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PubMed1978

Basic decisions in Emergency Department cases: a logical approach.

In the emergency department teaching program at Brooke Army Medical Center, housestaff rotating through the emergency department are given an algorithm for use in making basic diagnostic decisions. Housestaff frequently believe that the result of their contact with a patient should be establishment of the correct pathophysiological etiology of the patient's chief complaint followed by definitive therapy and feel anything less is unacceptable. The algorithm, which had been in use for nine months at the time of this report, was formulated in an attempt to deal with the problems such views may create, such as inappropriate management of patients who obviously require admission, second-best care, and delays for patients requiring emergency department evaluation. The algorithm has been successful in changing housestaff attitudes and actions and will continue to be used.

Diagnosis↗
PubMedDate not supplied

Screening of novel excipients for improving the stability of retroviral and adenoviral vectors.

In the past decade there has been an increase in the application of viral vectors in the laboratory and clinical trials of human gene therapy, retroviral and adenoviral vectors among the most used. However, the limited stability of these vectors creates problems in the design of experiments, transport, and storage. Vectors stored at -80 degrees C must be quickly shipped on dry ice, which is somewhat cumbersome. Alternatively, viral vectors can be preserved in a lyophilized form. However, loss of viral activity during lyophilization can also be a serious problem. In this report we identify novel candidate formulations containing new compatible solutes, ectoin, hydroxyectoin, and firoin, that allow better stability of retroviral and adenoviral vectors during storage. For retroviral vectors, the maximum stabilization for long-term storage was achieved through lyophilization followed by storage at -20 degrees C using a formulation of Tris buffer pH 7.2 containing firoin (0.5 M), a half-life of 340 days being obtained. Adenoviral vectors storage at -80 degrees C in solution using Tris buffer pH 8.0 with firoin was the best method for long-term storage, with a half-life exceeding 1 year.

Adenoviridae↗
PubMedDate not supplied

Targeted delivery of antisense oligodeoxynucleotide and small interference RNA into lung cancer cells.

Selective gene inhibition by antisense oligodeoxynucleotide (AS-ODN) or by small interference RNA (siRNA) therapeutics promises the treatment of diseases that cannot be cured by conventional drugs. However, antisense therapy is hindered due to poor stability in physiological fluids and limited intracellular uptake. To address these problems, a ligand targeted and sterically stabilized nanoparticle formulation has been developed in our lab. Human lung cancer cells often overexpress the sigma receptor and, thus, can be targeted with a specific ligand such as anisamide. AS-ODN or siRNA against human survivin was mixed with a carrier DNA, calf thymus DNA, before complexing with protamine, a highly positively charged peptide. The resulting particles were coated with cationic liposomes consisting of DOTAP and cholesterol (1:1, molar ratio) to obtain LPD (liposome-polycation-DNA) nanoparticles. Ligand targeting and steric stabilization were then introduced by incubating preformed LPD nanoparticles with DSPE-PEG-anisamide, a PEGylated ligand lipid developed earlier in our lab, by the postinsertion method. Nontargeted nanoparticles coated with DSPE-PEG were also prepared as a control. Antisense activities of nanoparticles were determined by survivin mRNA down-regulation, survivin protein down-regulation, ability to trigger apoptosis in tumor cells, tumor cell growth inhibition, and chemosensitization of the treated tumor cells to anticancer drugs. We found that tumor cell delivery and antisense activity of PEGylated nanoparticles were sequence dependent and rely on the presence of anisamide ligand. The uptake of oligonucleotide in targeted, PEGylated nanoparticles could be competed by excess free ligand. Our results suggest that the ligand targeted and sterically stabilized nanoparticles can provide a selective delivery of AS-ODN and siRNA into lung cancer cells for therapy.

Cell Line, Tumor↗
PubMed2006

Nanotools for megaproblems: probing protein misfolding diseases using nanomedicine modus operandi.

Misfolding and self-assembly of proteins in nanoaggregates of different sizes and morphologies (nanoensembles, primary nanofilaments, nanorings, filaments, protofibrils, fibrils, etc.) is a common theme unifying a number of human pathologies termed protein misfolding diseases. Recent studies highlight increasing recognition of the public health importance of protein misfolding diseases, including various neurodegenerative disorders and amyloidoses. It is understood now that the first essential elements in the vast majority of neurodegenerative processes are misfolded and aggregated proteins. Altogether, the accumulation of abnormal protein nanoensembles exerts toxicity by disrupting intracellular transport, overwhelming protein degradation pathways, and/or disturbing vital cell functions. In addition, the formation of inclusion bodies is known to represent a major problem in the production of recombinant therapeutic proteins. Formulation of these therapeutic proteins into delivery systems and their in vivo delivery are often complicated by protein association. Thus, protein folding abnormalities and subsequent events underlie a multitude of human pathologies and difficulties with protein therapeutic applications. The field of medicine therefore can be greatly advanced by establishing a fundamental understanding of key factors leading to misfolding and self-assembly responsible for various protein folding pathologies. This article overviews protein misfolding diseases and outlines some novel and advanced nanotechnologies, including nanoimaging techniques, nanotoolboxes and nanocontainers, complemented by appropriate ensemble techniques, all focused on the ultimate goal to establish etiology and to diagnose, prevent, and cure these devastating disorders.

Amyloidosis↗
PubMed2001

Comparison between light induced and chemically induced oxidation of rhVEGF.

PURPOSE: The primary objective of this study was to compare the effects of light-and chemical-induced oxidation of recombinant human vascular endothelial growth factor (rhVEGF) and the impact of these reactions on protein formulation. METHODS: A liquid formulation of rhVEGF was exposed to fluorescent light (2 x 10(4) lux for up to 4 weeks), hydrogen peroxide (H2O2), or t-butythydroperoxide (t-BHP) to induce oxidation of rhVEGF. All samples were then treated by tryptic digest and analyzed by reversed phase HPLC to determine the extent of oxidation. Chemically treated samples were also examined by near-UV and far-UV circular dichroism spectroscopy to determine the effect of oxidation on the structure of the protein. RESULTS: Exposure to light for 2 weeks resulted in 8 to 40% oxidation of all 6 methionine residues of rhVEGF (Met3 > Met18 > Met55 > Met78.81 > Met94). This amount of oxidation did not affect the binding activity of rhVEGF to its kinase domain receptor (KDR). Light exposure for 4 weeks increased metsulfoxide formation at Met3 and Met18 by an additional 16%, but did not affect the other residues. This oxidation decreased the receptor binding capacity to 73%. possibly due to the role of Met 18in receptor binding. Chemical oxidation of rhVEGF resulted in a greater extent of oxidation at all 6 methionines. Complete oxidation of Met3, Met18 and Met55 was observed after treatment with H2O2, while these residues underwent 40 to 60% oxidation after treatment with t-BHP. The receptor binding capacity was significantly reduced to 25% and 55% after treatment with H2O2 and t-BHP, respectively. After chemical oxidation, no changes in the secondary or tertiary structure were observed by far-UV and near-UV CD spectroscopy, respectively. CONCLUSIONS: Methionine residues with exposed surface areas greater than 65 A2 and sulfur surface areas greater than 16 A2 were most susceptible to oxidation. Chemical oxidation resulted in higher metsulfoxide formation and decreased binding activity of the protein to KDR than light-induced oxidation. The reduction in KDR binding was not caused by measurable conformational changes in the protein. Photooxidation was dependent on the amount of energy imparted to the protein, while the ability of t-BHP or H2O2 to react with methionine was governed by solvent accessibility of the methionine residues and steric limitations of the oxidizing agent. Significant chemical oxidation occurred on sulfurs with minimum surface areas of 16 A2, while increased photooxidation occurred as a function of increasing surface areas of solvent exposed sulfur atoms. Such differences in the extent of oxidation should be considered during protein formulation since it may help predict potential oxidation problems.

Amino Acid Sequence↗
PubMed1985

How much is an icon worth?

We report a new technique for assessing the amount of information extracted from the icon that follows a briefly presented picture. The problem of how to measure such information was formulated in terms of how much physical exposure of a picture an icon is worth. Consider two types of stimulus presentations, each with a base duration of d ms. The first is a d-ms picture followed by an icon, and the second is a d + a-ms picture not followed by an icon. How large does a have to be so that equivalent amounts of information are extracted in the two cases? To answer this question, we showed people pictures and later tested their memory for the pictures. We found that the physical exposure duration needed to reach a particular level of performance was approximately 100 ms longer when an icon was not permitted versus when the icon was permitted. This value was independent of the base duration and the luminance of the picture. Moreover, the same value was obtained using three different kinds of memory test and four different sets of pictures. We conclude that an icon is worth approximately 100 ms of additional physical exposure duration. A reasonable explanation for this robust equivalence between icon and stimulus is that the same encoding processes are responsible for extracting information from the icon and from the physical stimulus. Therefore, any variable that affects these encoding processes must affect extraction of information from the icon and the physical stimulus in an identical manner. This prediction was confirmed for one such variable, picture luminance.

Figural Aftereffect↗
PubMed2005

Framework for kernel regularization with application to protein clustering.

We develop and apply a previously undescribed framework that is designed to extract information in the form of a positive definite kernel matrix from possibly crude, noisy, incomplete, inconsistent dissimilarity information between pairs of objects, obtainable in a variety of contexts. Any positive definite kernel defines a consistent set of distances, and the fitted kernel provides a set of coordinates in Euclidean space that attempts to respect the information available while controlling for complexity of the kernel. The resulting set of coordinates is highly appropriate for visualization and as input to classification and clustering algorithms. The framework is formulated in terms of a class of optimization problems that can be solved efficiently by using modern convex cone programming software. The power of the method is illustrated in the context of protein clustering based on primary sequence data. An application to the globin family of proteins resulted in a readily visualizable 3D sequence space of globins, where several subfamilies and subgroupings consistent with the literature were easily identifiable.

Algorithms↗
PubMed2006

Formulation and evaluation of a vitamin C multiple emulsion.

Multiple phase emulsions are increasingly used as alternatives to simple emulsions in personal care products. One of the major advantages of these emulsions over simple emulsions is slow and controlled release of their ingredients. Other favorite cosmetic characteristics of multiple emulsions include occlusivity (in O/W/O emulsions), esthetics and consumer acceptance. Vitamin C (ascorbic acid) has been widely used in formulations of skin care products. Due to its effects on collagen biosynthesis, it is considered as moisturizing and anti-aging active ingredient. Instability problems such as oxidation susceptibility have made incorporating vitamin C in topical formulations a challenging issue. The O/W/O emulsions have been formulated using two-step procedure, to investigate vitamin C stability and its release profile. By using different surfactant types and ratios, volume ratio of phases, multiple emulsions containing vitamin C were prepared. Different parameters and formulation factors such as temperature of phases, duration and speed of mixing were evaluated. Based on our results, more stable emulsions were prepared from non-ionic siliconized surfactants, sorbitan derivatives and co-surfactants such as polyglyceryl derivatives. Physical stability was determined by microscopic examination, centrifugation and incubating emulsions in different temperatures. Vitamin C in vitro release studies from O/W and O/W/O emulsions were conducted using Franz diffusion cell (at room temperature) and UV spectrophotometry. The results showed that in the first four-hour period, about 14% of vitamin C released from O/W/O emulsions. It appears that in multiple emulsions the profile of release follows zero-order kinetics. Our data indicate that incorporating vitamin C in multiple emulsions significantly increased its stability possibly attributed to the formation of reverse micelles of surfactants (and/or co-surfactants), which entrapped vitamin C inside the micelles surrounded by hydrophilic heads of surfactant. Moreover, vitamin C was released from multiple emulsions in a zero order slow and controlled release manner.

Ascorbic Acid↗
PubMed2006

Investigating nurses' knowledge, attitudes, and skills patterns towards clinical management system: results of a cluster analysis.

To determine whether definable subtypes exist within a cohort of Hong Kong nurses as related to the clinical management system use in their clinical practices based on their knowledge, attitudes, skills, and background factors. Data were collected using a structured questionnaire. The sample of 242 registered nurses was recruited from three hospitals in Hong Kong. The study employs personal and demographic variables, knowledge, attitudes, and skills scale. A cluster analysis yielded two clusters. Each cluster represents a different profile of Hong Kong nurses on the clinical management system use in their clinical practices. The first group (Cluster 1) was labeled 'lower attitudes, less skilful and average knowledge' group, and represented 55.4% of the total respondents. The second group (Cluster 2) was labeled as 'positive attitudes, good knowledge but less skilful'. They comprised almost 44.6% of this nursing sample. Cluster 2 had more older nurses, the majority were educated to the baccalaureate or above level, with more than 10 years working experience, and they held a more senior ranking then Cluster 1. A clear profile of Hong Kong nurses may benefit healthcare professionals in making appropriate education or assistance to prompt the use of the clinical management system by nurses an officially recognized profession. The findings were useful in determining nurse-users' specific needs and their preferences for modification of the clinical management system. Such findings should be used to formulate strategies to encourage nurses to resolve actual problems following computer training and to increase the depth and breadth of nurses' knowledge, attitudes, and skills toward such system.

Adult↗
PubMed1982

Two-dimensional technique to calculate the EM power deposition pattern in the human body.

A numerical procedure to calculate the electromagnetic (EM) power deposition in two-dimensional models of cross sections in the human body is described. The procedure involves obtaining X-ray images of cross sections of specific areas with computer axial tomographic scans and then solving the EM boundary value problem by using the method of moments. The formulation thus takes into account not only the spatial distribution of the different tissue types, but also the radiation characteristics of the typical EM source. Numerical results are given to illustrate the accuracy of the developed procedure. Special emphasis is placed on characterizing and analyzing the EM power deposition patterns obtained using the annular phased array system recently developed by BSD Medical Corporation for hyperthermia treatments.

Computers↗
PubMed2001

The Ising model in physics and statistical genetics.

Interdisciplinary communication is becoming a crucial component of the present scientific environment. Theoretical models developed in diverse disciplines often may be successfully employed in solving seemingly unrelated problems that can be reduced to similar mathematical formulation. The Ising model has been proposed in statistical physics as a simplified model for analysis of magnetic interactions and structures of ferromagnetic substances. Here, we present an application of the one-dimensional, linear Ising model to affected-sib-pair (ASP) analysis in genetics. By analyzing simulated genetics data, we show that the simplified Ising model with only nearest-neighbor interactions between genetic markers has statistical properties comparable to much more complex algorithms from genetics analysis, such as those implemented in the Allegro and Mapmaker-Sibs programs. We also adapt the model to include epistatic interactions and to demonstrate its usefulness in detecting modifier loci with weak individual genetic contributions. A reanalysis of data on type 1 diabetes detects several susceptibility loci not previously found by other methods of analysis.

Algorithms↗
PubMed2006

Ocular powder: dry topical formulations of timolol are well tolerated in rabbits.

PURPOSE: Although eye drops are the most common form of ocular drugs, they have several limitations. Drug absorption into the eye is, in general, less than 5%, addition of preservatives is often necessary, and many drugs cannot be formulated as eye drops. Formulating ocular drugs as powder may solve these problems. The aim of this study was to investigate ocular irritation in rabbits following powder administration. METHODS: Timolol maleate (TM) powder was administered to pigmented lop rabbits. Both pure TM powder and freeze-dried with PVP-polymer (2.4% of mass) were tested in 1.0- and 0.1-mg doses. Additionally, 4 rabbits received 0.1 mg of the pure powder 3 times a day for 8 d. Redness of the bulbar conjunctiva and the amount of discharge was rated from photographs (0-3 points, randomized and masked evaluation). The 8-d experiment additionally included examination with a slit lamp and examination of hematoxylin-eosin stained sections of eyes with light microscopy. RESULTS: No serious or irreversible signs of irritation were noted. Doses of 1.0 mg were more irritating than 0.1-mg doses. There was no detectable difference in irritation between pure or freeze-dried powder. Slit-lamp examination, surface photographs and histology showed a negligible difference between drug and control eyes following the 8-d experiment. CONCLUSIONS: The results suggest that 0.1 mg of timolol powder does not irritate the eye and that testing topical timolol powder in humans is feasible.

Animals↗
PubMed2005

Integrated minimum-set primers and unique probe design algorithms for differential detection on symptom-related pathogens.

MOTIVATION: Differential detection on symptom-related pathogens (SRP) is critical for fast identification and accurate control against epidemic diseases. Conventional polymerase chain reaction (PCR) requires a large number of unique primers to amplify selected SRP target sequences. With multiple-use primers (mu-primers), multiple targets can be amplified and detected in one PCR experiment under standard reaction condition and reduced detection complexity. However, the time complexity of designing mu-primers with the best heuristic method available is too vast. We have formulated minimum-set mu-primer design problem as a set covering problem (SCP), and used modified compact genetic algorithm (MCGA) to solve this problem optimally and efficiently. We have also proposed new strategies of primer/probe design algorithm (PDA) on combining both minimum-set (MS) mu-primers and unique (UniQ) probes. Designed primer/probe set by PDA-MS/UniQ can amplify multiple genes simultaneously upon physical presence with minimum-set mu-primer amplification (MMA) before intended differential detection with probes-array hybridization (PAH) on the selected target set of SRP. RESULTS: The proposed PDA-MS/UniQ method pursues a much smaller number of primers set compared with conventional PCR. In the simulation experiment for amplifying 12 669 target sequences, the performance of our method with 68% reduction on required mu-primers number seems to be superior to the compared heuristic approaches in both computation efficiency and reduction percentage. Our integrated PDA-MS/UniQ method is applied to the differential detection on 9 plant viruses from 4 genera with MMA and PAH of 11 mu-primers instead of 18 unique ones in conventional PCR while amplifying overall 9 target sequences. The results of wet lab experiments with integrated MMA-PAH system have successfully validated the specificity and sensitivity of the primers/probes designed with our integrated PDA-MS/UniQ method.

Algorithms↗
PubMed2001

Comparison of agonistic flare-up-protocol and antagonistic multiple dose protocol in ovarian stimulation of poor responders: results of a prospective randomized trial.

The management of poor responders in IVF has always been a big problem. The ideal approach has yet to be formulated. In this study we aim to compare two alternative stimulation protocols. A total of 48 poor responder patients described from previous cycles were included and grouped into two: group I consisted of 24 patients in 24 cycles in which leuprolide acetate (40 microg s.c. per day) was initiated on cycle day 2 followed by exogenous gonadotrophins on cycle day 3; group II consisted of 24 patients in 24 cycles in which ovarian stimulation included gonadotrophin-releasing hormone (GnRH) antagonist (cetrorelix, 0.25 mg daily during late follicular phase) administration. While only the oestradiol concentrations on the day of HCG were lower in group II compared with group I, the clinical pregnancy and implantation rates among groups did not show any significance. The impact of these two regimens in ovarian stimulation of poor responders seem to be same and to establish these results further randomized studies with larger sample sizes are required.

Adult↗
PubMed1994

Problems and pitfalls in the use of estimated age in anthropometric measurements of children from 6 to 60 months of age: a case from Mali.

Estimates of the age of children are often used uncritically in anthropometric measures. This study shows that even with construction of calendars for use of determination of age, substantial training, a careful follow-up in the field by research assistants, and control of all questionnaires immediately after the interviews of the caretakers and weighing of the children, errors remain in estimating the age of children. Such errors may affect the results substantially, leading to errors in the estimation of age-based measures of nutritional status. In the case of Northern Mali, the effect was most likely an underestimation of malnutrition by perhaps as much as 10 to 30 percentage points. The biases in age estimation in many cases are not constant across subgroups of a population. Therefore age estimation problems may lead to wrong decisions regarding policy formulation, planning of development programs and activities, identification of target groups, and, in particular, evaluation of programs and activities. In situations where age has to be estimated, anthropometric measurements that are less influenced by errors in age estimation are recommended.

Age Factors↗
PubMed1983

"Orbiting the orbicularis"--restoration of muscle-ring continuity with myocutaneous flaps.

Eyelid repair by the Mustardé cheek flap or the Hughes tarsoconjunctival lid-sharing flap have been methods deservingly popular with plastic surgeons for many years. Recent attention given to the myocutaneous flap principle has prompted the formulation of a new approach to this difficult problem of replacing an eyelid. In these cases, we have taken what most plastic surgeons are currently "throwing away" in their blepharoplasties and used it to reconstruct up to an entire margin of the eyelid. This new method seems simple because it holds the promise of fewer procedures and perhaps more functional results.

Adult↗
PubMed1993

Chronic pancreatitis.

Chronic pancreatitis is caused most often by chronic excessive alcohol consumption. The disease can be diagnosed by investigations that measure function or assess morphology of the pancreas, thereby permitting a tailored management approach. In many patients, abdominal pain and steatorrhea can be managed effectively by enzyme supplementation, provided such supplements are administered in appropriate formulations and doses. Definition and correction of mechanical problems are possible by modern endoscopic approaches, and surgery plays an important role in the management of local and regional complications of the disease.

Alcoholism↗
PubMed2001

Stability of therapeutic drugs in serum collected in vacutainer serum separator tubes containing a new gel (SST II).

The stability of therapeutic drugs in sera collected in Becton-Dickinson Vacutainer serum separator SST tubes has been well studied. Although most therapeutic drugs are stable, certain drugs such as phenytoin, carbamazepine, and phenobarbital decrease in concentrations over a long storage time. To circumvent this problem, Becton-Dickinson devised a new gel formulation. The authors studied the stability of 14 commonly monitored drugs in sera when stored on the new gel of the SST II tubes and compared the concentrations of drugs in sera stored in plain tubes (no gel), those stored in the old SST tubes, and those stored in the SST II tubes containing a new serum separator gel. The concentrations of most drugs studied did not decline even after 24 hours of storage in SST II tubes. After storage for 7 days in SST II tubes, the concentration of carbamazepine declined by 10% and that of phenytoin decreased by 4%. This is a significant improvement over the existing tube, where concentrations of several drugs declined with prolonged storage. The authors conclude that new SST II tubes are effective in collecting blood for therapeutic drug monitoring.

Blood Specimen Collection↗