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At least 757 records · Page 42Linked to original sources
PubMed1993

In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. III. The kinetics of V region mutation and selection in germinal center B cells.

In the murine spleen, germinal centers are the anatomic sites for antigen-driven hypermutation and selection of immunoglobulin (Ig) genes. To detail the kinetics of Ig mutation and selection, 178 VDJ sequences from 16 antigen-induced germinal centers were analyzed. Although germinal centers appeared by day 4, mutation was not observed in germinal center B cells until day 8 postimmunization; thereafter, point mutations favoring asymmetrical transversions accumulated until day 14. During this period, strong phenotypic selection on the mutant B lymphocytes was inferred from progressively biased distributions of mutations within the Ig variable region, the loss of crippling mutations, decreased relative clonal diversity, and increasingly restricted use of canonical gene segments. The period of most intense selection on germinal center B cell populations preceded significant levels of mutation and may represent a physiologically determined restriction on B cells permitted to enter the memory pathway. Noncanonical Ig genes recovered from germinal centers were mostly unmutated although they probably came from antigen-reactive cells. Together, these observations demonstrate that the germinal center microenvironment is rich and temporally complex but may not be constitutive for somatic hypermutation.

Animals↗
PubMed2004

Cytotoxic T lymphocyte-based control of simian immunodeficiency virus replication in a preclinical AIDS vaccine trial.

Recently, encouraging AIDS vaccine trials in macaques have implicated cytotoxic T lymphocytes (CTLs) in the control of the simian human immunodeficiency virus SHIV89.6P that induces acute CD4(+) T cell depletion. However, none of these vaccine regimens have been successful in the containment of replication of the pathogenic simian immunodeficiency viruses (SIVs) that induce chronic disease progression. Indeed, it has remained unclear if vaccine-induced CTL can control SIV replication. Here, we show evidence suggesting that vaccine-induced CTLs control SIVmac239 replication in rhesus macaques. Eight macaques vaccinated with DNA-prime/Gag-expressing Sendai virus vector boost were challenged intravenously with SIVmac239. Five of the vaccinees controlled viral replication and had undetectable plasma viremia after 5 wk of infection. CTLs from all of these five macaques rapidly selected for escape mutations in Gag, indicating that vaccine-induced CTLs successfully contained replication of the challenge virus. Interestingly, analysis of the escape variant selected in three vaccinees that share a major histocompatibility complex class I haplotype revealed that the escape variant virus was at a replicative disadvantage compared with SIVmac239. These findings suggested that the vaccine-induced CTLs had "crippled" the challenge virus. Our results indicate that vaccine induction of highly effective CTLs can result in the containment of replication of a highly pathogenic immunodeficiency virus.

AIDS Vaccines↗
PubMed2005

CD44 is a determinant of inflammatory bone loss.

Chronic inflammation is a major trigger of local and systemic bone loss. Disintegration of cell-matrix interaction is a prerequisite for the invasion of inflammatory tissue into bone. CD44 is a type I transmembrane glycoprotein that connects a variety of extracellular matrix proteins to the cell surface. Tumor necrosis factor (TNF) is a major inducer of chronic inflammation and its overexpression leads to chronic inflammatory arthritis. By generating CD44(-/-) human TNF-transgenic (hTNFtg) mice, we show that destruction of joints and progressive crippling is far more severe in hTNFtg mice lacking CD44, which also develop severe generalized osteopenia. Mutant mice exhibit an increased bone resorption due to enhanced number, size, and resorptive capacity of osteoclasts, whereas bone formation and osteoblast differentiation are not affected. Responsiveness of CD44-deficient osteoclasts toward TNF is enhanced and associated with increased activation of the p38 mitogen-activated protein kinase. These data identify CD44 as a critical inhibitor of TNF-driven joint destruction and inflammatory bone loss.

Animals↗
PubMed2004

Molecular basis of pH and Ca2+ regulation of aquaporin water permeability.

Aquaporins facilitate the diffusion of water across cell membranes. We previously showed that acid pH or low Ca(2+) increase the water permeability of bovine AQP0 expressed in Xenopus oocytes. We now show that external histidines in loops A and C mediate the pH dependence. Furthermore, the position of histidines in different members of the aquaporin family can "tune" the pH sensitivity toward alkaline or acid pH ranges. In bovine AQP0, replacement of His40 in loop A by Cys, while keeping His122 in loop C, shifted the pH sensitivity from acid to alkaline. In the killifish AQP0 homologue, MIPfun, with His at position 39 in loop A, alkaline rather than acid pH increased water permeability. Moving His39 to His40 in MIPfun, to mimic bovine AQP0 loop A, shifted the pH sensitivity back to the acid range. pH regulation was also found in two other members of the aquaporin family. Alkaline pH increased the water permeability of AQP4 that contains His at position 129 in loop C. Acid and alkaline pH sensitivity was induced in AQP1 by adding histidines 48 (in loop A) and 130 (in loop C). We conclude that external histidines in loops A and C that span the outer vestibule contribute to pH sensitivity. In addition, we show that when AQP0 (bovine or killifish) and a crippled calmodulin mutant were coexpressed, Ca(2+) sensitivity was lost but pH sensitivity was maintained. These results demonstrate that Ca(2+) and pH modulation are separable and arise from processes on opposite sides of the membrane.

Amino Acid Sequence↗
PubMed2003

First case of Mycobacterium ulcerans disease (Buruli ulcer) following a human bite.

Mycobacterium ulcerans disease (MUD) is rapidly reemerging in many countries, especially in West African countries. Antecedent trauma has often been related to the lesions that characterize this frequently crippling disease. We report here the first case of MUD that followed a human bite at the site where the lesion later occurred.

Adolescent↗
PubMed2006

Familial osteoarthritis of the hip joint associated with acetabular dysplasia maps to chromosome 13q.

Genetic factors have been implicated in osteoarthritis (OA), particularly in OA of the hip joint (hip OA). Several instances of familial hip OA that show distinctive modes of inheritance but that differ from chondrodysplasia have been reported. Here, we report the characterization of a large Japanese family with an inherited disease of the hip that is indistinguishable from common hip OA, as evidenced by clinical symptoms and radiographs of the joint. This family contained eight patients in 4 generations. Affected individuals develop pain in the hip joint during adolescence, and the disease progresses to severe crippling before age 60 years. Patients generally are in good health, height is not reduced, and there is no extraskeletal involvement suggestive of chondrodysplasia. The skeletal change is bilateral acetabular dysplasia followed by OA, which occurs after age approximately 40 years and is indistinguishable from idiopathic nonfamilial dysplastic hip OA. This trait shows autosomal dominant inheritance, with a considerably consistent phenotype. Genomewide screening revealed linkage at chromosome 13q22, and haplotype analysis narrowed the locus to a 6.0-cM interval between markers D13S1296 and D13S162, with a maximal multipoint LOD score of 3.57. The family described here represents a novel genetic entity as a monogenic form of hip OA. Its further characterization can aid in elucidating the etiology and pathogenesis of a common idiopathic form of OA.

Chromosome Mapping↗
PubMed1999

Fine mapping of progressive pseudorheumatoid dysplasia: a tool for heterozygote identification.

Progressive pseudorheumatoid dysplasia is a skeletal genetic disorder affecting primarily the articular cartilage, causing joint stiffness and leading to a crippling status. More than two-thirds of the reported patients belong to Arab and Mediterranean populations. The disease locus has been mapped to chromosome 6q22 in a region of 12.9 cM using a Jordanian family. We examined two additional families, one Jordanian and one Palestinian, to test for homogeneity of the disorder and the presence of a common haplotype, to fine map the disorder, and to use all the information to derive a tool for heterozygote identification. The two families showed linkage to the same previously reported locus, thus suggesting homogeneity, but they did not share a common haplotype. They also provided information that refined the genetic region for the disease locus to 2.1 cM with three microsatellite markers. The absence of a common haplotype indicates that no common ancestor mutations were inherited by our patients. Genotyping for the three-marker haplotype showed that it can be used as a heterozygote identification tool.

Adolescent↗
PubMed2005

Reactive oxygen species production in the mitochondrial matrix: implications for the mechanism of mitochondrial mutation accumulation.

The vicious cycle theory postulates that typical mitochondrial DNA (mtDNA) mutations cause their host mitochondria to generate more superoxide and other reactive oxygen species (ROS) than do normal mitochondria, thereby promoting the occurrence of additional mtDNA mutations at an ever-accelerating rate. However, nearly all the loss-of-function mtDNA mutations seen in vivo are large deletions, which (as the original statement of the theory indeed noted, though this has been widely overlooked) should not trigger a vicious cycle because they will prevent the assembly of the potentially superoxide-generating enzyme complexes. Consistent with this is the observation that each cell exhibiting loss of mtDNA-encoded function in vivo contains copies of a single, evidently clonally expanded, mutant mtDNA species, whereas the vicious cycle theory predicts a spectrum of mutant forms in each cell. Two recent papers, however, unveil a way in which mtDNA mutations could indeed promote ROS production of their host mitochondria. MtDNA mutations probably shift the intramitochondrial NAD(+)/NADH redox couple towards NADH, and this is now shown in vitro to cause ROS production by alpha-ketoglutarate dehydrogenase, an essential enzyme of the TCA cycle. This does not revive the vicious cycle theory, but it has complex implications for the two most plausible more recent theories, known as "survival of the slowest" and "crippled mitochondria." It may also prove to explain other recent observations in mitochondrially mutant cells in vivo.

Cell Proliferation↗
PubMed2006

Telementoring in endocrine surgery: preliminary Indian experience.

Telemedicine is starting to play an important role in the health field in India. In this case report we describe the successful use of telementoring to remove a parathyroid tumor in a patient with residual hyperparathyroidism after two previous unsuccessful attempts in tumor excision. A 21-yr-old patient crippled with advanced hyperparathyroidism was taken up for third-time exploration at Amrita Institute of Medical Sciences (AIMS), Kochi, with guidance from the Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Lucknow, using telemedicine technology. These two centers are located 2,500 km apart, and telementoring from the more experienced endocrine surgeons at SGPGIMS resulted in successful tumor localization and removal. For this session both the institutions were provided with a dedicated 512 Kbps very small aperture terminal (VSAT) link and two-way video-audio connectivity. Even though two previous explorations were unsuccessful, with the help of telemedicine technology the same surgeon was successful in locating and removing the tumor. The video and audio quality was of good enough quality for the expert at SGPGIMS to guide the team at AIMS satisfactorily. The patient benefited since he did not have to travel to a far-off specialized center for surgery. This case report testifies to the usefulness of telemedicine in the field of surgery, especially in developing countries, which have few medical experts in certain specialized areas.

Adult↗
PubMed1976

Reciprocal Ia inhibition in spastic hemiplegia of man.

The results of the present electrophysiological investigation have shed some light on the mechanisms underlying many clinical signs, at least, in patients with capsular hemiplegia. A tentative interpretation of them is given below. Cerebral lesions due to haemorrhage or infarction in the area of the middle cerebral artery interrupt an extensive part of the corticospinal tract and disturb many other descending pathways involved in voluntary performance. In consequence, a marked reduction in the ability to drive the spinal motor apparatus occurs, resulting in weakness of motor power. Here, we refer only to muscle power but not to performance. For example, the disturbance of voluntary contraction by clonus is disregarded (cf. fig. 8). On the other hand, the same lesions also release the spinal reflexes from inhibition by the higher levels of the brain and cause increased excitability in flexors and extensors. In the lower extremity, this is much more makred in extensors and extensor spasticity becomes a dominant sign clinically. Any release effect on the flexor system is largely cancelled by the high activity of the reciprocal Ia inhibitory pathway from extensors and only a fragment of it is occasionally revealed in some patients as an H-reflex in pre-tibial muscles or as weak Ia inhibition of the triceps surae. Reduced driving power of the brain may be compensated by raised excitability in the spinal cord and spastic extensors are thus naturally in a better condition to preserve motor power. Flexor muscles are doubly crippled by reduced descending impulses and strong reciprocal inhibition by the Ia impulses from the spindles of the extensor muscles.

Adult↗
PubMedDate not supplied

Global control of vaccine-preventable diseases: how progress can be evaluated.

In the developing world, excluding China, less than 40% of infants receive a third dose of diphtheria-tetanus-pertussis or poliovirus vaccines. More than 3 million children still die annually from measles, neonatal tetanus, and pertussis, while more than a quarter of a million children are crippled by poliomyelitis. Acceleration of existing efforts, with the use of approaches that must differ according to the requirements of individual countries, constitutes the overriding priority for the Expanded Programme on Immunization (EPI). In evaluating immunization programs, priority should be placed on monitoring immunization coverage and disease incidence. Routine reports are essential for this purpose, although they may usefully be supplemented by surveys. The problems revealed by an evaluation of immunization programs can be taken as being generic to the health services as a whole, until proven otherwise. Therefore, in remedying these problems, approaches that improve the health services as a whole should be sought.

Communicable Disease Control↗
PubMedDate not supplied

Selective primary health care: strategies for control of disease in the developing world. IX. Poliomyelitis.

Poliomyelitis is an acute viral disease primarily afflicting children. It can be very mild, permanently crippling, or fatal. In the developed nations, poliomyelitis is controlled by the use of trivalent vaccines: killed virus administered by injection and/or attenuated virus administered orally. The latter is cheaper. A combination of the two may be required in some tropical countries. In many developing nations poliomyelitis remains endemic and prevalent, especially in children; 37,747 cases were reported to the World Health Organization in 1979, but greater than 200,000 cases probably occurred. Socioeconomic improvement and public health measures (i.e., immunizations) remain the major strategies for control. While global eradication may be a more distant goal, poliomyelitis could be controlled better. Effective programs for control include safe, efficacious, and inexpensive vaccines; methods for successful management of vaccine delivery systems; commitment and training of health personnel; public education; commitment of funds; and research to improve vaccines and their delivery. The major obstacle to control of poliomyelitis is failure to immunize an adequate number of susceptible children. Development of strategies for immunization is crucial to elimination of poliomyelitis as a major world health problem.

Adolescent↗
PubMedDate not supplied

Research: the prerequisite for innovative strategies and technologies.

The search for new strategies and technologies for the control of yaws, a genuine but much neglected tropical disease problem, has been largely unsuccessful. This disease, with conspicuous early symptoms and a late crippling pathology, attracted the attention of the first generation of tropical doctors. As soon as specific therapy became available in the early part of the 20th century, mass treatment campaigns were started. The availability and efficacy of penicillin led some to anticipate yaws eradication; this expectation was not met but rather induced a false sense of security. After varying intervals resurgences occurred in several endemic regions. It is important to analyze this failure so that mistakes and underestimated or overlooked factors can be identified. On the whole, the main difficulty has been a lack of interest in a presumably disappearing disease and a consequent failure to take advantage of the benefits offered by recent advances in basic biomedical technology. Solid clinical, epidemiologic, and sociocultural data in connection with mass treatment and control are still needed. Research of high quality, with continuous assessment in the field, is a prerequisite for innovative strategies and technologies.

Adolescent↗
PubMed1999

Propagation of a novel cytoplasmic, infectious and deleterious determinant is controlled by translational accuracy in Podospora anserina.

Some mutant strains of the filamentous fungus Podospora anserina spontaneously present a growth impairment, which has been called Crippled Growth (CG). CG is caused by a cytoplasmic and infectious factor, C. C is efficiently transmitted during mitosis but is not transmitted to the progeny after sexual crosses. C is induced by stationary phase and cured by various means, most of which stress the cells. Translational accuracy is shown to tightly regulate the propagation of C during the active growth period, because its propagation in dividing hyphae is restricted to cells that display an increased translational accuracy. However, induction of C in stationary phase proceeds independently from the translational accuracy status of the strain. CG does not seem to be accompanied by mitochondrial DNA modifications, although C activates the action of the Determinant of Senescence, another cytoplasmic and infectious element, which causes a disorganization of the mitochondrial genome. In addition, presence of C drastically modifies the spectrum of the mitochondrial DNA rearrangements in AS6-5 mat- cultures during Senescence. C seems to belong to the growing list of unconventional genetic elements. The biological significance of such elements is discussed.

Ascomycota↗
PubMed2001

eEF1A Controls ascospore differentiation through elevated accuracy, but controls longevity and fruiting body formation through another mechanism in Podospora anserina.

Antisuppressor mutations in the eEF1A gene of Podospora anserina were previously shown to impair ascospore formation, to drastically increase life span, and to permit the development of the Crippled Growth degenerative process. Here, we show that eEF1A controls ascospore formation through accuracy level maintenance. Examination of antisuppressor mutant perithecia reveals two main cytological defects, mislocalization of spindle and nuclei and nuclear death. Antisuppression levels are shown to be highly dependent upon both the mutation site and the suppressor used, precluding any correlation between antisuppression efficiency and severity of the sporulation impairment. Nevertheless, severity of ascospore differentiation defect is correlated with resistance to paromomycin. We also show that eEF1A controls fruiting body formation and longevity through a mechanism(s) different from accuracy control. In vivo, GFP tagging of the protein in a way that partly retains its function confirmed earlier cytological observation; i.e., this factor is mainly diffuse within the cytosol, but may transiently accumulate within nuclei or in defined regions of the cytoplasm. These data emphasize the fact that the translation apparatus exerts a global regulatory control over cell physiology and that eEF1A is one of the key factors involved in this monitoring.

Alleles↗
PubMed2002

The impact of price changes on demand for family planning and reproductive health services in Ecuador.

Donor funding for family planning and reproductive health (FP/RH) has declined in Latin America over the past decade, obliging providers to consider other financing mechanisms, including cost recovery through user fees. Pricing decisions are often difficult for providers, who fear that increased fees will cripple demand and create barriers to access for poor clients. Providers need information on how changes in price can affect utilization of services, and how to resolve trade-offs between generating income and serving poor clients. This paper reports on an experiment that measured the impact of higher client fees on utilization, revenue and client socioeconomic characteristics at 15 clinics operated by CEMOPLAF, an Ecuadoran not-for-profit FP/RH agency. The study improves on previous research by comparing effects of different price levels on demand for services. We conclude that demand was inelastic for three of CEMOPLAF's four main FP/RH services, and we found no evidence that the price increases had a disproportionate impact on utilization by poorer clients. The study therefore provided CEMOPLAF managers with knowledge that price increases at the levels tested would help to achieve sustainability goals (by increasing locally generated income) without undermining CEMOPLAF's social mission.

Adult↗
PubMed2005

Scaling up integrated management of childhood illness to the national level: achievements and challenges in Peru.

This paper presents the first published report of a national-level effort to implement the Integrated Management of Childhood Illness (IMCI) strategy at scale. IMCI was introduced in Peru in late 1996, the early implementation phase started in 1997, with the expansion phase starting in 1998. Here we report on a retrospective evaluation designed to describe and analyze the process of taking IMCI to scale in Peru, conducted as one of five studies within the Multi-Country Evaluation of IMCI Effectiveness, Cost and Impact (MCE) coordinated by the World Health Organization. Trained surveyors visited each of Peru's 34 districts, interviewed district health staff and reviewed district records. Findings show that IMCI was not institutionalized in Peru: it was implemented parallel to existing programmes to address acute respiratory infections and diarrhoea, sharing budget lines and management staff. The number of health workers trained in IMCI case management increased until 1999 and then decreased in 2000 and 2001, with overall coverage levels among doctors and nurses calculated to be 10.3%. Efforts to implement the community component of IMCI began with the training of community health workers in 2000, but expected synergies between health facility and community interventions were not realized because districts where clinical training was most intense were not those where community IMCI training was strongest. We summarize the constraints to scaling up IMCI, and examine both the methodological and policy implications of the findings. Few monitoring data were available to document IMCI implementation in Peru, limiting the potential of retrospective evaluations to contribute to programme improvement. Even basic indicators recommended for national monitoring could not be calculated at either district or national levels. The findings document weaknesses in the policy and programme supports for IMCI that would cripple any intervention delivered through the health service delivery system. The Ministry of Health in Peru is now working to address these weaknesses; other countries working to achieve high and equitable coverage with essential child survival interventions can learn from their experience.

Child Health Services↗
PubMed1984

Psychosocial assessment of chronic headache.

Chronic headache is often a crippling condition for those afflicted by it. The case of a headache sufferer is presented here against a framework that reviews the literature on the psychological, social, and familial issues related to the problem of chronic pain. The intent is to offer practitioners guidelines and a context within which clients with chronic headache can be understood and helped.

Chronic Disease↗