Intermittent etidronate therapy to prevent corticosteroid-induced osteoporosis

BACKGROUND AND METHODS: Osteoporosis is a recognized complication of corticosteroid therapy. Whether it can be prevented is not known. We conducted a 12-month, randomized, placebo-controlled study of intermittent etidronate (400 mg per day for 14 days) followed by calcium (500 mg per day for 76 days), given for four cycles, in 141 men and women (age, 19 to 87 years) who had recently begun high-dose corticosteroid therapy. The primary outcome measure was the difference in the change in the bone density of the lumbar spine between the groups from base line to week 52. Secondary measures included changes in the bone density of the femoral neck, trochanter, and radius and the rate of new vertebral fractures. RESULTS: The mean (+/-SE) bone density of the lumbar spine and trochanter in the etidronate group increased 0.61 +/- 0.54 and 1.46 +/- 0.67 percent, respectively, as compared with decreases of 3.23 +/- 0.60 and 2.74 +/- 0.66 percent, respectively, in the placebo group. The mean differences between the groups after one year were 3.72 +/- 0.88 percentage points for the lumbar spine (P = 0.02) and 4.14 +/- 0.94 percentage points for the trochanter (P = 0.02). The changes in the femoral neck and the radius were not significantly different between the groups. There was an 85 percent reduction in the proportion of postmenopausal woman with new vertebral fractures in the etidronate group as compared with the placebo group (1 of 31 patients vs. 7 of 32 patients, P = 0.05), and the etidronate-treated postmenopausal women also had significantly fewer vertebral fractures per patient (P = 0.04). CONCLUSIONS: Intermittent etidronate therapy prevents the loss of vertebral and trochanteric bone in corticosteroid-treated patients.     

Development of an enzyme-linked immunosorbent assay for measurement of serum-associated ALX40-4C

ALX40-4C is an antiretrovirus agent that has been found to have some inhibitory properties against human immunodeficiency virus (HIV) replication in vitro. The compound was designed as a competitor of the HIV Tat protein for TAR binding. In addition to its anti-HIV properties, it has demonstrated the ability to inhibit in vitro replication of herpes simplex virus types 1 and 2 as well as human cytomegalovirus. Subsequently, in vivo pharmacokinetic evaluation of ALX40-4C necessitated the establishment of a detection system for the measurement of ALX40-4C in subject serum. For this purpose, an indirect-competition enzyme-linked immunosorbent assay with generated rabbit anti-ALX40-4C antiserum was developed. The original assay took 12 h to complete and required many manipulations. Herein, we describe alterations to the system that resulted in the overall reduction in assay time and manipulation. We demonstrate that our alterations do not affect the specificity or sensitivity of the assay compared to that of the original system. ALX40-4C levels in spiked serum samples as well as drug levels from patient samples were used to validate the assay.     

Coronary artery stenosis in rats affects beta-adrenergic receptor signaling in myocytes

The rotational spectrum of (CH3OH)2 has been observed in the 8 to 24 GHz region with a pulsed-beam Fabry-Perot cavity Fourier-transform microwave spectrometer. Previously we demonstrated that each transition of the a-type R(J), Ka = 0 is split into 15 states of the 16 theoretically expected states by tunneling motions. Here we show that the K = 1 states are split into the 16 expected states through the assignment of the Ka = 1 a-type transitions and DeltaKa = 1 b-type transitions. The internal-rotation analysis of the two inequivalent methyl groups presented here was guided by the previous experimental observations and theory for multidimensional tunneling, which predicts 16 tunneling components for each R(J) transition from 25 distinct tunneling motions. The effective barrier to internal rotation for the donor methyl group of (CH3OH)2 is V3 = 183.0 cm-1, and is one-half of the value for the methanol monomer (370 cm-1), while the barrier to internal rotation of the acceptor methyl group is 120 cm-1, one-third of the methanol monomer. The structure of the methanol dimer complex is similar to that of water dimer with a hydrogen bond distance of 1.96(2) A and tilt of the acceptor methanol of 77(2)degrees from the O-H-O axis (one standard deviation uncertainty). This structure shows good agreement with the angular orientation of the methyl groups derived in the internal-rotation analysis. Copyright 1997 Academic Press. Copyright 1997Academic Press     

Angiogenesis and inflammation in invasive carcinoma of the breast

Transforming growth factor-beta (TGF-beta) plays an important role in the regulation of extracellular matrix (ECM) deposition by stimulating the synthesis of individual matrix proteins like tenascin and fibronectin. Cholesteatoma shows significant changes in the ECM, supporting the view of a disturbed cell-matrix interaction. The purpose of our present study was to evaluate the distribution of TGF-beta in comparison to the deposition of tenascin, fibronectin, and collagen as major components of the ECM in cholesteatoma (n = 12) by means of histochemistry and immunohistochemistry. We found TGF-beta in lymphocytes and fibrohistiocytes in the stroma of 7 cholesteatomas. In corresponding sections, a marked expression of tenascin and fibronectin was seen manifesting as a continuous band along the epidermal-stromal junction, extending to the deeper stroma. In addition, in those cases of TGF-beta expression, beginning collagen fibril formation was seen in adjacent deeper stroma layers, indicating beginning stromal fibrosis. These results suggest that TGF-beta may be involved in the stimulation of the synthesis of tenascin, fibronectin, and collagen. Furthermore, the enhanced expression of tenascin and fibronectin provides evidence for a deregulated cell-matrix interaction in cholesteatoma associated with the enhanced proliferative process of cholesteatoma formation.     

Hormonal regulation of epidermal growth factor receptor content and signaling in bovine mammary tissue

Mammary tissue from midpregnant heifers was cultured with epidermal growth factor (EGF) or transforming growth factor alpha for 1-3 days. After 1 day, 10 nM EGF or transforming growth factor alpha doubled DNA synthesis, whereas lower concentrations (0.1 or 1 nM) increased DNA synthesis 2- to 3-fold after 2-3 days in culture. In other studies, bovine mammary tissue was transplanted to ovariectomized athymic mice and treated for 10 days with saline, estradiol (1 microg/day), progesterone (1 mg/day), or estradiol + progesterone. Subsequent explant culture of the bovine tissue indicated that estradiol + progesterone augmented the ability of EGF to stimulate DNA synthesis. The increased response to EGF was associated with increased EGF binding and with increased EGF-induced tyrosine kinase that paralleled the increased EGF binding. In other studies, athymic mice bearing xenografted bovine mammary tissue were primed for 10 days with estradiol and progesterone, followed by 2-day treatment with saline (control), hydrocortisone (200 microg/day), PRL (1 mg/day), or hydrocortisone + PRL. Hydrocortisone and PRL alone decreased, and PRL + hydrocortisone eliminated, EGF-induced DNA synthesis. EGF receptor content was unaffected by hydrocortisone but was reduced by PRL or hydrocortisone + PRL. Furthermore, the ability of EGF to induce tyrosine kinase activity was decreased by PRL and by hydrocortisone + PRL. The decreased kinase activity was greater than the decrease in receptor binding, suggesting a specific modulation of EGF receptor kinase activity in response to lactogenic hormones.     

Application of a hybrid computational fluid dynamics and physiologically based inhalation model for interspecies dosimetry extrapolation of acidic vapors in the upper airways

This study provides a scientific basis for interspecies extrapolation of nasal olfactory irritants from rodents to humans. By using a series of short-term in vivo studies, in vitro studies with nasal explants, and computer modeling, regional nasal tissue dose estimates were made and comparisons of tissue doses between species were conducted. To make these comparisons, this study assumes that human and rodent olfactory epithelium have similar susceptibility to the cytotoxic effects of organic acids based on similar histological structure and common mode of action considerations. Interspecies differences in susceptibility to the toxic effects of acidic vapors are therefore assumed to be driven primarily by differences in nasal tissue concentrations that result from regional differences in nasal air flow patterns relative to the species-specific distribution of olfactory epithelium in the nasal cavity. The acute, subchronic, and in vitro studies have demonstrated that the nasal olfactory epithelium is the most sensitive tissue to the effects of inhalation exposure to organic acids and that the sustentacular cells are the most sensitive cell type of this epithelium. A hybrid computational fluid dynamics (CFD) and physiologically based pharmacokinetic (PBPK) dosimetry model was constructed to estimate the regional tissue dose of organic acids in the rodent and human nasal cavity. The CFD-PBPK model simulations indicate that the olfactory epithelium of the human nasal cavity is exposed to two- to threefold lower tissue concentrations of a representative inhaled organic acid vapor, acrylic acid, than the olfactory epithelium of the rodent nasal cavity when the exposure conditions are the same. The magnitude of this difference varies somewhat with the specific exposure scenario that is simulated. The increased olfactory tissue dose in rats relative to humans may be attributed to the large rodent olfactory surface area (greater than 50% of the nasal cavity) and its highly susceptible location (particularly, a projection of olfactory epithelium extending anteriorly in the dorsal meatus region). In contrast, human olfactory epithelium occupies a much smaller surface area (less than 5% of the nasal cavity), and it is in a much less accessible dorsal posterior location. In addition, CFD simulations indicate that human olfactory epithelium is poorly ventilated relative to rodent olfactory epithelium. These studies suggest that the human olfactory epithelium is protected from irritating acidic vapors significantly better than rat olfactory epithelium due to substantive differences in nasal anatomy and nasal air flow. Furthermore, the general structure of the hybrid CFD-PBPK model used for this study appears to be useful for target tissue dosimetry and interspecies dose comparisons for a wide range of inhaled vapors.     

Reductions in self-injury produced by transcutaneous electrical nerve stimulation

Transcutaneous electrical nerve stimulation is used to reduce pain but also may be useful for self-injurious behavior (SIB). In the current investigation, a microcurrent electromedical device, classified as a transcutaneous electrical nerve stimulator (TENS), was applied with a man with Down syndrome who displayed SIB that persisted in the absence of social contingencies. Although clinically significant results were not maintained, a clear difference in the rates of SIB during active and inactive TENS was observed.     

Experience with the Ultrex and Ultrex Plus inflatable penile prosthesis: new implantation techniques and surgical outcome

OBJECTIVE: To construct nomograms of the size of the fetal orbit and lens during gestation. SUBJECTS: The study group included 349 normal pregnant women at 14-36 weeks' gestation. METHODS: Routine biometric measurements were obtained in all the participants; these included biparietal diameter, head and abdominal circumferences, measurements of the long bones and the diameters of the fetal orbit and lens. The orbital and lens circumference measurements were also related to gestational ages. RESULTS: A linear growth function was observed between gestational age (GA) and orbital diameter (r = 0.94; p < 0.00001; y = -0.66 + 0.5 x GA), orbital circumference (r = 0.94; p < 0.00001; y = -2.1 + 1.5 x GA) and orbital area (r = 0.94; p < 0.00001; y = -98.1 + 8.3 x GA). Significant correlation was also found between femoral length (FL) and orbital diameter (r = 0.95; p < 0.00001; y = 3.3 + 1.9 x FL), orbital circumference (r = 0.95; p < 0.00001; y = 10.3 + 5.9 x FL) and orbital area (r = 0.93; p < 0.00001; y = -28.2 + 32.2 x FL). A linear growth function was observed between orbital circumference and biparietal diameter (r = 0.94; p < 0.00001) and head circumference (r = 0.95; p < 0.00001). A linear growth function was also observed between gestational age and the diameter of the lens (r = 0.89; p < 0.00001; y = 0.88 + 1.4 x GA) the circumference of the lens (r = 0.89; p < 0.00001; y = 2.78 + 0.4 x GA) and the area of the lens (r = 0.89; p < 0.00001; y = -7.95 + 1.0 x GA). The correlation was found between the ratios of the diameters, circumferences and areas of the lens and the orbit. CONCLUSIONS: These results provide normative data of the growth of the fetal orbit and lens and may aid future studies relating to fetal eye anomalies.     

Genotyping HIV-1 and HCV strains by a combinatorial DNA melting assay (COMA)

BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) strains can be genetically classified into genetic lineages known as genetic types or subtypes according to phylogenetic analyses of complete or partial nucleotide sequences of their genomes. The genetic classification of HIV-1 and HCV strains has important implications for the development of globally effective vaccines and for the management of patients. MATERIALS AND METHODS: A new method, termed combinatorial DNA melting assay (COMA), allows rapid accessing of comparative genetic information between related DNA sequences, making it possible to rapidly and accurately genotype unknown HIV-1 and HCV strains. COMA is mainly based on the differential melting properties of long DNA heteroduplexes. Combinatorial arrays of DNA heteroduplexes are formed when captured PCR-amplified reference DNA with known nucleotide sequences are combined with solution-phase complementary and antigenically labeled DNA with unknown sequences. Genetic divergence between the known and the unknown sequences is inferred as the experimentally derived melting curves of the two strands of the DNA heteroduplexes increasingly diverge. RESULTS: COMA was successfully applied to the genetic classification of HIV-1 and HCV strains into phylogenetic lineages or subtypes. CONCLUSIONS: Use of this assay should accelerate current efforts to understand the global molecular epidemiology of HIV-1 and HCV and may extend to the genetic characterization of other genetically diverse infectious pathogens associated with numerous diseases.