Administration of CD4+CD25highCD127-FoxP3+ Regulatory T Cells for Relapsing-Remitting Multiple Sclerosis: A Phase 1 Study.

BACKGROUND: Multiple sclerosis (MS) is an immune-mediated disease in which autoimmune T conventional (Tconv) cells break the blood-brain barrier and destroy neurons of the central nervous system. It is hypothesized that CD4+CD25highCD127-FoxP3+ T regulatory (Treg) cells may inhibit this destruction through suppressive activity exerted on Tconv cells. METHODS: We present the results of a phase 1b/2a, open-label, two-arm clinical trial in 14 patients treated with autologous Treg cells for relapsing-remitting MS. The patients received either expanded ex vivo Treg cells intravenously (intravenous [IV] group, n = 11; dose 40 × 106 Treg cells/kg of body weight) or freshly isolated Treg cells intrathecally (intrathecal [IT] group, n = 3; dose 1.0 × 106 Treg cells). Importantly, patients were not treated with any other disease-modifying drugs for at least 6 months before the recruitment and during the follow-up. RESULTS: No severe adverse events were observed. Self-assessed quality of life (EuroQol-5 Dimensions [EQ-5D] form) did not change and did not differ significantly between the groups. A total of 12 relapses were noted in five intravenously treated patients, who had from one to three attacks per year. Three out of ten participants who completed the trial in the IV group deteriorated more than 1 point on the Expanded Disability Status Scale (EDSS) during the follow-up. At the same time, no patients in the IT group experienced a relapse or such a deterioration in the EDSS. No significant differences were found in the Multiple Sclerosis Functional Composite (MSFC) scale in both the IV and IT groups. Magnetic resonance imaging (MRI) scans revealed a significantly lower change in the T2 lesion volume in the IT group compared to the IV group. The increase in the number of new T2 lesions during the follow-up was significant for the IV group only. There were no significant changes in the level of Treg cells or Tconv cells in the peripheral blood throughout the follow-up or between the groups. Interestingly, Treg cells in all patients consisted of two different phenotypes: peripheral Treg cells Helios(-) (≈ 20%) and thymic Treg cells Helios(+) (≈ 80%). The analysis of the cytokine pattern revealed higher levels of transforming growth factor-α and proinflammatory factors MCP3, CXCL8, and IL-1RA in the IT group compared with the IV group. CONCLUSIONS: No serious adverse events were reported in the 14 patients with MS treated with Treg cells in this study. The results suggest that IT administration is more promising than IV administration. Because of the low number of patients recruited, the statistical results may be underpowered and further studies are necessary to reach conclusions on efficacy and safety. TRIAL REGISTRATION: EudraCT: 2014-004320-22; registered 18 November 2014.

Aging and Hypertension - Independent or Intertwined White Matter Impairing Factors? Insights From the Quantitative Diffusion Tensor Imaging.

Aging disrupts white matter integrity, and so does continuous elevated blood pressure that accompanies hypertension (HTN). Yet, our understanding of the interrelationship between these factors is still limited. The study aimed at evaluating patterns of changes in diffusion parameters (as assessed by quantitative diffusion fiber tracking - qDTI) following both aging, and hypertension, as well as the nature of their linkage. 146 participants took part in the study: the control group (N = 61) and the patients with hypertension (N = 85), and were divided into three age subgroups (25-47, 48-56, 57-71 years). qDTI was used to calculate the values of fractional anisotropy, mean, radial and axial diffusivity in 20 main tracts of the brain. The effects of factors (aging and hypertension) on diffusion parameters of tracts were tested with a two-way ANOVA. In the right hemisphere there was no clear effect of the HTN, nor an interaction between the factors, though some age-related effects were observed. Contrary, in the left hemisphere both aging and hypertension contributed to the white matter decline, following a functional pattern. In the projection pathways and the fornix, HTN and aging played part independent of each other, whereas in association fibers and the corpus callosum if the hypertension effect was significant, an interaction was observed. HTN patients manifested faster decline of diffusion parameters but also reached a plateau earlier, with highest between-group differences noted in the middle-aged subgroup. Healthy and hypertensive participants have different brain aging patterns. The HTN is associated with acceleration of white matter integrity decline, observed mainly in association fibers of the left hemisphere.

Diabetic foot syndrome: Charcot arthropathy or osteomyelitis? Part I: Clinical picture and radiography.

One of significant challenges faced by diabetologists, surgeons and orthopedists who care for patients with diabetic foot syndrome is early diagnosis and differentiation of bone structure abnormalities typical of these patients, i.e. osteitis and Charcot arthropathy. In addition to clinical examination, the patient's medical history and laboratory tests, imaging plays a significant role. The evaluation usually begins with conventional radiographs. In the case of osteomyelitis, radiography shows osteopenia, lytic lesions, cortical destruction, periosteal reactions as well as, in the chronic phase, osteosclerosis and sequestra. Neurogenic arthropathy, however, presents an image resembling rapidly progressing osteoarthritis combined with aseptic necrosis or inflammation. The image includes: bone destruction with subluxations and dislocations as well as pathological fractures that lead to the presence of bone debris, osteopenia and, in the later phase, osteosclerosis, joint space narrowing, periosteal reactions, grotesque osteophytes and bone ankylosis. In the case of an unfavorable course of the disease and improper or delayed treatment, progression of these changes may lead to significant foot deformity that might resemble a "bag of bones". Unfortunately, radiography is non-specific and frequently does not warrant an unambiguous diagnosis, particularly in the initial phase preceding bone destruction. For these reasons, alternative imaging methods, such as magnetic resonance tomography, scintigraphy, computed tomography and ultrasonography, are also indicated.

Ultrasound-diagnosed bone and joint destruction as a typical image in advanced Charcots arthropathy - case report.

The paper presents a case of Charcot foot in a patient with long standing type 2 diabetes and complicated by peripheral neuropathy. It was initially diagnosed by an ultrasound examination and subsequently confirmed by an X-ray and an magnetic resonance imaging. Diabetic neuropathy is nowadays the most frequent cause of Charcot arthropathy, although it can be also a result of other diseases of the nervous system. In the acute phase the patient usually presents with edema, redness and increased temperature of the foot, which can suggest many other diagnoses including bacterial infection, gout, venous thrombosis or trauma. Because of its non specific clinical presentation and unsufficient awareness of the specificity of the diabetic foot syndrome among health professionals and the patients the diagnosis of this process is in many cases delayed. In the acute phase appropriate treatment needs to be initiated (mainly off loading and immobilization of the foot in a total contact cast), otherwise a rapidly progressing destruction of the bones and joints will usually begin, leading to fractures, dislocations and a severe foot deformity. Increased awareness among doctors taking care of the diabetic patients and appropriate use of the imaging methods can definitely improve efficacy of the diagnostic process and help to optimize the treatment of Charcot arthropathy. The standard approach usually includes use of radiography, magnetic resonance imaging and scintigraphy. In some cases a sonographer may be the first one to notice typical signs of bony destruction in a patient with Charcot arthropathy and suggest immediate further imaging in order to confirm the diagnosis and to minimize the risk of mutilating complications.

Thrombosis of the persistent median artery as a cause of carpal tunnel syndrome - case study.

Carpal tunnel syndrome is the most frequent neuropathy of the upper extremity, that mainly occurs in manual workers and individuals, whose wrist is overloaded by performing repetitive precise tasks. In the past it was common among of typists, seamstresses and mechanics, but nowadays it is often caused by long hours of computer keyboard use. The patient usually complains of pain, hypersensitivity and paresthesia of his hand and fingers in the median nerve distribution. The symptoms often increase at night. In further course of the disease atrophy of thenar muscles is observed. In the past the diagnosis was usually confirmed in nerve conduction studies. Nowadays a magnetic resonance scan or an ultrasound scan can be used to differentiate the cause of the symptoms. The carpal tunnel syndrome is usually caused by compression of the median nerve passing under the flexor retinaculum due to the presence of structures reducing carpal tunnel area, such as an effusion in the flexor tendons sheaths (due to overload or in the course of rheumatoid diseases), bony anomalies, muscle and tendon variants, ganglion cysts or tumors. In some cases diseases of upper extremity vessels including abnormalities of the persistent median artery may also result in carpal tunnel syndrome. We present a case of symptomatic carpal tunnel syndrome caused by thrombosis of the persistent median artery which was diagnosed in ultrasound examination. The ultrasound scan enabled for differential diagnosis and resulted in an immediate referral to clinician, who recommended instant commencement on anticoagulant treatment. The follow-up observation revealed nearly complete remission of clinical symptoms and partial recanalization of the persistent median artery.