Anti-malarial drugs and the prevention of malaria in the population of malaria endemic areas

Anti-malarial drugs can make a significant contribution to the control of malaria in endemic areas when used for prevention as well as for treatment. Chemoprophylaxis is effective in preventing deaths and morbidity from malaria, but it is difficult to sustain for prolonged periods, may interfere with the development of naturally acquired immunity and will facilitate the emergence and spread of drug resistant strains if applied to a whole community. However, chemoprophylaxis targeted to groups at high risk, such as pregnant women, or to periods of the year when the risk from malaria is greatest, can be an effective and cost effective malaria control tool and has fewer drawbacks. Intermittent preventive treatment, which involves administration of anti-malarials at fixed time points, usually when a subject is already in contact with the health services, for example attendance at an antenatal or vaccination clinic, is less demanding of resources than chemoprophylaxis and is now recommended for the prevention of malaria in pregnant women and infants resident in areas with medium or high levels of malaria transmission. Intermittent preventive treatment in older children, probably equivalent to targeted chemoprophylaxis, is also highly effective but requires the establishment of a specific delivery system. Recent studies have shown that community volunteers can effectively fill this role. Mass drug administration probably has little role to play in control of mortality and morbidity from malaria but may have an important role in the final stages of an elimination campaign.     

Effect of Nucleotides and Other Inhibitors on the Inactivation of Glutamate Decarboxylase

Abstract: The effects of 17 nucleotides and nucleotide analogs and 11 other compounds on the glutamate-promoted inactivation of brain glutamate decarboxylase were examined. Among the nucleotides, the major determinant of potency was the polyphosphate chain, Glutamate-promoted inactivation was strongly enhanced by low concentrations (<100 μM) of adenosine tetraphosphate and all eight nucleoside triphosphates tested. Nucleoside diphosphates enhanced inactivation, but were much less effective than the nucleoside triphosphates; nucleoside monophosphates were not effective. Modification of the polyphosphate chain of the nucleoside triphosphates also affected potency; adenylylimidodiphosphate and α,β-methylene ATP were about as effective as nucleoside diphosphates, but α,β-methylene ATP was nearly as effective as ATP. The nucleoside base had only a small effect on potency; purine nucleotides were more potent than pyrimidine nucleotides, and one nucleotide with a tricyclic base, 1, N⁶-etheno ATP, was as effective as the purine nucleoside triphosphates. The 2'-hydroxyl group of ribose was unimportant, since deoxy ATP was as effective as ATP. Three nonnucleotide polyanions were strong promoters of inactivation; inositol hexasulfate and 5-phosphorylribose 1-pyrophosphate were at least as effective as ATP; inositol hexaphosphate (phytate) was as effective as the nucleoside diphosphates. These results suggest that a major determinant of potency was a strong negative charge on the molecule. Negative charge was not sufficient, however, since fructose 1,6-bisphosphate did not promote inactivation. Inactivation by all of these compounds was slow, requiring more than 20 min for full effect. Two competitive inhibitors, chloride and glutarate, acted immediately and also reduced rather than enhanced glutamate-promoted inactivation.     

Stochastic Demography and the Neutral Substitution Rate in Class-Structured Populations

The neutral rate of allelic substitution is analyzed for a class-structured population subject to a stationary stochastic demographic process. The substitution rate is shown to be generally equal to the effective mutation rate, and under overlapping generations it can be expressed as the effective mutation rate in newborns when measured in units of average generation time. With uniform mutation rate across classes the substitution rate reduces to the mutation rate.     

Clinical trials of disease-modifying therapies for neurodegenerative diseases: the challenges and the future

Neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease represent a crucial and exponentially increasing challenge to health care systems throughout the world. There is an urgent need for effective treatments that will both delay their onset and slow their inexorable progression. Many obstacles stand in the way of realizing these goals. It is expected that future advances will have a major impact on how and when the diagnosis will be made. It is hoped that these will eventually make it possible to initiate effective disease-modifying therapies long before the neurodegenerative process becomes established and symptomatic.     

Vaccination: the present and the future

Vaccines have undoubtedly saved the lives of millions, and along with improved sanitation, they remain one of the cornerstones of modern medicine. Many diseases that were once widespread are now eradicated, but vaccine programs face ongoing challenges. Safety concerns as well as limited funding have led to pockets of reduced vaccine coverage around the world - including in developed countries. Chronic and recurrent diseases such as human immunodeficiency virus (HIV), tuberculosis, and malaria remain without effective vaccines. This review will briefly describe vaccines and the two major issues faced by modern vaccination programs: insufficient vaccine coverage and developing effective vaccines for chronic and recurrent diseases.     

An approximation method for the determination of diffusion and permeability coefficients in nerve trunks

A recently introduced approximation method is applied in order to obtain an expression for the amount of a substance remaining within a nerve at any time, the nerve having been soaked for a long time in a solution containing the substance until the time zero when it is bathed in the same solution but without the substance. The case of a uniform nerve without a sheath leads to substantially the same results as previously obtained by A. V. Hill (1928) for this case. A solution is given for the case of a nerve without sheath but having fibers which are permeable. In this case it is shown how an effective diffusion coefficient for the interstitial fluid can be obtained, as well as the effective inward and outward fiber permeabilities. A solution is given for the case of a nerve with a sheath in which the substance considered does not penetrate the fibers, and it is shown how the effective diffusion coefficients of the sheath and the interstitial fluid can be obtained.     

实验猴麻疹预防和治疗方案初探

实验猴麻疹是造成断奶仔猴死亡的重要传染病之一,本文对该病的临床诊断、护理、预防和治疗方案进行了初步研究,并提出了行之有效的预防、护理及治疗措施。经临床实践证明,该方案对实验猴麻疹的治愈率可达90%以上,值得在国内实验猴生产及科研单位推广应用。     

Progress and obstacles in the development of an AIDS vaccine

Recent experimental observations suggest approaches to immunization that might finally result in at least a partially effective vaccine against infection with HIV-1. In particular, advances in our understanding of the contribution of vaccine-elicited cellular immunity to protecting memory CD4(+) T cells from virus-mediated destruction provide rational strategies for the development of this vaccine. This is therefore an ideal time to review our current understanding of HIV-1 and its control by the immune system, as well as the remaining problems that must be solved to facilitate the development of an effective vaccine against AIDS.     

The Effect of Spatial Inhomogeneity of the Cornea on the Deformation Properties of the Eyeball and the Results of Maklakoff Applanation Tonometry

A two-component model of the eyeball that represents the cornea as a momentless, linearly elastic deformable surface and the scleral region, as an elastic element that responds to intraocular pressure changes by volume changes, has been used to analyze the effect of spatial inhomogeneity in the distribution of effective corneal stiffness on the mechanical properties of the eye. The effective stiffness of the cornea characterized both the elastic properties and the thickness of the cornea within the framework of the model. Various axisymmetric forms of the effective stiffness distribution characterized by monotonic increase along the arc between a point on the corneal surface and the apex of the cornea were studied. The considered distributions simulated both natural inhomogeneity and apical region weakening due to surgical interventions. Numerical simulation yielded the dependences of deformation parameters on intraocular pressure changes. These parameters characterized the deformation properties of both the cornea (apex displacement) and the eyeball as a whole (intraocular volume change). In the case of moderate inhomogeneity, the dependences were only slightly different from those for a homogeneous cornea with an effective stiffness equal to the mean value for the corresponding inhomogeneous distribution. A noticeable increase in the integral response of the cornea and the eyeball as a whole to changes in pressure was observed if the effective stiffness amplitude was very high (two or more times higher than the mean value). The effect of inhomogeneity on the results of tonometric measurements with a Maklakoff tonometer (flat stamp) was studied. The tonometric difference, that is, the difference between the tonometric pressure (in the loaded eye) and the true pressure (before loading), mainly depended on the average stiffness of the cornea in this case as well, with a substantial increase observed at very high stiffness amplitudes only. Apical weakening of the cornea led to an increase (although not very pronounced) of the tonometric difference.     

Ten simple rules for maximizing the recommendations of the NIH data management and sharing plan

The National Institutes of Health (NIH) Policy for Data Management and Sharing (DMS Policy) recognizes the NIH’s role as a key steward of United States biomedical research and information and seeks to enhance that stewardship through systematic recommendations for the preservation and sharing of research data generated by funded projects. The policy is effective as of January 2023. The recommendations include a requirement for the submission of a Data Management and Sharing Plan (DMSP) with funding applications, and while no strict template was provided, the NIH has released supplemental draft guidance on elements to consider when developing a plan. This article provides 10 key recommendations for creating a DMSP that is both maximally compliant and effective.     

On the concept of effective number.

A generalized conceptual basis for Wright's notion of effective size is presented. The concept is applied to the calculation of effective numbers based on the rate of change of genetic variability. With particular reference to the inbreeding, the eigen value, and the newly introduced "diversity" effective size, the use of the concept as a means for discrimination between and identification of various effective sizes is demonstrated.     

Exploring the structure of genetic variation and the influences of demography on effective population size in the gag grouper Mycteroperca microlepi (Goode & Bean)

Using 11 microsatellite markers, genetic analyses of three successive year-classes of gag Mycteroperca microlepis juveniles across the north-eastern Gulf of Mexico revealed a lack of spatial structure and very little temporal variation between year-classes. These results are consistent with long-term effective population sizes on the order of 30 000 adults. The importance of reproductive-style and sex-ratio variation is discussed as an important influence on long-term effective sizes.     

Cholecystokinin-33 inhibits meal size and prolongs the subsequent intermeal interval

There are various forms of the satiety gut-brain peptide cholecystokinin (CCK), a short, widely utilized form or CCK-8, and a long, putatively more effective form or CCK-33. The issue of which of these forms is a more effective satiety peptide is not resolved. Here, we compared the satiety responses, including the sizes of the first three meals (MS) and intermeal intervals (IMI) as well as their calculated satiety ratios (SR), evoked by both peptides. CCK-8 and 33 (1, 3 and 5 nmol/kg, i.p) reduced the size of the first meal similarly, only CCK-33 prolonged the first IMI and increased SR and both peptides failed to affect second and third MS and IMI. As such, CCK-33 is a more effective satiety peptide than CCK-8. The current results confirm previous findings which showed that both peptides reduce food intake by inhibiting meal size, whereas only CCK-33 reduces food intake by prolonging the intermeal interval.     

Interplay of cytokines and adjuvants in the regulation of mucosal and systemic HIV-specific CTL

We examined the interplay between cytokines and adjuvants to optimize the induction of CTL by a mucosal HIV peptide vaccine. We show synergy between IL-12 and GM-CSF when administered together with the HIV peptide PCLUS3-18IIIB and cholera toxin (CT) in the induction of CTL activity and protection against mucosal viral transmission. Further, we examine the efficacy of mutant Escherichia coli labile toxin, LT(R192G), as a less toxic adjuvant than CT. LT(R192G) was as effective as or more effective than CT at inducing a mucosal CTL response. Moreover, LT(R192G) was as effective without IL-12 as CT was when combined with IL-12, and the response elicited by LT(R192G) with the vaccine was not further enhanced by the addition of IL-12. GM-CSF synergized with LT(R192G) without exogenous IL-12. Therefore, LT(R192G) may induce a more favorable cytokine response by not inhibiting IL-12 production. In particular, less IL-4 is made after LT(R192G) than CT immunization, and the response is less susceptible to anti-IL-12 inhibition. Thus, the choice of mucosal adjuvant affects the cytokine environment, and the mucosal response and protection can be enhanced by manipulating the cytokine environment with synergistic cytokine combinations incorporated in the vaccine.     

PCR-DGGE技术在土壤微生物多样性研究中的应用

DGGE是一种有效的微生物多样性研究技术。本文简要介绍了DGGE(denaturing gradient gel electrophoresis)的基本原理,及其在研究土壤微生物类群多样性中的应用,并对该技术自身存在的缺陷进行了评价。     

Sometimes the result is not the answer: the truths and the lies that come from using the complementation test

It is standard genetic practice to determine whether or not two independently obtained mutants define the same or different genes by performing the complementation test. While the complementation test is highly effective and accurate in most cases, there are a number of instances in which the complementation test provides misleading answers, either as a result of the failure of two mutations that are located in different genes to complement each other or by exhibiting complementation between two mutations that lie within the same gene. We are primarily concerned here with those cases in which two mutations lie in different genes, but nonetheless fail to complement each other. This phenomenon is often referred to as second-site noncomplementation (SSNC). The discovery of SSNC led to a large number of screens designed to search for genes that encode interacting proteins. However, screens for dominant enhancer mutations of semidominant alleles of a given gene have proved far more effective at identifying interacting genes whose products interact physically or functionally with the initial gene of interest than have SSNC-based screens.     

Comparing the accuracy of ThinPrep Pap tests and conventional Papanicolaou smears on the basis of the histologic diagnosis: a clinical study of women with cervical abnormalities

OBJECTIVE: To confirm that the ThinPrep Pap test (TP) is as effective as or more effective than the conventional Papanicolaou smear (CS) in detecting epithelial cell abnormalities in a population with cervical abnormalities. STUDY DESIGN: In a blinded, split-sample, matched-pair study, a CS was prepared using a cytobrush, and then TP slides were prepared from the remainder of the sample. All slides were evaluated as defined and classified by the Bethesda System. The results of the two cytologic tests were compared in 483 women relative to the histologic diagnoses of subsequent colposcopically directed cervical biopsies in 158 cases. RESULTS: The cytologic diagnoses from the two methods agreed exactly in 91.4% of cases. The comparison between the two cytologic diagnoses with reference to the histologic diagnosis of subsequent colposcopically directed cervical biopsies showed that TP was significantly more specific for diagnosing lesions than was CS. The sensitivity of the two methods was equivalent. CONCLUSION: In a population with cervical abnormalities, TP is more specific than and as effective as CS in detecting cervical epithelial cell abnormalities. TP improved the specificity of disease detection by reducing the atypical squamous cells of undetermined significance category and/or false positive cases.     

Synthesis of 3'-C-methyladenosine and 3'-C-methyluridine diphosphates and their interaction with the ribonucleoside diphosphate reductase from Corynebacterium nephridii.

Two nucleoside diphosphate analogs, 3'-C-methyl-ADP and 3'-C-methyl-UDP, have been tested as substrate and/or allosteric effectors using the adenosylcobalamin-dependent ribonucleoside diphosphate reductase of Corynebacterium nephridii. Neither analog was a substrate for the reductase. However, they did function as allosteric effectors and as inhibitors of the reduction of ADP and UDP, respectively. The nucleotide analogs did not stimulate the hydrogen exchange reaction between [5'-3H2]adenosylcobalamin and the solvent, indicating that the cleavage of the 3'-carbon-hydrogen bond is a prerequisite for the exchange reaction. A reinvestigation of the requirements for the exchange reaction revealed that the deoxyribonucleoside diphosphate products are very effective promoters of this reaction. Indeed, the deoxyribonucleoside diphosphates were found to be more effective in promoting the exchange reaction than the ribonucleoside diphosphate substrates. In contrast, the deoxyribonucleoside triphosphate effectors, dATP, dUTP, and dTTP, were only marginally effective as promoters of this reaction.     

Synthesis and preliminary chemotherapeutic evaluation of the fully C-linked glucuronide of N-(4-hydroxyphenyl)retinamide

All-trans retinoic acid analogues such as N-(4-hydroxyphenyl)retinamide (4-HPR) are effective chemopreventive and chemotherapeutic agents but their utility has been hampered by dose-limiting side effects. The glucuronide derivatives of 4-HPR, the oxygen-linked 4-HPROG and the carbon-linked 4-HPRCG, have been found to be more effective agents. The synthetic route to the fully C-linked analogue of 4-HPROG (4-HBRCG), which employs Suzuki coupling and Umpolung chemistries as key methodologies, is shown. The results of this study show 4-HBRCG to be an effective chemotherapeutic agent in a rat mammary tumor model while being devoid of classical retinoid toxicities.     

Comparison of zeatin indoleacetate with zeatin and indoleacetic Acid in the tobacco bioassay

Zeatin indole-3-acetate, 6-[4-(indole-3-acetoxy)-3-methyl-trans-2-butenylamino]purine, is at least as effective as zeatin on a molar basis in satisfying the cytokinin requirement for growth and bud formation in tobacco bioassays. It is less effective than indole-3-acetic acid and is needed as a variable function of the cytokinin concentration for satisfying the optimal requirement of an auxin. Comparisons of the types of growth and yield of tissue obtained with serial concentration of the ester and with equimolar mixtures of its free base and acid indicate that the relative requirement for auxin changes with the concentration of cytokinin and is related to the types of callus growth and differentiation which occur. The results also suggest that the ester serves as a source of auxin only after modification, presumably by hydrolysis to indoleacetic acid.