Bradycardia and Syncope in Children Not Controlled by Pacing: Beta-Adrenergic Hypersensitivity

Cardiac pacing is frequently employed in the therapy of children with syncope and documented bradycardia. This report describes two children, ages 7 and 9 years, who underwent placement of demand ventricular pacing systems for documented bradycardia and syncope. Cardiac catheterization and intracardiac electrophysiological studies failed to show evidence of structural abnormalities, sinus node or conduction system disease, inducible arrhythmias, or VA conduction in each patient. Both patients had persistent symptoms after pacemaker implantation. Autonomic function testing with continuous heart rate and blood pressure monitoring revealed exaggerated beta-adrenergic responses to simple standing and small doses of isoproterenol. Symptoms were completely eliminated with atenolol. In these two children, cardiac pacing alone was not adequate for relief of symptoms. Autonomic mechanisms of bradycardia and hypotension should be considered prior to implantation of permanent pacing systems in children.     

Characteristics of human large granular lymphocytes and relationship to natural killer and K cells

Recent evidence, has demonstrated an association between a subpopulation of peripheral blood mononuclear cells, morphologically identified as large granular lymphocytes (LGL), and natural killer (NK) activity. We have now evaluated more directly the role of LGL in both NK activity and antibody- dependent cellular cytotoxicity (ADCC), by using highly enriched populations of LGL, obtained by centrifugation of peripheral blood mononuclear cells on Percoll discontinuous density gradients. Both spontaneous and interferon- augmented NK and ADCC activities were exclusively associated with the LGL- enriched, low density fractions. The majority of LGL formed conjugates with NK-susceptible and antibody-coated target cells. Approximately 20 percent of small conventional lymphocytes also formed conjugates with the target cells for NK, but this was not associated with cytotoxic activity. Virtually all LGL were found to have receptors for the Fc portion of IgG (FcγR). The frequency of LGL among blood leukocytes was 2-6 percent. LGL could be enriched to an average purity of 95 percent by combining discontinuous density gradient centrifugation with subsequent adsorptions of the low density fractions on monolayers of immobilized immune complexes. About 50 percent of LGL were found to be FcγR-bearing T cells (T(G)), forming low affinity rosettes with sheep erythrocytes at 4 degrees C. Only 10-20 percent of LGL formed high affinity rosettes with sheep erythrocytes at 29 degrees C. LGL could be enriched to a purity of more than 90 percent by depleting high affinity rosette-forming cells from low density Percoll fractions. LGL were only a subpopulation of T(G) cells, because some lymphocytes with conventional morphology also adhered to the immobilized immune complex monolayers and formed high affinity rosettes with sheep erythrocytes. Separation of these cells from LGL by discontinuous density gradient centrifugation indicated that they are not cytotoxic, suggesting a morphological and functional subdivision of T(G) cells. The verification in this study that virtually all human NK and K cells have a characteristic morphology adds a useful parameter to the monitoring of human lymphocytes, and the ability to purify these cells by simple physical procedures should be invaluable in their further characterization.     

Clinical failure of vancomycin in a dialysis patient with methicillin-susceptible vancomycin-heteroresistant S. aureus

We report a case of recurrent Staphylococcus aureus bacteremia in a patient who failed vancomycin due to a vancomycin-heteroresistant strain lacking methicillin resistance. Although initial isolates were susceptible, isolates obtained after vancomycin chemotherapy were vancomycin heteroresistant. This case thus illustrates the clinical emergence of vancomycin heteroresistance.     

First rotavirus vaccine licensed: Is there really a need?

The first rotavirus vaccine was licensed in the United States on 31 August 1998 for the prevention of severe rotavius diarrhea in children. Despite this landmark in new vaccines, many pediatricians and public health professionals in Europe are uncertain of the need for this vaccine for the routine immunization of infants. In Europe, ample evidence suggests that rotavirus is the most common cause of hospitalizations for severe diarrhea among children, but proper studies documenting the disease burden of rotavirus or th cost-effectiveness of a rotavirus immunization program have only been conducted in the United Kingdom following epidemiologic models used in the United States. All children are infected with rotavirus during their first few years of life, 30-50% of diarrheal hospitalizations among children <5 years are due to this agent, and, by the age of 5 years, between 1 in 40 and 1 in 77 children in Europe and the United States may be hospitalized for rotavirus. The first vaccine is a live, oral preparation combining four different serotypes of rotavirus and administered in three doses with other childhood immunizations. The good efficacy against severe rotavirus diarrhea, the low risk of adverse side effects and the positive costeffectiveness equation have led the two major immunization advisory groups in the U.S. to recommend this vaccine for routine use in American infants. European physicians and policymakers should re-examine the epidemiology and disease burden of rotavirus diarrhea now that an effective method of prevention is at hand. □ Childhood immunization, diseases, rotavirus, vaccination .     

Germline mutation in BRAF codon 600 is compatible with human development: de novo p.V600G mutation identified in a patient with CFC syndrome

Champion KJ, Bunag C, Estep AL, Jones JR, Bolt CH, Rogers RC, Rauen KA, Everman DB. Germline mutation in BRAF codon 600 is compatible with human development: de novo p.V600G mutation identified in a patient with CFC syndrome. BRAF, the protein product of BRAF, is a serine/threonine protein kinase and one of the direct downstream effectors of Ras. Somatic mutations in BRAF occur in numerous human cancers, whereas germline BRAF mutations cause cardio‐facio‐cutaneous (CFC) syndrome. One recurrent somatic mutation, p.V600E, is frequently found in several tumor types, such as melanoma, papillary thyroid carcinoma, colon cancer, and ovarian cancer. However, a germline mutation affecting codon 600 has never been described. Here, we present a patient with CFC syndrome and a de novo germline mutation involving codon 600 of BRAF, thus providing the first evidence that a pathogenic germline mutation involving this critical codon is not only compatible with development but can also cause the CFC phenotype. In vitro functional analysis shows that this mutation, which replaces a valine with a glycine at codon 600 (p.V600G), leads to increased ERK and ELK phosphorylation compared to wild‐type BRAF but is less strongly activating than the cancer‐associated p.V600E mutation.     

Exploring the utility of whole‐exome sequencing as a diagnostic tool in a child with atypical episodic muscle weakness

The advent of whole‐exome next‐generation sequencing (WES) has been pivotal for the molecular characterization of Mendelian disease; however, the clinical applicability of WES has remained relatively unexplored. We describe our exploration of WES as a diagnostic tool in a 3½‐year old female patient with a 2‐year history of episodic muscle weakness and paroxysmal dystonia who presented following a previous extensive but unrevealing diagnostic work‐up. WES was performed on the proband and her two parents. Parental exome data was used to filter potential de novo genomic events in the proband and suspected variants were confirmed using di‐deoxy sequencing. WES revealed a de novo non‐synonymous mutation in exon 21 of the calcium channel gene CACNA1S that has been previously reported in a single patient as a rare cause of atypical hypokalemic periodic paralysis. This was unexpected, as the proband's original differential diagnosis had included hypokalemic periodic paralysis, but clinical and laboratory features were equivocal, and standard clinical molecular testing for hypokalemic periodic paralysis and related disorders was negative. This report highlights the potential diagnostic utility of WES in clinical practice, with implications for the approach to similar diagnostic dilemmas in the future.     

Isolation and characterization of human and rabbit sperm tail fibrous sheath

Using mechanical and chemical dissection methods, fibrous sheath was isolated both from normal ejaculated human spermatozoa and from rabbit cauda epididymal spermatozoa. The same techniques did not produce a pure preparation of fibrous sheath from ejaculated rabbit spermatozoa, suggesting that further cross-linking and stabilization of sperm structures occurs in response to components of the seminal plasma. The isolation procedures were monitored by phase contrast microscopy and the purity of the fibrous sheath was verified by electron microscopy. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) of isolated human fibrous sheath revealed at least 14 protein bands of which the most intensely stained were of molecular weight 84, 72, 66.2, 57, 32 and 28.5 kDa. The rabbit fibrous sheath revealed at least 10 protein bands, of which the most intensely stained were 35.2, 32.7 and 28.5 kDa. The amino acid composition of the purified fibrous sheath from human and rabbit spermatozoa was similar, being high in aspartic acid and/or asparagine and glutamic acid and/or glutamine, serine, alanine, leucine, lysine and glycine, but low in histidine, tyrosine and isoleucine. This composition is similar to that reported for the rat and suggests that mammalian sperm tail fibrous sheaths are composed of similar types of proteins, although there are apparent differences in protein components between species.