Government informative, Government performative, Citizen informative, and Citizen performative. Within each of these categories sub categories such as separate vs. compound, and individual vs. general is used for the purpose of make an even more fine-grained classificatio

Fast Alpha Activity in EEG of Patients With Alzheimer's Disease Is Paralleled by Changes in Cognition and Cholinergic Markers During Encapsulated Cell Biodelivery of Nerve Growth Factor.

Background Basal forebrain cholinergic neurons are dependent on nerve growth factor (NGF) for growth and survival and these cells are among the first to degenerate in Alzheimer's disease (AD). Targeted delivery of NGF has been suggested as a potential therapy for AD. This hypothesis was tested in a clinical trial with encapsulated cell biodelivery of NGF (NGF-ECB) in AD patients. Three of six patients showed improved biomarkers for cognition by the end of the study. Here, we report on the effects of targeted delivery of NGF on human resting EEG. Materials and methods NGF-ECB implants were implanted bilaterally in the basal forebrain of six AD patients for 12 months. EEG recordings and quantitative analysis were performed at baseline, 3 and 12 months of NGF delivery, and analyzed for correlation with changes in Mini-mental state examination (MMSE) and levels of the cholinergic marker choline acetyltransferase (ChAT) in cerebrospinal fluid (CSF). Results We found significant correlations between the topographic variance of EEG spectral power at the three study points (baseline, 3 and 12 months) and changes in MMSE and CSF ChAT. This possible effect of NGF was identified in a narrow window of alpha frequency 10-11.5 Hz, where a stabilization in MMSE score during treatment was related to an increase in EEG alpha power. A similar relation was observed between the alpha power and ChAT. More theta power at 6.5 Hz was on the contrary associated with a decrease in CSF ChAT during the trial period. Conclusion In this exploratory study, there was a positive correlative pattern between physiological high-frequency alpha activity and stabilization in MMSE and increase in CSF ChAT in AD patients receiving targeted delivery of NGF to the cholinergic basal forebrain

Longer Leukocyte Telomere Length Is Associated with Smaller Hippocampal Volume among Non-Demented APOE ε3/ε3 Subjects

Telomere length shortens with cellular division, and leukocyte telomere length is used as a marker for systemic telomere length. The hippocampus hosts adult neurogenesis and is an important structure for episodic memory, and carriers of the apolipoprotein E ε4 allele exhibit higher hippocampal atrophy rates and differing telomere dynamics compared with non-carriers. The authors investigated whether leukocyte telomere length was associated with hippocampal volume in 57 cognitively intact subjects (29 ε3/ε3 carriers; 28 ε4 carriers) aged 49–79 yr. Leukocyte telomere length correlated inversely with left (rs = −0.465; p = 0.011), right (rs = −0.414; p = 0.025), and total hippocampus volume (rs = −0.519; p = 0.004) among APOE ε3/ε3 carriers, but not among ε4 carriers. However, the ε4 carriers fit with the general correlation pattern exhibited by the ε3/ε3 carriers, as ε4 carriers on average had longer telomeres and smaller hippocampi compared with ε3/ε3 carriers. The relationship observed can be interpreted as long telomeres representing a history of relatively low cellular proliferation, reflected in smaller hippocampal volumes. The results support the potential of leukocyte telomere length being used as a biomarker for tapping functional and structural processes of the aging brain

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes