Multiple myeloma diagnosed during early pregnancy: a case report

Only five pregnant women with multiple myeloma have been reported in literature. We present the case of one woman with multiple myeloma diagnosed in early pregnancy, who decided to postpone therapy until after delivery. A cesarean section was performed at the 34th week due to the progression of the disease and a normal healthy baby was delivered.     

Prenatal ultrasound diagnosis of Toriello-Carey syndrome

Toriello-Carey syndrome is a rare malformative complex, described for the first time in 1988, characterized by agenesis of the corpus callosum, facial anomalies, cardiac defects and hypotonia. Relatively few neonatal cases have been reported. We describe here the first prenatal ultrasound diagnosis of the syndrome based on the detection of agenesis of the corpus callosum and spongious cardiomyopathy in a 22-week-old fetus of a couple with positive family history. The first sib of the couple was diagnosed with Toriello-Carey syndrome at 1 year of age, and had, in addition to the typical facial anomalies not detectable by ultrasound, agenesis of the corpus callosum and the same heart lesion (spongious cardiomyopathy). This report demonstrates that prenatal diagnosis of Toriello-Carey syndrome is feasible in the second trimester of pregnancy.     

Steroid-cell autoantibodies are preferentially expressed in women with premature ovarian failure who have adrenal autoimmunity

OBJECTIVE: To determine the prevalence of steroid-cell autoantibodies, 3beta-hydroxysteroid dehydrogenase (3beta-HSD) antibodies, 17alpha-hydroxylase (17alpha-OH) antibodies, and P450 side-chain cleavage antibodies in premature ovarian failure. DESIGN: Cross-sectional, observational study. SETTING: Academic research hospitals. PATIENT(S): Eighty-one women with premature ovarian failure, 20 women with Addison disease not associated with premature ovarian failure, 42 women with type 1 diabetes mellitus, and 90 healthy women. MAIN OUTCOME MEASURE(S): Serum levels of steroid-cell autoantibodies, 17alpha-OH antibodies, P450 side-chain cleavage antibodies, and 3beta-HSD antibodies. RESULT(S): Steroid-cell autoantibodies were present in none of 57 women with isolated premature ovarian failure or premature ovarian failure plus nonadrenal autoimmune disease and in 21 of 24 (87%) women with Addison disease-related premature ovarian failure. 17alpha-Hydroxylase antibodies and P450 side-chain cleavage antibodies were significantly more frequent in women positive for adrenal autoantibodies than in those negative for adrenal autoantibodies (50% vs. 0% and 71% vs. 2%, respectively). The presence of 17alpha-OH antibodies or P450 side-chain cleavage antibodies was strongly associated with presence of steroid-cell autoantibodies. Two of 24 (8%) women with Addison disease-related premature ovarian failure and 1 of 57 (2%) women with isolated premature ovarian failure or premature ovarian failure plus nonadrenal autoimmune disease were positive for 3beta-HSD antibodies. None of 20 adult women with autoimmune Addison disease and none of 42 adult women with type 1 diabetes mellitus not associated with premature ovarian failure was positive for 3beta-HSD antibodies. CONCLUSION(S): Markers of steroid-cell autoimmunity are found only rarely in idiopathic premature ovarian failure not associated with Addison disease. Most women with Addison disease-related premature ovarian failure were positive for steroid-cell autoantibodies, 17alpha-OH antibodies, or P450 side-chain cleavage antibodies. 3beta-Hydroxysteroid dehydrogenase antibodies do not appear to be a major marker of steroid-cell autoimmunity.     

PCR assay for the detection and the identification of atypical canine coronavirus in dogs

Comparative sequence analysis of the PCR products of the M gene and fragments of the pol1a and pol1b genes of canine coronavirus (CCoV) have demonstrated that two separate clusters of CCoV are present in dogs. This note describes a PCR assay to identify atypical CCoV strains with nucleotide substitutions in the M gene. A total of 177 faecal samples from dogs CCoV positive previously with the PCR assay were analysed. Sixty-two of the 177 samples were amplified with the PCR described in the present study and were thus considered atypical CCoVs. The specificity of the PCR typing assay was confirmed by sequence analysis of the PCR products.     

Bone involvement in eugonadal male patients with adrenal incidentaloma and subclinical hypercortisolism

Adrenal incidentalomas (AI) are not associated, by definition, with clinically evident syndromes; however, some AI patients may show biochemical indexes of subclinical hypercortisolism (SH). Previous data on female AI patients indicated that SH may lead to bone loss, at least at spine. No data are available on bone involvement in samples of only AI male patients. We measured bone metabolism and bone mineral density at spine and femur by dual-energy x-ray absorptiometry in 38 consecutive eugonadal male AI patients and 38 healthy matched control subjects. Patients were subdivided according to the presence or absence of SH (group SH+ and group SH-, respectively). Mean Z-score levels of spinal bone mineral density measured by dual-energy x-ray absorptiometry were lower (P < 0.05) in group SH+ (-0.42 +/- 1.62) in comparison with group SH- (0.6 +/- 1.13) and controls (0.47 +/- 1.06). Thus, in order for the most appropriate management to be individually tailored, bone mass evaluation is strongly indicated in AI male patients with SH, irrespective of their gonadal status.     

Effect of estrogen replacement plus low-dose alendronate treatment on bone density in surgically postmenopausal women with osteoporosis

This prospective randomized, double-blind, placebo-controlled, clinical trial was performed to evaluate the effectiveness of estrogens plus low-dose alendronate on bone metabolism. A total of 150 surgically postmenopausal women with osteoporosis were randomized in three groups: group A, micronized E2 (2 mg/d) plus standard-dose alendronate (10 mg/d); group B, micronized E2 plus low-dose alendronate (5 mg/d); and group C, micronized E2 plus placebo (one tablet per day). In all women, bone mineral density (BMD) and serum bone metabolism markers were assessed at admission and every 6 months for 2 yr. After 2 yr, BMD significantly increased compared with baseline in all groups. The percentage BMD change was significantly higher in groups A and B than in group C. The differences in BMD detected between groups A and B were not statistically significant. Since the 6-month follow-up and throughout the study, serum osteocalcin and bone alkaline phosphatase levels and urinary deoxypyridinoline and pyrilinks-D excretion were significantly reduced in all groups. Serum bone alkaline phosphatase levels significantly decreased in groups A and B, without difference between them, in comparison with group C. In conclusion, in surgically postmenopausal osteoporotic women treated with estrogen replacement, the addition of alendronate at a low dose of 5 mg daily induces a gain of bone mass not significantly different in comparison with that obtained using a standard dose of 10 mg daily.     

Optimal requirements for high affinity and use-dependent block of skeletal muscle sodium channel by N-benzyl analogs of tocainide-like compounds

Newly synthesized tocainide analogs were tested for their state-dependent affinity and use-dependent behavior on sodium currents (INa) of adult skeletal muscle fibers by means of the Vaseline-gap voltage clamp method. The drugs had the pharmacophore amino group constrained in position alpha [N-(2,6-dimethylphenyl)pyrrolidine-2-carboxamide (To5)] or beta [N-(2,6-dimethylphenyl)pyrrolidine-3-carboxamide (To9)] in a proline-like cycle and/or linked to a lipophilic benzyl moiety as in N-benzyl-tocainide (Benzyl-Toc), 1-benzyl-To5 (Benzyl-To5), and 1-benzyl-To9 (Benzyl-To9). INa were elicited with pulses to -20 mV from different holding potentials (-140, -100, and -70 mV) and stimulation frequencies (2 and 10 Hz). All compounds were voltage-dependent and use-dependent channel blockers. The presence of a proline-like cycle increased the potency; i.e., To5 was 3- and 10-fold more effective than Toc in blocking INa at the holding potential of -140 and -70 mV, respectively. The benzyl group on the amine further enhanced drug effectiveness with the following scale: Benzyl-To9 >/= Benzyl-Toc > Benzyl-To5. At a holding potential of -100 mV and 10-Hz stimulation, Benzyl-To9 blocked INa with a half-maximal concentration of 0.5 microM, being 60 and 400 times more potent than To9 and Toc, respectively. The similar effectiveness of Benzyl-Toc and Benzyl-To9 was paralleled by a similar spatial arrangement by equilibrium geometry modeling. In addition, the latter had a higher pKa value that probably contributed to a slow kinetic during its high use-dependent behavior. Benzyl-To5 had its lowest energy level at a more folded conformation that justifies the less favorable profile among the N-benzylated analogs. The new compounds are the most potent tocainide-like sodium channel blockers so far described and have high therapeutic potentials.     

Different ability of clenbuterol and salbutamol to block sodium channels predicts their therapeutic use in muscle excitability disorders

Activation of muscle beta(2)-adrenergic receptors successfully counteracted sarcolemma inexcitability in patients suffering from hyperkalemic periodic paralysis (HPP), a hereditary disease caused by mutations in the gene encoding the skeletal muscle sodium channel. Looking for potential modulation of these channels by beta(2)-adrenergic pathway using patch-clamp technique, we found that clenbuterol blocked sodium currents (I(Na)) in rat skeletal muscle fibers and in tsA201 cells transfected with the human channel isoform, whereas salbutamol did not. The effects of clenbuterol were independent of beta-adrenoceptor stimulation. Instead, clenbuterol structure and physicochemical characteristics as well as I(Na) blocking properties resembled those of local anesthetics, suggesting direct binding to the channels. Similar experiments with the chemically similar beta-antagonists propranolol and nadolol, suggested the presence of two hydroxyl groups on the aromatic moiety of the drugs as a molecular requisite for impeding sodium channel block. Importantly, clenbuterol use-dependently inhibited action potential firing in rat skeletal muscle fibers, owing to beta-adrenoceptor-independent I(Na) block. From a clinical point of view, our study defines the rationale for the safe use of salbutamol in HPP patients, whereas clenbuterol may be more indicated in patients suffering from myotonic syndromes, a condition characterized by sarcolemmal overexcitability, because use-dependent I(Na) block can inhibit abnormal runs of action potentials.     

Reversal of multidrug resistance in mouse lymphoma cells by phenothiazines

Various compounds were tested with regard to their reversal of multidrug resistance (MDR) in mouse tumor cells transfected with the human MDR1 gene. Phenothiazines containing aromatic moieties were bound through stacking interaction involving the polarization of the aromatic aminoacid substituents at the target site of p-glycoprotein (Pgp) 170, as a consequence of their large dipoles (as in the binding of phenothiazine to calmodulin-like structures). Acting as a calcium channel blocker, verapamil may induce conformational changes in the calcium channel-like structures of the transmembrane regions of Pgp. Most probably the tyrosine moieties of Pgp are involved in the action of verapamil and phenothiazines. Tomato lectin specifically binds to the polylactosamine moiety of Pgp170 at the first loop of Pgp. Other targets in the membrane may exist in close proximity to Pgp170, such as conA-reactive glycoproteins with terminal mannosyl residues. WGA-reactive N-acetyl glucosamine residues can also be modified resulting in conformational changes in trans-membrane regions of the ABC transporter. Our results demonstrate that MDR can be reversed by interaction of various compounds with Pgp or by modification of the membrane structure around the Pgp.