Magnesium salts in the treatment of ventricular tachycardia

We report the results of magnesium sulphate (MgSO4) infusion in 10 patients with different ventricular arrhythmias: 6 torsade de pointes (2 with total A-V block, 1 with acute myocardial infarction and 3 with lengthening of the Q-Tc due to antiarrhythmic and/or diuretic treatment), 1 bidirectional ventricular tachycardia (on chronic treatment with digoxin (0.5 mg/day) and diuretics), and 3 polymorphic ventricular ectopic beats plus ventricular tachycardia runs (2 with hypertensive and 1 with ischemic cardiomyopathy). MgSO4 in normal saline was given at low rate (50 mg/min) and continued 2 hours after disappearance of arrhythmia, and the infusion was repeated at the same rate for 60-90 min twice daily for the next 3-4 days. In all patients the drug was effective and no side effects were observed. The heart rate and Q-Tc interval remained unchanged from baseline values. Serum creatinine concentration was normal. Serum Mg++, 60 minutes after the beginning of the infusion, was comparable to control values in all the patients, except 2 with hypomagnesemia. Finally, we can conclude that MgSO4 is an useful therapeutic tool for the treatment of various ventricular tachycardias.     

Tension-free vaginal tape for the treatment of urodynamic stress incontinence with intrinsic sphincteric deficiency

The purpose of this study was to evaluate the outcome of tension-free vaginal tape (TVT) procedure in women with urodynamic stress incontinence diagnosed as having intrinsic sphincteric deficiency (ISD). The combination of a maximal urethral closure pressure <20 cm H₂O and a Valsalva leak point pressure <60 cm H₂O was considered as diagnostic of ISD. Subjects with detrusor overactivity on preoperative urodynamics were excluded. A total of 35 patients with both low closure pressure and leak point pressure were enrolled. Bladder perforation occurred in three (8.6%) cases. Postoperative urinary voiding difficulties occurred in nine (25.7%) women. Two patients underwent surgical detension of the tape, with complete resolution of urinary retention and no relapse of incontinence. Women with postoperative voiding dysfunction had a significantly lower detrusorial pressure at the peak flow on preoperative urodynamics compared to those who voided efficiently after TVT. The mean (range) follow-up time was 12.5 months (3–36). The objective cure rate for stress incontinence was 91.4%. Two of the three (66%) patients in whom the TVT procedure failed had a fixed urethra. De novo urge incontinence was found in five (14.3%) patients.     

Efficacy and tolerability of estraderm MX, a new estradiol matrix patch

Objectives: To assess the efficacy and tolerability of a new matrix patch delivering 0.05 mg estradiol per day (Estraderm MX 50) in postmenopausal women with moderate to severe postmenopausal symptoms. Methods: A multicenter, double-blin, randomized, between-patient, placebo controlled trial in 109 postmenopausal women was carried out. Patches were applied twice weekly for 12 weeks. Patients were assessed at 4, 8 and 12 weeks of treatment. The primary efficacy variable was change from baseline in mean number of moderate to severe hot flushes (including night sweats) per 24 h during the last 2 weeks of treatment. Other variables included Kupperman Index, local and systemic tolerability. Plasma concentrations of estradiol (E2), estrone (E1) and estrone sulfate (E1S) were determined before and after treatment. Results: Estraderm MX was significantly superior to placebo (P < 0.001) in reducing mean number of moderate to severe hot flushes (including night sweats) per 24 h after 4, 8 and 12 weeks of treatment. The estimate of treatment group differences after 12 weeks was 4.2 hot flushes (95% confidence interval: 2.6–5.5). Estraderm MX also significantly reduced Kupperman Index at all time points compared to placebo (P < 0.001). Estraderm MX induced increases in mean E2, E1 and E1S plasma levels as expected (E2: baseline 2.7 pg/ml, 12 weeks 38.9 pg/ml; E1: baseline 18.8 pg/ml, 12 weeks 41.6 pg/ml; E1S: baseline 235.6 pg/ml, 12 weeks 765.1 pg/ml). Overall rates of adverse experiences were similar for Estraderm MX and placebo. The number of patients reporting skin irritation was low and similar in both groups. Conclusions: Estraderm MX 50, a new matrix patch, offers an effective and well tolerated dosage form for transdermal delivery of 0.05 mg E2 per day.     

Differential control of in-phase and anti-phase coupling of rhythmic movements of ipsilateral hand and foot

Summary Rhythmic flexion-extensions of ipsilateral hand and foot are easily performed (easy association) when the two segments are moved in phase (isodirectionally), whereas great care and attention are required (difficult association) to move them in phase opposition. We searched for features distinguishing the two types of coupling by analyzing, on ten subjects: 1) the frequency limit in each association; and, 2) if coupling is modified by inertial or elastic loading of the hand. 1) Subjects were asked to oscillate hand and foot at various paced frequencies, in the easy or in the difficult association for one minute at least. In the easy coupling, the task was performed up to 2.0–2.5 Hz, the duration being thereafter shortened by muscular fatigue. In the difficult coupling when the frequency was increased above 0.7–1.7 Hz, the performance rapidly shortened, not because of fatigue but because of an inevitable reversal to the in-phase movement. The frequency-duration curve always followed a similar decay, although it covered different frequency ranges in the various subjects. 2) The effect of charging the hand with inertial or elastic loads was studied at the subject's preferred frequency, chosen when the hand was unloaded. Without loading, in the easy association the hand cycle slightly lagged the foot cycle while in the difficult one an almost perfect phase opposition was maintained. Under inertial load (inertial momentum: 9 gm²), in the easy association the hand lag was increased by 10° to 45°, despite a compensatory advanced activation of the forearm EMG; in the difficult association, instead, the hand lag was small (less than 10°), thanks to an even earlier onset of the forearm EMG. The elastic load (torque: 4 gm) had negligible effects on the phase relation between movements but improved the phase relation between EMGs. These findings show that coupling is tighter in the difficult than in the easy association, a feature that is emphasized by the effect of the load. This supports the idea that kinaesthetic afferences have more pronounced influences on control of the anti-phase than the in-phase coupling.     

Combination therapy with interleukin-6 receptor superantagonist Sant7 and dexamethasone induces antitumor effects in a novel SCID-hu In vivo model of human multiple myeloma.

Interleukin-6 (IL-6) protects multiple myeloma cells against apoptosis induced by glucocorticoids. Here, we investigated whether inhibition of the IL-6 signaling pathway by the IL-6 receptor superantagonist Sant7 enhances the in vivo antitumor effects of dexamethasone on the IL-6-dependent multiple myeloma cell line INA-6. For this purpose, we used a novel murine model of human multiple myeloma in which IL-6-dependent INA-6 multiple myeloma cells were directly injected into human bone marrow implants in severe combined immunodeficient (SCID) mice (SCID-hu). The effect of in vivo drug treatments on multiple myeloma cell growth was monitored by serial determinations of serum levels of soluble IL-6 receptor (shuIL-6R), which is released by INA-6 cells and served as a marker of tumor growth. In SCID-hu mice engrafted with INA-6 cells, treatment with either Sant7 or dexamethasone alone did not induce significant reduction in serum shuIL-6R levels. In contrast, the combination of Sant7 with dexamethasone resulted in a synergistic reduction in serum shuIL-6R levels after 6 consecutive days of treatment. Gene expression profiling of INA-6 cells showed down-regulation of proliferation/maintenance and cell cycle control genes, as well as up-regulation of apoptotic genes in multiple myeloma cells triggered by Sant7 and dexamethasone combination. In vitro colony assays showed inhibition of myeloid and erythroid colonies from normal human CD34(+) progenitors in response to dexamethasone, whereas Sant7 neither inhibited colony growth nor potentiated the inhibitory effect of dexamethasone. Taken together, these results indicate that inhibition of IL-6 signaling by Sant7 significantly potentiates the therapeutic action of dexamethasone against multiple myeloma cells, providing the preclinical rationale for clinical trials of Sant7 in combination with dexamethasone to improve patient outcome in multiple myeloma.     

De novo microduplication of the FMR1 gene in a patient with developmental delay,epilepsy and hyperactivity

Loss-of-function due to expansion of a CGG repeat located in the 5''UTR of the FMR1 gene is the most frequent cause of fragile X syndrome. Less than 1% of individuals with fragile X syndrome have been reported to have a partial or full deletion or point mutation of the FMR1 gene. However, whether a copy number gain of the FMR1 gene could result in certain clinical phenotypes has not been fully investigated. Here, we report the case of a child who presented with developmental delay starting at 9 months of age, fine motor and speech delay, progressive seizures since 18 months of age and hyperactivity. Molecular workup identified a de novo microduplication in the Xq27.3 region, including the FMR1 gene and the ASFMR1 gene. The expression level of the FMR1 gene in peripheral blood did not differ from that of the controls. In addition, an inherited 363-kb duplication on the chromosome 1q44 region and an inherited deletion of 168 kb on the chromosome 4p15.31 region were detected. It is not clear whether these inherited copy number variations (CNVs) also have a modifying role in the clinical phenotype of this patient.