Clinical application of neurotrophic factors: the potential for primary auditory neuron protection

Sensorineural hearing loss, as a result of damage to or destruction of the sensory epithelia within the cochlea, is a common cause of deafness. The subsequent degeneration of the neural elements within the inner ear may impinge upon the efficacy of the cochlear implant. Experimental studies have demonstrated that neurotrophic factors can prevent this degeneration in animal models of deafness, and can even provide functional benefits. Neurotrophic factor therapy may therefore provide similar protective effects in humans, resulting in improved speech perception outcomes among cochlear implant patients. There are, however, numerous issues pertaining to delivery techniques and treatment regimes that need to be addressed prior to any clinical application. This review considers these issues in view of the potential therapeutic application of neurotrophic factors within the auditory system.     

Mesenchymal stem cells induced to secrete neurotrophic factors attenuate quinolinic acid toxicity: a potential therapy for Huntington's disease

Huntington's disease (HD) is a hereditary, progressive and ultimately fatal neurodegenerative disorder. Excitotoxicity and reduced availability of neurotrophic factors (NTFs) likely play roles in HD pathogenesis. Recently we developed a protocol that induces adult human bone marrow derived mesenchymal stem cells (MSCs) into becoming NTF secreting cells (NTF(+) cells). Striatal transplantation of such cells represents a promising autologous therapeutic approach whereby NTFs are delivered to damaged areas. Here, the efficacy of NTF(+) cells was evaluated using the quinolinic acid (QA) rat model for excitotoxicity. We show that NTF(+) cells transplanted into rat brains after QA injection survive transplantation (19% after 6 weeks), maintain their NTF secreting phenotype and significantly reduce striatal volume changes associated with QA lesions. Moreover, QA-injected rats treated with NTF(+) cells exhibit improved behavior; namely, perform 80% fewer apomorphine induced rotations than PBS-treated QA-injected rats. Importantly, we found that MSCs derived from HD patients can be induced to become NTF(+) cells and exert efficacious effects similarly to NTF(+) cells derived from healthy donors. To our knowledge, this is the first study to take adult bone marrow derived mesenchymal stem cells from patients with an inherited disease, transplant them into an animal model and evidence therapeutic benefit. Using MRI we demonstrate in vivo that PBS-treated QA-injected striatae exhibit increasing T(2) values over time in lesioned regions, whereas T(2) values decrease in equivalent regions of QA-injected rats treated with NTF(+) cells. We conclude that NTF cellular treatment could serve as a novel therapy for managing HD.     

Organizing language intervention relative to the client's personal experience: A clinical case study

An analysis is presented of two different therapeutic activities designed for a profoundly deaf adult with cerebral palsy, DP. The study draws on techniques of qualitative methodology to identify elements that contribute to effective intervention practices for DP. Results indicate that therapeutic materials and activities must first of all be relevant to the client's needs, interest, and personal experience to be maximally effective. The results are consistent with recent research on language and language development, particularly the cognitive linguistic view that our linguistic knowledge is rooted in our experience with the world (Kecskes). These results are also consistent with a “socially valid and consumer focused method of tracking outcome” (Simmons‐Mackie and Damico) in that language intervention must typically capture the personal experience of communicatively disordered individuals. Specific recommendations are made for optimizing language intervention.     

Translating monotherapy trials into clinical practice: a look into the abyss

To be approved for monotherapy by regulatory authorities, new antiepileptic drugs (AEDs) must first be tested in well-controlled studies in refractory patients (conversion to monotherapy trials) or in patients with newly diagnosed epilepsy. However, the applicability of the information obtained in these trials to day-to-day clinical practice is limited. Clinical trials in newly diagnosed patients, particularly those allowing dose flexibility, offer more useful information, but a close scrutiny of methodological details is required to avoid misinterpretation of the findings. In many instances, the neurologist has a drug with a label, but lacks critical information on optimal titration rates, optimal target and maintenance dosages, response rates in populations with different epilepsy syndromes, different age ranges and comorbidities, and long-term safety data. Such information becomes available only through general clinical experience, well-designed phase IV studies, and postmarketing surveillance.     

Organizing language intervention relative to the client's personal experience: a clinical case study

An analysis is presented of two different therapeutic activities designed for a profoundly deaf adult with cerebral palsy, DP. The study draws on techniques of qualitative methodology to identify elements that contribute to effective intervention practices for DP. Results indicate that therapeutic materials and activities must first of all be relevant to the client's needs, interest, and personal experience to be maximally effective. The results are consistent with recent research on language and language development, particularly the cognitive linguistic view that our linguistic knowledge is rooted in our experience with the world (Kecskes). These results are also consistent with a "socially valid and consumer focused method of tracking outcome" (Simmons-Mackie and Damico) in that language intervention must typically capture the personal experience of communicatively disordered individuals. Specific recommendations are made for optimizing language intervention.     

Integrin-linked kinase: A potential therapeutic target for the treatment of glioma

The diffuse infiltrative nature of cerebral glioma is a primary reason for failure of current treatment regimes. An improved understanding of the molecular determinants of tumour invasion is imperative in order to achieve therapeutic advances. Integrin-linked kinase has been shown to be key in the regulation of cell migration, as well as proliferation and apoptosis. The involvement of integrin-linked kinase in glioma biology, and its potential as a possible therapeutic target, is discussed.     

Prognostic factors for therapeutic outcome in normal-pressure hydrocephalus. Review of the literature and personal study

In view of the unpredictable percentage of NPH patients who benefit from surgery and the risk of postoperative complications, the study of predictive parameters appears essential. The literature shows many conflicting results in studies which focus on predictive values. The present study is based on a series of 63 patients, all of whom underwent surgery for NPH. Fifty one historical, clinical, paraclinical and neuropsychological parameters were submitted to statistical analysis on the basis of the postoperative results. Nine of these parameters were correlated with the postoperative evolution: aetiology, chronic alcoholism and seven neuropsychological signs, in particular verbal signs. A statistical analysis by logistical regression allows us to describe an optimum predictive model. The most significant results are discussed.     

Therapeutic potential of human stem cell transplantations for Vanishing White Matter: A quest for the Goldilocks graft

IntroductionVanishing white matter (VWM) is a leukodystrophy that leads to neurological dysfunction and early death. Astrocytes are indicated as therapeutic target, because of their central role in VWM pathology. Previous cell replacement therapy using primary mouse glial precursors phenotypically improved VWM mice.AimsThe aim of this study was to determine the translational potential of human stem cell‐derived glial cell replacement therapy for VWM. We generated various glial cell types from human pluripotent stem cells in order to identify a human cell population that successfully ameliorates disease hallmarks of a VWM mouse model. The effects of cell grafts on motor skills and VWM brain pathology were assessed.ResultsTransplantation of human glial precursor populations improved the VWM phenotype. The intrinsic properties of these cells were partially reflected by cell fate post‐transplantation, but were also affected by the host microenvironment. Strikingly, the spread of transplanted cells into the white matter versus the gray matter was different when grafted into the VWM brain as compared to a healthy brain.ConclusionsTransplantation of human glial cell populations can have therapeutic effects for VWM. For further translation to the clinic, the microenvironment in the VWM patient brain should be considered as an important moderator of cell replacement therapy.     

Translating the neuroscience of alcoholism into clinical treatments: From blocking the buzz to curing the blues

Understanding the pathophysiology of addictive disorders is critical for development of new treatments. A major focus of addiction research has for a long time been on systems that mediate acute positively reinforcing effects of addictive drugs, most prominently the mesolimbic dopaminergic (DA) system and its connections. This research line has been successful in shedding light on the physiology of both natural and drug reward, but has not led to therapeutic breakthroughs. The role of classical reward systems is perhaps least clear in alcohol addiction. Here, recent work is summarized that points to some clinically important conclusions. First, important pharmacogenetic differences exist with regard to positively reinforcing effects of alcohol and the ability of this drug to activate classical reward pathways. This offers an opportunity for personalized treatment approaches in alcoholism. Second, brain stress and fear systems become pathologically activated in later stages of alcoholism and their activation is a major influence in escalation of alcohol intake, sensitization of stress responses, and susceptibility to relapse. These findings offer a new category of treatment mechanisms. Corticotropin-releasing hormone (CRH) signaling through CRH1 receptors is a major candidate target in this category, but recent data indicate that antagonists for substance P (SP) neurokinin 1 (NK1) receptors may have a similar potential.     

Translating the neuroscience of alcoholism into clinical treatments: From blocking the buzz to curing the blues

Understanding the pathophysiology of addictive disorders is critical for development of new treatments. A major focus of addiction research has for a long time been on systems that mediate acute positively reinforcing effects of addictive drugs, most prominently the mesolimbic dopaminergic (DA) system and its connections. This research line has been successful in shedding light on the physiology of both natural and drug reward, but has not led to therapeutic breakthroughs. The role of classical reward systems is perhaps least clear in alcohol addiction. Here, recent work is summarized that points to some clinically important conclusions. First, important pharmacogenetic differences exist with regard to positively reinforcing effects of alcohol and the ability of this drug to activate classical reward pathways. This offers an opportunity for personalized treatment approaches in alcoholism. Second, brain stress and fear systems become pathologically activated in later stages of alcoholism and their activation is a major influence in escalation of alcohol intake, sensitization of stress responses, and susceptibility to relapse. These findings offer a new category of treatment mechanisms. Corticotropin-releasing hormone (CRH) signaling through CRH1 receptors is a major candidate target in this category, but recent data indicate that antagonists for substance P (SP) neurokinin 1 (NK1) receptors may have a similar potential.     

The potential of small molecule brain-derived neurotrophic factor: mimetics to treat inherited retinal degeneration

<正>Is there a need for small molecule neuroprotectants in inherited retinal degeneration(iRDs)?iRDs are a heterogeneous cluster of diseases which lead to blindness in 1 in every 2–3000 people.A plethora of causative genetic defects were revealed in the last 30years.Current research focuses on development of pharmacological,biological or mechanical implant treatments.Gene therapy     

Improving the clinical diagnosis of personal neglect: a reformulated comb and razor test

Beschin and Robertson (1997) devised a simple clinical test of left personal neglect, which characterises personal grooming behaviour according to the proportion of the total activity that is directed to the left side of the body. Although this test proved highly reliable, and more sensitive than prior diagnostic techniques, its formulation may yet be improved. The present paper reports a reanalysis of Beschin and Robertson's (1997) data, using additional control subjects, and a formula which characterises personal neglect as a lateral bias of behaviour rather than as a lateralised deficit. It is shown that this formula greatly enhances the test's sensitivity to the behavioural abnormalities of brain damaged patients, and it is recommended that this modification be adopted for the future diagnosis of personal neglect.     

Understanding the personal and clinical utility of psychiatric advance directives: a qualitative perspective

Psychiatric advance directives (PADs) are legal tools that allow competent individuals to declare preferences for future mental health treatment when they may not be capable of doing so as a result of a psychiatric crisis. PADs allow individuals to maintain self-determination during times when they are most vulnerable to loss of autonomy and in need of assistance to make their preferences known and honored. This article describes the content of twenty-eight open-ended, semi-structured qualitative interviews of adults with PADs who have experienced psychiatric crises. The qualitative analysis revealed three major themes from the interviews: (1) PADs as tools for empowerment and self-determination, (2) limited knowledge of PADs among service providers; and (3) difficulties communicating PADs to inpatient staff. In general, many participants expressed enthusiasm of the implementation of PADs but concern regarding clinicians' general lack of awareness about them. Additionally, some consumers discussed discomfort in even mentioning that they had a PAD to clinicians for fear of a negative response from them, or some type of involuntary treatment during their hospitalization. However, participants consistently viewed PADs as a positive tool to promote autonomy with the potential to facilitate stronger patient-provider relationships. Therefore, when working with individuals in psychiatric crisis who have a PAD, and who have never before experienced a sense of control over their own treatment, clinicians must recognize the potential troubling disequilibrium this sense of control may engender. In sum, though the most significant challenges facing the implementation of PADs involve clinicians' familiarity with and education about PADs, much promise for the future growth of PADs lies in the benefits perceived by the patients.     

Culture of neuronal cells from postnatal rat brain: application to the study of neurotrophic factors.

1. The authors developed a primary culture technique for neuronal cells from postnatal rat brains and studied the effects of neurotrophic factors on the naturally developed neurons. 2. We demonstrated changes in the neurotrophic role of nerve growth factor (NGF) during the developmental stages of the rat: NGF was shown to act as a differentiation factor in the early stages and as a survival factor later. 3. It appeared that interleukin-6 (IL-6) supported the survival of septal cholinergic neurons obtained from 10-day-old rats. IL-6, however, did not induce the differentiation of embryonic rat septal cholinergic neurons. IL-6 improved the survival of mesencephalic catecholaminergic neurons from postnatal and embryonic rat brains, which have known not to be response to NGF.     

影响门诊精神分裂症首次发病患者随访一年疗效的相关因素研究

目的 探讨影响精神分裂症首次发病(以下简称首发)患者疗效和复发的相关因素.方法 采用前瞻性队列研究,结合全病程管理模式,对453例符合国际疾病分类第10版精神分裂症和分裂样精神障碍诊断标准、基线阳性和阴性症状量表(PANSS)总分≥60分、病程≤5年的患者,进行1年随访,对13项相关因素与近期疗效及复发情况进行单因素分析,并采用Spearman相关分析和t检验.结果 PANSS总分减分率与性别(r=0.083)、病程(r=-0.228)、起病形式(r=-0.180)、发病诱因(r=0.080)、持续用药时间(r=0.153)存在相关关系(P<0.05～0.01);疾病复发与性别(r=-0.131)、持续用药时间(r=0.131)亦存在相关关系(P<0.01).结论 女性、病程短、起病形式急、病前有诱因、持续用药时间长的精神分裂症首发患者1年的疗效相对好;男性患者及持续用药时间短的患者易复发.