AAV gene therapy for Tay-Sachs disease.

Tay-Sachs disease (TSD) is an inherited neurological disorder caused by deficiency of hexosaminidase A (HexA). Here, we describe an adeno-associated virus (AAV) gene therapy expanded-access trial in two patients with infantile TSD (IND 18225) with safety as the primary endpoint and no secondary endpoints. Patient TSD-001 was treated at 30 months with an equimolar mix of AAVrh8-HEXA and AAVrh8-HEXB administered intrathecally (i.t.), with 75% of the total dose (1 × 1014 vector genomes (vg)) in the cisterna magna and 25% at the thoracolumbar junction. Patient TSD-002 was treated at 7 months by combined bilateral thalamic (1.5 × 1012 vg per thalamus) and i.t. infusion (3.9 × 1013 vg). Both patients were immunosuppressed. Injection procedures were well tolerated, with no vector-related adverse events (AEs) to date. Cerebrospinal fluid (CSF) HexA activity increased from baseline and remained stable in both patients. TSD-002 showed disease stabilization by 3 months after injection with ongoing myelination, a temporary deviation from the natural history of infantile TSD, but disease progression was evident at 6 months after treatment. TSD-001 remains seizure-free at 5 years of age on the same anticonvulsant therapy as before therapy. TSD-002 developed anticonvulsant-responsive seizures at 2 years of age. This study provides early safety and proof-of-concept data in humans for treatment of patients with TSD by AAV gene therapy.

Disclosure after medical error.

PURPOSE OF REVIEW: Disclosure after medical error is a complex process that goes beyond a single provider and the patient. The types and severity of errors occurring in the practice of anesthesiology may have more implications for patients, requiring a thoughtful approach to the patient, their families and the healthcare system as a whole. RECENT FINDINGS: Tenants of the disclosure have been established. Simulation for trainees and practitioners allows for education and preparation for such events. SUMMARY: Despite education and systems-based improvements in quality and safety in medicine, errors will undoubtably occur. Communication with patients and their families after an event is key in maintaining trust in the therapeutic relationship. A concerted effort is required by a team to ensure a well-executed disclosure.

First steps to define murine amniotic fluid stem cell microenvironment.

Stem cell niche refers to the microenvironment where stem cells reside in living organisms. Several elements define the niche and regulate stem cell characteristics, such as stromal support cells, gap junctions, soluble factors, extracellular matrix proteins, blood vessels and neural inputs. In the last years, different studies demonstrated the presence of cKit+ cells in human and murine amniotic fluid, which have been defined as amniotic fluid stem (AFS) cells. Firstly, we characterized the murine cKit+ cells present both in the amniotic fluid and in the amnion. Secondly, to analyze the AFS cell microenvironment, we injected murine YFP+ embryonic stem cells (ESC) into the amniotic fluid of E13.5 wild type embryos. Four days after transplantation we found that YFP+ sorted cells maintained the expression of pluripotency markers and that ESC adherent to the amnion were more similar to original ESC in respect to those isolated from the amniotic fluid. Moreover, cytokines evaluation and oxygen concentration analysis revealed in this microenvironment the presence of factors that are considered key regulators in stem cell niches. This is the first indication that AFS cells reside in a microenvironment that possess specific characteristics able to maintain stemness of resident and exogenous stem cells.

Nationwide newspaper coverage of physician-assisted suicide: a community structure approach.

Using a community structure approach linking city characteristics and variations in media coverage, the authors examined newspaper coverage of physician-assisted suicide. A nationwide sample of 15 city newspapers yielded 288 articles in a four year period. Content analysis of article "prominence" (placement, headline size, story length, presence of photos) and overall article direction (favorable, unfavorable, or balanced/neutral) yielded a combined and widely varied single score "Media Vector" or measure of issue "projection" for each newspaper. Correlation and factor analysis yielded two significant city characteristic factors: a "stakeholder" factor, age (percent over 75) associated with unfavorable coverage of physician-assisted suicide (r = -.491; p = 000); and an "access" factor--combining media access (newspaper circulation, cable stations, FM or AM stations) and health care access (health care facilities, physicians)--linked to favorable coverage (r = .472; p = .000), combining to account for 46.3 percent of the variance. Western US newspapers and public opinion are most favorable to physician-assisted suicide.

Tobacco industry direct marketing after the Master Settlement Agreement.

Although Master Settlement Agreement (MSA) provisions have led to significant changes in tobacco marketing, expenditures and emphasis on marketing strategies and populations not bound by the MSA have increased significantly. This article discusses tobacco industry direct marketing practices, including direct mail, coupons, sweepstakes, brand loyalty programs, event sponsorship, and tobacco industry magazines, and the implications of such strategies. An analysis of a survey of New Jersey adult smokers provides context and documents notable rates of participation. In addition to bypassing marketing restrictions, many of these strategies operate out of sight of the public health community and most of the public and so go unchecked by either tobacco control advocates or public opinion. This article suggests that a first step in countering these practices is to increase awareness and understanding of them, followed by development of strategies to address them and to limit or eliminate their use in tobacco marketing.

The unclear status of nonprofit directors: an empirical survey of director liability.

Nonprofit boards of directors are fiduciaries for the organization. However, there have been various legal interpretations of their duties. The authors review the conflicting standards of conduct that exist, and they report the results of a survey which sampled director opinion concerning the liability issue. The proposition that directors were unaware of their legal responsibilities was supported, and the implications of this finding for organizational procedures and public policy are discussed.

[Purine metabolism in ankylosing spondylitis: clinical study]. / Metabolismo de las purinas en la espondilitis anquilosante: estudio clínico.

We undertook a prospective study of 23 male patients with Ankylosing Spondylitis (AS) (New York Criteria), 18 HLA-B27 positive and 5 HLA-B27 negative, five of them had hyperuricemia. The following data of evolution were taken into consideration: age at onset of disease, time course of the disease, presence of urolithiasis, heart disease, flares of uveitis. Clinical activity and degree of disability were evaluated every one to 3 months; on each visit, every patient had determinations of serum and urinary uric acid levels, serum and phosphorus, erythrocyte sedimentation rate (ESR), serum protein electrophoresis, as well as X-ray films of the vertebral spine and pelvis. Three groups of patients were detected, all of them with equal age at onset, duration of disease, frequency of B27, peripheral arthritis, and leukocytosis. One group had hyperuricemia (5 of 23 patients, 80% of them HLA-B27 positive) and a lesser degree of clinical activity of the disease (p less than .001, a higher frequency of uveitis (40%, lower levels of serum gammaglobulins (p less than 0.05) and ESR (p less than 0.05), a lesser degree of ankylosis of the spine, and a better functional prognosis than the other groups. Another group (8 of 23 patients, 75% of them were HLA-B27 positive) had normouricemia and hyperuricosuria, and showed a higher frequency of fever (50%), an abnormal urinalysis, and urolithiasis (25%).

[Functional abnormalities of complement in familial and sporadic ankylosing spondylitis]. / Anormalidades funcionales del complemento en la espondilitis anquilosante familiar y esporádica.

Levels of complement fractions of 12 patients with sporadic ankylosing Spondylitis and 6 patients with familial Ankylosing Spondylitis (N. Y. Criteria) were studied by an hemolytic and functional method (microhemolysis in plate. Cordis Lab. Miami, Fla. USA). Abnormal levels were found in 94% of them high levels of C1 and C2 (p 0.002), and C3 (p 0.05) C8 and C9 (p 0.001) deficiencies, mixed or isolated, correlated with the severity of the diseases. C9 deficiency belongs to familial Ankylosing Spondylitis. These functional deficiencies of serum complement can favor the colonization and persistence of germs, which could mediate in the genesis of Ankylosing Spondylitis.

[Cardiovascular manifestations in mixed connective tissue disease in adults]. / Manifestaciones cardiovasculares en la enfermedad mixta del tejido conectivo en adultos.

Twenty two patients with mixed connective tissue disease (MCTD) were studied with noninvasive cardiovascular techniques. Fifty percent of the cases presented cardiovascular abnormalities which in order of importance were: pericarditis with effusion (28%), myocarditis (14%) and one case; myocardial infarction. Complications of less importance were: supraventricular and ventricular premature beats, enlargement of left and right cardiac chambers, septal hypertrophy and type A paradoxical septal movement. We consider that patients with MCTD should have a routine cardiological evaluation.