Biomedical subjects

N Friedman

Publications and source records attributed to N Friedman.

At least 37 records · Page 2Linked to original sources

PubMed2000

Using Bayesian networks to analyze expression data.

DNA hybridization arrays simultaneously measure the expression level for thousands of genes. These measurements provide a "snapshot" of transcription levels within the cell. A major challenge in computational biology is to uncover, from such measurements, gene/protein interactions and key biological features of cellular systems. In this paper, we propose a new framework for discovering interactions between genes based on multiple expression measurements. This framework builds on the use of Bayesian networks for representing statistical dependencies. A Bayesian network is a graph-based model of joint multivariate probability distributions that captures properties of conditional independence between variables. Such models are attractive for their ability to describe complex stochastic processes and because they provide a clear methodology for learning from (noisy) observations. We start by showing how Bayesian networks can describe interactions between genes. We then describe a method for recovering gene interactions from microarray data using tools for learning Bayesian networks. Finally, we demonstrate this method on the S. cerevisiae cell-cycle measurements of Spellman et al. (1998).

Algorithms↗

PubMed2000

Determinants of hospital utilization: the situation in Israel and selected countries.

BACKGROUND: In 1995 hospital costs constituted about 42% of the health expenditures in Israel. Although this proportion remained stable over the last decade, hospital discharge rates per 1,000 population increased, while hospitalization days per 1,000 population and average length of stay declined. OBJECTIVE: To gain an insight into the forces behind these changes, we compared the trends in hospital utilization in Israel with those in 21 developed countries with available data. MATERIALS AND METHODS: Our data were derived from The "Hospitals and Day Care Units, 1995" report by the Health Information and Computer Services of the Israel Ministry of Health, and the Organization for Economic Cooperation and Development Health Data, 98. We examined the numbers of acute care hospital beds, of patients on dialysis and of doctors' consultations, health expenditures and age structure of the population in 1995 or closest year with available data, as well as changes in DRs, HDs and ALOS between 1976 and 1995. RESULTS: In Israel the DRs increased from 130 in 1976 to 177 in 1995 (36%), HDs declined from 992 to 818 (18%), and ALOS declined from 7.60 to 4.51 days (41%). Relative to other countries, in 1995 Israel had the lowest ALOS; low HDs similar to those in the UK, Portugal, Spain, the USA and Sweden; and intermediate DRs similar to those in Belgium, Germany, Sweden and Australia. The number of acute care beds per 1,000 population was directly related to HDs (r = 0.954, P = 0.000) and to DRs (r = 0.419, P = 0.052). Health expenditures (% of the gross national product) correlated with the number of patients on dialysis per 1,000,000 population (r = 0.743, P = 0.000). Between 1976 and 1995, HDs and ALOS declined in most countries, however the trends in DRs varied from an increase by 119% in the UK to a decline by 29% in Canada. CONCLUSIONS AND HYPOTHESES: The increase in DRs in Israel from 1976 to 1995 was shared by many but not all countries. This variability may be related to differences in trends in local practice norms and in available hospital beds. If the number of patients on dialysis is a valid index for use of expensive treatment modalities, the correlation of health expenditures with the number of patients on dialysis suggests that the use of expensive technology is a more important determinant of health care costs than the age of the population or hospital utilization. Since the use of expensive technology is highest during the first few days in hospital, decisions about health care policy should consider the possibility that the savings incurred by a further decline in HDs and ALOS may be offset by a possible increase in per diem hospital costs and in health care expenditures after discharge from hospital.

Australia↗

PubMed1999

Generation of the O630 photointermediate of bacteriorhodopsin is controlled by the state of protonation of several protein residues.

The last stages of the photocycle of the photosynthetic pigment all-trans bacteriorhodopsin (bR570), as well as its proton pump mechanism, are markedly pH dependent. We have measured the relative amount of the accumulated O630 intermediate (Phir), as well as its rise and decay rate constants (kr and kd, respectively), over a wide pH range. The experiments were carried out in deionized membrane suspensions to which varying concentrations of metal cations and of large organic cations were added. The observed pH dependencies, s-shaped curves in the case of Phir and bell-shaped curves for kr and kd, are interpreted in terms of the titration of three protein residues denoted as R1, R2, and R3. The R1 titration is responsible for the increase in Phir, kr, and kd upon lowering the pH from pH approximately 9.5 to 7. At low pH Phir exhibits a secondary rise which is attributed to the titration of a low pKa group, R2. After reaching a maximum at pH approximately 7, kr and kd undergo a decrease upon decreasing the pH, which is attributed to the titration of R3. All three titrations exhibit pKa values which decrease upon increasing the salt concentration. As in the case of the Purple (bR570) if Blue (bR605) equilibrium, divalent cations are substantially more effective than monovalent cations in shifting the pKa values. Moreover, bulky organic cations are as effective as small metal cations. It is concluded that analogously to the Purple if Blue equilibrium, the salt binding sites which control the pKa values of R1, R2, and R3 are located on, or close to, the membrane surface. Possible identifications of the three protein residues are considered. Experiments with the E204Q mutant show that the mutation has markedly affected the R2 (Phir) titration, suggesting that R2 should be identified with Glu-204 or with a group whose pKa is affected by Glu-204. The relation between the R1, R2 and R3 titrations and the proton pump mechanism is discussed. It is evident that the pH dependence of Phir is unrelated to the measured pKa of the group (XH) which releases the proton to the extracellular medium during the photocycle. However, since the same residue may exhibit different pKa values at different stages of the photocycle, it cannot be excluded that R2 or R3 may be identified with XH.

Amino Acids↗

PubMed1998

Rubber foam and staples: do they secure skin grafts? A model analysis and proposal of pressure enhancement techniques.

The significance of even pressure application and protection against shearing forces using a tie-over dressing of skin grafts has been stressed previously. Several methods for pressure enhancement have been described with no quantification or comparison between the different techniques. Rubber foam and metal staples are commonly used for simple and quick application of the dressings. We developed a model for analyzing the contact interface of the dressing with the skin graft and the pressure exerted by it. A stapled rubber foam tie-over dressing was compared with the original silk thread tie-over dressing. Six different embodiments were also analyzed, all constructed using only rubber foam and metal staples. Imprint and maximal projection analyses of the undersurfaces were performed. The original silk thread tie-over dressing exerted a relatively low pressure but was uniformly distributed. A regular stapled tie-over dressing applied a ring-shaped pressure with minimal projection. Other methods are described providing different contact areas with the grafts and different pressures.

Bandages↗

PubMed1998

An evaluation of the iatrosedative process for treating dental fear.

The iatrosedative process is an interpersonal-cognitive technique by which fearful patients are calmed by the behavior, attitude, and communicative stance of the dentist. The process consists of an iatrosedative interview and a clinical encounter. In our study, 58 fearful dental patients were assigned to 1 of 3 treatment groups. The Corah Dental Anxiety Scale was administered at admission to the clinic, immediately after the iatrosedative interview or standard interview, and again after the first and second clinical encounters. Participants who received the iatrosedative interview had a significantly greater reduction in dental anxiety after the interview than those who received the standard interview. After the two clinical encounters, however, the difference in anxiety reduction between the two groups was not significant. In addition, there was no significant difference in anxiety reduction between iatrosedative participants who had the same dentist for both the interview and the clinical encounter and participants who had different dentists for each part of the study. It is concluded that an iatrosedative interview is more effective than a standard dental interview in decreasing anxiety.

Adult↗

PubMed1998

Using a precision-metered injection system to minimize dental injection anxiety.

In this study, 90% of dental patients reported being at least mildly anxious about receiving dental injections. A new precision-metered injection system has been developed that can greatly increase the probability of painless injections of local anesthetic. Surveys were administered to patients to quantify their fears of dental injections and to measure the desensitization effect of using the new injection system. According to survey results, fear levels decreased significantly when the new technology was used.

Adult↗

PubMed1997

Titration kinetics of Asp-85 in bacteriorhodopsin: exclusion of the retinal pocket as the color-controlling cation binding site.

The spectrum (the purple blue transition) and function of the light-driven proton pump bacteriorhodopsin are determined by the state of protonation of the Asp-85 residue located in the vicinity of the retinal chromophore. The titration of Asp-85 is controlled by the binding/unbinding of one or two divalent metal cations (Ca2+ or Mg2+). The location of such metal binding site(s) is approached by studying the kinetics of the cation-induced titration of Asp-85 using metal ions and large molecular cations, such as quaternary ammonium ions, R4N+ (R = Et, Pr, a divalent 'bolaform ion' [Et3N+-(CH2)4-N+Et3] and the 1:3 molecular complex formed between Fe2+ and 1,10-phenanthroline (OP). The basic multi-component kinetic features of the titration, extending from 10(-2) to 10(4) s, are unaffected by the charge and size of the cation. This indicates that cation binding to bR triggers the blue --> purple titration in a fast step, which is not rate-determining. In view of the size of the cations involved, these observations indicate that the cation binding site is in an exposed location on, or close to, the membrane surface. This excludes previous models, which placed the color-controlling Ca2+ ion in the retinal binding pocket.

Aspartic Acid↗

PubMed1997

Time-resolved titrations of ASP-85 in bacteriorhodopsin: the multicomponent kinetic mechanism.

The Asp-85 residue, located in the vicinity of the retinal chromophore, plays a key role in the function of bacteriorhodopsin (bR) as a light-driven proton pump. In the unphotolyzed pigment the protonation of Asp-85 is responsible for the transition from the purple form (lambdamax = 570 nm) to the blue form (lambdamax = 605 nm) of bR (pKa = 3.5 in 20 mM NaCl). The Purple <=> Blue transition can also be induced by deionization (cation removal). These color changes offer a unique opportunity for time resolving the titration of a protein residue using conventional stopped-flow methodologies. We have studied the Purple <=> Blue equilibration kinetics in bR by exposing the system to pH and to cation jumps. Independently of the equilibration direction (Purple-->Blue or Blue-->Purple) and of the inducing concentration jump ([H+] or [cation]), the kinetics are found to exhibit analogous multicomponent features. Analysis of the data over a range of cation concentrations and pH values leads to the conclusion that the rate-determining step in the overall titration of Asp-85 is proton translocation through a specific proton channel. The multicomponent kinetics, extending over a wide time range (10(-2)-10(4) s), are accounted for in terms of a pH-dependent heterogeneity of proton channels. A model is presented in which the relative weight of four proton channels is determined by the state of protonation of two interacting, channel-controlling, protein residues A1 and A2. These findings bear on the mechanism of the vectorial proton translocation associated with the photocycle of bR.

Aspartic Acid↗

PubMed1997

Trp86 --> Phe replacement in bacteriorhodopsin affects a water molecule near Asp85 and light adaptation.

Illumination of the Trp86 --> Phe mutant of bacteriorhodopsin causes anomalous light adaptation, i.e., isomerization of the retinal from all-trans to 13-cis, 15-syn. FTIR spectral analysis shows that illumination at 250 K yields two 13-cis photoproducts, the conventional 13-cis, 15-syn state, BR(C), and another termed BR(X). BR(X) is different from BR(C) because it has a lower N-H in-plane bending frequency and a higher C14-C15 stretching frequency, as well as an absence of coupling between these modes. BR(X), which is stable at 275 K, is more abundant in the photosteady state produced by longer wavelength light and detected as the only photoproduct at 170 K. Its different structural features result from distortion of the C14-C15 bond of the chromophore. In the W86F mutant protein, the small structural changes of a water molecule in the conversion between the all-trans and 13-cis, 15-syn forms and in the formation of the K photointermediate are absent, but the larger changes of water molecule(s) that normally occur in the L and M intermediates are present. We propose that Trp86, together with Asp85, is involved in binding the water molecule and in preventing the formation of the 13-cis, 15-syn photoproducts, BR(C) and BR(X), when the wild type protein is illuminated.

Aspartic Acid↗

PubMed1997

Interaction between Asp-85 and the proton-releasing group in bacteriorhodopsin. A study of an O-like photocycle intermediate.

Upon light adaptation by continuous (or pulsed) illumination, the artificial bacteriorhodopsin (bR) pigments, I and II, derived from synthetic 14F retinal and a short polyenal, respectively produce a long-lived red-shifted species denoted O1. An analogous phenomenon was observed by Sonar, S., et al. [(1993) Biochemistry 32, 2263-2271], in the case of the Y185F mutant (pigment III). The nature of these O1 species was investigated by studying a series of effects, primarily their red light photoreversibility, the associated proton uptake and release processes, and the effects of pH on their relative amounts, which are interpreted in terms of pH-dependent acid-base equilibria. Experiments were also carried out with pigments I and II derived from the mutants D96A, E204Q, R82Q, and D85N. The O1 species of pigments I and II (and possibly also that of pigment III) are identified as an unusually long-lived (all-trans) intermediate of the photocycle of their 13-cis isomer. It is concluded that in O1, Asp-85 is protonated, a process associated with proton uptake from the extracellular side. Subsequent proton release (to the same side of the membrane) occurs from Glu-204 (or from a group closely interacting with it) prior to the decay of O1. At high pH (>9), O1 reversibly converts to a purple form, due to deprotonation of Asp-85, while at still higher pH (> 11), a blue-shifted species characterized by a deprotonated Schiff base is generated. These transitions constitute the first demonstration of the titration of a photocycle intermediate of a retinal protein. The respective pKa values are determined and discussed in relation to those pertaining to the unphotolyzed (dark-adapted) pigments. It appears that the pKa values are controlled by a hydrogen bond network involving water molecules, which binds the protonated Schiff base with Asp-85 and Glu-204. The disruption of this network in pigments I-III may also be responsible for the long lifetime of the O1 species, due to the inhibition of thermal trans-13-cis isomerization. The results are relevant to the molecular mechanism of the photocycles of both 13-cis- and all-trans-bR, primarily to the nature and to the deprotonation mechanism of the proton-releasing group.

Arylsulfonates↗

PubMed1997

Evidence for a controlling role of water in producing the native bacteriorhodopsin structure.

The experiments reported in this paper, based on reconstitution of bacteriorhodopsin (bR) from apomembrane at varying environmental conditions, demonstrate that the presence of water is a controlling factor in generating a native wild-type bR conformation. If water is lacking during this reconstitution process, then a non-native bR structure is formed that exhibits altered M formation and decay kinetics, as well as different behavior following extensive dehydration. It is shown that mutants affecting the ability of bR to form appropriate structures of water in specific protein cavities also affect the ability to generate a native bR conformation. The results suggest that aspartic acid 96 plays a major role in anchoring the appropriate water structure conformation associated with bR. It is also demonstrated that the glutamic acid 204 residue is pivotal in controlling the protein/water affinity. This water affinity can be further controlled by modifying the charge environment of the protein with altered pH. These data, based on kinetic absorption spectroscopy and Fourier transform infrared spectroscopy, highlight the central role of water in this protein.

Aspartic Acid↗

PubMed1997

Effect of carbonated water on gastric emptying and intragastric meal distribution.

Carbonated water has long been advocated to relieve dyspeptic symptoms, suggesting that it may alter gastric motility via gastric distension. This study aimed to determine the effect of carbonated water on gastric emptying of a radiolabeled mixed meal in eight healthy volunteers. Meal emptying and its distribution within the stomach were assessed with carbonated and still water in a crossover study. Emptying of both solid and liquid, including the duration of the lag phase, was identical for both drinks. However, the proximal stomach contained a greater proportion of solids (74 +/- 7% vs 56 +/- 8%, P < 0.05) and liquids (43 +/- 5% vs 27 +/- 4%, P < 0.05) with carbonated water as opposed to still water. Retention of the meal within the proximal stomach ended with the lag phase and was likely related to proximal distension. In conclusion, carbonated water did not alter overall gastric emptying but profoundly modified intragastric distribution of the meal.

Adult↗

PubMed1997

The role of a secondary pediatric ambulatory care service within the community.

OBJECTIVE: To describe the establishment and function of a secondary pediatric ambulatory care service within the community, to assess the utilization of a pediatric community service ("The Center"), and to assess parents' degree of satisfaction with the quality of care in the center. DESIGN: Personal information and information regarding all visits was recorded and analyzed. A structured telephone interview was used to evaluate parents' satisfaction with the quality of care in the center. SETTING: A pediatric community centre managed by board certified pediatricians. The clinic offers primary and secondary care. PARTICIPANTS: A random sampling of parents of children who visited the center (n = 615). RESULTS: The number of children treated in the center increased five-fold within three years. Most visits took place during evening hours and over the weekends. The most common presenting symptoms were fever, respiratory and gastrointestinal complaints, earache, and trauma. Eighty-nine percent of parents were satisfied or very satisfied with the quality of care in the center; 95% were satisfied or very satisfied with the attitudes of physicians and nurses providing treatment. CONCLUSION: The center is widely utilized by parents with a great degree of satisfaction. The availability and extended working hours of the center provided medical care for a large number of children seeking "after hours" medical attention, as well as a backup for the primary care physicians. The center, therefore, provides a model for improved quality of medical care within the community.

Ambulatory Care↗

PubMed1996

Steric interaction between the 9-methyl group of the retinal and tryptophan 182 controls 13-cis to all-trans reisomerization and proton uptake in the bacteriorhodopsin photocycle.

The hypothesis was tested whether in bacteriorhodopsin (BR) the reduction of the steric interaction between the 9-methyl group of the chromophore all-trans-retinal and the tryptophan at position 182 causes the same changes as observed in the photocycle of 9-demethyl-BR. For this, the photocycle of the mutant W182F was investigated by time-resolved UV-vis and pH measurements and by static and time-resolved FT-IR difference spectroscopy. We found that the second half of the photocycle was similarly distorted in the two modified systems: based on the amide-I band, the protonation state of D96, and the kinetics of proton uptake, four N intermediates could be identified, the last one having a lifetime of several seconds; no O intermediate could be detected; the proton uptake showed a pronounced biphasic time course; and the pKa of group(s) on the cytoplasmic side in N was reduced from 11 in wild type BR to around 7.5. In contrast to 9-demethyl-BR, in the W182F mutant the first part of the photocycle does not drastically deviate from that of wild type BR. The results demonstrate the importance of the steric interaction between W182 and the 9-methyl group of the retinal in providing tight coupling between chromophore isomerization and the late proton transfer steps.

Halobacterium↗

PubMed1996

Medical patients assessment protocol: a tool for evaluating the appropriateness of utilizing hospital-stay days for acute medical patients; development, reliability and applications.

An attempt was made to formulate a tool that, when compared to the appropriateness evaluation protocol (AEP) used for evaluating the utilization of hospital services for medical patients, would be an improvement. To establish this, a four-phase project was evolved, which included: (a) taxonomy definition of medical and nonmedical reasons for acute-care hospital bed utilization for a day of care, (b) use of the preliminary protocol by trained nurses to extend the range of clinical conditions included, (c) independent review of the protocol by three senior physicians, and (d) comparative interrater reliability and feasibility study between the new instrument-the medical patients assessment protocol (MPAP) and the AEP. We found the MPAP to have a higher inter-rater reliability than the AEP (kappa = 0.94 and 0.78, respectively), to be more clinically oriented, more comprehensive, and similar to the AEP regarding the time required for investigation of cases. Therefore, we recommend the use of the MPAP for management and quality control of medical hospitalized patients.

Case Management↗

PubMed1996

Diabetes and managed care: the Lovelace Health System's Episode of Care Program.

In order to efficiently manage the care of large populations, the health of that population must be evaluated. People identified with chronic medical disorders, such as diabetes mellitus, should have their disease managed proactively in the most cost-effective manner across the continuum of care. Lovelace Health System has established an Episode of Care disease management program based on the principles of clinical practice improvement. The diabetes program is described as an example of this approach to define and monitor best practice and to decrease variation among providers. This approach optimizes the use of health care resources and improves patient outcomes.

Continuity of Patient Care↗

PubMed1995

Nitric oxide potentiates hydrogen peroxide-induced killing of Escherichia coli.

Previously, we reported that nitric oxide (NO) provides significant protection to mammalian cells from the cytotoxic effects of hydrogen peroxide (H2O2). Murine neutrophils and activated macrophages, however, produce NO, H2O2, and other reactive oxygen species to kill microorganisms, which suggests a paradox. In this study, we treated bacteria (Escherichia coli) with NO and H2O2 for 30 min and found that exposure to NO resulted in minimal toxicity, but greatly potentiated (up to 1,000-fold) H2O2-mediated killing, as evaluated by a clonogenic assay. The combination of NO/H2O2 induced DNA double strand breaks in the bacterial genome, as shown by field-inverted gel electrophoresis, and this increased DNA damage may correlate with cell killing. NO was also shown to alter cellular respiration and decrease the concentration of the antioxidant glutathione to a residual level of 15-20% in bacterial cells. The iron chelator desferrioxamine did not stop the action of NO on respiration and glutathione decrease, yet it prevented the NO/H2O2 synergistic cytotoxicity, implicating metal ions as critical participants in the NO/H2O2 cytocidal mechanism. Our results suggest a possible mechanism of modulation of H2O2-mediated toxicity, and we propose a new key role in the antimicrobial macrophagic response for NO.

Catalase↗

PubMed1995

Influence of the 9-methyl group of the retinal on the photocycle of bacteriorhodopsin studied by time-resolved rapid-scan and static low-temperature Fourier transform infrared difference spectroscopy.

The photocycle of bacteriorhodopsin (BR) regenerated with all-trans-9-demethylretinal was investigated by time-resolved rapid-scan Fourier transform infrared difference spectroscopy, by static low-temperature difference spectroscopy at 80, 170, and 213 K and by static steady-state difference spectroscopy at 278 K. In addition, the formation and decay of M intermediate was monitored at 412 nm with conventional flash photolysis experiments. Our data show that the removal of the 9-methyl group strongly changes the photocycle of BR. The reaction cycle is slowed down about 250-fold. The photoreaction is characterized by a slow rise of the M intermediate and by a very long-lived N intermediate. No O intermediate could be observed. The low-temperature spectra indicate that already at 80 K a KL-like photoproduct is formed. L can be obtained as in native BR at 170 K, but its decay appears to be inhibited, since it can still be observed at 213 K and high pH, in addition to the M intermediate. As in native BR, the 15-hydrogen out-of-plane modes of the L and N intermediates (observed in 2H2O) are very similar. Evidence for the existence of three N substates which differ in the protonation state of Asp96 and in the amide I bands is presented. This is explained by the extremely slowed-down reisomerization of the chromophore. The results are discussed with respect to alterations in the chromophore-protein interaction, caused by the removal of the 9-methyl group.

Bacteriorhodopsins↗