PubMed Health⌕ Search

Biomedical subjects

S A Goldstein

Publications and source records attributed to S A Goldstein.

At least 19 recordsLinked to original sources
PubMed2004

The mechanical consequences of mineralization in embryonic bone.

The purpose of this study was to examine the effect of mineralization on the mechanical properties of embryonic bone rudiments. For this purpose, four-point bending experiments were performed on unmineralized and mineralized embryonic mouse ribs at 16 and 17 days of gestational age. Young's modulus was calculated using force-displacement data from the experiment in combination with finite element analysis (FEA). For the unmineralized specimens, a calculated average for the Young's modulus of 1.11 (+/- 0.62) MPa was established after corrections for sticking to the four-point bending device and aspect ratio, which is the ratio between the length of the bone and its diameter. For the mineralized specimens, the value was 117 (+/- 62) MPa after corrections. Hence, Young's moduli of embryonic bone rudiments increase by two orders of magnitude within 1 day, during endochondral ossification. As an effect, the hypertrophic chondrocytes in the calcifying cartilage experience a significant change in their mechanical environment. The chondrocytes are effectively stress shielded, which means that they do not carry stresses since stresses are supported by the stiffest parts of the tissue, which are in this case the diaphyseal cortex and the calcified matrix. The deformability of the hypertrophic chondrocytes is, therefore, severely reduced. Since the transition is so sudden and enormous, it can be seen as a process of 'catastrophic' proportion for the hypertrophic chondrocytes. The subsequent resorption of calcified cartilage and the expansion of the marrow cavity could be consequential to stress shielding.

Animals↗
PubMed2004

Mechanical environment alters tissue formation patterns during fracture repair.

Fracture repair has previously been shown to be sensitive to mechanical environment, yet the specific relationship between strain character, magnitude and frequency, as well as other mechanical parameters, and tissue formation is not well understood. This study aimed to correlate strain distribution within the healing fracture gap with patterns of tissue formation using a rat model of a healing osteotomy subject to mechanical stimulation in bending. Finite element models based on realistic tissue distributions were used to estimate both the magnitude and spatial distribution of strains within the fracture gap. The spatial distribution of regenerating tissue was determined by microcomputed tomography and histology, and was confirmed using reverse transcription-polymerase chain reaction (RT-PCR). Results suggest that tensile strains suppress chondrogenesis during the mechanical stimulation period. After stimulation ends, however, tensile strains increased chondrogenesis followed by rapid bone formation. In contrast, in compressive environments, bone is formed primarily via intramembranous ossification. Taken together, these results suggest that intermittent tensile strains during fracture repair stimulate endochondral ossification and promote eventual bone healing compared to intermittent compressive strains and unstimulated fractures. Further understanding of these relationships may allow proposal of optimal therapeutic strategies for improvement of the fracture repair process.

Animals↗
PubMed2003

Combination of local and systemic parathyroid hormone enhances bone regeneration.

Parathyroid hormone is one of the most promising therapeutic agents for osteoporosis, but its use to facilitate bone regeneration in osseous defects is less clear. The purpose of the current study was to determine the effects of combining systematic parathyroid hormone and a local parathyroid hormone gene therapy in a critical-sized osteotomy model. Rats received bilateral femoral osteotomies followed by implantation of a gene-activated matrix encoding parathyroid hormone (1-34) on one side and a control gene-activated matrix on te opposite side. Systematic parathyroid hormone (1-34) or vehicle was injected daily and rats were sacrificed 6 weeks later. Systematic parathyroid hormone increased bone mineral density and bone mineral content measured by dual-energy xray absorptiometry analysis of tibias and vertebrae, and increased serum osteocalcin levels during healing of osteotomies. Furthermore, comparing osteotomy sites that received the same gene-activated matrices as vehicle-injected rats, parathyroid hormone-injected rats showed trends of greater bone areas via histomorphometric and microradiographic analyses and higher osteocalcin messenger ribonucleic acid expression via Northern blot analyses. The combination of systemic and local parathyroid hormone led to higher bone mineral density, bone mineral content, and bone area, a trend for greater radiographic-detected bone area and higher expression of osteocalcin in osteotomy sites when compared with the individual treatment or control groups. Local parathyroid hormone gene therapy enhanced the anabolic effect of systemic parathyroid hormone during osteotomy healing. This study supports the concept of a combined local and systemic approach for enhancing the repair of a fracture at risk for nonunion.

Absorptiometry, Photon↗
PubMed2003

Transgenic models of metabolic bone disease: impact of estrogen receptor deficiency on skeletal metabolism.

Estrogen has protective effects on the skeleton via its inhibition of bone resorption. Mechanisms for these effects and the selectivity to the estrogen receptor alpha (ER alpha) or ER beta are unclear. The purpose of our study was to determine the impact of the ER alpha on skeletal metabolism using murine models with targeted disruption of the ER alpha and beta. Mice generated by homologous recombination and Cre/loxP technology yielding a deletion of the ER alpha exon 3 were evaluated and also crossed with mice with a disruption of the exon 3 of the ER beta to result in double ER alpha and ER beta knockout mice. Skeletal analysis of long bone length and width, radiographs, dual X-ray absorptiometry, bone histomorphometry, micro computerized tomography, biomechanical analysis, serum biochemistry, and osteoblast differentiation were evaluated. Male ER alpha knockout mice had the most dramatic phenotype consisting of reduced bone mineral density (BMD), and bone mineral content (BMC) of femurs at 10 and 16 weeks and 8-9 months of age. Female ER alpha knockout mice also had reduced density of long bones but to a lesser degree than male mice. The reduction of trabecular and cortical bone in male ER alpha knockout mice was statistically significant. Male double ER alpha and ER beta knockouts had similar reductions in bone density versus the single ER alpha knockout mice suggesting that the ER alpha is more protective than the ER beta in bone. In vitro analysis revealed no differences in osteoblast differentiation or mineralized nodule formation among cells from ER alpha genotypes. These data suggest that estrogens are important in skeletal metabolism in males; the ER alpha plays an important role in estrogen protective effects; osteoblast differentiation is not altered with loss of the ER alpha; and compensatory mechanisms are present in the absence of the ER alpha and/or another receptor for estrogen exists that mediates further effects of estrogen on the skeleton.

Absorptiometry, Photon↗
PubMed2002

Cancellous bone mechanical properties from normals and patients with hip fractures differ on the structure level, not on the bone hard tissue level.

Osteoporosis is currently defined in terms of low bone mass. However, the source of fragility leading to fracture has not been adequately described. In particular, the contributions of bone tissue properties and architecture to the risk or incidence of fracture are poorly understood. In an earlier experimental study, it was found that the architectural anisotropy of cancellous bone from the femoral heads of fracture patients was significantly increased compared with age- and density-matched control material (Ciarelli et al., J Bone Miner Res 15:32-40; 2000). Using a combination of compression testing and micro-finite element analysis on a subset of cancellous bone specimens from that study, we calculated the hard tissue mechanical properties and the apparent (macroscopic) mechanical properties. The tissue modulus was 10.0 GPa (SD 2.2) for the control group and 10.8 GPa (SD 3.3) for the fracture group (not significant). There were no differences in either the apparent yield strains, percentages of highly strained tissue, or the relationship between apparent yield stress and apparent elastic modulus. Hence, a difference in the tissue yield properties is unlikely. At the apparent level, the fracture group had a significantly decreased transverse stiffness, resulting in increased mechanical anisotropy. These changes suggest that bone in the fracture group was "overadapted" to the primary load axis, at the cost of fragility in the transverse direction. We conclude that individuals with a history of osteoporotic fractures do not have weaker bone tissue. Architectural and mechanical anisotropy alone renders their bone weaker in the nonprimary loading direction.

Aged↗
PubMed2001

KCNKØ: opening and closing the 2-P-domain potassium leak channel entails "C-type" gating of the outer pore.

Essential to nerve and muscle function, little is known about how potassium leak channels operate. KCNKØ opens and closes in a kinase-dependent fashion. Here, the transition is shown to correspond to changes in the outer aspect of the ion conduction pore. Voltage-gated potassium (VGK) channels open and close via an internal gate; however, they also have an outer pore gate that produces "C-type" inactivation. While KCNKØ does not inactivate, KCNKØ and VGK channels respond in like manner to outer pore blockers, potassium, mutations, and chemical modifiers. Structural relatedness is confirmed: VGK residues that come close during C-type gating predict KCNKØ sites that crosslink (after mutation to cysteine) to yield channels controlled by reduction and oxidization. We conclude that similar outer pore gates mediate KCNKØ opening and closing and VGK channel C-type inactivation despite their divergent structures and physiological roles.

Animals↗
PubMed2001

Immunity to K1 killer toxin: internal TOK1 blockade.

K1 killer strains of Saccharomyces cerevisiae harbor RNA viruses that mediate secretion of K1, a protein toxin that kills virus-free cells. Recently, external K1 toxin was shown to directly activate TOK1 channels in the plasma membranes of sensitive yeast cells, leading to excess potassium flux and cell death. Here, a mechanism by which killer cells resist their own toxin is shown: internal toxin inhibits TOK1 channels and suppresses activation by external toxin.

Gene Expression Regulation, Fungal↗
PubMed2001

Block of Kcnk3 by protons. Evidence that 2-P-domain potassium channel subunits function as homodimers.

KCNK subunits have two pore-forming P domains and four predicted transmembrane segments. To assess the number of subunits in each pore, we studied external proton block of Kcnk3, a subunit prominent in rodent heart and brain. Consistent with a pore-blocking mechanism, inhibition was dependent on voltage, potassium concentration, and a histidine in the first P domain (P1H). Thus, at pH 6.8 with 20 mm potassium half the current passed by P1H channels was blocked (apparently via two sites approximately 10% into the electrical field) whereas channels with an asparagine substitution (P1N) were fully active. Furthermore, pore blockade by barium was sensitive to pH in P1H but not P1N channels. Although linking two Kcnk3 subunits in tandem to produce P1H-P1H and P1N-P1N channels bearing four P domains did not alter these attributes, the mixed tandems P1H-P1N and P1N-P1H were half-blocked at pH approximately 6.4, apparently via a single site. This implicates a dimeric structure for Kcnk3 channels with two (and only two) P1 domains in each pore and argues that P2 domains also contribute to pore formation.

Animals↗
PubMed2001

MiRP2 forms potassium channels in skeletal muscle with Kv3.4 and is associated with periodic paralysis.

The subthreshold, voltage-gated potassium channel of skeletal muscle is shown to contain MinK-related peptide 2 (MiRP2) and the pore-forming subunit Kv3.4. MiRP2-Kv3.4 channels differ from Kv3.4 channels in unitary conductance, voltage-dependent activation, recovery from inactivation, steady-state open probability, and block by a peptide toxin. Thus, MiRP2-Kv3.4 channels set resting membrane potential (RMP) and do not produce afterhyperpolarization or cumulative inactivation to limit action potential frequency. A missense mutation is identified in the gene for MiRP2 (KCNE3) in two families with periodic paralysis and found to segregate with the disease. Mutant MiRP2-Kv3.4 complexes exhibit reduced current density and diminished capacity to set RMP. Thus, MiRP2 operates with a classical potassium channel subunit to govern skeletal muscle function and pathophysiology.

Animals↗
PubMed2001

Catheter-based electromechanical mapping to assess regional myocardial function: a comparative analysis with transthoracic echocardiography.

Recent studies using a nonfluoroscopic three-dimensional left ventricular mapping system showed considerable changes in voltage potentials and mechanical activity detected in ischemic and infarcted myocardial regions with mechanical dysfunction. This study examined the electromechanical characteristics in relation to regional wall motion assessed by echocardiography in patients with coronary artery disease. A 12-segment model of mapping (apical, mid, basal of septal, anterior, lateral, and inferior/posterior segments) was compared to echo wall motion score in 74 patients (836 segments). Unipolar voltage and local endocardial shortening signals were distinguished according to graded echo segmental rest scores (0 = normal, 1 = mild hypokinesis, 2 = moderate hypokinesis, 3 = severe hypokinesis, 4 = akinesis). Results show a significant difference in voltage potentials and shortening values in groups distinguished according to echocardiography motion score. The average voltage potentials and shortening values were highest in myocardial segments with normal or slightly reduced contractility and lowest in myocardial segments with moderate to severely impaired contractility scores (voltage: 12.3 +/- 5.0, 12.1 +/- 5.3, 10.7 +/- 5.4, 8.7 +/- 3.9, 7.1 +/- 3.0 mV, P = 0.0001; local shortening: 9.7 +/- 6.5, 8.4 +/- 5.9, 8.0 +/- 5.4, 5.6 +/- 6.3, 5.1 +/- 4.6%, P = 0.0001 in regions with segmental scores of 0, 1, 2, 3, 4 by echo, respectively). Using receiver-operating curve calculations, the area under the curve was 0.72 +/- 0.06 (voltage) and 0.67 +/- 0.05 (local shortening) without a significant difference between the two curves. The 90% thresholds for defining preserved vs. impaired contractility were 12.8 and 5.6 mV for voltage and 12.6% and 1.6% for local shortening. We conclude that electromechanical mapping correlates with regional changes in wall motion scores assessed by echo, showing a gradual proportional decrease in measured voltage and shortening signals in segments with impaired function.

Adult↗
PubMed2001

Hierarchical structure of bone and micro-computed tomography.

Bone is highly complex, with multiple hierarchical levels of structure. Micro-CT has been able to provide much information about the properties of bone at several of these levels at the mid-range of bone's hierarchical structure, and it will continue to provide a valuable tool for further characterizing bone in various conditions and explaining mechanisms of bone failure.

Animals↗
PubMed2001

Kcnkø: single, cloned potassium leak channels are multi-ion pores.

KCNKØ was the first clone to show attributes of a leak conductance: voltage-independent potassium currents that develop without delay. Its novel product is predicted to have two nonidentical P domains and four transmembrane segments and to assemble in pairs. Here, the mechanistic basis for leak is examined at the single-channel level. KCNKØ channels open at all voltages in bursts that last for minutes with open probability close to 1. The channels also enter a minutes-long closed state in a tightly regulated fashion. KCNKØ has a common relative permeability series (Eisenman type IV) but conducts only thallium and potassium readily. KCNKØ exhibits concentration-dependent unitary conductance, anomalous mole fraction behavior, and pore occlusion by barium. These observations argue for ion-channel and ion-ion interactions in a multi-ion pore and deny the operation of independence or constant-field current formulations. Despite their unique function and structure, leakage channels are observed to operate like classical potassium channels formed with one-P-domain subunits.

Animals↗
PubMed2001

Potassium leak channels and the KCNK family of two-P-domain subunits.

With a bang, a new family of potassium channels has exploded into view. Although KCNK channels were discovered only five years ago, they already outnumber other channel types. KCNK channels are easy to identify because of their unique structure--they possess two preforming domains in each subunit. The new channels function in a most remarkable fashion: they are highly regulated, potassium-selective leak channels. Although leak currents are fundamental to the function of nerves and muscles, the molecular basis for this type of conductance had been a mystery. Here we review the discovery of KCNK channels, what has been learned about them and what lies ahead. Even though two-P-domain channels are widespread and essential, they were hidden from sight in plain view--our most basic questions remain to be answered.

Animals↗
PubMed2001

KCNK2: reversible conversion of a hippocampal potassium leak into a voltage-dependent channel.

Potassium leak channels are essential to neurophysiological function. Leaks suppress excitability through maintenance of resting membrane potential below the threshold for action potential firing. Conversely, voltage-dependent potassium channels permit excitation because they do not interfere with rise to threshold, and they actively promote recovery and rapid re-firing. Previously attributed to distinct transport pathways, we demonstrate here that phosphorylation of single, native hippocampal and cloned KCNK2 potassium channels produces reversible interconversion between leak and voltage-dependent phenotypes. The findings reveal a pathway for dynamic regulation of excitability.

Animals↗
PubMed2001

Concept, development, administration, and analysis of a certifying examination in echocardiography for physicians.

In 1993, the American Society of Echocardiography appointed a committee to develop an objective examination in echocardiography. In 1995, a pilot of this examination was administered, with operational examinations offered each year from 1996 to 1999. This report describes the development of the examination, including its underlying philosophy, the test itself, and the scoring process, and includes results from the first 4 examinations. To date, 1266 physicians have taken the examination, and roughly 60% of those have passed. The number of echocardiograms performed or interpreted each week had the largest effect on examination scores; the effects of both the amount of training and the practice discipline were small but significant. The evolution of the original committee and new directions for the testing organization are also discussed.

Certification↗
PubMed2001

Pulmonary venous flow in large, uncomplicated atrial septal defect.

BACKGROUND: The pulmonary venous flow velocity pattern (PVFVP) in atrial septal defect (ASD) has not been previously studied in detail. Normally, PVFVP is primarily determined by the left heart performance. We hypothesized that the impact of left-sided heart dynamics on PVFVP is diminished in patients with ASD because of the presence of a left-to-right shunt into the low-resistance right side of the heart. METHODS AND RESULTS: Transesophageal echocardiography was performed in 19 adults and 3 children with a large, uncomplicated secundum ASD (maximum diameter 0.6 to 3.0 cm). All patients were in normal sinus rhythm with an average heart rate of 78 bpm in adults and 116 bpm in children. In 21 subjects the antegrade PVFVP lacked distinct systolic (S) and diastolic (D) waves. Instead, we observed a single continuous antegrade wave extending from the beginning of systole to the onset of atrial contraction. Furthermore, the amplitude of the atrial reversal (AR) wave was smaller than in historical controls. In 3 patients in whom ASD was surgically repaired, we observed an immediate return of distinct S and D waves postoperatively. This confirmed that PVFVP abnormality was indeed the result of the ASD. Also a large increase in the AR wave amplitude (46 + 15 cm/s) was noted postoperatively. CONCLUSIONS: This previously unrecognized PVFVP comprising a single continuous antegrade wave and a diminished AR wave sheds new light on the hemodynamics of ASDs. Its presence may also alert the echocardiographer to the possibility of an ASD when the septal defect cannot be visualized directly.

Adolescent↗