Use of risk stratification to target therapies in patients with recent onset arthritis; design of a prospective randomized multicenter controlled trial

Background  

Early and intensive treatment is important to inducing remission and preventing joint damage in patients with rheumatoid arthritis. While intensive combination therapy (Disease Modifying Anti-rheumatic Drugs and/or biologicals) is the most effective, rheumatologists in daily clinical practice prefer to start with monotherapy methotrexate and bridging corticosteroids. Intensive treatment should be started as soon as the first symptoms manifest, but at this early stage, ACR criteria may not be fulfilled, and there is a danger of over-treatment. We will therefore determine which induction therapy is most effective in the very early stage of persistent arthritis. To overcome over-treatment and under-treatment, the intensity of induction therapy will be based on a prediction model that predicts patients' propensity for persistent arthritis.     

用于鼻腔测量的声反射技术——应用与进展

本文综述了声反射鼻腔测量（acoustic rhinometry,AR）近年来在临床中的应用和研究。主要阐述了声反射测量的工作原理,在鼻周期以及正常人鼻腔测量相关参数建立等基础研究,在耳鼻喉科疾病诊断和药物作用等临床研究中的进展。     

Carotid body autotransplantation in Parkinson disease: a clinical and positron emission tomography study

Background

Carotid body (CB) glomus cells are highly dopaminergic and express the glial cell line derived neurotrophic factor. The intrastriatal grafting of CB cell aggregates exerts neurotrophic actions on nigrostriatal neurons in animal models of Parkinson disease (PD).

Objective

We conducted a phase I–II clinical study to assess the feasibility, long term safety, clinical and neurochemical effects of intrastriatal CB autotransplantation in patients with PD.

Methods

Thirteen patients with advanced PD underwent bilateral stereotactic implantation of CB cell aggregates into the striatum. They were assessed before surgery and up to 1–3 years after surgery according to CAPIT (Core Assessment Programme for Intracerebral Transplantation) and CAPSIT‐PD (Core Assessment Programme for Surgical Interventional Therapies in Parkinson''s Disease) protocols. The primary outcome measure was the change in video blinded Unified Parkinson''s Disease Rating Scale III score in the off‐medication state. Seven patients had ¹⁸F‐dopa positron emission tomography scans before and 1 year after transplantation.

Results

Clinical amelioration in the primary outcome measure was observed in 10 of 12 blindly analysed patients, which was maximal at 6–12 months after transplantation (5–74%). Overall, mean improvement at 6 months was 23%. In the long term (3 years), 3 of 6 patients still maintained improvement (15–48%). None of the patients developed off‐period dyskinesias. The main predictive factors for motor improvement were the histological integrity of the CB and a milder disease severity. We observed a non‐significant 5% increase in mean putaminal ¹⁸F‐dopa uptake but there was an inverse relationship between clinical amelioration and annual decline in putaminal ¹⁸F‐dopa uptake (r = −0.829; p = 0.042).

Conclusions

CB autotransplantation may induce clinical effects in patients with advanced PD which seem partly related to the biological properties of the implanted glomus cells.Parkinson disease (PD) is a progressive neurodegenerative disorder of unknown aetiology. Its main pathological hallmark is the degeneration of midbrain dopaminergic neurons projecting to the striatum, although other neuronal systems are also affected.¹ Current pharmacological and surgical therapies are symptomatically effective but their long term utility is limited because of disease progression.^2,3 Therefore, there is a need for neuroprotective and/or neurorestorative therapies capable of arresting or reversing the neurodegenerative process.Over the past two decades, cell replacement therapies have been tested in PD patients with the objective of restoring the striatal dopaminergic deficit.⁴ Transplantation of fetal mesencephalic neurons, the most frequently used technique, can increase the striatal dopamine storage, but does not always produce the expected clinical benefit and may induce disabling off‐medication dyskinesias.^5,6 Thus it appears that the ectopic placement of dopamine secreting cells in the striatum is not the ideal approach to compensate for progressive nigrostriatal neuronal loss.⁷ Given this scenario, the clinical applicability of other transplantation procedures based on a similar rationale (eg, intrastriatal grafting of porcine mesencephalic neurons, retinal pigment epithelial cells or stem cell derived dopaminergic neurons) is, for the moment, uncertain.More recently, other strategies aiming to protect or restore the nigrostriatal pathway have emerged. Glial cell line derived neurotrophic factor (GDNF) has been shown to exert neuroprotective and neurorestorative actions in animal models of PD.^8,9,10 The clinical efficacy of GDNF has been assayed in clinical trials, but the method of delivery is a critical issue. Whereas intraventricular administration failed to induce clinical benefit,¹¹ intraputaminal infusion showed promising results,^12,13 although a placebo controlled trial using this route has been halted because of lack of efficacy and safety concerns about recombinant human GDNF administration.¹⁴ Other alternative methods being tested experimentally in parkinsonian animals include in vivo gene therapy using GDNF encoding viral vectors^15,16,17 and the intrastriatal grafting of recombinant GDNF producing cell lines.^18,19,20,21 Carotid body (CB) glomus cells are neural crest derived dopaminergic cells that express high levels of GDNF. Glomus cell GDNF production is resistant to 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine administration, and maintained in aged rodents or after intrastriatal grafting.^22,23 The survival rate of these cells after transplantation (>70%) is particularly high as hypoxia stimulates their growth and function. Moreover, CB grafts performed in young rats remain active for the entire animal lifespan.^22,23 Transplantation of CB cell aggregates has been shown to induce a neurotrophic mediated recovery in animal models of PD^{22,23,24,25,26,27} and stroke.^28,29We conducted a phase I–II video blinded clinical study to assess the long term safety, clinical and neurochemical effects of intrastriatal CB autotransplantation in patients with advanced PD. In a pilot report of our first six patients, we showed this procedure to be feasible.³⁰ Here we report the clinical outcomes and prognostic factors in the whole study (n = 13), as well as ¹⁸F‐dopa positron emission tomography (PET) outcomes in a subgroup of patients (n = 7).     

Providing monovalent oral polio vaccine type 1 to newborns: findings from a pilot birth-dose project in Moradabad district, India

Problem

Poliovirus transmission remained a public health challenge in western Uttar Pradesh, India in late 2005 and early 2006. In 2006, the India Expert Advisory Group for Polio Eradication concluded that, given the peak incidence of polio among children 6 to 12 months of age, a targeted birth dose of oral polio vaccine may be necessary to interrupt intense poliovirus transmission in high risk areas.

Approach

The Government of Uttar Pradesh, the National Polio Surveillance Project and the United Nations Children’s Fund (UNICEF) implemented a pilot birth-dose project aimed at identifying and vaccinating all newborns with a dose of oral polio vaccine within 72 hours of birth in an effort to evaluate operational feasibility and potential impact on population immunity.

Local setting

The project was piloted in Moradabad district: zone 7 in Moradabad City (urban setting), Kunderki block (rural setting) and in select birthing hospitals.

Relevant changes

Between July 2006 and February 2007, 9740 newborns were identified, of which 6369 (65%) were vaccinated by project personnel within 72 hours of birth. Project coverage (for total newborns vaccinated) ranged from 39% (in zone 7) to 76% (in Kunderki block) of the estimated number of newborns vaccinated during previous supplemental immunization activities.

Lessons learned

Birth-dose coverage among newborns was lower than expected. Expansion costs were estimated to be high, with marginal impact. The project, however, provided opportunities to strengthen newborn tracking systems which have increased the number of newborns and young infants vaccinated during supplemental immunization activities and enrolled in routine programmes.     

Prevalence of GB virus type C/hepatitis G virus RNA and of anti-E2 in individuals at high or low risk for blood-borne or sexually transmitted viruses: evidence of sexual and parenteral transmission

BACKGROUND: The first epidemiologic evidence of GB virus type C (GBV- C)/hepatitis G virus (HGV) infection showed a high prevalence of asymptomatic carriers in blood donors and in populations at risk for blood-borne viruses. However, by using only viral RNA polymerase chain reaction, those studies underestimated the true spread of GBV-C/HGV infection. The combined detection of GBV-C/HGV RNA and of anti-E2 (which reflects recovery from infection) is necessary to define accurately the prevalence of GBV-C/HGV. STUDY DESIGN AND METHODS: The presence of both anti-E2 and GBV-C/HGV RNA was searched for in 1438 serum samples collected from various groups of individuals at low or high risk for blood-borne or sexually transmitted viruses (blood donors, organ donors, unselected pregnant women, immunocompetent or immunodepressed multiply transfused patients, HIV-positive or HIV- negative homosexual men, intravenous drug addicts). RESULTS: The presence of GBV-C/HGV RNA and/or anti-E2 (exposure to GBV-C/HGV) was frequent in populations at risk for blood-borne or sexually transmitted viruses. GBV-C/HGV appeared also to be sexually transmitted, with transmission from male to female more efficient than vice versa. A particularly elevated level of exposure to GBV-C/HGV was observed in homosexual men. In immunocompetent individuals, the prevalence of anti- E2 was about twice that of GBV-C/HGV RNA, which suggests the frequency of recovery from GBV-C/HGV infection. Most of the GBV-C/HGV RNA- positive individuals had no biochemical evidence of liver damage. CONCLUSIONS: GBV-C/HGV is frequent in populations at risk for blood- borne or sexually transmitted viruses. GBV-C/HGV is not a hepatitis virus, and it seems appropriate to rename it.     

The final destiny of acantholytic cells in pemphigus is Fas mediated

Background  Pemphigus is an autoimmune disease characterized by the formation of intra-epidermal blisters. Patients develop auto-antibodies against desmoglein 1 and 3 proteins and induce acantholysis.
Objective  This work addresses the issue of whether the Fas pathway mediates acantholysis. Furthermore, the possible suppliers of the Fas pathway were investigated.
Methods  Seventeen biopsies of pemphigus patients were studied by haematoxylin and eosin staining, and apoptosis was defined by TUNEL. The expression of Fas, FasL and caspase 3 was studied by in situ hybridization and immunohistochemistry. Cell infiltrates were studied by immunofluorescence with monoclonal anti-CD3, CD4, CD8, CD19 and CD69.
Results  All of the biopsies showed intra-epidermal blisters, acantholytic cells and inflammatory infiltrates. The blisters expressed Fas, FasL and caspase 3. Cell infiltrates were composed of CD8 and a few CD4⁺CD69⁺ cells. Additionally, CD19⁺ cells were detected. Interestingly, the Fas expression was increased in acantholytic cells and perilesional keratinocytes. Incidentally, these cells exhibited apoptotic features. Interestingly, the CD8 cells expressed FasL.
Conclusion  This paper presents the morphological evidence that apoptosis and acantholysis are linked. Therefore, the Fas pathway is associated with CD8 cells in pemphigus lesions.

Conflicts of interest

None declared.