Effects of a Shortage of Imiglucerase on Three Patients with Type I Gaucher Disease

Background: Children with Gaucher disease type I (GD1) are usually treated with enzyme replacement therapy (ERT) at a dose of 30-60U/Kg/2W. Recently, due to an acute shortage supply of imiglucerase, a reduced dose or a reduced infusion frequency was recommended. Objective: To evaluate the effects of a reduced infusion frequency of imiglucerase over 15 months of follow-up. Patients and Methods: Three patients (1M:2F) were treated with ERT since a median age of 7 years (range 5-12). Only one had bone crisis and Erlenmeyer deformations. Median duration of treatment before dose reduction was 3 years (range 1-8). ERT resulted in total regression of symptoms, normalization of hematological parameters and progressive improvement of chitotriosidase in all patients. In August 2009 infusion schedule was changed from a media 45U/Kg every two weeks to every four weeks. Results: All patients remained asymptomatic and with no major change on hematological parameters except for the patient with bone crisis who presented subnormal platelet count. All patients showed an upward trend in chitotriosidase values. Comments: Although a longer follow-up is needed, is probable that even children completely stabilized can probably not be kept on lower doses even though the reduction of frequency of the infusions represent a lower social burden.

Origem Anómala da Artéria Coronária Esquerda a Partir da Artéria Pulmonar

OBJECTIVE: To assess the frequency and severity of the anomalous origin of the left coronary artery (ALCA) from the pulmonary artery (PA). DESIGN OF THE STUDY: Prospective study of case series between March 1991 and December 1994. SETTING: Referral-based Paediatric Cardiology Department of a Tertiary Care Center. PATIENTS AND METHODS: Five consecutive patients (pts) with anomalous origin of the LCA from the PA; there were three infants aged 4 months and two children one 8 year and one 9 year old. There were three girls and two boys. All pts had clinical and 2D-echo and Doppler investigation prior to cardiac catheterization (CC). Indication for CC was based in the association of symptoms and signs of myocarditis or dilated cardiomyopathy of acute or subacute onset and electrocardiographic (ECG) signs of ischemia in infants. In older patients (pts) diagnosis was suspected mainly from ECG. During CC in all pts, aortograms and when necessary selective coronary angiograms were performed. Surgical correction was performed in all children. In two pts stress exercise ECG and stress Thallium studies before and after surgery were performed. RESULTS: two pts had "adult" an three had "infantile" type of ALCA from the PA. CC was performed and diagnosis was confirmed at surgery in all cases. In one child, correct diagnosis was made by ECO prior to CC and in one case LCA to PA fistula was suspected on Colour-Doppler study. No complications were attributed to CC. Several types of surgery were performed: reimplantation of the ALCA from the PA to the aorta (three pts); tunnel connection of the aorta to the ALCA via the PA (one pt) and left internal mammary to LCA anastomosis (one pt). Two infants died intraoperatively due to extensive myocardial infarction and poor left ventricular function. All the three survivors are asymptomatic after a mean follow up of 34 months. Two oldest pts are currently in New York Heart Association functional class I with normal ECG and improved myocardial perfusion on Thallium scan despite almost total occlusion of LCA at the site of implantation in the aorta as diagnosed on coronary angiogram. CONCLUSIONS: ALCA from PA is associated with major morbidity and mortality. Diagnosis should be suspected in pts with unexplained myocardial ischemia on ECG and even more if it is associated to clinical signs of dilated cardiomyopathy or myocarditis. Careful assessment on ECO and pulsed Doppler and colour flow mapping should make the diagnosis in most cases. Although surgery can be performed based only on ECO diagnosis, we strongly advise for angiography in all cases as in our experience there are false negative diagnosis by ECO. Preoperative Thallium studies can be useful for the selection of the type of surgery as pts with very little viable myocardium will not survive the establishment of a direct systemic to coronary blood flow and may be candidates for heart transplantation.

Recalcitrant Leg Ulcers as the Only Manifestation of Essential Type 2 Cryoglobulinemia

Chronic leg ulcers are persistent conditions that might be a diagnostic and therapeutic challenge, with great impact in health care costs and patients’ quality of life. We report a case of a 60-year-old woman, with long-lasting recalcitrant leg ulcers, which led to left leg amputation 10 years ago. Several attempts to heal the right leg were made, including skin grafting in three different occasions and several surgical debridements, all with unsatisfactory outcome. Some months before the ulcers began, the patient had been diagnosed with undifferentiated connective tissue disease because of arthralgia and positive antinuclear antibodies, therefore low dose systemic corticosteroids and azathioprine were prescribed. For the last 4 years she has been followed in our department and since then no evidence of clinical or laboratorial criteria for autoimmune diseases was found, thus the immunosuppressive therapy was stopped. She maintained ever since a high rheumatoid factor but without other evidence of autoimmune disease. Medical history was otherwise irrelevant. Several cutaneous biopsies were performed, with no evidence of malignancy or vasculitis. Recently, cryoglobulins became positive, with type 2b cryoglobulin identification on immunofluorescence. Serology for Hepatitis C virus was consistently negative, hence an Essential type 2 Cryoglobulinemia diagnosis was established. No renal impairment, vascular purpura, arthralgia or arthritis was found. The authors emphasize the importance of considering less common etiologies for chronic leg wounds, even in the absence of other suggestive symptomatology, as well as the pertinence of reconsidering diagnosis in highly suspect cases.

Evolution of the Human Immunodeficiency Virus Type 2 Envelope in the First Years of Infection is Associated with the Dynamics of the Neutralizing Antibody Response

Background: Differently from HIV-1, HIV-2 disease progression usually takes decades without antiretroviral therapy and the majority of HIV-2 infected individuals survive as elite controllers with normal CD4+ T cell counts and low or undetectable plasma viral load. Neutralizing antibodies (Nabs) are thought to play a central role in HIV-2 evolution and pathogenesis. However, the dynamic of the Nab response and resulting HIV-2 escape during acute infection and their impact in HIV-2 evolution and disease progression remain largely unknown. Our objective was to characterize the Nab response and the molecular and phenotypic evolution of HIV-2 in association with Nab escape in the first years of infection in two children infected at birth. Results: CD4+ T cells decreased from about 50% to below 30% in both children in the first five years of infection and the infecting R5 viruses were replaced by X4 viruses within the same period. With antiretroviral therapy, viral load in child 1 decreased to undetectable levels and CD4+ T cells recovered to normal levels, which have been sustained at least until the age of 12. In contrast, viral load increased in child 2 and she progressed to AIDS and death at age 9. Beginning in the first year of life, child 1 raised high titers of antibodies that neutralized primary R5 isolates more effectively than X4 isolates, both autologous and heterologous. Child 2 raised a weak X4-specific Nab response that decreased sharply as disease progressed. Rate of evolution, nucleotide and amino acid diversity, and positive selection, were significantly higher in the envelope of child 1 compared to child 2. Rates of R5-to-X4 tropism switch, of V1 and V3 sequence diversification, and of convergence of V3 to a β-hairpin structure were related with rate of escape from the neutralizing antibodies. Conclusion: Our data suggests that the molecular and phenotypic evolution of the human immunodeficiency virus type 2 envelope are related with the dynamics of the neutralizing antibody response providing further support for a model in which Nabs play an important role in HIV-2 pathogenesis.

Two Novel CMY-2-Type β-Lactamases Encountered in Clinical Escherichia Coli Isolates

BACKGROUND: Chromosomally encoded AmpC β-lactamases may be acquired by transmissible plasmids which consequently can disseminate into bacteria lacking or poorly expressing a chromosomal bla AmpC gene. Nowadays, these plasmid-mediated AmpC β-lactamases are found in different bacterial species, namely Enterobacteriaceae, which typically do not express these types of β-lactamase such as Klebsiella spp. or Escherichia coli. This study was performed to characterize two E. coli isolates collected in two different Portuguese hospitals, both carrying a novel CMY-2-type β-lactamase-encoding gene. FINDINGS: Both isolates, INSRA1169 and INSRA3413, and their respective transformants, were non-susceptible to amoxicillin, amoxicillin plus clavulanic acid, cephalothin, cefoxitin, ceftazidime and cefotaxime, but susceptible to cefepime and imipenem, and presented evidence of synergy between cloxacilin and cefoxitin and/or ceftazidime. The genetic characterization of both isolates revealed the presence of bla CMY-46 and bla CMY-50 genes, respectively, and the following three resistance-encoding regions: a Citrobacter freundii chromosome-type structure encompassing a blc-sugE-bla CMY-2-type -ampR platform; a sul1-type class 1 integron with two antibiotic resistance gene cassettes (dfrA1 and aadA1); and a truncated mercury resistance operon. CONCLUSIONS: This study describes two new bla CMY-2-type genes in E. coli isolates, located within a C. freundii-derived fragment, which may suggest their mobilization through mobile genetic elements. The presence of the three different resistance regions in these isolates, with diverse genetic determinants of resistance and mobile elements, may further contribute to the emergence and spread of these genes, both at a chromosomal or/and plasmid level.