Short QT Syndrome in a Pediatric Patient

Short QT syndrome (SQTS) is a recently described genetic syndrome characterized by abnormally brisk ventricular repolarization. Similar to long QT syndrome, SQTS might result in ventricular arrhythmias, syncope, and sudden death. The clinical diagnosis of SQTS is supported by the finding of an abnormally short QT interval on the resting electrocardiogram in combination with a suggestive clinical or family history. To date, few pediatric cases have been reported and the ideal therapy is unknown. We report a teenage boy who suffered a witnessed ventricular fibrillation arrest and was subsequently diagnosed with SQTS. Additional data from nine other pediatric patients diagnosed with SQTS are presented.     

A missense mutation in the conserved C2B domain of otoferlin causes deafness in a new mouse model of DFNB9

Mutations of the otoferlin gene have been shown to underlie deafness disorders in humans and mice. Analyses of genetically engineered mice lacking otoferlin have demonstrated an essential role for this protein in vesicle exocytosis at the inner hair cell afferent synapse. Here, we report on the molecular and phenotypic characterization of a new ENU-induced missense mutation of the mouse otoferlin gene designated Otof(deaf5Jcs). The mutation is a single T to A base substitution in exon 10 of Otof that causes a non-conservative amino acid change of isoleucine to asparagine in the C2B domain of the protein. Although strong immunoreactivity with an otoferlin-specific antibody was detected in cochlear hair cells of wildtype mice, no expression was detected in mutant mice, indicating that the missense mutation has a severe effect on the stability of the protein and potentially its localization. Auditory brainstem response (ABR) analysis demonstrated that mice homozygous for the missense mutation are profoundly deaf, consistent with an essential role for otoferlin in inner hair cell neurotransmission. Vestibular-evoked potentials (VsEPs) of mutant mice, however, were equivalent to those of wildtype mice, indicating that otoferlin is unnecessary for vestibular function even though it is highly expressed in both vestibular and cochlear hair cells.     

Fully implantable hearing device as a new treatment of conductive hearing loss in Franceschetti syndrome

The objective is to investigate a new therapeutic option for treatment of conductive hearing loss in children with Franceschetti syndrome. A Carina fully implantable device with the MET V transducer for conductive applications was implanted in a 14-year-old male suffering from bilateral conductive hearing loss (mean PTA loss: 70 dB on the right ear and 64 dB on the left ear) secondary to Franceschetti (a.k.a Treacher Collins) syndrome with bilateral agenesis of external ear canal and ossicular malformation. Postoperative unaided PTA was unchanged by the surgical procedure. When the implant was activated, mean PTA was 29 dB improved on the implanted ear. The capacity of the Carina MET ossicular stimulator to provide appropriate gain relative to the degree of hearing loss indicates that the device may be a viable treatment for children with agenesis of external auditory canal and severe malformation of the middle ear. However, these initial results need to be furthered by: (1) additional studies including a greater number of patients to confirm these preliminary results and (2) a long-term follow-up must be carried out to detect possible long-term cochlear adverse effects, in particular on the basilar membrane.     

Immune function during and after 60 min of moderate exercise wearing protective clothing

INTRODUCTION: As exercise while wearing protective clothing exacerbates body heat storage compared to exercise in the heat, and as exercise alters immune responses, it appeared worthwhile to examine immune and stress responses while wearing protective clothing during moderate exercise. METHODS: Eight subjects completed two bouts of exercise at 45% Vo2(max) in a thermoneutral environment: once while wearing shorts only (Control trial, CON) and again while wearing protective clothing (PRO). Venous blood samples were taken to analyze TNF-alpha mRNA by RT-PCR in LPS stimulated blood, plasma catecholamines, and cortisol. Blood cell count was analyzed by flow cytometry. Rectal temperature (T(re)) was monitored continuously. RESULTS: Exercise with PRO resulted in significantly greater increases in T(re) (39.2 +/- 0.2 degrees C in PRO vs. 38.0 +/- 0.1 degrees C in CON) and plasma epinephrine and norepinephrine (+70% and 150%, respectively). Plasma cortisol increased only at the end of PRO exercise (+33%). Leukocyte and lymphocyte cell count was 14% and 18% higher, respectively, but there were no significant changes in T cytotoxic and NK cell counts compared to the CON trial. Only T helper lymphocyte count was lower (-29%). During both exercise trials, T helper lymphocytes were significantly decreased at the end of exercise and recovery. With or without protective clothing, exercise was associated with an inhibition of TNF- alpha expression in stimulated monocytes (approximately -50% at min 20 and 40, and approximately -30% at min 60). DISCUSSION: Protective clothing wearing induces significant thermal challenge during exercise. The inhibition of TNF-alpha appears to be mediated primarily by exercise and not the added thermal load associated with protective clothing.     

Lupus vulgaris with squamous cell carcinoma

Tuberculosis is still a significant problem in developing countries. Cutaneous forms of tuberculosis account for approximately 10% of all cases of extrapulmonary tuberculosis. Cutaneous tuberculosis may be because of true infection with Mycobacterium tuberculosis or because of tuberculids. Tuberculids are immunological reactions to haematogenously spread antigenic components of M. tuberculosis. True cutaneous tuberculosis may be because of inoculation or haematogenous spread of M. tuberculosis to the skin. Lupus vulgaris is the commonest form of true cutaneous tuberculosis. Other forms of true cutaneous tuberculosis are tuberculous chancre, tuberculosis verrucosa cutis, scrofuloderma, periorificial tuberculosis and miliary tuberculosis of the skin. Lupus vulgaris is usually chronic and progressive. It occurs in patients with moderate to high immunity against M. tuberculosis as evidenced by strongly positive tuberculin test. Long-standing cases of lupus vulgaris may be complicated by squamous cell carcinoma (SCC). We describe a patient who had undiagnosed lupus vulgaris for 35 years until she developed SCC on the lesion of lupus vulgaris.     

Benefits and side effects of different vegetable oil vectors on apoptosis, oxidative stress, and P2X7 cell death receptor activation

PURPOSE: Ocular side effects in patients using eye drops may be due to intolerance to the vector used in eye drops. Castor oil is the commonly used lipophilic vector but has been shown to be cytotoxic. Effects on cells of four oils (olive, camelina, Aleurites moluccana, maize) were compared with those of castor oil in human conjunctival cells. METHODS: Human conjunctival cells were incubated with the oils for 15 minutes. After a 24-hour recovery period, cells were tested for viability, proliferation, apoptosis (P2X7 cell death receptor and caspase 3 activation), intracellular redox potential, and reactive oxygen species production. Fatty acid incorporation in cell membranes was also analyzed. In vivo ocular irritation was assessed using the Draize test. RESULTS: Compared to the four other oils, castor oil was shown to induce significant necrosis and P2X7 cell death receptor and caspase 3 activation and to enhance intracellular reactive oxygen species production. Aleurites moluccana and camelina oils were not cytotoxic and increased cell membrane omega-3 fatty acid content. None of the five tested oils showed any in vivo ocular irritation. CONCLUSIONS: The results demonstrated that castor oil exerts cytotoxic effects on conjunctival cells. This cytotoxicity could explain the side effects observed in some patients using eye drops containing castor oil as a vehicle. The lack of cytotoxic effects observed with the four other oils, Aleurites, camelina, maize, and olive, suggest that they could be chosen to replace castor oil in ophthalmic formulations.     

Interactions between carbamazepine and polyethylene glycol (PEG) 6000: characterisations of the physical, solid dispersed and eutectic mixtures

The influence of a hydrophilic carrier (PEG 6000) on the polymorphism of carbamazepine, an antiepileptic drug, was investigated in binary physical mixtures and solid dispersions by means of differential scanning calorimetry (DSC), thermal gravimetry, hot-stage microscopy (HSM), and X-ray diffractometry, respectively. This study provides also an attempt to develop a method to calculate more precisely the eutectic composition. In rather ideal physical mixtures, carbamazepine was found as monoclinic Form III. In solid dispersions, the drug was found to crystallize as trigonal Form II; a eutectic invariant in the PEG 6000-rich composition domain (6% of carbamazepine mass) was evidenced by DSC experiments and confirmed by HSM observations. In the binary phase diagram the ideal carbamazepine liquidus curve was located at temperatures higher than the respective experimental ones. This suggests that drug can be maintained in the liquid state in the temperature–mass fraction (T–x) region between the two carbamazepine liquidus curves. This indicates in turn that attractive interactions occur between carbamazepine and PEG 6000-chains. These interactions have been also claimed to prevent carbamazepine from degradation into iminostilbene (a compound resulting from the chemical degradation of carbamazepine which is postulated to be responsible for the idiosyncratic toxicity of the drug) and thought to lead to the crystallization of metastable Carbamazepine II from melt. The negative excess entropy for eutectic mixtures indicated that the drug crystals are finely dispersed in the bulk of polymer chains.     

Dexamethasone-based regimens versus melphalan-prednisone for elderly multiple myeloma patients ineligible for high-dose therapy

Dexamethasone alone increases life expectancy in patients with relapsed multiple myeloma (MM); however, no large randomized study has compared dexamethasone and dexamethasone-based regimens with standard melphalan-prednisone in newly diagnosed MM patients ineligible for high-dose therapy. In the Intergroupe Francophone du Myélome (IFM) 95-01 trial, 488 patients aged 65 to 75 years were randomized between 4 regimens of treatment: melphalan-prednisone, dexamethasone alone, melphalan-dexamethasone, and dexamethasone-interferon alpha. Response rates at 6 months (except for complete response) were significantly higher among patients receiving melphalan-dexamethasone, and progression-free survival was significantly better among patients receiving melphalan (P < .001, for both comparisons), but there was no difference in overall survival between the 4 treatment groups. Moreover, the morbidity associated with dexamethasone-based regimens was significantly higher than with melphalan-prednisone, especially for severe pyogenic infections in the melphalan-dexamethasone arm and hemorrhage, severe diabetes, and gastrointestinal and psychiatric complications in the dexamethasone arms. Overall, these results indicated that dexamethasone should not be routinely recommended as first-line treatment in elderly patients with MM. In the context of the IFM 95-01 trial, the standard melphalan-prednisone remained the best treatment choice when efficacy and patient comfort were both considered. These results might be useful in the context of future combinations with innovative drugs.