Global FKRP Registry: observations in more than 300 patients with Limb Girdle Muscular Dystrophy R9.

OBJECTIVE: The Global FKRP Registry is a database for individuals with conditions caused by mutations in the Fukutin-Related Protein (FKRP) gene: limb girdle muscular dystrophy R9 (LGMDR9, formerly LGMD2I) and congenital muscular dystrophies MDC1C, Muscle-Eye-Brain Disease and Walker-Warburg Syndrome. The registry seeks to further understand the natural history and prevalence of FKRP-related conditions; aid the rapid identification of eligible patients for clinical studies; and provide a source of information to clinical and academic communities. METHODS: Registration is patient-initiated through a secure online portal. Data, reported by both patients and their clinicians, include: age of onset, presenting symptoms, family history, motor function and muscle strength, respiratory and cardiac function, medication, quality of life and pain. RESULTS: Of 663 registered participants, 305 were genetically confirmed LGMDR9 patients from 23 countries. A majority of LGMDR9 patients carried the common mutation c.826C > A on one or both alleles; 67.9% were homozygous and 28.5% were compound heterozygous for this mutation. The mean ages of symptom onset and disease diagnosis were higher in individuals homozygous for c.826C > A compared with individuals heterozygous for c.826C > A. This divergence was replicated in ages of loss of running ability, wheelchair-dependence and ventilation assistance; consistent with the milder phenotype associated with individuals homozygous for c.826C > A. In LGMDR9 patients, 75.1% were currently ambulant and 24.6%, nonambulant (unreported in 0.3%). Cardiac impairment was reported in 23.2% (30/129). INTERPRETATION: The Global FKRP Registry enables the collection of patient natural history data, which informs academics, healthcare professionals and industry. It represents a trial-ready cohort of individuals and is centrally placed to facilitate recruitment to clinical studies.

Safety, tolerability, and efficacy of KP-1461 as monotherapy for 124 days in antiretroviral-experienced, HIV type 1-infected subjects.

Treatment of HIV infection with conventional antiretroviral therapy (ART) is a lifelong challenge with significant long-term risks of adverse events and treatment failure-induced HIV resistance being major concerns. One potential alternative to standard treatment is the use of viral decay accelerators, antiviral agents that theoretically can drive the rate of viral mutation beyond the compensatory capacity of the virus, thereby inducing viral extinction. One such drug, KP-1461, was tested in a population of HIV-infected persons not receiving ART to assess the safety, tolerability, and efficacy of the strategy in vivo. Of 24 highly treatment-experienced HIV-infected patients who received at least one dose of KP-1461, 13 completed the planned 4 months of monotherapy. The drug was generally well tolerated; it did not significantly affect either HIV viral load or CD4 lymphocyte count over the period of dosing. Pharmacokinetic sampling suggested adequate drug exposure was achieved. There were no new mutations induced by KP-1461 that changed viral susceptibility to standard antiretroviral agents. After the study was completed, analysis of more than 7 million base pairs of HIV samples from study patients and controls demonstrated changes in the pattern of viral mutations that differed significantly from what would be encountered naturally. The identified alterations were consistent with an effect resulting from KP-1461's proposed mechanism of action. These findings suggest that the novel antiretroviral approach illustrated by this study should be further investigated, particularly given the relatively good tolerability and the demonstrated excellent safety in this limited cohort study.

Safety, Tolerability, and Pharmacokinetics of KP-1461 in Phase I Clinical Studies: A Single Oral Dose Study in Non-HIV-Infected Adults, and a 14-Day Dose-Escalating Study in Highly Antiretroviral-Experienced HIV-Infected Adults.

BACKGROUND: KP-1461 is a prodrug to KP-1212. KP-1212 is a viral mutagen designed to increase viral error rate. METHODS: We describe 2 phase I studies: KP1461-101 (double-blind, placebo-controlled, single, escalating doses, 100 to 1600 mg study in 42 non-HIV-infected participants) and KP-1461-102 (double-blind placebo-controlled dose escalation 14-day study in HIV-infected participants, 400-3200 mg). Primary objectives were safety/tolerability. Secondary objectives included pharmacokinetic analysis with exploratory objective to characterize KP-1212 effects on viral load. RESULTS: KP-1461 was well tolerated. Majority of adverse events were grade 1 (neurological, gastrointestinal, cardiovascular). Four participants experienced grade 3 and 1 experienced a grade 4 event. Analysis demonstrated no difference in pharmacokinetic parameters at day 1 or 14. Linear pharmacokinetics found in 1600 mg arm. Compared to placebo, only at the 3200 mg dose demonstrated a marginally statistically significant virologic response. CONCLUSIONS: These studies provide safety/tolerability information and suggest virologic efficacy. KP-1212, a first-in-class antiretroviral, demonstrates the ability to induce viral eradication in vitro. Viral reduction in vivo may foretell a paradigm shift in HIV pharmacotherapy.

Mutation of HIV-1 genomes in a clinical population treated with the mutagenic nucleoside KP1461.

The deoxycytidine analog KP1212, and its prodrug KP1461, are prototypes of a new class of antiretroviral drugs designed to increase viral mutation rates, with the goal of eventually causing the collapse of the viral population. Here we present an extensive analysis of viral sequences from HIV-1 infected volunteers from the first "mechanism validation" phase II clinical trial of a mutagenic base analog in which individuals previously treated with antiviral drugs received 1600 mg of KP1461 twice per day for 124 days. Plasma viral loads were not reduced, and overall levels of viral mutation were not increased during this short-term study, however, the mutation spectrum of HIV was altered. A large number (N = 105 per sample) of sequences were analyzed, each derived from individual HIV-1 RNA templates, after 0, 56 and 124 days of therapy from 10 treated and 10 untreated control individuals (>7.1 million base pairs of unique viral templates were sequenced). We found that private mutations, those not found in more than one viral sequence and likely to have occurred in the most recent rounds of replication, increased in treated individuals relative to controls after 56 (p = 0.038) and 124 (p = 0.002) days of drug treatment. The spectrum of mutations observed in the treated group showed an excess of A to G and G to A mutations (p = 0.01), and to a lesser extent T to C and C to T mutations (p = 0.09), as predicted by the mechanism of action of the drug. These results validate the proposed mechanism of action in humans and should spur development of this novel antiretroviral approach.

[Early lumbar puncture and cutaneous rash: a clear CSF is not always a normal CSF]. / Ponction lombaire précoce et rash cutané: un liquide céphalorachidien normal peut en cacher un autre.

The clinical and biological characteristics of adult bacterial meningitis are usually unequivocal, but more subtle clinical presentations can be observed. A 24-year-old woman was admitted with fever and abdominal discomfort, which had been developing for 24 hours. There were no meningeal signs, but a transient cutaneous rash was observed on admission. A clear CSF was obtained showing no cytological or biochemical abnormality. Ceftriaxone 2 g was administrated intravenously. In the following hours of admission, a frank meningeal syndrome with purpura appeared, leading to a second lumbar puncture, which revealed purulent CSF. The culture of the first CSF yielded Neisseria meningitidis, while the second CSF remained sterile. This case showed a probable meningococcal rash. This is a reminder that a normal CSF can be obtained early in the course of a proved bacterial meningitis, and that CSF bacterial eradication can occur very rapidly after a single dose of third-generation cephalosporin.

The alpha1-adrenergic blocker urapidil improves contractile function in patients 3 months after coronary stenting: a randomized, double-blinded study.

BACKGROUND: The recovery of left ventricular function (LVF) after revascularization takes time. alpha-Adrenergic blockade acutely improves coronary blood flow and LVF, whereas the effects of more prolonged alpha-adrenergic blockade on LVF recovery after stenting are unknown. METHODS: In 32 patients (age 58 +/- 12 y) with an 82% +/- 6% stenosis, ejection fraction (EF) and systolic thickening (%Th) were measured by transthoracic echocardiography before and 30 minutes to 2 hours after revascularization. In a double-blinded protocol, either 200 microg/kg urapidil or placebo was given intravenously, and LVF was measured 10 minutes later. Two hours later, oral treatment with 30 mg/d drug or placebo was started, and LVF measured again after 24 hours and 3 months. RESULTS: Before revascularization, EF was 49.4% +/- 8.5% (+/-SD) and 51.3% +/- 8.8% in the urapidil-treated and the placebo groups, respectively. Thirty minutes to 2 hours after coronary stenting, EF was unchanged. After intravenous drug administration, EF increased to 56.5% +/- 9.7%). At 24 hours and 3 months after revascularization, EF became 59.5% +/- 7.9% and 59.6% +/- 8.2% in the urapidil-treated group, respectively, whereas EF in the placebo group did not change (50.4% +/- 5.7% and 49.7% +/- 4.9%, respectively). Revascularization did not acutely improve %Th. Intravenous urapidil improved %Th from 31.4% +/- 17.6% to 44.2% +/- 11.6%, whereas there was no change in the placebo group. At 3 months, %Th was 49.5% +/- 12.9% in the urapidil-treated group and 39.7% +/- 8.9% in the placebo group. CONCLUSIONS: These data suggest that long-term alpha-adrenergic blockade might improve LVF at midterm after coronary revascularization.

Mutational analysis of cell wall biosynthesis in Mycobacterium avium.

The cell wall of the environmental pathogen Mycobacterium avium is important to its virulence and intrinsic antimicrobial resistance. To identify genes involved in cell wall biosynthesis, "transposome" insertion libraries were screened for mutants with altered colony morphology on medium containing the lipoprotein stain Congo red. Nineteen such mutants were isolated and mapped, including 10 with insertions in a functional island of cell wall biosynthetic genes that spans approximately 40 kb of the M. avium genome.

Characterization of IS999, an unstable genetic element in Mycobacterium avium.

An IS3-family insertion element, IS999, was identified in the opportunistic pathogen Mycobacterium avium. The 1347 bp element has 29 bp inverted repeats and two overlapping open reading frames coding for putative transposases. It was detected in the genomes of ten of 12 M. avium isolates examined. Copy numbers ranged from four to 16. IS999 is less stable than IS1245, the most commonly-used marker for typing M. avium isolates. Among 60 colonies picked from a single patient isolate, there were two distinct IS1245 restriction fragment length polymorphism banding patterns compared to eight distinct IS999 patterns (five in one IS1245 group and three in the other). In view of its instability, we asked whether transposition of IS999 might have phenotypic consequences. Nucleotide sequence analysis of insertion sites in four isolates revealed 16 putative structural genes that were variably disrupted by IS999. Insertions into hdhA, a gene that codes for a putative short chain alcohol dehydrogenase, were distributed non-randomly between colony type variants, consistent with phenotypic consequences that exert selective pressure. These observations illustrate the genetic heterogeneity that can exist within populations of M. avium that appear to be homogeneous by IS1245 analysis. IS999 may be a useful marker for tracking, at the sub-strain level, the rapid genetic drift that M. avium isolates undergo in nature and in the laboratory.

[Heart failure with preserved left ventricular function: clinical, echocardiographic, and clinical course features. Prognostic factors]. / L'insuffisance cardiaque à fonction ventriculaire systolique préservée: aspects cliniques, échocardiographiques et évolutifs. Facteurs du pronostic.

Heart failure is clinically associated with inadequate myocardial contraction, a significant reduction of left ventricular systolic function and ejection fraction and a cardiac enlargement. Some studies have reported that patients with symptomatic heart failure may have an impaired left ventricular filling with a normal or preserved left ventricular systolic function and an ejection fraction > 45%. These patients have a "diastolic heart failure" often neglected or misdiagnosed. The aims of our study is to describe clinical, echocardiographic and hemodynamic characteristics of 64 patients hospitalized for symptomatic heart failure, to determine possible variables with prognosis relevance, and for evaluating the severity of this diastolic left ventricular dysfunction. All patients were assessed by physical and radiographic examination, 12 leads electrocardiogram, and usual laboratory tests. The internal diameter of left atrium and left ventricular end diastolic and tele-systolic diameter were measured following the recommendations of the American Society of Echocardiography, Ejection fraction was determined following Simpson's method. Left ventricular filling patterns were evaluated by pulsed Doppler mitral or venous pulmonary flow. The following parameters were assessed: maximum velocity of E and A waves, E/A ratio, E wave deceleration time and isovolumic relaxation time. The patients were studied following Appleton's classification. 45 patients were submitted to left heart catheterization and coronary angiography. All subjects were routinely followed by cardiologic examinations and the mean follow up is 18 +/- 4, 5 months. 29 women (45.3%) and 35 men with a mean age of 72.5 +/- 3.2 years were included in this study. Left ventricular ejection fraction was in mean 48.5 +/- 4.2%. 65% of patients had ischemic cardiomyopathy with severe coronary stenosis > 50%, often associated with hypertension. 52% of patients had hypertensive heart disease and 38% were diabetics. 34 patients were re-hospitalized for recurrent heart failure despite medical treatment with diuretics, ACE inhibitors (90% of patients), beta-blockers, (37%) or nitrates (36%). 24 patients have been treated by coronary angioplasty. In hospital mortality was 6.2% and during the follow up at 18 months the mortality reaches 18.7%. The factors of poor prognosis are age > 75 years, left ventricular restrictive pattern at doppler diastolic trans mitral flow evaluation, (p < 0.001), history of myocardial infarction, and renal insufficiency defined by creatinemia > 150 micromoles (p = 0.002). In conclusion heart failure with preserved left systolic ventricular function is frequent in women with hypertensive heart disease. The prognosis at mean term is better that prognosis of patients with systolic dysfunction but despite medical treatment there is a high morbidity with numerous re hospitalizations. Restrictive left ventricular filling pattern is significantly related to the occurrence of events and mortality.

Colony morphotypes on Congo red agar segregate along species and drug susceptibility lines in the Mycobacterium avium-intracellulare complex.

Isolates of the Mycobacterium avium-intracellulare complex (MAC) have long been known to segregate into transparent opaque and rough colony morphotypes that differ from each other in clinically important parameters including drug susceptibility and virulence. Here the authors report additional morphotypic variation that occurs on two levels: interspecific (between M. avium and M. intracellulare) and intraspecific (within individual M. avium isolates). Clinical isolates of M. avium grown on Congo red (CR) plates formed red, pink or mixed (red and white) opaque colonies, while M. intracellulare isolates formed purely white opaque colonies. A quantitative CR binding assay showed that this interspecific differential applies to transparent as well as opaque colony variants; however, it was less pronounced among laboratory reference strains than among recent clinical isolates. Opaque colonies of M. avium isolates with 'mixed' phenotypes segregated into stable opaque red and white variants with shared IS1245 banding patterns (intraspecific segregation). White segregants of M. avium were more flocculent and significantly more resistant to ciprofloxacin and rifamycin drugs than were red segregants. Thus, cultivation on CR agar revealed a previously unknown multidrug resistant colony morphotype of M. avium.

Magnetic Properties of a Series of Trinuclear Complexes (CuL)(2)Mn.xB (L Representing the Deprotonated Form of N-(4-Methyl-6-oxo-3-azahept-4-enyl)oxamic Acid and B Representing Respectively H(2)O (x = 5, 4.5, 3, 1), (CH(3))(2)SO (x = 2), and C(5)H(5)N (x = 4)). Crystal and Molecular Structure of (CuL)(2)Mn.2(CH(3))(2)SO.

A series of (Cu, Mn, Cu) complexes have been prepared and characterized. They may be described by the overall formula (CuL)(2)Mn.xB where L stands for the deprotonated form of N-(4-methyl-6-oxo-3-azahept-4-enyl)oxamic acid and B for respectively H(2)O (with x = 5, 4.5, 3, 1), (CH(3))(2)SO (with x = 2), and C(5)H(5)N (with x = 4). The crystal and molecular structures of (CuL)(2)Mn.2(CH(3))(2)SO have been solved. The crystals are monoclinic, space group P2(1)/n with cell constants a = 8.362(2) Å, b = 14.426(3) Å, c = 24.442(6) Å, and Z = 4. In each (Cu, Mn, Cu) molecular unit the central Mn(II) ion is bridged to two copper(II) ions through two oxamato groups. Short intermolecular Cu.Cu distances lead to the formation of a chain-like packing pattern running parallel to the c-axis. Magnetic susceptibility measurements have been performed for the six complexes. Five complexes display the same behavior which corresponds to the occurrence of antiferromagnetic Cu-Mn interactions within isolated trinuclear units. The J values are between -29.4(2) and -33.8(5) cm(-)(1). Surprisingly the field and temperature dependence of the magnetization for (CuL)(2)Mn.4.5H(2)O confirms that a magnetic phase transition occurs at low temperature and that, below T(c) = 37 K, the complex displays weak ferromagnetism.