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Biomedical subjects

S Holtzman

Publications and source records attributed to S Holtzman.

At least 19 recordsLinked to original sources
PubMed2001

The Drosophila proboscis is specified by two Hox genes, proboscipedia and Sex combs reduced, via repression of leg and antennal appendage genes.

The proboscis is one of the most highly modified appendages in Drosophila melanogaster. However, the phenotypes of proboscipedia (pb) mutants, which transform the proboscis into leg or antenna, indicate a basic homology among these limbs. Recent genetic studies have revealed a developmental system for patterning appendages and identified several genes required for limb development. Among these are: extradenticle (exd), homothorax (hth), dachshund (dac), Distal-less (Dll) and spalt (sal). These limb genes have not been well studied in wild-type mouthparts and their role if any in this appendage is not well understood. Here we demonstrate that the homeotic gene products Proboscipedia (Pb) and Sex combs reduced (Scr) regulate the limb genes in the labial disc to give rise to a unique type of appendage, the proboscis. Pb inhibits exd, dac and sal expression and downregulates DLL: This observation explains the ability of Pb to inhibit the effects of ectopically expressed trunk Hox genes in the proboscis, to suppress leg identity in the trunk and to transform antenna to maxillary palp. Scr suppresses sal expression and also downregulates Dll in the labial discs; discs mutant for both pb and Scr give rise to complete antennae, further demonstrating appendage homology. In the labial disc, Pb positively regulates transcription of Scr, whereas in the embryo, Scr positively regulates pb. Additionally, our results suggests a revised fate map of the labial disc. We conclude that the proboscis constitutes a genetically distinct type of appendage whose morphogenesis does not require several important components of leg and/or antennal patterning systems, but retains distal segmental homology with these appendages.

Animals↗
PubMed2000

Gallbladder ejection fraction: correlation of scintigraphic and ultrasonographic techniques.

PURPOSE: The assessment of gallbladder function and ejection fraction using sincalide-enhanced biliary scintigraphy is a useful way to evaluate patients with recurrent right upper quadrant pain but no gallstones. MATERIALS AND METHODS: We wanted to determine whether gallbladder contraction measured by ultrasonography could be used in place of biliary scintigraphy. Biliary scans with an infusion of sincalide and concurrent ultrasonography were performed in 17 patients with histories of recurrent abdominal pain and no evidence of gallstones by ultrasound. RESULTS: Gallbladder ejection fractions calculated by ultrasound and scintigraphy using standard techniques showed only a weak correlation. The poor performance of ultrasound appears to arise because the variable shape of the gallbladder invalidates the calculation of its volume by the formula for a prolate spheroid. When gallbladders that were ellipsoidal were subselected, correlation was improved. The level of training of the sonologist did not have a significant effect on the results. CONCLUSION: Gallbladder ejection fraction calculated by ultrasonography cannot be used routinely as a substitute for biliary scintigraphy.

Abdominal Pain↗
PubMed2000

In silico toxicology.

It is toxicology's job to discover a new substance's harmful effects and suggest ways to prevent or mitigate those harmful effects. This paper offers a new possibility--in silico toxicology--to help address this multifaceted challenge.

Computer Simulation↗
PubMed1999

Characterization of the Tribolium Deformed ortholog and its ability to directly regulate Deformed target genes in the rescue of a Drosophila Deformed null mutant.

We have analyzed the Tribolium castaneum ortholog of the Drosophila homeotic gene Deformed (Dfd) and determined its expression pattern during embryogenesis in this beetle. Tc Deformed (Tc Dfd) is expressed in the blastoderm and the condensing germ rudiment in a region that gives rise to gnathal segments. During germ band extension Tc Dfd is expressed in the mandibular and maxillary segments, their appendages, and the dorsal ridge. Comparison of insect Dfd protein sequences reveals several highly conserved regions. To determine whether common molecular features reflect conserved regulatory functions we used the Gal4 system to express the Tribolium protein in Drosophila embryos. When Tc Dfd is expressed throughout embryonic ectoderm under the control of P69B, the beetle protein autoregulates the endogenous Dfd gene. In addition, the Drosophila proboscipedia gene (a normal target of Dfd) is ectopically activated in the antennal and thoracic segments. We also compared the ability of the beetle and fly proteins to rescue defects in Dfd- mutants by expressing each throughout the embryonic during embryogenesis. Both proteins rescued Dfd- defects to the same extent in that they each restore the development of mouth hooks and cirri, as well as cause gain-of-function abnormalities of posterior mouth parts. As before, pb was ectopically activated in the antennal segment. This is the first demonstration of the ability of a heterologous homeotic selector protein to directly regulate a target gene independent of an endogenous Drosophila autoregulatory loop.

Amino Acid Sequence↗
PubMed1999

Decision analysis and Alzheimer disease: three case studies.

Decision analysis may be useful to people facing Alzheimer disease (AD) decisions. The use of decision analysis in three such cases is reported. The first case involved a middle-aged person worried about early-onset AD and deciding whether to seek genetic testing. The analysis let the participant reject testing and consider innovative care options. The second case involved a middle-aged person concerned about later-onset AD. The analysis for her was more complex, and led to the assignment of some limited value on genetic testing for her. The third case revolved around a caregiver's treatment decisions for a patient with severe AD. It led her to recognize the importance of factors she had not previously considered. In each of the three cases, the intensive process of decision analysis appears to have improved the subject's decision.

Adult↗
PubMed1998

Caffeine and schizophrenia.

Although the database is small and not completely consistent, it appears that patients with schizophrenia have high caffeine intakes. The reasons are unclear. In nonhumans, caffeine enhances the effects of dopamine, which might be expected to worsen positive symptoms and improve negative symptoms of schizophrenia and worsen tardive dyskinesia. Eliminating caffeine among patients with schizophrenia does not appear to make them better or worse. Acute intake of large amounts of caffeine may increase psychoses and hostility. However, those who chronically use large amounts of caffeine may develop enough tolerance that these adverse effects do not occur, but whether this conjecture is true has not been tested. Interestingly, persons with schizophrenia do not develop anxiety at high doses of caffeine. Although there was initial concern that caffeine might inactivate liquid doses of neuroleptics, the clinical significance of this concern is unclear. On the other hand, caffeine might increase the level of clozapine, and more research in this area is needed.

Animals↗
PubMed1994

Naloxone pretreatment blocks acute morphine-induced sensitization to naltrexone.

The present experiment was designed to examine whether the acute sensitization to naltrexone that is induced by a single dose of morphine could be blocked by pretreatment with naloxone. Food-deprived male Sprague-Dawley rats were trained to respond for food on a multiple-trial fixed interval 3-min schedule. Reinforcement was contingent upon a response within a 10-s limited hold period following a fixed interval of 3 min. A trial consisted of three fixed intervals separated by a 10-min timeout period during which responses were not reinforced. The rate decreasing effects of the opioid antagonist naltrexone were determined by cumulative dosing. Pretreatment with morphine (3.0 mg/kg, SC) resulted in a 70-fold increase in sensitivity to the response rate decreasing effect of naltrexone compared with saline pretreatment. The increased sensitivity was dose-dependently blocked by naloxone administration 10 min before morphine. The blockade by naloxone was overcome by increasing the pretreatment dose of morphine to 10 mg/kg. The results provide further evidence that acute agonist-induced sensitization to the rate-reducing effects of naltrexone is mediated by opioid receptors.

Animals↗
PubMed1994

Association of clinical risk factors with treatment outcomes.

A patient's decision to accept treatment recommended by his dental health care provider will be strongly influenced by the quality of the information he is given. Estimates of prognosis and treatment predictability must be based on the evidence available from the literature and the practitioners' own experience. Thorough, accurate, and relevant clinical and adjunctive diagnostic data will be a major influence in the development of the patient's individualized treatment strategy. Some clinical findings such as severity of disease for age, deepening pockets accompanied by loss of clinical attachment, frequent bleeding on probing, and bone loss can be considered as risk and prognosis factors. "Hard" data implicating specific clinical or diagnostic findings as risk factors or markers are difficult to find because there are few randomized longitudinal trials available. A new approach which attempts to focus on reducing the risk of undesirable outcomes while improving the probability of successful outcomes following treatment has been referred to as the Treatment Predictability Model. A key feature of this approach is the focus on individual patient circumstances and preferences through the use of decision analysis techniques. A large scale, long-term project utilizing a practice-based research network (PBRN) provided some descriptive information about factors that could distinguish between responders and nonresponder patients undergoing treatment for advanced periodontitis. Bacterial colonization, level of post-treatment plaque control, and smoking were major predictive variables in this group of periodontitis patients. The predictive treatment approach may be one way to develop evidence that will improve the predictability of outcomes for individual patients.

Databases, Factual↗
PubMed1992

Field testing as clinical trial methodology in periodontics.

In the early 1950s the randomized control trial (RCT) was introduced and became widely accepted as the definitive proof of efficacy of a specific medical treatment. In fact, the acceptance and application of this methodology were instrumental in converting medicine from an unpredictable art to a science. At present no other methodologies exist that allow the evaluation of therapeutic efficacy with confidence comparable to that achieved with randomized controlled trials. In recent years researchers have applied new experimental designs and data analysis techniques to clinical trials conducted in a field trial environment to facilitate the understanding of proper use of new therapeutic agents and procedures. Since many of the new methodologies are still evolving or have only recently been introduced, this review considers some of the major trends and developments, as well as experiences of the authors, in field trial methodology. This manuscript addresses the following questions: 1) are there current clinical trial needs that are not met by RCT? 2) If so, what considerations are necessary for new approaches to have scientific usefulness? and 3) What are the strengths and weaknesses of the field trial's setting relative to an institutional environment?

Bias↗
PubMed1992

Decision analysis for periodontal therapy.

Current decision-making approaches in clinical medicine and dentistry are based on principles developed when diagnostic and therapeutic options were few. The rapid pace of new technology development and the role of third-party payment systems are increasingly requiring that health-care providers and patients confront very complex decisions. These decisions typically involve significant uncertainty (e.g., How will a specific patient respond to each possible treatment?) and difficult tradeoffs (e.g., How much are patients willing to pay in money, time, and treatment effectiveness to avoid pain and discomfort?). This paper discusses high-quality decision-making. High-quality diagnostic and therapeutic decisions result from a well-developed decision basis that represents the alternatives, information, and preferences pertaining to the decision at hand. An effective decision basis is framed to address patients' and clinicians' key concerns. The resulting recommendation for action is based on an understanding of what factors are most sensitive in determining the best course of action. Moreover, the value of additional information-gathering efforts (e.g., further diagnosis) can be measured before the information is obtained to determine whether it is worth more than it costs. The paper illustrates the need for better decision-making methods with a sample patient case, discusses key decision analysis principles and methods, identifies specific areas where periodontal decision-making can be improved by decision analysis, and presents a periodontal decision analysis case. It then discusses how intelligent decision system technology can make decision analysis widely available in a clinical setting and concludes by exploring how a future dental office might use this technology on a routine basis.

Decision Making↗
PubMed1989

Decision analysis: a framework for critical care decision assistance.

The ultimate goal of medical computer systems is to help clinicians make good decisions. Such systems must be based on sound principles. Decision analysis is a 25-year-old discipline that provides the needed rigorous foundation for decision assistance. Decision analysis comprises the philosophy, procedures, and tools that can correct the flaws in existing critical care decision-making practice. Intelligent decision systems--computer-based systems that automate decision analysis--make it practical to apply decision analysis to critical care. Orchestra is a pilot intelligent decision system (now under development) that coordinates the efforts of the critical care specialist, the bedside physician, and the bedside nurse in building decision models that can provide recommendations and insight for ventilator management decisions. Decision analysis delivered by intelligent decision systems has great potential for improving critical care decision-making.

Algorithms↗
PubMed1988

Retinyl acetate inhibits estrogen-induced mammary carcinogenesis in female ACI rats.

Two groups of female ACI rats were placed on powdered AIN-76 diets containing retinyl acetate (412,000 i.u. per kg diet) and two groups of rats were placed on placebo diets. Two weeks later one group from each diet was subcutaneously implanted with a 20 mg pellet containing 1 mg of 17 alpha-ethinylestradiol (EE2) mixed with cholesterol, and the remaining groups received 20 mg cholesterol pellet implants. The four groups of animals were maintained on their respective diet for 24 weeks after pellet implantation. The EE2-treated rats were hyperphagic and weighed less than the cholesterol-treated rats. Retinyl acetate had no effect on food consumption or body wt changes. None of the rats that received pellets composed of cholesterol only exhibited mammary carcinomas (MC) or pituitary tumors. All rats with an EE2 implant had pituitary tumors: 88% of the rats on the placebo diet had one or more MC; 70% of the rats on the retinyl acetate diet had one or more MC. The difference between the two EE2-treated groups for incidence of animals with at least one MC was not significant (chi 2). However, the EE2-treated rats on the placebo diet had approximately twice as many MC as the EE2-treated rats on the retinyl acetate diet. Thus, retinyl acetate inhibited estrogen-induced mammary carcinogenesis in female ACI rats, without evidence of gross toxicity.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1987

Assessment of interaction among three carcinogens on rat mammary carcinogenesis in a factorially designed experiment.

Female Sprague-Dawley rats were given by stomach tube 7,12-dimethylbenz[a]anthracene [(DMBA) CAS: 57-97-6] on the 77th day of age at the rate of 1.6 mg/100 g body weight, or procarbazine [(PCZ) CAS: 671-16-9] on the 84th day of age at the rate of 10 mg/100 g body weight, or 0.5 Gy of total-body x-rays on the 91st day of age, singly or in all possible combinations or no treatment. All rats were studied for mammary carcinogenesis for 370 days after the 84th day of age. Three measures of mammary carcinogenesis were studied. These were the incidence of rats with mammary adenocarcinomas, or mammary fibroadenomas, or mammary neoplasia of either type. Each of these measures was studied also for rats with 2 or more or 3 or more mammary neoplasms. Assessment of possible interaction among the three carcinogens with regard to the incidence of neoplasms was done by time-independent or time-dependent methods, both of which gave remarkably consistent results. For rats with 1 or more adenocarcinomas, 1 or more fibroadenomas, or 1 or more adenocarcinomas and/or fibroadenomas, both methods showed no interaction among the carcinogens, which can, therefore, be considered to have produced additive effects. An exception to this finding of additivity was an apparent synergistic interaction between DMBA and PCZ when the measures of rats with 2 or more, or 3 or more mammary neoplasms of either type, or 3 or more fibroadenomas were analyzed; these analyses, however, were based on relatively small numbers of rats with multiple tumors. Since no interactions were found for the usual measure of carcinogenesis, namely, incidence of rats with 1 or more neoplasms, the overall conclusion is that DMBA, PCZ, and x-ray act additively in the induction of mammary neoplasms in the female Sprague-Dawley rat.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1985

Carcinogenic responses to chemicals applied directly to rat mammary glands in situ.

In four experiments, concentrated glycerin suspensions of 7,12-dimethylbenz[a]anthracene (DMBA), or the water-soluble compounds, N-methyl-N-nitrosourea (MNU), N-ethyl-N-nitrosourea (ENU), and 4-nitroquinoline-N-oxide (4-NQO) were delivered into pockets in the mammary fat pads in female Sprague-Dawley rats. In a 90-day experiment, each of three groups of 20-22 rats were treated with either 25, 50 or 100 micrograms DMBA delivered to each of four sites in each rat per group. Dose-related responses were detected for incidence of rats with mammary adenocarcinoma (MAC), and for number of MAC per treated site. In a 120-day study, each of three groups of 20 animals were treated with either 250, 500 or 1000 micrograms MNU at each of 80 sites per group. Dose-related MAC responses were detected for incidence of rats with MAC, number of MAC per treated site, and time to detection of MAC. In two experiments of 90 days duration, groups of 20 females were treated with either 1000 micrograms ENU or 1000 micrograms 4-NQO at each of 80 sites per group. ENU produced a total of 27 MAC sites in 65% of the rats, and 4-NQO produced a total of 26 MAC in 60% of the rats. A comparison of the time to detection of all MAC data for the three water-soluble compounds at the 1000 micrograms treatment level, or on the basis of moles per treatment, yielded a carcinogenic potency relationship of 4-NQO greater than ENU greater than MNU.

4-Nitroquinoline-1-oxide↗