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PubMedDate not supplied

Treatment of autoimmune disease: time for a paradigm shift?

Current treatment of human autoimmune diseases (AIDs) was developed empirically and relies mostly on non-selective suppression of the immune system. Traditional non-selective immunosuppressants such as corticosteroids, cyclophosphamide, and methotrexate and more novel means such as monoclonal antibodies to CD3, CD4, or CD25 do not discriminate between pathogenic and beneficial T cells. Importantly, the severe side effects seen with current therapies are related to the fact that these treatments not only suppress the pathogenic disease-inducing cells, but also cells influential in combating infections and killing malignant cells. Severe infections and malignancies are the inevitable result of non-selective immune suppression. Many of the novel forms of therapy of AID were developed in experimental animals, and their translation to the human disease was associated with the revelation of unexpected and sometimes catastrophic side effects. These surprises underscore the major differences between the relative simplicity of the experimental model and the complexity of the human disease. How can this current state of treatment of AID be improved? Which principles should guide us in the design of new treatments? This review attempts to offer a new look at these questions.

Allergy and Immunology↗
PubMed2003

NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development.

There is an urgent need to improve the pharmacotherapy of schizophrenia despite the introduction of important new medications. New treatment insights may come from appreciating the therapeutic implications of model psychoses. In particular, basic and clinical studies have employed the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, ketamine, as a probe of NMDA receptor contributions to cognition and behavior. These studies illustrate a translational neuroscience approach for probing mechanistic hypotheses related to the neurobiology and treatment of schizophrenia and other disorders. Two particular pathophysiologic themes associated with schizophrenia, the disturbance of cortical connectivity and the disinhibition of glutamatergic activity may be modeled by the administration of NMDA receptor antagonists. The purpose of this review is to consider the possibility that agents that attenuate these two components of NMDA receptor antagonist response may play complementary roles in the treatment of schizophrenia.

Animals↗
PubMed2006

Genetics of preeclampsia: paradigm shifts.

Segregation of preeclampsia into early-onset, placental and late-onset, maternal subtypes along with the acknowledgement of the contribution of epigenetics in placentally expressed genes proved to be a key first step in the identification of essential gene variants associated with preeclampsia. Application of this insight to other populations and related pregnancy-induced syndromes, such as HELLP, and acknowledgment of the features shared between chromosomal loci associated with preeclampsia in different populations provide the rationale for new strategies for the identification of susceptibility genes and for new and more effective diagnostic strategies.

Chromosome Mapping↗
PubMed2006

Conventional and novel modes of exine patterning in members of the Araceae--the consequence of ecological paradigm shifts?

In the family Araceae, the members of all subfamilies except Aroideae follow the conventional mode of exine formation pattern, which conforms with the textbook view of sporoderm stratification and chemistry (sporopollenin ektexine formed before the endexine). Only members of the subfamily Aroideae show a quite uncommon mode of exine formation pattern, with an endexine formed prior to the nonsporopollenin, polysaccharidic outer exine layer. The intine is formed simultaneously with this non-sporopollenin layer. From the differing timetable and especially from the different origin it is concluded that this outer exine layer is not homologous to the angiosperm ektexine. The fundamental question, why members of the Aroideae lack an elaborated sporopollenin ektexine, is discussed in terms of functionality of the nonsporopollenin outer exine layer. It seems that a major change in aroid evolution took place at the point when the family phylogenetically and ecologically shifted from bisexual (most subfamilies) to unisexual flowers (Aroideae only). The hypothesis is that ephemeral spathes and the absence of sporopollenin are the consequence of an adaptive syndrome for a short pollination time window in many members of the Aroideae, with short-lived pollen, an energetically not costly pollen wall, rapid germination of pollen tube, and brief receptivity of stigma.

Araceae↗
PubMed2004

The concept of bimaxillary transverse osteodistraction: a paradigm shift?

Severe crowding due to narrow upper and lower apical bases can be corrected by the extraction of four premolars, or by bimaxillary transverse osteodistraction. The first strategy is prone to unaesthetic changes in lip posture, nasolabial angle and buccal corridors. Life-long retention is necessary because of the known correlation between increased intercanine distance and relapse of crowding. The second strategy involves surgery and the final outcome regarding stability is not yet known. Theoretically, because the canines have not been moved outside of the skeletal envelope, and because the functional matrix positively influences the dental arches, relapse of crowding should be less. Facial appearance is improved because of the reduction of the buccal corridors and the fullness of the mouth both at rest, and upon smiling.

Adolescent↗
PubMed1994

Bacterial meningitis in the pediatric population: paradigm shifts and ramifications for otolaryngology-head and neck surgery.

Various population-based studies have suggested that the incidence and epidemiology of bacterial meningitis is changing. No studies have been published which examine a sample population of the United States at large. Records of pediatric patients age 5 and under who were treated for bacterial meningitis (n = 470) at all US Army medical facilities between 1986 and 1991 were reviewed. The incidence of bacterial meningitis declined by 75% in the study group during this period. The largest decrease occurred in infants less than 1 year of age. The bacterial organisms isolated most commonly, in decreasing frequency were: Haemophilus influenza type b (HIB), pneumococcal, streptococcal, and staphylococcal. The most dramatic abatement occurred in Haemophilus meningitis following the introduction of HIB vaccinations. Neurologic sequelae were identified in 10% of meningitis survivors. The 2 most common impairments were hearing loss and speech/language delay. Economic modeling demonstrates tremendous savings in health care dollars from the decrease in disease incidence. These changes will have substantial bearing on training programs and practitioners, since the management of neurologic sequelae requires the expertise of multiple subspecialists. In the face of a medical onslaught, once devastating diseases are in retreat.

Child, Preschool↗
PubMed2005

Protein sorting in the Golgi complex: shifting paradigms.

The paradigms for transport along the biosynthetic route have changed dramatically over the past 15 years. Unlike the situation 15 years ago, the current paradigm involves sorting signals practically at every step of the pathway. In particular, at the exit from the Golgi complex, apical, basolateral and lysosomal targeting signals result in the generation of a variety of routes. Furthermore, it is now quite clear that not all sorting in the biosynthetic route occurs in the Golgi complex or the Trans Golgi Network (TGN). Sorting may occur distally to the Golgi, in recycling endosomes or in budded tubulosaccular structures, or it may occur proximally to the Golgi complex, at the exit from the ER. Several adaptors are candidates to sort apical and basolateral proteins but only AP1B and AP4 are currently involved. Progress is fast and future work should elucidate many of the open questions.

Adaptor Proteins, Vesicular Transport↗
PubMed2006

Recent clinical failures in Parkinson's disease with apoptosis inhibitors underline the need for a paradigm shift in drug discovery for neurodegenerative diseases.

Understanding the mechanisms of neuronal death in concert with the identification of drugable molecular targets key to this process has held great promise for the development of novel chemical entities (NCEs) to halt neurodegenerative disease progression. Two key targets involved in the apoptotic process identified over the past decade include the mixed lineage kinase (MLK) family and glyceraldehyde phosphate dehydrogenase (GAPDH). Two NCEs, CEP-1347 and TCH346, directed against these respective targets have progressed to the clinic. For each, robust neuroprotective activity was demonstrated in multiple in vitro and in vivo models of neuronal cell death, but neither NCE proved effective Parkinson's disease (PD) patients. These recent clinical failures require a reassessment of both the relevance of apoptosis to neurodegenerative disease etiology and the available animal models used to prioritize NCEs for advancement to the clinic in this area.

Animals↗