bluuebunny/crossref_metadata_2025 huggingface dataset:
INFLUENCE OF pH AND OF CERTAIN OTHER CONDITIONS ON THE STABILITY OF THE INFECTIVITY AND RED CELL AGGLUTINATING ACTIVITY OF INFLUENZA VIRUS
Authors: Miller Gail Lorenz
Published: June 2004

A study has been made of the pH stability of centrifugally purified strains of influenza virus with respect to the biological properties of mouse infectivity and chicken red blood cell agglutinating activity. Observations also were made on the importance of composition of buffer, temperature of storage, and concentration of virus protein to the stability of the virus.

When tested for stability at a protein concentration of 0.1 mg. per cc. in phosphate buffer, the infectivity of PR8 virus was found to be most stable at pH 6.5–7; the swine virus, at pH 7–7.9; and the Lee strain, at a pH of 7.9 or higher. The CCA activity of the PR8 virus in phosphate buffer was most stable at pH 7, that of the swine virus at pH 7–8, and that of the Lee virus at a pH greater than 9. Furthermore, the Lee virus was much less stable in dilute solution in phosphate buffer, even under optimum conditions of pH, than either the PR8 or swine strains.

The different strains of influenza virus were found to possess certain characteristics in common. They lost infectivity and CCA activity on the acid side of optimum pH conditions much more rapidly than on the alkaline side. Under suitable conditions of buffer and pH, the infectivity decreased while the CCA activity remained unchanged. In general, the rate of loss in infectivity was greater than the rate of loss in CCA activity.

When tests of stability were carried out at a protein concentration of 0.1 mg. per cc. in a composite phosphate-glycine-NaCl buffer, the virus strains showed less marked differences and possessed much higher stabilities of CCA activity and infectivity than when stored at the same concentration in phosphate buffer alone. Under the modified conditions, all three viruses possessed maximum stabilities of CCA activity and infectivity at pH 7–8 with the exception of the PR8 virus whose infectivity appeared more stable at pH 7 than at pH 8. In detailed experiments with the Lee virus, it was found that the infectivity and CCA activity of this strain at pH 7 and at a protein concentration of 0.1 mg. per cc. were maintained best in the composite phosphate-glycine-NaCl buffer, less well in a buffer containing glycine and NaCl, and least well in phosphate buffer alone.

In tests with PR8 virus, the activity was found to be much more stable at 4° C. than at 23° C.

When stored at a concentration of 2 mg. per cc. at 4° C. in phosphate buffer at pH 7, the PR8 and Lee strains were found to be much more stable than when stored at the concentration of 0.1 mg. per cc. At the higher concentration, no significant losses in either infectivity or CCA activity were observed over a period of 2 months.
IMMUNITY IN MUMPS
Authors: Kane Lewis W. , Enders John F.
Published: June 2004

1. Fifty-one patients exhibiting signs and symptoms compatible with the clinical syndrome of acute aseptic meningoencephalitis have been studied by means of the complement fixation test for the demonstration of antibody reacting with the virus of mumps or its products.

2. In 17 of these individuals in whom the clinical diagnosis could be made with assurance because of an associated enlargement of the salivary glands, the test yielded evidence of recent infection with the virus.

3. In 16 patients without involvement of the salivary glands the results of the test likewise indicated recent infection with this virus.

4. In the remaining 18 patients the test gave no evidence of a recent infection with the virus.

5. Except for histories of recent exposure obtained from certain of the individuals in whom the complement fixation test was considered to be positive, the characteristics of the disease and the data afforded by the usual laboratory studies failed to distinguish the last 2 groups.

6. On the basis of these findings, it is concluded that the complement fixation test should be of value in the diagnosis of those cases of acute aseptic meningoencephalitis in which the virus of mumps is the etiologic agent and in which involvement of the salivary glands is slight or absent.
STUDIES ON MENINGOCOCCAL INFECTION
Authors: Scherp Henry W. , Rake Geoffrey
Published: June 2004

Absorption tests indicated that the protective antibody (Type I) in four antimeningococcal horse sera corresponded closely to one of the components of the polysaccharide preparation previously isolated by the authors from Type I meningococci. This antibody was, however, a minor fraction in the three therapeutic sera tested, being secondary in amount to non-protective antibody corresponding to another component of the polysaccharide preparation, plus antibody corresponding to agar. In one case, removal of the agar-antibody diminished the protective titer by 30 per cent.
THE VIRUS-NEUTRALIZING ACTION OF SERUM FROM MICE INFECTED WITH POLIOMYELITIS VIRUS
Authors: Brown Gordon C. , Francis Thomas
Published: June 2004

Evidence is presented that the serum of mice paralyzed with the Lansing strain of poliomyelitis virus possesses the capacity to protect normal mice against the same virus when mixtures of virus and serum are inoculated intracerebrally.

The virus-neutralizing action was present mainly in mice paralyzed between the 3rd and 6th days following inoculation and was rarely demonstrable in the serum of mice developing paralysis more than 10 days after inoculation.

Serum from non-paralyzed mice had approximately the same neutralizing capacity when obtained during the same period following inoculation in which serum from paralyzed mice showed the greatest effect.

Neutralization of the virus was not obtained with serum from normal mice or from mice inoculated with normal nervous tissue.

Further investigation of the phenomenon is in progress.
BLOOD VESSELS IN FAT TISSUE. RELATION TO PROBLEMS OF GAS EXCHANGE
Authors: Gersh Isidore , Still Mary A.
Published: June 2004

1. The ratio of the surface of the capillary bed to the volume of tissue supplied by the vessels (S/V ratio) for both open and closed capillaries in fat-rich tissue of the rat is 51.9, in fat-poor tissue of the same sort 222.2. About one-half of the capillaries in fat-rich tissue, to one-fourth in fat-poor tissue, are open during ordinary activity. The total capillary bed of fat-rich tissue is one-third as great as in muscle; the total capillary bed of fat-poor tissue has about the same density as that of the most poorly supplied muscle. This establishes the fact quantitatively that the capillary bed of fat is relatively inadequate, compared to other tissues, for transferring inert gases from fat tissue at a sufficiently rapid rate to prevent the occurrence of extravascular bubbles following rapid decompression from high pressure atmospheres. It also explains the greater distention of the blood vessels in fat tissue, due to gas, than in any other tissue following decompression. The observations have a bearing also on the estimation of the permeability of the blood-fat barrier to inert gases.

2. The volume of protoplasm of fat cells may be very small; a method is presented for estimating it quantitatively. Since it alone is important in metabolism, recalculation of the basic data on a basis of the ratio of surface area of capillaries to volume of protoplasm of fat cell in fat tissue yields a more useful figure. For fat-rich fat tissue S/V (protoplasm) = 2159.0 (for total capillary surface) or 977.6 (for open capillary surface). This means that for purpose of metabolism, the capillary bed is far richer than that of muscle.
HEMOGLOBIN AND PLASMA PROTEIN
Authors: Miller L. L. , Robscheit-Robbins F. S. , Whipple G. H.
Published: June 2004

Hemoglobin (presumably its essential protein globin), given intraperitoneally to a protein-fasting dog, will be used effectively to supply the protein requirements of the body. Nitrogen balance may thus be maintained for 20 days under favorable conditions. New hemoglobin and plasma protein will be formed related to hemoglobin injections in depleted dogs where there is urgent need for these proteins (anemia and hypoproteinemia). Obviously this calls for supplementary amino acids which in globin are low and we assume these amino acids must be contributed from body protein stores.

Plasma proteins (in plasma) tested in the same manner are completely utilized with no loss of nitrogen, positive nitrogen balance, weight balance, and no change in the albumin-globulin ratios.

Hemoglobin (globin) is less effectively utilized as compared with plasma protein given parenterally and there is some increase in urinary nitrogen above control periods. The albumin-globulin ratio may be somewhat modified by hemoglobin injections intraperitoneally. Hemoglobin (globin) digests contribute effectively to body maintenance of nitrogen equilibrium. These digests are about as effective as whole hemoglobin in maintaining nitrogen balance but cause a rise in undetermined nitrogen not seen when hemoglobin alone is given intraperitoneally.

Pigment radicles derived from hemoglobin given intraperitoneally are thrown away and appear as surplus bile pigment even when there is urgent need for all available nitrogenous material—given protein fasting, anemia, and hypoproteinemia in a bile fistula dog. The body evidently prefers to make rather than conserve the pyrrol aggregate (pigment radicle).

We assume that the injected hemoglobin (globin) or hemoglobin digests contribute to the body protein pool and from this pool various proteins emerge to supply protein requirements of tissue or organ cells or to produce new hemoglobin or plasma protein if needed. We have no explanation as to what determines the pattern of this protein flow but new hemoglobin is very high on the priority list.
THE SYNTHESIS, STORAGE, AND EXCRETION OF CREATINE, CREATININE, AND GLYCOCYAMINE IN PROGRESSIVE MUSCULAR DYSTROPHY AND THE EFFECTS OF CERTAIN HORMONES ON THESE PROCESSES
Authors: Hoagland Charles L. , Gilder Helena , Shank Robert E.
Published: June 2004

The diminished excretion of creatinine in progressive muscular dystrophy is a more striking and specific phenomenon than the excess excretion of creatine, marked though this is. While creatinuria is invariably encountered in all cases of long-standing dystrophy, the extent to which the excretion of creatinine is decreased provides a more reliable indication of the severity of the disease since an excess output of creatine may occur physiologically in normal human subjects and in many pathological conditions not known to be associated with muscle disease.

In progressive muscular dystrophy the residual muscle mass, as inferred from the excretion of creatinine, provides a useful index of the state of the disease at any given time.

Although there is excessive creatinuria in progressive muscular dystrophy, there is no evidence that a deprivation of methyl stores occurs through a loss of urinary creatine. The loss of methyl groups contained in the excess creatine is, under ordinary conditions of diet, almost exactly compensated for by a drop in the excretion of methyl groups in the urinary creatinine.

Testosterone propionate, administered over variable periods of time, resulted in the retention of creatine both in normal male children and in male children with progressive muscular dystrophy, as shown in the normal subjects by a diminution in creatine output, and in both by an excess creatinuria for variable periods of time following withdrawal of the hormone. An increase in the excretion of creatine in progressive muscular dystrophy occurred following the administration of methyl testosterone. Neither testosterone propionate nor methyl testosterone appeared to effect any consistent change in the output or urinary creatinine.

No effects on the excretion of creatine and creatinine were observed following the prolonged administration of concentrate of gonadotropic and thyrotropic principles of the hypophysis, or from the administration of desoxycorticosterone acetate to patients with progressive muscular dystrophy.

Except in one case, in which marked improvement was observed following the administration of testosterone propionate, no effects on the clinical course of the patients with progressive muscular dystrophy were observed as a result of treatment by any of the various hormones employed in this study.
PLASMA PROTEIN METABOLISM—ELECTROPHORETIC STUDIES
Authors: Zeldis L. J. , Alling E. L.
Published: June 2004

Electrophoretic patterns of normal dog plasma in veronal buffer at pH 8.5 are shown to be essentially similar to patterns of human plasma. Dog albumin has a higher mobility than human albumin and in a mixture of dog and human plasmas migrates as a partially separated peak. Normal dog plasma frequently shows four alpha globulin peaks.

Rates of restoration of plasma protein components in dogs subjected to acute plasmapheresis have been studied by electrophoresis. During the first 24 hours following such acute depletion, appreciable quantities of all electrophoretic components of the plasma proteins enter the circulating blood stream even when food is not given and has not been given for 12 hours before plasmapheresis. In such fasting periods albumin and total globulin appear in approximately the proportions present in normal plasma. Alpha and beta globulins continue relatively elevated during subsequent days in which caloric and protein intakes are adequate for weight and nitrogen gains. Initial albumin levels, however, are regained more slowly than those of total globulin.

The relative proportions of the electrophoretic components of plasma proteins may be disturbed from normal following a single acute depletion for as long as 2 to 3 weeks after the total protein level has returned to normal.

Abnormally high beta globulin and fibrinogen, but a low albumin, were found in a dog with an acute and chronic cholangitis and hepatitis. Similar elevation of gamma globulin was noted in a dog in which a hemolytic reaction occurred.
CELLULAR DYNAMICS IN THE INTESTINAL MUCOSA: THE EFFECT OF IRRADIATION ON EPITHELIAL MATURATION AND MIGRATION
Authors: Friedman Nathan B.
Published: June 2004

Although irradiation of the duodenum of rats inhibits mitosis in the crypts and halts the normal passage of cells up the villi, the maturation of goblet cells is not affected. The ripening of mucous elements while arrested in the crypts, where they form, instead of during their migration along the villi, results in the so called mucous change, which has hitherto been considered a form of degeneration. During the phase of recovery, the reestablishment of normal migration and desquamation is marked by the appearance of strata of fully formed goblet cells at successive levels out along the villi. It is suggested that some gastrointestinal disturbances known to occur in spontaneous and experimental vitamin deficiency might be explained in terms of aberrations in the cellular replacement of the intestinal mucosa.
INDIVIDUAL BLOOD DIFFERENCES IN MEXICAN INDIANS, WITH SPECIAL REFERENCE TO THE Rh BLOOD TYPES AND Hr FACTOR
Authors: Wiener Alexander S. , Zepeda J. Preciado , Sonn Eve B. , Polivka H. R.
Published: June 2004

98 Mexican Indians were tested for the blood properties A-B-O, A1-A2, M-N, P, Rh'-Rh''-Rh0-rh, and Hr. Of the 98 Indians, 90.8 per cent belonged to group 0, 6.1 per cent belonged to A1, and 3.1 per cent to group B. There were 61.2 per cent of type M, 3.1 per cent of type N, and 35.7 per cent of type MN. Of the 95 Mexican Indians tested with anti-P serum, 21.1 per cent were found to lack the P agglutinogen.

In tests for the Rh blood types, 48.0 per cent of the Indians were found to belong to type Rh1, 9.2 per cent to type Rh2, 41.8 per cent to type Rh1Rh2, and 1 per cent to type Rh0. There were no bloods giving intermediate reactions. Of the 95 Indians tested for the Hr factor 44.2 per cent were found to lack this property.

The reactions for the Rh blood types and Hr factor were correlated with each other and the results supported the conclusion of Race et al. that in addition to the six standard allelic genes and the so called intermediate genes, there is one or possibly two genes having the property of determining agglutinogens which react with anti-Rh' and anti-Rh'' sera, but not with anti-Hr serum. This gene (or genes) appears to be relatively common among Mexican Indians (approximately 3.3 per cent) in contrast to its rareness in white individuals.
INDUCED ANTIBODIES THAT REACT IN VITRO WITH SEDIMENTABLE CONSTITUENTS OF NORMAL AND NEOPLASTIC TISSUE CELLS
Authors: Friedewald William F. , Kidd John G.
Published: June 2004

Antibodies were found in the blood of certain rabbits carrying one or another of four transplanted cancers (Brown-Pearce and V2 carcinomas; RSI and Kato sarcomas) which will fix complement in vitro in mixture with saline extracts of various normal and neoplastic rabbit tissues—including liver, kidney, spleen, and the four tumors mentioned—and chick embryo tissue as well. These antibodies, which have been called induced tissue antibodies, are similar to the natural antibodies previously described (2) in that they react with those constituents of the various tissue cells that prove readily sedimentable in the high speed centrifuge; they differ from the natural antibodies in being absent from the blood of normal rabbits and in withstanding 65° C. for 30 minutes.

Certain quantitative differences suggest that the induced tissue antibodies have somewhat various affinities, depending in part upon the type of neoplasm carried by the host. They may perhaps be consequent on antigenic differences between the sedimentable constituents of the tumor cells and those of the new hosts; for they were not found in the blood of rabbits carrying papillomas and cancers composed of the animals' own cells, and not in that of rabbits in which multiple vaccinia or fibroma virus lesions had recently regressed.

The characters of the sedimentable constituents of normal and neoplastic tissue cells, as revealed thus far by chemical, morphological, and serological studies, have recently been discussed (2,8). In this relation, it has seemed essential to recognize the induced antibodies here described, particularly since they may complicate serological studies aimed at disclosing distinctive sedimentable substances in tissue cells. In an associated paper experiments are reported which bear upon the relation between the induced tissue antibodies and an antibody that reacts specifically with a distinctive sedimentable constituent of Brown-Pearce carcinoma cells (7).
PLASMA PROTEIN METABOLISM—ELECTROPHORETIC STUDIES
Authors: Zeldis L. J. , Alling E. L. , McCoord A. B. , Kulka J. P.
Published: June 2004

The findings on electrophoretic analysis of plasma proteins during many weeks of low protein feeding in dogs accord in general with those of chemical analysis as concerns the alterations in plasma albumin and globulin concentrations. Long continued restriction of dietary protein results in decreased albumin levels while plasma globulin concentrations remain essentially normal. The degree of depletion of electrophoretic albumin is, however, considerably greater than that of chemical albumin.

When large amounts of protein are fed to such depleted dogs complete restoration of normal plasma albumin concentrations requires several weeks. During these weeks large quantities of nitrogen are retained, presumably as tissue protein reserves. Prompt production of plasma globulin is apparent during such periods. These relationships are more clearly shown in electrophoretic than in chemical analyses and are more conspicuous when only moderate protein intakes are fed. These data may indicate that plasma globulins and certain tissue proteins, in contrast to plasma albumin, enjoy prior demands on the total available pool of body protein materials under emergency conditions. Total electrophoretic globulin areas are increased during depletion. Such increases result largely from elevated alpha globulin peaks and are not disclosed by chemical analysis. They are found to be associated with elevated plasma lipid levels which occur in these depleted dogs.

These experiments suggest that in potency tests for dietary protein materials, factors other than the quality of fed protein may influence the relative production of plasma albumin and globulin.
THE PROTECTIVE ACTION OF TRYPAN RED AGAINST INFECTION BY A NEUROTROPIC VIRUS
Authors: Wood Harland G. , Rusoff Irving I.
Published: June 2004

Trypan red, when injected intraperitoneally into mice, has been found greatly to lower the incidence of the infection of mice inoculated intraperitoneally with the neurotropic MM virus. The protective action of the dye is overcome if the virus is inoculated in too high concentration. The lowered incidence of infection was observed in mice inoculated with virus for as long as 29 days after the last dye injection. Of a number of dyes tested, trypan red, brilliant vital red, and Congo red were found effective.

In cotton rats inoculated intraperitoneally with MM virus, trypan red was likewise found to lower the incidence of infection.

With monkeys and a typical poliomyelitis virus no protection was observed against the virus inoculated intraperitoneally. The latter experiment is considered to have been inadequate for a critical test of the effect of trypan red on poliomyelitis infection.

When either the MM virus or Lansing virus were inoculated intracerebrally into mice, the effect of the dye on incidence of infection was small. In the case of the Lansing virus the difference was statistically significant, however. The possible relation of alteration in the permeability of the barrier between the blood and the central nervous system as a cause of the effect of trypan red is discussed.
STUDIES ON THE ETIOLOGY OF PRIMARY ATYPICAL PNEUMONIA
Authors: Eaton Monroe D. , Meiklejohn Gordon , van Herick William , Corey Marilla
Published: June 2004

Experiments to determine the optimum conditions for propagation of the virus of atypical pneumonia in chick embryos are described. Variations in the activity of infected chick embryo material were investigated.

The highest dilution of chick embryo suspension producing pulmonary lesions in hamsters and cotton rats is not over 10–3. Dilutions of 10–4 infect chick embryos.

The virus is unstable at room temperature and also loses activity when stored in a dry-ice refrigerator unless the suspensions are kept in sealed glass tubes.

Filtration experiments indicate a maximum particle size of 180 to 250 mµ.

The virus propagated in chick embryos produces pulmonary lesions in hamsters and cotton rats which have been immunized to their own non-bacterial agents inducing pulmonary lesions. Of these, the pneumonia virus of hamsters most frequently causes intercurrent respiratory infections, and methods of controlling epizootics due to this agent are described.
PLASMA PROTEIN METABOLISM—ELECTROPHORETIC STUDIES
Authors: Zeldis L. J. , Alling E. L. , McCoord A. B. , Kulka J. P.
Published: June 2004

Electrophoretic patterns of human and dog plasma are markedly altered by the extraction of a large part of the plasma lipids. Total electrophoretic areas, relative areas of individual electrophoretic components, and electrophoretic albumin: globulin ratios undergo change.

For human plasma, such extractions confirm previous observations that a particularly rich lipid content characterizes beta globulin. Abnormally large beta peaks regularly occur in the presence of elevated plasma lipids. Marked increases in gamma globulin, however, are also found to be due in large part to elevated plasma lipid levels in certain abnormal human plasmas.

The greatest relative amount of lipid in dog plasma, in contrast to human plasma, is associated not with the beta globulin, but with components usually designated as alpha globulins. Not only the areas, but the configuration and the number of alpha globulin peaks in dog plasma are altered by the extraction of plasma lipids. The results demonstrate that increased alpha globulin areas which occur in the plasma of hypoproteinemic dogs are due in large part to elevated plasma lipid levels.
STUDIES ON PNEUMONIA VIRUS OF MICE (PVM)
Authors: Horsfall Frank L. , Curnen Edward C.
Published: June 2004

The results of neutralization tests with PVM and serum obtained from numerous animal species indicate that antibodies agaiust this virus were present in the blood of all mammalian species tested, as not in that of fowls, and that their incidence in various species was widely different. They indicate, also, that in certain species, particularly the cotton rat, there were marked seasonal variations in the incidence of such antibodies; in the late winter and spring the incidence was much higher than during the summer and fall seasons. Cotton rats and hamsters which did not possess neutralizing antibodies against PVM were susceptible to manifest pulmonary infection with this virus, irrespective of the effects of previous experiments upon them, whereas those which possessed such antibodies were immune. It is suggested that circulating antibodies against PVM were present as a result of preceding infection with a latent virus; either PVM or an agent closely related to it in antigenic composition.

Appropriate non-specific stimuli, e.g. the intranasal injection of suspensions of normal chick embryos, induced the development of neutralizing antibodies against PVM with significantly greater frequency in each of three species than occurred in control animals. Materials derived from patients with primary atypical pneumonia yielded results almost identical to those obtained with normal chick embryo suspensions. It is suggested that such materials, like the other non-specific stimuli employed, were effective in evoking a specific antibody response, because they unbalanced an equilibrium which previously existed between animal host and latent pneumotropic virus.
The Net Effects of Large Plant Locations and Expansions on County Employment*
Authors: Edmiston Kelly D.
Published: June 2004

This paper argues that the net economic impact of new firm locations or expansions is determined by a multitude of opposing forces. Using a unique database, I set out to evaluate the net effects of these opposing forces by looking at the net change in local employment and population arising from large (greater than 300 new jobs) firm locations or expansions in the State of Georgia. The analysis suggests that the employment multipliers associated with new firm locations are much less than one; that is, the net employment effect of a large firm opening is smaller than the gross employment impact. This result is consistent with other empirical economic impact studies, which find multipliers much smaller than those of typical input–output models, often less than unity, and a previous study showing little net effect of large plant openings. Expansions of existing establishments are shown to have substantial multiplicative effects, however, with an average employment multiplier of 2.0. I discuss possible reasons for differential impacts across new and expanding firms, focusing on the nature of the firms. Differences in net impact across industries and high‐tech versus low‐tech firms also is evaluated. I find that the impact of large firm locations or expansions on population in the resident county generally is negative, but positive for the broader region encompassing the county of location and its contiguous neighbors.
Reproducibility of patch test results: a concurrent right‐versus‐left study using TRUE Test™
Authors: Ale S. Iris , Maibach Howard I.
Published: June 2004

Wide variations in the reproducibility rate of positive patch test responses have been reported. We hypothesized that a major source of non‐reproducibility resides in the methodological pitfalls of routine patch testing. Simultaneous duplicate patch testing on opposite sides of the upper back was performed on 500 consecutive patients, using the TRUE Test™ system consisting of 2 panels, each one containing 12 standard allergens. A rigorous methodological design was applied and relevance was assessed for all discordant patch test reactions. A total of 435 positive patch test reactions were observed either on one or both sides in 289 patients (58.8%). Of these, 22 (5%) were discordant, i.e. interpreted as positive allergic on one side whilst negative or doubtful on the opposite side. The allergens responsible for discordant reactions were nickel sulfate (4 patients), cobalt chloride (3), lanolin alcohol (3), fragrance mix (2), carba mix (2), thiuram mix (2), colophonium (1), potassium dichromate (1), p‐phenylenediamine (1), formaldehyde (1), balsam of Peru (Myroxylon pereirae resin) (1) and thimerosal (1). Of the 19 (4%) patients with discordant patch test reactions, the allergen was deemed to be of definite present or past relevance in 9 patients (1.8% of the total and 3.1% of all patients with positive patch test reactions) and of possible relevance in a further 2 patients. These data suggest that patch testing is a reasonably reproducible procedure as long as methodological error is minimized.
Effects of regular consumption of grapefruit juice on the pharmacokinetics of simvastatin
Authors: Lilja Jari J. , Neuvonen Mikko , Neuvonen Pertti J.
Published: June 2004

Aims

Simvastatin, a substrate for CYP3A4, is extensively metabolized during the first pass. Our aim was to investigate the effect of regular consumption of grapefruit juice on the pharmacokinetics of simvastatin.

Methods

In a randomized cross‐over study with two phases, 10 healthy volunteers ingested grapefruit juice 200 ml or water (control) for 3 days. On day 3, a single 40‐mg dose of simvastatin was administered with grapefruit juice 200 ml or water. Plasma concentrations of simvastatin and simvastatin acid were determined up to 24 h.

Results

Grapefruit juice increased the area under the plasma concentration–time curves from 0 to 24 h [AUC(0–24)] of simvastatin 3.6‐fold (range 1.8–6.0‐fold; P < 0.01) and that of simvastatin acid 3.3‐fold (range 2.1–5.6‐fold; P < 0.01), respectively. The peak concentrations (Cmax) of simvastatin and simvastatin acid were increased 3.9‐fold (range 2.3–9.3‐fold; P < 0.01) and 4.3‐fold (range 2.7–7.9‐fold; P < 0.01) by grapefruit juice.

Conclusions

Even one glass of grapefruit juice, taken daily, considerably increases the plasma concentrations of simvastatin and simvastatin acid. Grapefruit juice may increase both the cholesterol‐lowering effect and the risk of adverse effects of simvastatin.
Comparative cardiac safety of low‐dose thioridazine and low‐dose haloperidol
Authors: Hennessy Sean , Bilker Warren B. , Knauss Jill S. , Kimmel Stephen E. , Margolis David J. , Morrison Mary F. , Reynolds Robert F. , Glasser Dale B. , Strom Brian L.
Published: June 2004

Aim To compare the rate of ventricular arrhythmia, sudden death and unexplained or unattended death among users of thioridazine and haloperidol.

Methods Observational cohort study of thioridazine and haloperidol users in the UK General Practice Research Database (GPRD) using data from 1987 through 29 June 2000. Patients were followed for 30 days following each study prescription. The event of interest was a diagnosis of ventricular arrhythmia, sudden death, or unexplained or unattended death. Cox regression was used to calculate rate ratios (RRs) and 95% confidence intervals (CIs), to examine potential confounding factors, and to examine dose–response relationships.

Results Use of thioridazine and haloperidol in the GPRD was primarily in older patients, at low dose (median daily dose 31 mg thioridazine, 1.8 mg haloperidol). There was no association between thioridazine use and the rate of ventricular arrhythmia, sudden death, and unexplained or unattended death (adjusted RR 0.9, 95% CI 0.7, 1.1). The rate did not appear to increase with dose for either drug over the range observed.

Conclusions These results suggest that low‐dose thioridazine and haloperidol have similar cardiac safety.
Thiopurine S‐methyltransferase genetic polymorphism in the Thai population
Authors: Srimartpirom Somrudee , Tassaneeyakul Wongwiwat , Kukongviriyapan Veerapol , Tassaneeyakul Wichittra
Published: June 2004

Aims

To determine the incidence of the thiopurine S‐methyltransferase (TPMT) genetic polymorphism in the Thai population.

Methods

Genomic DNAs were isolated from peripheral blood leucocytes of 200 healthy Thais. The frequencies of five allelic variants of the TPMT gene, TPMT*2, *3A, *3B, *3C and *6 were determined using allele specific polymerase chain reaction (PCR) or PCR‐Restriction fragment length polymorphism technique.

Results

Of the 200 Thai subjects participating in this study, 181 subjects (90.5%) were homozygous for TPMT*1, 18 subjects (9.0%) were heterozygous for TPMT*1/*3C. Only one subject (0.5%) was homozygous for TPMT*3C. The frequency of TPMT*3C mutant allele was 0.050.

Conclusions

Although the TPMT*3C is the most prevalent mutant allele in Asian populations, the frequency of this defective allele is significantly higher in Thais than has been reported in other Asian populations.
Quantitative justification for target concentration intervention – parameter variability and predictive performance using population pharmacokinetic models for aminoglycosides
Authors: Matthews Ivan , Kirkpatrick Carl , Holford Nicholas
Published: June 2004

Aims  [1] To quantify the random and predictable components of variability for aminoglycoside clearance and volume of distribution [2] To investigate models for predicting aminoglycoside clearance in patients with low serum creatinine concentrations [3] To evaluate the predictive performance of initial dosing strategies for achieving an aminoglycoside target concentration.

Methods  Aminoglycoside demographic, dosing and concentration data were collected from 697 adult patients (>=20 years old) as part of standard clinical care using a target concentration intervention approach for dose individualization. It was assumed that aminoglycoside clearance had a renal and a nonrenal component, with the renal component being linearly related to predicted creatinine clearance.

Results  A two compartment pharmacokinetic model best described the aminoglycoside data. The addition of weight, age, sex and serum creatinine as covariates reduced the random component of between subject variability (BSVR) in clearance (CL) from 94% to 36% of population parameter variability (PPV). The final pharmacokinetic parameter estimates for the model with the best predictive performance were: CL, 4.7 l h–1 70 kg–1; intercompartmental clearance (CLic), 1 l h–1 70 kg–1; volume of central compartment (V1), 19.5 l 70 kg–1; volume of peripheral compartment (V2) 11.2 l 70 kg–1.

Conclusions  Using a fixed dose of aminoglycoside will achieve 35% of typical patients within 80–125% of a required dose. Covariate guided predictions increase this up to 61%. However, because we have shown that random within subject variability (WSVR) in clearance is less than safe and effective variability (SEV), target concentration intervention can potentially achieve safe and effective doses in 90% of patients.
Determining the reporting quality of RCTs in clinical pharmacology
Authors: Mills Edward , Loke Yoon K. , Wu Ping , Montori Victor M. , Perri Daniel , Moher David , Guyatt Gordon
Published: June 2004

Background  The Consolidated Standards for Reporting Trials (CONSORT) are recommendations for improving the quality of reports of randomized controlled trials (RCTs).

Objective  To determine the extent to which clinical pharmacology journals implement specific CONSORT recommendations.

Design and setting  Analysis of RCTs published between May 2002 and May 2003 in four clinical pharmacology journals.

Main outcome measures  Proportion of RCTs that published a participant flow diagram and that reported on randomization and restriction methods, allocation concealment, blinding, intention‐to‐treat analysis, ethical considerations, adverse events and source of funding.

Results  Of 482 clinical trials, 193 were RCTs. Healthy participants were involved in 129 [66.8%, 95% confidence interval (CI) 59.9, 73.1] trials, patients who required treatment in 61 (31.6%, 95% CI 25.4, 38.4) trials and both in three (1.6%, 95% CI 0.5, 4.4) trials. The following items were infrequently reported: sequence generation (17%), allocation concealment (3%), use of restriction (16%), description of blinding (26%), and flow diagrams of study participants (2%). In contrast, the following areas were often reported: use of intention‐to‐treat analysis (79%), description of withdrawals (92.2%) and description of adverse events (71%), ethics review (94%) and informed consent (95%). Sources of funding were reported in 56% of studies.

Conclusion  The use of the selected CONSORT items is limited in these journals, possibly as many items may not be relevant to the types of studies published in clinical pharmacology journals. Further efforts are required to determine the applicability of CONSORT to RCTs in clinical pharmacology.
Tyrosine phosphorylation of calponins
Authors: Abouzaglou Julien , Bénistant Christine , Gimona Mario , Roustan Claude , Kassab Rhida , Fattoum Abdellatif
Published: June 2004

The phosphorylation‐dephosphorylation of serine and threonine residues of calponin is known to modulate in vitro its interaction with F‐actin and is thought to regulate several biological processes in cells, involving either of the calponin isoforms. Here, we identify, for the first time, tyrosine‐phosphorylated calponin h3 within COS 7 cells, before and after their transfection with the pSV vector containing cDNA encoding the cytoplasmic, Src‐related, tyrosine kinase, Fyn. We then describe the specific tyrosine phosphorylation in vitro of calponin h1 and calponin h3 by this kinase. 32P‐labeling of tyrosine residues was monitored by combined autoradiography, immunoblotting with a specific phosphotyrosine monoclonal antibody and dephosphorylation with the phosphotyrosine‐specific protein phosphatase, YOP. PhosphorImager analyses showed the incorporation of maximally 1.4 and 2.0 mol of 32P per mol of calponin h3 and calponin h1, respectively. As a result, 75% and 68%, respectively, of binding to F‐actin was lost by the phosphorylated calponins. Furthermore, F‐actin, added at a two‐ or 10‐fold molar excess, did not protect, but rather increased, the extent of 32P‐labeling in both calponins. Structural analysis of the tryptic phosphopeptides from each 32P‐labeled calponin revealed a single, major 32P‐peptide in calponin h3, with Tyr261 as the phosphorylation site. Tyr261 was also phosphorylated in calponin h1, together with Tyr182. Collectively, the data point to the potential involvement, at least in living nonmuscle cells, of tyrosine protein kinases and the conserved Tyr261, located in the third repeat motif of the calponin molecule, in a new level of regulation of the actin–calponin interaction.
A novel type of highly negatively charged lipooligosaccharide from Pseudomonas stutzeri OX1 possessing two 4,6‐O‐(1‐carboxy)‐ethylidene residues in the outer core region
Authors: Leone Serena , Izzo Viviana , Silipo Alba , Sturiale Luisa , Garozzo Domenico , Lanzetta Rosa , Parrilli Michelangelo , Molinaro Antonio , Di Donato Alberto
Published: June 2004

Pseudomonas stutzeri OXI is a Gram‐negative microorganism able to grow in media containing aromatic hydrocarbons. A novel lipo‐oligosaccharide from P. stutzeri OX1 was isolated and characterized. For the first time, the presence of two moieties of 4,6‐O‐(1‐carboxy)‐ethylidene residues (pyruvic acid) was identified in a core region; these two residues were found to possess different absolute configuration. The structure of the oligosaccharide backbone was determined using either alkaline or acid hydrolysis. Alkaline treatment, aimed at recovering the complete carbohydrate backbone, was carried out by mild hydrazinolysis (de‐O‐acylation) followed by de‐N‐acylation using hot KOH. The lipo‐oligosaccharide was also analyzed after acid treatment, attained by mild hydrolysis with acetic acid, to obtain information on the nature of the phosphate and acyl groups. The two resulting oligosaccharides were isolated by gel permeation chromatography, and investigated by compositional and methylation analyses, by MALDI mass spectrometry, and by 1H‐, 31P‐ and 13C‐NMR spectroscopy. These experiments led to the identification of the major oligosaccharide structure representative of core region‐lipid A. All sugars are d‐pyranoses and α‐linked, if not stated otherwise. Based on the structure found, the hypothesis can be advanced that pyruvate residues are used to block elongation of the oligosaccharide chain. This would lead to a less hydrophilic cellular surface, indicating an adaptive response of P. sutzeri OX1 to a hydrocarbon‐containing environment.
Evolutionary relationships of the prolyl oligopeptidase family enzymes
Authors: Venäläinen Jarkko I. , Juvonen Risto O. , Männistö Pekka T.
Published: June 2004

The prolyl oligopeptidase (POP) family of serine proteases includes prolyl oligopeptidase, dipeptidyl peptidase IV, acylaminoacyl peptidase and oligopeptidase B. The enzymes of this family specifically hydrolyze oligopeptides with less than 30 amino acids. Many of the POP family enzymes have evoked pharmaceutical interest as they have roles in the regulation of peptide hormones and are involved in a variety of diseases such as dementia, trypanosomiasis and type 2 diabetes. In this study we have clarified the evolutionary relationships of these four POP family enzymes and analyzed POP sequences from different sources. The phylogenetic trees indicate that the four enzymes were present in the last common ancestor of all life forms and that the β‐propeller domain has been part of the family for billions of years. There are striking differences in the mutation rates between the enzymes and POP was found to be the most conserved enzyme of this family. However, the localization of this enzyme has changed throughout evolution, as three archaeal POPs seem to be membrane bound and one third of the bacterial as well as two eukaryotic POPs were found to be secreted out of the cell. There are also considerable distinctions between the mutation rates of the different substrate binding subsites of POP. This information may help in the development of species‐specific POP inhibitors.
Chromokinetics of metabolic pathways
Authors: Stucki Jörg W.
Published: June 2004

Some methods to study and intuitively understand steady‐state flows in complicated metabolic pathways are discussed. For this purpose, a suitable decomposition of complex metabolic schemes into smaller subsystems is used. These independent subsystems are then interpreted as basic colors of a chromatic coloring scheme. The mixture of these basic colors allows an intuitive picture of how a steady state in a metabolic pathway can be understood. Furthermore, actions of drugs can be more easily investigated on this basis. An anaerobic variant of pyruvate metabolism in rat liver mitochondria is presented as a simple example. This experiment allows measurement of the percentage that each basic color contributes to the steady states resulting from different experimental conditions. Possible implementations of existing algorithms and rational design of new drugs are discussed. A mathematica program, based on a new algorithm for finding all basic colors of stoichiometric networks, is included.
Molecular and functional characterization of novel CRFR1 isoforms from the skin
Authors: Pisarchik Alexander , Slominski Andrzej
Published: June 2004

In our continued studies on corticotropin releasing factor receptor (CRFR1) signaling in the skin, we tested functional activity of CRFR1α, e, f, g and h isoforms after transfection to COS cells. Both membrane‐bound and soluble variants are translated in vivo into final protein products that undergo further post‐translational modifications. CRFR1α was the only isoform coupled directly to adenylate cyclase with the exception of an artificial isoform (CRFR1h2) with the insertion of 37 amino acids between the ligand binding domain and the first extracellular loop that was capable of producing detectable levels of cyclic AMP (cAMP). Soluble isoforms could modulate cell response with CRFR1e attenuating and CRFR1h amplifying CRFR1α‐coupled cAMP production stimulated by urocortin. Testing with plasmids containing the luciferase reporter gene, and inducible cis‐elements (CRE, CaRE, SRE, AP1 or NF‐κB) demonstrated that only CRFR1α was involved directly in the transcriptional regulation, while CRFR1g inhibited CRE activity. Significantly higher reporter gene expression by CRF was observed than that mediated by 4β‐phorbol 12‐myristate 13‐acetate and forskolin alone, being compatible with the concomitant treatment by phorbol 12‐myristate 13‐acetate and forskolin. This suggests that both protein kinase A and C can be involved in CRF‐dependent signal transduction.
Remote sensing of upland vegetation: the potential of high spatial resolution satellite sensors
Authors: Mehner Henny , Cutler Mark , Fairbairn David , Thompson Gillian
Published: June 2004

Aim  Traditional methodologies of mapping vegetation, as carried out by ecologists, consist primarily of field surveying or mapping from aerial photography. Previous applications of satellite imagery for this task (e.g. Landsat TM and SPOT HRV) have been unsuccessful, as such imagery proved to have insufficient spatial resolution for mapping vegetation. This paper reports on a study to assess the capabilities of the recently launched remote sensing satellite sensor Ikonos, with improved capabilities, for mapping and monitoring upland vegetation using traditional image classification methods.

Location  The location is Northumberland National Park, UK.

Methods  Traditional remote sensing classification methodologies were applied to the Ikonos data and the outputs compared to ground data sets. This enabled an assessment of the value of the improved spatial resolution of satellite imagery for mapping upland vegetation. Post‐classification methods were applied to remove noise and misclassified pixels and to create maps that were more in keeping with the information requirements of the NNPA for current management processes.

Results The approach adopted herein for quick and inexpensive land cover mapping was found to be capable of higher accuracy than achieved with previous approaches, highlighting the benefits of remote sensing for providing land cover maps.

Main conclusions  Ikonos imagery proved to be a useful tool for mapping upland vegetation across large areas and at fine spatial resolution, providing accuracies comparable to traditional mapping methods of ground surveys and aerial photography.
Dependence of broad‐scale geographical variation in fleshy‐fruited plant species richness on disperser bird species richness
Authors: Márquez Ana L. , Real Raimundo , Vargas J. Mario
Published: June 2004

Aim  We analysed the interdependence of avian frugivore‐ and fruited plant‐species richness at the scale of major river basins across Europe, taking into account several environmental factors along different spatial gradients.

Location  Continental Europe and the British Isles.

Methods  We focused on wintering birds and autumn/winter fruiting plants, and used major river basins as geographical units and Structural Equation Modelling as the principal analytical tool.

Results  The statistical influence of disperser species richness on fleshy‐fruited plant species richness is roughly double that of the reverse. Broad‐scale variation in frugivore richness is more dependent on environmental factors than on fruited plant richness. However, the influence of disperser richness on plant richness is four times higher than the influence of environmental factors. Environmental influences on both birds and plants are greater than purely spatial influences.

Main conclusions  Our results are interpreted as indicating that biotic dispersal of fruits strongly affects broad‐scale geographical trends of fleshy‐fruited plant species richness, whereas richness of fruited plants moderately affects frugivore richness.