Showing papers by "University of Maryland, Baltimore published in 1995"
TL;DR: Women with multiple risk factors and low bone density have an especially high risk of hip fracture and maintaining body weight, walking for exercise, avoiding long-acting benzodiazepines, minimizing caffeine intake, and treating impaired visual function are among the steps that may decrease the risk.
Abstract: Background Many risk factors for hip fractures have been suggested but have not been evaluated in a comprehensive prospective study. Methods We assessed potential risk factors, including bone mass, in 9516 white women 65 years of age or older who had had no previous hip fracture. We then followed these women at 4-month intervals for an average of 4.1 years to determine the frequency of hip fracture. All reports of hip fractures were validated by review of x-ray films. Results During the follow-up period, 192 women had first hip fractures not due to motor vehicle accidents. In multivariable age-adjusted analyses, a maternal history of hip fracture doubled the risk of hip fracture (relative risk, 2.0; 95 percent confidence interval, 1.4 to 2.9), and the increase in risk remained significant after adjustment for bone density. Women who had gained weight since the age of 25 had a lower risk. The risk was higher among women who had previous fractures of any type after the age of 50, were tall at the age of 25, rated their own health as fair or poor, had previous hyperthyroidism, had been treated with long-acting benzodiazepines or anticonvulsant drugs, ingested greater amounts of caffeine, or spent four hours a day or less on their feet. Examination findings associated with an increased risk included the inability to rise from a chair without using one's arms, poor depth perception, poor contrast sensitivity, and tachycardia at rest. Low calcaneal bone density was also an independent risk factor. The incidence of hip fracture ranged from 1.1 (95 percent confidence interval, 0.5 to 1.6) per 1,000 woman-years among women with no more than two risk factors and normal calcaneal bone density for their age to 27 (95 percent confidence interval, 20 to 34) per 1,000 woman-years among those with five or more risk factors and bone density in the lowest third for their age. Conclusions Women with multiple risk factors and low bone density have an especially high risk of hip fracture. Maintaining body weight, walking for exercise, avoiding long-acting benzodiazepines, minimizing caffeine intake, and treating impaired visual function are among the steps that may decrease the risk.
3,587 citations
TL;DR: It is demonstrated that copolymer 1 treatment can significantly and beneficially alter the course of relapsing-remitting multiple sclerosis in a well-tolerated fashion.
Abstract: We studied copolymer 1 (Copaxone) in a multicenter (11-university) phase III trial of patients with relapsing-remitting multiple sclerosis (MS). Two hundred fifty-one patients were randomized to receive copolymer 1 (n = 125) or placebo (n = 126) at a dosage of 20 mg by daily subcutaneous injection for 2 years. The primary end point was a difference in the MS relapse rate. The final 2-year relapse rate was 1.19 +/- 0.13 for patients receiving copolymer 1 and 1.68 +/- 0.13 for those receiving placebo, a 29% reduction in favor of copolymer 1 (p = 0.007) (annualized rates = 0.59 for copolymer 1 and 0.84 for placebo). Trends in the proportion of relapse-free patients and median time to first relapse favored copolymer 1. Disability was measured by the Expanded Disability Status Scale (EDSS), using a two-neurologist (examining and treating) protocol. When the proportion of patients who improved, were unchanged, or worsened by > or = 1 EDSS step from baseline to conclusion (2 years) was evaluated, significantly more patients receiving copolymer 1 were found to have improved and more receiving placebo worsened (p = 0.037). Patient withdrawals were 19 (15.2%) from the copolymer 1 group and 17 (13.5%) from the placebo group at approximately the same intervals. The treatment was well tolerated. The most common adverse experience was an injection-site reaction. Rarely, a transient self-limited systemic reaction followed the injection in 15.2% of those receiving copolymer 1 and 3.2% of those receiving placebo.(ABSTRACT TRUNCATED AT 250 WORDS)
1,866 citations
TL;DR: KCa channels activated by Ca2+ sparks appeared to hyperpolarize and dilate pressurized myogenic arteries because ryanodine and thapsigargin depolarized and constricted these arteries to an extent similar to that produced by blockers of KCa channels.
Abstract: Local increases in intracellular calcium ion concentration ([Ca2+]i) resulting from activation of the ryanodine-sensitive calcium-release channel in the sarcoplasmic reticulum (SR) of smooth muscle cause arterial dilation. Ryanodine-sensitive, spontaneous local increases in [Ca2+]i (Ca2+ sparks) from the SR were observed just under the surface membrane of single smooth muscle cells from myogenic cerebral arteries. Ryanodine and thapsigargin inhibited Ca2+ sparks and Ca(2+)-dependent potassium (KCa) currents, suggesting that Ca2+ sparks activate KCa channels. Furthermore, KCa channels activated by Ca2+ sparks appeared to hyperpolarize and dilate pressurized myogenic arteries because ryanodine and thapsigargin depolarized and constricted these arteries to an extent similar to that produced by blockers of KCa channels. Ca2+ sparks indirectly cause vasodilation through activation of KCa channels, but have little direct effect on spatially averaged [Ca2+]i, which regulates contraction.
1,364 citations
TL;DR: The crystal structure of the K. aerogenes enzyme has been determined and provides important insight into the mechanism of catalysis, and accessory genes have been shown to be required for activation of urease apoprotein, and roles for the accessory proteins in metallocenter assembly have been proposed.
1,244 citations
TL;DR: A degenerate peptide library is used to show that each of nine tyrosine kinases investigated has a unique optimal peptide substrate, and indicates that a point mutation in the RET receptor-type tyosine kinase, which causes multiple endocrine neoplasia type 2B, results in a shift in peptide substrates specificity.
Abstract: HOW do distinct protein-tyrosine kinases activate specific downstream events? Src-homology-2 (SH2) domains on tyrosine kinases or targets of tyrosine kinases recognize phosphotyrosine in a specific sequence context and thereby provide some specificity1–3. The role of the catalytic site of tyrosine kinases in determining target specificity has not been fully investigated. Here we use a degenerate peptide library to show that each of nine tyrosine kinases investigated has a unique optimal peptide substrate. We find that the cytosolic tyrosine kinases preferentially phosphorylate peptides recognized by their own SH2 domains or closely related SH2 domains (group I; ref. 3), whereas receptor tyrosine kinases preferentially phosphorylate peptides recognized by subsets of group III SH2 domains3. The importance of these findings for human disease is underscored by our observation that a point mutation in the RET receptor-type tyrosine kinase, which causes multiple endocrine neoplasia type 2B, results in a shift in peptide substrate specificity.
947 citations
TL;DR: The role of joint lavage and arthroscopic debridement in patients with OA of the knee who are unresponsive to conservative medical therapy needs further study, and these procedures cannot be routinely recommended for all patients at this time as mentioned in this paper.
Abstract: Treatment of patients with OA of the knee should be individualized and tailored to the severity of the symptoms. In individuals with mild symptomatic OA, treatment may be limited to patient education, physical and occupational therapy and other nonpharmacologic modalities, and pharmacologic therapy including non-opioid oral and topical analgesics. In patients who are unresponsive to this treatment regimen, the use of NSAIDs in addition to nonpharmacologic therapy is appropriate unless medically contraindicated. Judicious use of intraarticular steroid injections has a role either as monotherapy or an adjunct to systemic therapy in patients with knee OA who have symptomatic effusions. The role of joint lavage and arthroscopic debridement in patients with OA of the knee who are unresponsive to conservative medical therapy needs further study, and these procedures cannot be routinely recommended for all patients at this time. Patients with severe symptomatic OA of the knee require an aggressive approach to decreasing pain, increasing mobility, and decreasing functional impairment; such patients may benefit from orthopedic consultation and evaluation for osteotomy or total joint arthroplasty.
905 citations
TL;DR: Ketamine-induced psychotic symptoms were strikingly reminiscent of the subject's symptoms during active episodes of their illness, and antagonism of NMDA-sensitive glutamatergic transmission in brain exacerbates symptoms of schizophrenia.
890 citations
TL;DR: It is demonstrated that a trait for an elevated level of serum total IgE is coinherited with a traits for bronchial hyperresponsiveness and that a gene governing bronchiahyperresponsiveness is located near a major locus that regulates serum IgE levels on chromosome 5q.
Abstract: Background Bronchial hyperresponsiveness, a risk factor for asthma, consists of a heightened bronchoconstrictor response to a variety of stimuli. The condition has a heritable component and is closely related to serum IgE levels and airway inflammation. The basis for these relations is unknown, as is the mechanism of genetic susceptibility to bronchial hyperresponsiveness. We attempted to define the interrelation between atopy and bronchial hyperresponsiveness and to investigate the chromosomal location of this component of asthma. Methods We studied 303 children and grandchildren of 84 probands with asthma selected from a homogeneous population in the Netherlands. Ventilatory function, bronchial responsiveness to histamine, and serum total IgE were measured. The association between the last two variables was evaluated. Using analyses involving pairs of siblings, we tested for linkage between bronchial hyperresponsiveness and genetic markers on chromosome 5q31-q33, previously shown to be linked to a genet...
789 citations
01 Jan 1995
TL;DR: Copolymer 1 (Copaxone) was studied in a multicenter (11-university) phase III trial of patients with relapsing-remitting multiple sclerosis and significantly more patients receiving copolym 1 were found to have improved and more receiving placebo worsened.
Abstract: Article abstract-We studied copolymer 1 (Copaxone) in a multicenter (11-university) phase III trial of patients with relapsing-remitting multiple sclerosis (MS). Two hundred fifty-one patients were randomized to receive copolymer 1 (n = 125) or placebo (n = 126) at a dosage of 20 mg by daily subcutaneous injection for 2 years. The primary end point was a difference in the MS relapse rate. The final 2-year relapse rate was 1.19 ± 0.13 for patients receiving copolymer 1 and 1.68 ± 0.13 for those receiving placebo, a 29% reduction in favor of copolymer 1 (p = 0.007) (annualized rates = 0.59 for copolymer 1 and 0.84 for placebo). Trends in the proportion of relapse-free patients and median time to first relapse favored copolymer 1. Disability was measured by the Expanded Disability Status Scale (EDSS), using a two-neurologist (examining and treating) protocol. When the proportion of patients who improved, were unchanged, or worsened by ≥1 EDSS step from baseline to conclusion (2 years) was evaluated, significantly more patients receiving copolymer 1 were found to have improved and more receiving placebo worsened (p = 0.037). Patient withdrawals were 19 (15.2%) from the copolymer 1 group and 17 (13.5%) from the placebo group at approximately the same intervals. The treatment was well tolerated. The most common adverse experience was an injection-site reaction. Rarely, a transient self-limited systemic reaction followed the injection in 15.2% of those receiving copolymer 1 and 3.2% of those receiving placebo. This reaction was characterized by flushing or chest tightness with palpitations, anxiety, or dyspnea and commonly lasted for 30 seconds to 30 minutes. This rigorous study confirmed the findings of a previous pilot trial and demonstrated that copolymer 1 treatment can significantly and beneficially alter the course of relapsing-remitting MS in a well-tolerated fashion.
778 citations
TL;DR: There was no decrease in mortality between placebo and TNF-α MAb in all infused patients, and in septic shock patients who received T NF- α MAb, a significant reduction in mortality was present 3 days after infusion; however, although a trend toward reduced mortality continued at 28 days following treatment with TTFMAb, the difference in mortality among shock patients treated with placebo or TFB was not significant.
Abstract: Objective. —To evaluate the efficacy and safety of anti—tumor necrosis factor α monoclonal antibody (TNF-α MAb) in the treatment of patients with sepsis syndrome. Design. —Randomized, prospective, multicenter, double-blind, placebo-controlled clinical trial. Setting. —A total of 31 hospitals in the United States and Canada. Patients. —There were 994 patients with sepsis syndrome enrolled in this clinical trial, and 971 patients were infused with the study drug. Intervention. —Patients were prospectively stratified into shock or nonshock groups and then randomized to receive a single infusion of 15 mg/kg of TNF-α MAb, 7.5 mg/kg of TNF-α MAb, or placebo. Patients received standard aggressive medical and surgical care during the 28-day postinfusion period. Outcome Measure. —Twenty-eight-day all-cause mortality. Results. —The distribution of variables describing demographics, organ system dysfunction or failure, preinfusion Acute Physiology and Chronic Health Evaluation II score, number of organs failing at baseline, initial sites of infection, infecting microorganisms, antimicrobials used, and initial invasive procedures was similar among patients in the TNF-α MAb and placebo treatment arms. Among all infused patients, there was no difference in all-cause mortality in patients who received placebo as compared with those who received TNF-α MAb. In septic patients with shock (n=478), there was a trend toward a reduction in all-cause mortality, which was most evident 3 days after infusion: 25 of 162 patients treated with 15 mg/kg of TNF-α MAb died, 22 of 156 patients treated with 7.5 mg/kg of TNF-α MAb died, and 44 of 160 patients in the placebo group died (15 mg/kg: 44% reduction vs placebo, P =.01; 7.5 mg/kg: 48.7% reduction vs placebo, P =.004). At day 28, the reduction in mortality for shock patients was not significant for either dose of TNF-α MAb relative to placebo (15 mg/kg, 61 deaths among 162 patients [37.7% mortality]; 7.5 mg/kg, 59 deaths among 156 patients [37.8% mortality]; placebo, 73 deaths among 160 patients [45.6% mortality]; P =.20 for 7.5 mg/kg and P =.15 for 15 mg/kg). Serious adverse events were reported in 4.6% of all infused patients. No immediate hypersensitivity allergic reactions due to TNF-α MAb were reported. Serum sickness—like reactions were seen in 2.5% of patients receiving TNF-α MAb. Conclusions. —There was no decrease in mortality between placebo and TNF-α MAb in all infused patients. In septic shock patients who received TNF-α MAb, a significant reduction in mortality was present 3 days after infusion. Although a trend toward reduced mortality continued at 28 days following treatment with TNF-α MAb, the difference in mortality among shock patients treated with placebo or TNF-α MAb was not significant. ( JAMA . 1995;273:934-941)
757 citations
TL;DR: In this paper, the authors identified the components of exercise rehabilitation programs that were most effective in improving claudication pain symptoms in patients with peripheral arterial disease, and they identified the optimal exercise program for improving the patient's pain.
Abstract: Objective. —To identify the components of exercise rehabilitation programs that were most effective in improving claudication pain symptoms in patients with peripheral arterial disease. Data Sources. —English-language articles were identified by a computer search using Index Medicus and MEDLINE, followed by an extensive bibliography review. Study Selection. —Studies were included if they provided the mean or individual walking distances or times to the onset of claudication pain and to maximal pain during a treadmill test before and after rehabilitation. Data Extraction. —Walking distances and times and characteristics of the exercise programs were independently abstracted by two observers. Data Synthesis. —Thirty-three English-language studies were identified, of which 21 met the inclusion criteria. Overall, following a program of exercise rehabilitation, the distance (mean±SD) to onset of claudication pain increased 179% from 125.9±57.3 m to 351.2±188.7 m ( P P P Conclusions. —The optimal exercise program for improving claudication pain distances in patients with peripheral arterial disease uses intermittent walking to near-maximal pain during a program of at least 6 months. Such a program should be part of the standard medical care for patients with intermittent claudication. ( JAMA . 1995;274:975-980)
TL;DR: Deregulation of [Ca2+] results in a number of phenomena from activation of signaling mechanisms and alterations in cellular structure to alterations in gene expression, all of which contribute to or play a critical role in cellular toxicity, including carcinogenesis and cell death.
Abstract: The effect of intracellular ion deregulation, particularly of [Ca2+], on the events following acute cell injury and the progression of change from initiation (reversible) to maintenance (reversible-irreversible) phases and finally to cell death has been the major thrust of experimentation in our laboratory for over 20 years. Cell death, which plays an important role in both normal and pathological phenomena, has been classified into two principal types, accidental and programmed. Recent exploration of programmed cell death (or apoptosis) has revealed extensive data showing it is an important mechanism for the normal maintenance and also differentiation of a variety of cell types and organs. From the results from our laboratory and those of others, we continue to expand and refine our working hypothesis: deregulation of [Ca2+] results in a number of phenomena from activation of signaling mechanisms and alterations in cellular structure to alterations in gene expression, all of which contribute to or play a critical role in cellular toxicity, including carcinogenesis and cell death. Therefore, although much more experimentation is needed to clarify some of these phenomena, the implications of such data for understanding the mechanisms and processes involved in carcinogenesis and the chemotherapeutic killing of cancer cells are extremely exciting. These relationships between [Ca2+], cell injury, and cell death are briefly reviewed here within the framework of our hypothesis.
TL;DR: Compared longitudinal changes in resting metabolic rate, body composition, and physical activity in a cohort of healthy premenopausal women who experienced menopause with changes in these variables in a cohorts of women who remained pre menopausal.
Abstract: Objective: To describe the effects of menopause on resting metabolic rate, body composition, fat distribution, physical activity during leisure time, and fasting insulin levels. Design: A longitudi...
Journal Article•
TL;DR: The findings suggest that the costimulatory roles of CD40: CD40L and B7-2 differ in the GC; administration of anti-CD40L abrogates an established GC reaction, whereas Ab to B 7-2 suppresses Ig hypermutation and entry into the B cell memory compartment.
Abstract: Costimulatory interactions between T and B lymphocytes are crucial for T cell activation and B cell proliferation and differentiation. We have compared the roles of CD40L and B7-2 in the initiation and maturation of humoral immunity by administering anti-CD40 ligand (L) or anti-B7-2 Ab during the early (days -1 to 3) or late (days 6-10) phases of primary responses to thymus-dependent (Td) and -independent (Ti) Ags. Germinal center (GC) formation in response to a Td Ag was inhibited completely by the early administration of anti-CD40L or anti-B7-2 Abs. Later in the response, established GCs remained sensitive to anti-CD40L but were resistant to treatment with anti-B7-2. However, Ig hypermutation was reduced dramatically in GCs of anti-B7-2-treated mice and humoral memory was impaired. Early administration of anti-CD40L reduced serum Ab levels to approximately 10% of controls, whereas early treatment with anti-B7-2 reduced Ab production by only 50%. Later treatments with either Ab had no effect on Ab production. Response to a type II Ti Ag was more resistant than Td responses to interruption of costimulatory interactions. Our findings suggest that the costimulatory roles of CD40:CD40L and B7-2:CD28/CTLA-4 differ in the GC; administration of anti-CD40L abrogates an established GC reaction, whereas Ab to B7-2 suppresses Ig hypermutation and entry into the B cell memory compartment. Once B cells have entered the differentiation pathway to Ab production, neither CD40L nor B7-2 is necessary for their continued differentiation and persistence.
TL;DR: This review focuses on recent findings that elucidate the biochemical nature of secretory product interaction in the formation of free radicals, particularly the highly reactive hydroxyl radical.
Abstract: Phagocytes mediate their innate immunological response by releasing products that damage invading microorganisms. These products include proteins such as lysozyme, peroxidases, and elastase as well as reactive oxygen species such as superoxide, hydrogen peroxide, hypohalous acid, and hydroxyl radical. Although it is clear that many phagocytic secretory products have direct cytotoxic potential, understanding is limited of how multiple products interact to generate and modulate the cytotoxic response. This review focuses on recent findings that elucidate the biochemical nature of secretory product interaction in the formation of free radicals, particularly the highly reactive hydroxyl radical. The possible role of these reactions in phagocyte microbicidal activity and inflammatory tissue injury is discussed.
TL;DR: The first experimental demonstration of two-dimensional spatial solitary waves in second-order nonlinear optical material is reported.
Abstract: We report the first experimental demonstration of two-dimensional spatial solitary waves in second-order nonlinear optical material When an intense optical beam is focused into a phase-matchable second-order nonlinear material, the fundamental and generated second-harmonic fields are mutually trapped as a result of the strong nonlinear coupling which counteracts both diffraction and beam walkoff
TL;DR: The most efficacious "Ca2+ signal" for activating Ca2+ release from the SR may be a transient microdomain of high [Ca2-]i beneath an individual, open L-type Ca2- channel.
Abstract: Excitation-contraction coupling was studied in mammalian cardiac cells in which the opening probability of L-type calcium (Ca2+) channels was reduced. Confocal microscopy during voltage-clamp depolarization revealed distinct local transients in the concentration of intracellular calcium ions ([Ca2+]i). When voltage was varied, the latency to occurrence and the relative probability of occurrence of local [Ca2+]i transients varied as predicted if Ca2+ release from the sarcoplasmic reticulum (SR) was linked tightly to Ca2+ flux through L-type Ca2+ channels but not to that through the Na-Ca exchanger or to average [Ca2+]i. Voltage had no effect on the amplitude of local [Ca2+]i transients. Thus, the most efficacious "Ca2+ signal" for activating Ca2+ release from the SR may be a transient microdomain of high [Ca2+]i beneath an individual, open L-type Ca2+ channel.
TL;DR: The noncompetitive NMDA antagonist ketamine, given to schizophrenic individuals in subanesthetic doses, produced a short-lived, discrete activation of their psychotic symptoms, which had striking similarities to symptoms of their usual psychotic episodes as discussed by the authors.
Abstract: The non-competitive NMDA antagonist ketamine, given to schizophrenic individuals in subanesthetic doses, produced a short-lived, discrete activation of their psychotic symptoms, which had striking similarities to symptoms of their usual psychotic episodes. To further study this psychotomimetic property of ketamine, we administered 0.3 mg kg-1 of the drug to schizophrenic individuals during a [15O] water cerebral blood flow study. Regional cerebral blood flow (rCBF) was measured using H2(15)O and positron emission tomography (PET) before and after ketamine administration to identify regions of flow change, rCBF was increased in anterior cingulate cortex and was reduced in the hippocampus and primary visual cortex (lingual and fusiform gyri). These data encourage further consideration of altered glutamatergic transmission in schizophrenic and PCP-induced psychoses.
TL;DR: The methods of assessing cardiovascular conditions among older adults recruited to the Cardiovascular Health Study (CHS), a cohort study of risk factors for coronary disease and stroke, are described.
TL;DR: Nonwhite physicians are more likely to care for minority, medically indigent, and sicker patients than were non-Hispanic white patients and caring for less affluent and Sicker patients may financially penalize nonwhite physicians and make them particularly vulnerable to capitation arrangements.
Abstract: Objective. —To examine the relationship between physician race and care of racial minority and ethnic minority patients and medically indigent patients. Design. —Secondary analysis of data from the 1987 National Medical Expenditure Survey, a cross-sectional survey of Americans designed to provide national estimates of health care utilization and expenditures. Setting. —A sample representative of the total civilian noninstitutionalized US population with oversampling of minorities and the medically indigent. Patients. —Survey respondents aged 18 years or older who identified a specific physician as their usual source of care (n=15081, corresponding to a national population estimate of 116 million Americans). Main Outcome Measure. —Identification of a nonwhite physician as usual source of care. Results. —Of adult Americans who identified a usual-source-of-care physician, 14.4% identified a nonwhite physician as that source of care. Minority patients were more than four times more likely to receive care from nonwhite physicians than were non-Hispanic white patients. Low-income, Medicaid, and uninsured patients were also more likely to receive care from nonwhite physicians. Individuals who receive care from nonwhite physicians were more likely to report worse health, visit an emergency department, and be hospitalized. Individuals who receive care from nonwhite physicians reported more acute complaints, chronic conditions, functional limitations, and psychological symptoms as well as longer visits. Conclusions. —Nonwhite physicians are more likely to care for minority, medically indigent, and sicker patients. Caring for less affluent and sicker patients may financially penalize nonwhite physicians and make them particularly vulnerable to capitation arrangements. ( JAMA . 1995;273:1515-1520)
TL;DR: There is substantial evidence that psychoeducational family interventions reduce the rate of patient relapse and suggestive, though not conclusive, evidence that these interventions improve patient functioning and family well-being.
Abstract: This article reviews the existing evidence for the efficacy and effectiveness of psychoeducational family interventions in the treatment of persons with schizophrenia. There is substantial evidence that psychoeducational family interventions reduce the rate of patient relapse. There is suggestive, though not conclusive, evidence that these interventions improve patient functioning and family well-being. Interventions with multifamily groups that include the patient may be of superior benefit for subgroups of patients. More research is necessary to determine the critical ingredients of family interventions, to expand the groups of patients included in these studies, and to evaluate a broader range of outcomes.
TL;DR: Phosphorylation of the RyR by protein kinase A increased the responsiveness of the channel to Ca2+ and accelerated the kinetics of adaptation, which demonstrated that RyR adaptation is rapid in canine heart muscle when physiological Mg2+ concentrations are present.
Abstract: Channel adaptation is a fundamental feature of sarcoplasmic reticulum calcium release channels (called ryanodine receptors, RyRs). It permits successive increases in the intracellular concentration of calcium (Ca2+) to repeatedly but transiently activate channels. Adaptation of RyRs in the absence of magnesium (Mg2+) and adenosine triphosphate is an extremely slow process (taking seconds). Photorelease of Ca2+ from nitrophenyl-EGTA, a photolabile Ca2+ chelator, demonstrated that RyR adaptation is rapid (milliseconds) in canine heart muscle when physiological Mg2+ concentrations are present. Phosphorylation of the RyR by protein kinase A increased the responsiveness of the channel to Ca2+ and accelerated the kinetics of adaptation. These properties of the RyR from heart may also be relevant to other cells in which multiple agonist-dependent triggering events regulate cellular functions.
TL;DR: It is concluded that SHC interacts directly with the IR and that phosphorylation of Tyr-960 within the IR juxtamembrane domain is necessary for efficient interaction.
Abstract: The SHC proteins have been implicated in insulin receptor (IR) signaling. In this study, we used the sensitive two-hybrid assay of protein-protein interaction to demonstrate that SHC interacts directly with the IR. The interaction is mediated by SHC amino acids 1 to 238 and is therefore independent of the Src homology 2 domain. The interaction is dependent upon IR autophosphorylation, since the interaction is eliminated by mutation of the IR ATP-binding site. In addition, mutational analysis of the Asn-Pro-Glu-Tyr (NPEY) motif within the juxtamembrane domain of the IR showed the importance of the Asn, Pro, and Tyr residues to both SHC and IR substrate 1 (IRS-1) binding. We conclude that SHC interacts directly with the IR and that phosphorylation of Tyr-960 within the IR juxtamembrane domain is necessary for efficient interaction. This interaction is highly reminiscent of that of IRS-1 with the IR, and we show that the SHC IR-binding domain can substitute for that of IRS-1 in yeast and COS cells. We identify a homologous region within the IR-binding domains of SHC and IRS-1, which we term the SAIN (SHC and IRS-1 NPXY-binding) domain, which may explain the basis of these interactions. The SAIN domain appears to represent a novel motif which is able to interact with autophosphorylated receptors such as the IR.
TL;DR: Elderly Caucasian women with moderate to severe radiographic hip OA had higher BMD in the hip, spine, and appendicular skeleton than did women without hip OO, and these findings are consistent with a role of elevated B MD in the pathogenesis of Hip OA.
Abstract: Objective. To examine the cross-sectional association between radiographic features of hip osteoarthritis (OA) and bone mineral density (BMD) of the hip, spine, and appendicular skeleton among Caucasian women ages 65 and older who were participating in the Study of Osteoporotic Fractures.
Methods. Pelvis radiographs of 4,855 subjects were assessed for individual radiographic features of hip OA: osteophytes, joint space narrowing, subchondral sclerosis, cysts, and femoral head deformity. Hips were graded on a summary scale of 0 (no OA) to 4 (severe OA) based on the number of radiographic features present. Appendicular BMD was measured in all subjects, and hip and spine BMD in 84% of the group. We used linear regression to examine the association of BMD with hip OA, and to adjust for age, weight, and other determinants of bone mass.
Results. Three hundred fifty-one women (7.2%) had mild (grade 2) and 228 (4.7%) had moderate to severe (grade 3–4) radiographic evidence of hip OA. Women with grade 3–4 hip OA had a higher age-adjusted BMD at the femoral neck and Ward's triangle (9–10%; P < 0.0001), trochanter (4%; P < 0.01), lumbar spine (8%; P < 0.0001), and distal radius and calcaneus (5%; P < 0.0001 [for each comparison]) compared with those with grade 0–1 OA in the worse hip. Elevations in BMD were greatest in the femoral neck of hips with OA, in women with bilateral hip OA, and in women with hip osteophytes. These findings were essentially unchanged by adjustment for determinants of bone mass.
Conclusion. Elderly Caucasian women with moderate to severe radiographic hip OA had higher BMD in the hip, spine, and appendicular skeleton than did women without hip OA. Our findings are consistent with a role of elevated BMD in the pathogenesis of hip OA.
TL;DR: These experiments indicate that prolonged seizures cause a preferential neuronal loss in layer III of the medial EC and that this lesion may be related to a pathological elevation of intracellular calcium ion concentrations.
Abstract: We recently described a pronounced neuronal loss in layer III of the entorhinal cortex (EC) in patients with intractable temporal lobe epilepsy (Du et al., 1993a). To explore the pathophysiology underlying this distinct neuropathology, we examined the EC in three established rat models of epilepsy using Nissl staining and parvalbumin immunohistochemistry. Adult male rats were either electrically stimulated in the ventral hippocampus for 90 min or injected with kainic acid or lithium/pilocarpine. Animals were observed for behavioral changes for up to 6 hr and were killed 24 hr or 4 weeks after the experimental treatments. At 24 hr, all animals that had exhibited a bout of acute status epilepticus showed a consistent pattern of neuronal loss in the EC in Nissl-stained sections. Neurodegeneration was most pronounced in layer III of the medial Ec at all dorsoventral levels. A few surviving neurons were frequently present in the lesioned area. An identical pattern of nerve cell loss was also seen in the EC of rats killed 4 weeks following the treatments. This lesion was completely prevented by an injection of diazepam and pentobarbital, given 1 hr after kainic acid administration. Immunohistochemistry demonstrated a relative resistance of parvalbumin-positive neurons in layer III of the medial EC. Taken together, these experiments indicate that prolonged seizures cause a preferential neuronal loss in layer III of the medial EC and that this lesion may be related to a pathological elevation of intracellular calcium ion concentrations.
TL;DR: It is shown that, despite a huge literature on arterial mechanics, much remains unknown and a pressing need exists for detailed nonlinear three-dimensional constitutive relations for the passive and active arterial wall as a function of position along the arterial tree and disease.
Abstract: The goals of this article are threefold: to briefly review the theory of finite elasticity and its application to arterial mechanics; to review what is known about the mechanical behavior of arteries in health and disease; and to review several clinically relevant aspects of arterial mechanics, as for example, aging, aneurysms, angioplasty, embolectomy, heat therapies, hypertension, trauma, and the disruption of atherosclerotic plaques It is shown that, despite a huge literature on arterial mechanics, much remains unknown In particular, a pressing need exists for detailed nonlinear three-dimensional constitutive relations for the passive and active arterial wall as a function of position along the arterial tree and disease Arterial mechanics has, therefore, yet to reach its full potential as an important and consistent contributor to vascular medicine and surgery, but the possibilities remain great
TL;DR: Results suggest that ZOT activates a complex intracellular cascade of events that regulate tight junction permeability, probably mimicking the effect of physiologic modulator(s) of epithelial barrier function.
Abstract: The intracellular signaling involved in the mechanism of action of zonula occludens toxin (ZOT) was studied using several in vitro and ex vivo models. ZOT showed a selective effect among various cell lines tested, suggesting that it may interact with a specific receptor, whose surface expression on various cells differs. When tested in IEC6 cell monolayers, ZOT-containing supernatants induced a redistribution of the F-actin cytoskeleton. Similar results were obtained with rabbit ileal mucosa, where the reorganization of F-actin paralleled the increase in tissue permeability. In endothelial cells, the cytoskeletal rearrangement involved a decrease of the soluble G-actin pool (-27%) and a reciprocal increase in the filamentous F-actin pool (+22%). This actin polymerization was time- and dose-dependent, and was reversible. Pretreatment with a specific protein kinase C inhibitor, CGP41251, completely abolished the ZOT effects on both tissue permeability and actin polymerization. In IEC6 cells ZOT induced a peak increment of the PKC-alpha isoform after 3 min incubation. Taken together, these results suggest that ZOT activates a complex intracellular cascade of events that regulate tight junction permeability, probably mimicking the effect of physiologic modulator(s) of epithelial barrier function.
TL;DR: These results are interpreted to mean that weakly hydrated ions (chaotropes) are "pushed" onto weakly Hydrated surfaces by strong water-water interactions and that the transition from strong ionic hydration to weak ionic Hydration occurs where the strength of ion- water interactions approximately equals thestrength of water-Water interactions in bulk solution.
Abstract: Aqueous gel sieving chromatography on Sephadex G-10 of the Group IA cations (Li+, Na+, K+, Rb+, Cs+) plus NH4+ as the Cl- salts, in combination with previous results for the halide anions (F-, Cl-, Br-, I-) as the Na+ salts [Washabaugh, M.W. & Collins, K.D. (1986) J. Biol. Chem. 261, 12477-12485], leads to the following conclusions. (i) The small monovalent ions (Li+, Na+, F-) flow through the gel with water molecules attached, whereas the large monovalent ions (K+, Rb+, Cs+, Cl-, Br-, I-) adsorb to the nonpolar surface of the gel, a process requiring partial dehydration of the ion and implying that these ions bind the immediately adjacent water molecules weakly. (ii) The transition from strong to weak hydration occurs at a radius of about 1.78 A for the monovalent anions, compared with a radius of about 1.06 A for the monovalent cations (using ionic radii), indicating that the anions are more strongly hydrated than the cations for a given charge density. (iii) The anions show larger deviations from ideal behavior (an elution position corresponding to the anhydrous molecular weight) than do the cations and dominate the chromatographic behavior of the neutral salts. These results are interpreted to mean that weakly hydrated ions (chaotropes) are "pushed" onto weakly hydrated surfaces by strong water-water interactions and that the transition from strong ionic hydration to weak ionic hydration occurs where the strength of ion-water interactions approximately equals the strength of water-water interactions in bulk solution.
TL;DR: It is concluded that longer brachial artery occlusion results in more vasodilatation despite similar hyperemic responses, vasodILatation persists substantially beyond hyperemia, and CAD patients have impaired flow-mediated vasoactivity using this noninvasive technique.
Abstract: Flow-mediated brachial artery vasoactivity has been recently proposed as a noninvasive means for assessing endothelial function. To better characterize this technique, we measured brachial artery diameter and flow using 7.5-MHz ultrasound following 1, 3, and 5 min of upper arm blood pressure cuff occlusion in 19 normal volunteers and 13 patients with coronary artery disease (CAD). Although similar flow increases were observed with each protocol, statistically significant vasodilatation (12.6 +/- 5.7%) was observed in the normals only after 5 min of occlusion. With the use of this protocol, postocclusion blood flow increased 528 +/- 271 and 481 +/- 247% in the normals and CAD patients, respectively (P = NS). More vasodilatation was observed in the normals compared with the CAD patients (11.3 +/- 5.4 vs. 1.6 +/- 5.2%, P < 0.001). Interestingly, vasodilatation persisted for 20 min despite return of blood flow to baseline in 2 min. With the use of lower arm occlusion, arterial diameter was found to decrease 4.4 +/- 3.9% in response to a 85 +/- 7% decrease in flow. We conclude that 1) longer brachial artery occlusion results in more vasodilatation despite similar hyperemic responses, 2) vasodilatation persists substantially beyond hyperemia, and 3) CAD patients have impaired flow-mediated vasodilatation using this noninvasive technique.
TL;DR: All 4 EAggEC isolates showed a modest degree of gentamicin protection in HEp-2 cells, and 042 did not express this fimbria as determined by immunogold electron microscopy and genetic probe hybridization.
Abstract: Enteroaggregative Escherichia coli (EAggEC) are diarrheal pathogens defined by aggregative adherence to HEp-2 cells. In an effort to identify pathogenic EAggEC isolates, four groups of 5 volunteers were fed 1 of 4 different EAggEC strains, each at a dose of 10(10) cfu. Strain 042 caused diarrhea in 3 of 5 adults; 3 other EAggEC isolates (17-2, 34b, and JM221) failed to elicit diarrhea. A gene encoding enterotoxin EAST1 was found in strains 042 and 17-2 but not 34b or JM221; a 108-kDa cytotoxin was expressed in all 4 isolates. All 4 isolates showed a modest degree of gentamicin protection in HEp-2 cells. 17-2, 34b, and JM221 expressed the fimbrial antigen AAF/I; 042 did not express this fimbria as determined by immunogold electron microscopy and genetic probe hybridization.