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PubMed1983

Pharmacokinetic properties of benzodiazepine hypnotics.

The kinetic properties of three benzodiazepine hypnotics are reviewed. Flurazepam serves as a precursor for at least two rapidly appearing and rapidly cleared metabolites that may contribute to sleep induction and are nonaccumulating. The final metabolite of flurazepam (N-desalkylflurazepam), however, has a long half-life and accumulates during repeated dosage. Temazepam has a relatively slow rate of absorption and an intermediate half-life in the range of 10 to 20 hours. Triazolam has an intermediate rate of absorption; due to its ultrashort half-life (1.5 to 5 hours), triazolam is a non-accumulating hypnotic. Taken together with sleep laboratory studies and clinical trials, knowledge of the kinetic profile of benzodiazepine hypnotics can assist in evaluating their clinical benefits and disadvantages.

Absorption↗
PubMed2000

Aging and cancer in America. Demographic and epidemiologic perspectives.

It has been stated in this article and elsewhere that cancer patients aged 65 years and older deserve special attention as a target group for research efforts across the cancer-control spectrum. The available data show that the vulnerability of older persons to cancer is unmistakable. Clinicians will be treating more older patients as the nation ages. The future needs of this segment of the population must be anticipated. In this context, the following generic treatment questions are pertinent. What are the peculiarities of the aged host of which clinicians must be aware in evaluating the older cancer patient? Do various forms of cancer present differently in the elderly? How can be complications caused by the multiple pathologies inherent in the older patient be anticipated? What are the potential hazards and limitations of surgery, radiotherapy, and chemotherapy for older persons with cancer? What is known regarding increased risk of adverse reactions to medications, drugs, and interaction of drugs in older patients? The surveillance data and population estimates and projections presented in this article illustrate the extent of the problems of cancer in the elderly at the macro level. For the individual patient, the special knowledge of aging individuals and their health status based on geriatric medicine and gerontology that has been accumulating for the past several decades needs to be incorporated into the oncology armamentarium that has developed during the same period. The information and expertise from both fields must converge, and new knowledge must be developed at the aging/cancer interface and applied for the optimal treatment of cancer in the elderly.

Aged↗
PubMed2004

LINE-1 distribution in Afrotheria and Xenarthra: implications for understanding the evolution of LINE-1 in eutherian genomes.

Long interspersed nuclear elements (LINEs) comprise about 21% of the human genome (of which L1 is most abundant) and are preferentially accumulated in AT-rich regions, as well as the X and Y chromosomes. Most knowledge of L1 distribution in mammals is restricted to human and mouse. Here we report the first investigation of L1 distribution in the genomes of a wide variety of eutherian mammals, including species in the two basal clades, Afrotheria and Xenarthra. Our results show L1 accumulation on the X of all eutherian mammals, an observation consistent with an ancestral involvement of these elements in the X-inactivation process (the Lyon repeat hypothesis). Surprisingly, conspicuous accumulation of L1 in AT-rich regions of the genome was not observed in any species outside of Euarchontoglires (represented by human, mouse and rabbit). Although several features were common to most species investigated, our comprehensive survey shows that the patterns observed in human and mouse are, in many aspects, far from typical for all mammals. We discuss these findings with reference to models that have previously been proposed to explain the AT distribution bias of L1 in human and mouse, and how this relates to the evolution of these elements in other eutherian genomes.

Animals↗
PubMed2002

Seasonal variation of persistent organochlorine accumulation in birds from Lake Baikal, Russia, and the role of the south Asian region as a source of pollution for wintering migrants.

Concentrations of persistent organochlorines (OCs) such as polychlorinated biphenyls (PCBs), DDT and its metabolites (DDTs), hexachlorocyclohexane isomers (HCHs), and chlordane compounds (CHLs) were determined in whole body soft tissue homogenates and in muscles of resident and migratory birds collected from Lake Baikal, Russia. The residue pattern in both resident and migratory birds was in the following order: PCBs > DDTs > HCHs > CHLs. OC concentrations in migratory birds varied, depending on the feeding habit. The maximum levels of OCs were found in piscivores, followed by insectivores, omnivores, and herbivores. OC residue levels in Lake Baikal birds were lower than those in the Great Lakes region as well as in other lakes in Europe and Japan. Concentrations of HCHs and DDTs in most of the migratory birds collected in the spring were higher than for those collected in the autumn, indicating a notable accumulation in wintering grounds. Compilation and analysis of the available data in fish and birds from Asia suggested that the tropical and subtropical regions in south Asian countries may be a source of pollution for the wintering accumulation of migratory birds from Lake Baikal. Relatively higher compositions of alpha- and gamma-HCH in total HCHs, p,p'-DDT in total DOTs were observed in some migratory species, indicating recent exposure to HCHs and DDTs in Lake Baikal or wintering areas. PCB isomer patterns were different between residents and migrants, with the predominance of lower chlorinated congeners in migratory species, suggesting recent PCB accumulation in stopover sites during wintering. TEQ concentrations of toxic non- and mono-ortho coplanar PCBs in common terns from Lake Baikal were comparable to those reported in some species from Japan, the United States, and Europe. Relative contributions of non-ortho coplanar congeners to toxic equivalents (TEQs) were predominant, in which CB-126 accounted for the highest toxicity contribution. Estimated TEQ concentrations in the common tern from Lake Baikal exceeded the levels associated with enzyme induction in bald eagles. To our knowledge, this is the first comprehensive study showing the seasonal variations of OC accumulation in the birds from Lake Baikal.

Animals↗
PubMed1984

Metabolites of cardiac antiarrhythmic drugs: their clinical role.

Most antiarrhythmic drugs are extensively metabolized, and the accumulation of the metabolites of several of these drugs has been documented. In some cases, the steady-state plasma concentrations of metabolites are considerably greater than is the concentration of the parent drug. Several of these metabolites have been evaluated in animal models for antiarrhythmic activity and their potencies have been defined relative to the activity of their parent compound. Evaluations of activity are generally conducted in animal arrhythmia models, and very few metabolites of antiarrhythmic drugs have been evaluated directly in patients. However, from knowledge of antiarrhythmic activity in animals and the degree to which a metabolite accumulates in the plasma of patients, one can make qualitative judgments about its therapeutic role. Such judgments, however, need to be recognized as tenuous. Quantitative judgments require further information regarding the relationship between the parent drug and metabolite when present simultaneously in the myocardium. One must consider whether the effects of the parent drug and metabolite are additive, synergistic, or even antagonistic. The latter case is most possible with drug-metabolite pairs where the metabolite accumulates substantially, but does not have significant antiarrhythmic potency. Other considerations include noncardiac effects of the metabolites. As in the case of the mono-desethyl metabolite of lidocaine, the significance of its accumulation relates more to central nervous system side effects than to direct cardiac actions. The role of active metabolites also much be considered in regard to differences in the disposition kinetics between the parent drug and metabolite. The most obvious situation where this is important is in designing clinical drug evaluation protocols. As illustrated by the metabolites of encainide and lorcainide, the time course of accumulation and disappearance of the metabolites may be much longer than that of the parent drug. Clinical evaluations at steady state must take into account the time required to achieve steady-state concentrations of the metabolites as well. Similarly, after discontinuation of drug administration, the time required before washout is complete may be totally dependent on the kinetics of the metabolite, and not the parent drug. Variability in metabolic activity also needs to be considered. It has been shown with procainamide and encainide that genetic factors can influence the rate of production of active metabolites and consequently influence the clinical efficacy of these drugs. Another consideration that deserves attention is the question of drug interactions.(ABSTRACT TRUNCATED AT 400 WORDS)

Amiodarone↗
PubMed2004

Receptor biology and signal transduction in pancreatic acinar cells.

PURPOSE OF REVIEW: Secretagogue receptors and their intracellular signaling pathways regulate pancreatic physiology and may be altered in pathophysiology. Therefore, understanding of the continued progress into their nature and function is relevant to both biology and disease. RECENT FINDINGS: The major secretagogue receptors on acinar cells include those binding cholecystokinin and acetylcholine, whereas secretin receptors regulate duct cells. Two physical models of the cholecystokinin receptor and ligand binding have been proposed through extensive structure-activity studies. Receptor oligomerization has been described for both cholecystokinin and secretin receptors. Ca plays a central role in the control of digestive enzyme secretion and is largely mobilized from intracellular stores. Inositol trisphosphate has been joined by two other Ca-releasing messengers, cyclic ADP ribose and nicotinic acid adenine dinucleotide phosphate, in initiating and coordinating Ca signaling. Progress has also been made in determining the roles of specific organelles in Ca release. Ca triggers secretion, and knowledge of the function and regulation of the proteins involved in exocytosis is accumulating. Continuing advances have also been made in understanding the signaling pathways regulating protein synthesis and growth in adult pancreas. The protein kinase mammalian target of rapamycin and its downstream targets play a central role in protein synthesis, whereas the protein phosphatase calcineurin was recently reported to regulate pancreatic growth. Other signaling molecules include the MAP kinases, PKCs, cytoplasmic tyrosine kinases, and nitric oxide. SUMMARY: The current findings reviewed here are illuminating the structure and function of receptors on pancreatic acinar and duct cells and the multiple intracellular signaling pathways that they initiate. Understanding of these mechanisms is contributing to knowledge of normal pancreatic functions and alterations in disease such as pancreatitis and pancreatic cancer.

Journal Article↗
PubMed2006

Comparative effects of bone morphogenetic proteins and sox9 overexpression on extracellular matrix metabolism of bovine nucleus pulposus cells.

STUDY DESIGN: An in vitro biologic study of the effects of adenovirus expressing bone morphogenetic proteins (BMPs) and adenovirus expressing Sox9 on extracellular matrix metabolism by bovine nucleus pulposus cells. OBJECTIVE: To compare the effects of recombinant adenoviral vectors expressing various BMPs (2, 3, 4, 5, 7, 8, 10, 11, 12, 13, 14, and 15) and Sox9 on extracellular matrix accumulation by bovine nucleus pulposus cells. SUMMARY OF BACKGROUND DATA: Nucleus pulposus matrix production may be promoted by transducing the cells with genes that permit the sustained expression of growth factors. The choice of the particular factors or BMPs to be studied for these applications has been largely based on the commercial availability of such products. To our knowledge, this study is the first effort to evaluate systematically the relative effectiveness of the various members of the BMP family in promoting intervertebral disc matrix repair. METHODS: Adult bovine nucleus pulposus cells cultured in monolayer were transduced with adenoviruses expressing human BMP-2, 3, 4, 5, 7, 8, 10, 11, 12, 13, 14, and 15, and adenovirus expressing Sox9. Proteoglycan and collagen accumulation, and cell proliferation were measured 6 days after viral transduction. As a positive control, cells were cultured without any exogenous gene in the presence of recombinant human (rh)BMP-7. RESULTS: Nucleus pulposus cells transduced with adenoviruses expressing BMP-2, 3, 4, 5, 7, 8, 10, 13, 15, and Sox9 accumulated more proteoglycans than nucleus pulposus cells transduced with adenovirus expressing green fluorescent protein (control). It is noteworthy that nucleus pulposus cells transduced with adenoviruses expressing BMP-2 and 7 resulted in essentially as great a stimulation of proteoglycan accumulation as nucleus pulposus cells maintained in the presence of rhBMP-7 (adenoviruses expressing BMP-2: 104% increase; adenoviruses expressing BMP-7: 162% increase; and rhBMP-7: 120% increase). Nucleus pulposus cells transduced with BMP-2, 4, 5, 7, 8, 10, 14, 15, and Sox9 accumulated significantly more collagen compared to nucleus pulposus cells transduced with adenovirus expressing green fluorescent protein; adenoviruses expressing BMP-4 and 14 were the most effective (552% and 661% increase, respectively). Nucleus pulposus cells also proliferated, as measured by deoxyribonucleic acid content, when transduced with adenoviruses expressing BMP-2 and 8. CONCLUSIONS: To our knowledge, for the first time, we have shown the relative effectiveness of 12 different BMPs and Sox9 in stimulating proteoglycan and collagen production by nucleus pulposus cells. Adenoviruses expressing BMP-2 and 7 were the most effective in stimulating proteoglycan accumulation, while adenoviruses expressing BMP-4 and 14 were the most effective in stimulating collagen accumulation. To our knowledge, this study is the first to compare the relative effectiveness of various BMPs and Sox9 on extracellular matrix accumulation by nucleus pulposus cells, and could help to develop more efficacious approaches to the treatment of degenerating intervertebral discs.

Adenoviridae↗
PubMed1997

DROSOPOSON: a knowledge base on chromosomal localization of transposable element insertions in Drosophila.

MOTIVATION: What forces maintain transposable elements (TEs) in genomes and populations is one of the main questions to understand the dynamics of these elements, but the exact nature of these forces is still a matter of speculation. To test theoretical models of TE population dynamics, we need many data on the genomic distributions of various elements. These data are now accumulating for the species Drosophila melanogaster, but they are scattered in the literature. RESULTS: The knowledge base DROSOPOSON thus brings together: (1) data available on Drosophila chromosomal localizations of TE insertions and on features of the polytene chromosomes (DNA content, recombination rate, break-points, etc); (2) statistical methods aimed at analysing the distribution of the TE insertions along the chromosomes. In this paper, we present the structure of the base, the data and the statistical methods. Theoretical models of containment of TE copy number in Drosophila can thus be tested.

Animals↗
PubMed1998

SR4987 and L1210 cell lines: two models in which cholera toxin susceptibility does not correlate with cAMP accumulation and ganglioside content.

The CT-mediated signaling mechanisms have been widely used as a tool for helping the knowledge of the more complex mechanisms regulating cell growth and proliferation in which gangliosides are involved as receptors and cAMP as second messenger. In the present study we compare the susceptibility of two murine cell lines (SR-4987 stromal cells and L1210 leukemic cells) to inhibitory effect of cholera toxin (CT) on cell growth and correlate their sensitivity to CT with ganglioside content and intracellular cAMP accumulation. The results indicate a very different response of the two cell lines to CT treatment. L1210 cells (which contain GM1a ganglioside) are sensitive to the inhibiting activity of CT (IC50 in the clonogenic assay = 10(-9) M) but no cAMP accumulation was observed after the treatment. SR-4987 cells (which lack GM1a) show a dramatic increase of intracellular cAMP without any inhibition of cell growth following the CT treatment until 10(-8) M. However, after SR4987 cells have incorporated GM1a they became susceptible to CT (with a IC50 value = 10(-11) M). The comparison of these results with our previous studies on WEHI-3B leukemia cells confirms the remarkable heterogeneity of cell sensitivity to the growth inhibition by CT by emphasizing that this inhibition is the final event of very different mechanisms in which CT binding to a specific ganglioside seems to be necessary and sufficient whereas cAMP accumulation may not be coupled with the antiproliferative effect of CT.

Animals↗
PubMed1995

Similarities in Gene Expression during the Postharvest-Induced Senescence of Spears and Natural Foliar Senescence of Asparagus.

Changes in gene expression and tissue composition were investigated during foliar development and natural senescence of asparagus (Asparagus officinalis L.). Three phases in development and senescence of the foliage were characterized: early fern growth, mature fern, and senescence, when a marked loss of chlorophyll, sucrose, and protein occurred and major changes in translatable mRNAs were detected. Transcripts for three asparagus spear harvest-induced cDNA clones, pTIP9, pTIP11, and pTIP12 (G.A. King and K.M. Davies [1992] Plant Physiol 100: 1661-1669), accumulated during natural foliar senescence, suggesting that the underlying regulatory mechanisms may be similar in both developmental situations. We have used our knowledge of asparagus spear physiology, the probable proteins encoded by the cDNA clones, and our fern development data to propose that sugar depletion regulates the accumulation of at least pTIP12 transcripts in senescing asparagus tissue.

Journal Article↗
PubMed1992

The method of relative drug accumulation: a simple method for illustrating the effects of different drug dosing regimens and variability in drug elimination on time courses of drug concentrations.

A simple method is presented for graphically illustrating time courses of relative drug concentrations and accumulation during multiple dosing. This method is based on the drug amount ratio and requires knowledge of only the elimination half-life and the dosing interval. It involves the use of relative drug concentrations, where a concentration of unity is assigned to the time-averaged concentration at steady state in a reference subject for the dosing regimen(s) being evaluated. Examples of application of the method of relative drug accumulation involve simulations of the effects of different multiple-dose regimens and variability in drug elimination on time courses of drug concentrations and drug accumulation.

Computer Simulation↗
PubMed2001

Pelvic and aortic lymphadenectomy.

Pelvic and aortic lymphadenectomy for gynecologic malignancies has changed from a random "picking" of some pelvic and aortic lymph nodes to a well-established technique based on adequate knowledge of the patterns of spread of the primary tumor. The identification of the node groups to remove, the number of nodes to count, and the border of dissection in the different clinical situations make pelvic and aortic lymphadenectomy a reproducible surgical intervention. The large experience accumulated over the years has greatly improved the technique and perioperative and complication management. The improved knowledge of the natural history of gynecologic tumors has refined the indications for lymph node dissection. Today, pelvic and aortic lymphadenectomy is primarily a staging procedure. The therapeutic value of lymphadenectomy is recognized in the surgical treatment of cervical cancer, but it is still under evaluation in ovarian and endometrial tumors.

Aorta, Thoracic↗
PubMed1991

Neutrophil accumulation in the lung in alpha 1-antitrypsin deficiency. Spontaneous release of leukotriene B4 by alveolar macrophages.

The emphysema of alpha 1-antitrypsin (alpha 1AT) deficiency is conceptualized to result from insufficient alpha 1AT allowing neutrophil elastase to destroy lung parenchyma. In addition to the deficiency of alpha 1AT in these individuals resulting from mutations in the alpha 1AT gene, it is recognized that, for unknown reasons, there are also increased numbers of neutrophils in their lungs compared with normal individuals. With the knowledge that alveolar macrophages have surface receptors for neutrophil elastase, we hypothesized that the neutrophil accumulation in the lower respiratory tract in alpha 1AT deficiency may result, in part, from release of neutrophil chemotactic activity by alveolar macrophages as they bind uninhibited neutrophil elastase. Consistent with this hypothesis, alpha 1AT-deficient alveolar macrophages spontaneously released nearly threefold more neutrophil chemotactic activity than normal alveolar macrophages. Analysis of alpha 1AT-deficient macrophage supernates by reverse-phase HPLC, molecular sieve chromatography, radioimmunoassay, and absorption with anti-LTB4 antibody revealed that the majority of the chemotactic activity was leukotriene B4 (LTB4), a mediator absent from normal macrophage supernates. Consistent with this hypothesis, incubation of normal macrophages with human neutrophil elastase resulted in the release of the same neutrophil chemotactic mediator. Furthermore, purified human alpha 1AT was able to prevent the neutrophil elastase from stimulating the macrophages to release the chemotactic factor. Together, these findings suggest that the absence of a normal antineutrophil elastase screen in the lower respiratory tract permits free neutrophil elastase to bind to alveolar macrophages, resulting in the release of LTB4, a process which attracts neutrophils to the alveoli of alpha 1AT deficient individuals, thus accelerating the lung destruction that characterizes this disorder.

Adult↗
PubMedDate not supplied

Immunolocalization of tenascin-C in human type II fiber atrophy.

Tenascin-C is a multifunctional extracellular matrix glycoprotein with stimulatory and anti-adhesive or inhibitory properties for axon growth. Its location and discontinuous expression are restricted in innervated muscle tissues. Tenascin-C accumulated interstitially among human denervated muscle fibers and close to normal-sized fibers. To expand our knowledge of the expression of tenascin-C in human neuromuscular disorders, we investigated immunohistologically 20 human muscle specimens with type II myofiber atrophy of children and adults. Tenascin-C immunoreactivity in adult type II atrophy was frequent, and accumulation in children was sparse and weak. In both groups, tenascin-C immunoreactivity was found: 1. Interstitially around normal-sized type II muscle fibers. 2. Around atrophic type II muscle fibers. 3. Around small-caliber myofibers with centrally located nuclei. These results indicate that tenascin-C immunoreactivity: (1) is detectable around early denervated and reinnervated muscle fibers and, therefore, (2) may reflect in part the molecularly ongoing process of denervation and reinnervation in human type II fiber atrophy.

Adult↗
PubMed2006

Beta-catenin signaling in fibroproliferative disease.

BACKGROUND: Beta-catenin has been historically recognized as both an intermediate in the "canonical Wnt signaling pathway" and as a component of functional adherens junctions. MATERIALS AND METHODS: Cellular accumulation of beta-catenin levels can result in transactivation of gene transcription and cellular proliferation during normal cellular and disease development. Recent evidence has identified beta-catenin in an additional role as a component of cutaneous wound healing. RESULTS: This finding is in keeping with previous observations that post-translational modifications of beta-catenin that are associated with its cytoplasmic accumulation are frequently observed in fibroproliferative diseases with characteristics of dysregulated wound healing. These diseases include hypertrophic scar formation, aggressive fibromatoses, Lederhose disease, and Dupuytren's contracture (DC). CONCLUSIONS: While its precise roles in disease initiation and progression remain to be explored, this review highlights our current knowledge of beta-catenin regulation and describes some potential upstream mediators of beta-catenin accumulation and signaling in fibroproliferative disease.

Animals↗
PubMed1985

Enzymes converting procollagens to collagens.

Conversion from procollagen to collagen is a specific process that is a requirement for proper alignment of collagen molecules to form functional fibers. This process is catalyzed by at least three structurally and functionally distinct enzymes cleaving collagen types I-III. The cleavage processes possibly taking place in the more recently discovered collagen types are not known to any extent at this time. Two amino-terminal proteinases, one cleaving type I and type II procollagens and the other cleaving type III procollagen, have been purified close to homogeneity, and the more unspecific activity of carboxy-terminal proteinase has been isolated from several tissues. In our experimental model, however, cleavage of the carboxy-terminal propeptides of types I and III procollagen is differently affected by lysine. This suggests the presence of at least two distinct enzymes for the removal of carboxyl-terminal propeptides. The regulation of the reaction process from procollagen to collagen is not well known at present. The importance of the phenomenon in terms of fibril formation, however, is demonstrated by several elegant studies in vitro; and certain genetic disorders in which this process is defective demonstrate the significance in vivo. Moreover, the factors shown to effect the cleavage process may be potentially beneficial in the treatment of the pathological processes with abnormal collagen accumulation such as fibrosis. In this paper we briefly review the current knowledge of the converting enzymes, including some very recent findings of our laboratory as well as the evidence presented for the biological significance of the conversion process.

Animals↗
PubMed1991

Electrophysiologic mapping of the segmental anatomy of the muscles of the lower extremity.

Our knowledge of the specific root innervation of skeletal muscles is derived from accumulated clinical experience. While performing selective posterior rhizotomy for treatment of spasticity in children with cerebral palsy, we made direct electrophysiologic measurement of the root innervation of the lower extremity. We stimulated ventral roots from L2 to S2 while recording from all muscles simultaneously. The size of the evoked compound muscle action potential was used as an indication of the amount of innervation derived from stimulation of a given spinal root. We found the major root innervation for the 8 muscles studied to be: adductor longus, vastus medialis, and vastus lateralis, L3; tibialis anterior; L4; peroneus longus, L5; and medial gastrocnemius, lateral gastrocnemius, and gluteus maximus, S1. In general, each muscle received innervation from 3 or more roots. Prefixed or postfixed innervation patterns were found in 27.9% of legs examined, and there was asymmetry of innervation in 29.8%. We conclude that the segmental innervation of lower extremity muscles is broader than previously thought. Anomalous innervation occurs so frequently that caution should be used in attributing any pattern of clinical or EMG findings to a specific spinal level.

Cerebral Palsy↗
PubMed1999

Basal ganglia calcification induced by excitotoxicity: an experimental model characterised by electron microscopy and X-ray microanalysis.

Activation of glutamate receptors induces an excitotoxic neurodegenerative process characterised in some brain areas by the formation of calcium precipitates. To examine the pathogenesis of basal ganglia calcification (BGC), an improved procedure of X-ray microanalysis was used to study experimental excitotoxic calcification in the rat. Three weeks after injection of ibotenic acid (IBO) in the rat basal forebrain, calcified inclusions within hypertrophied astrocytes were characterised. They appeared to form part of a filamentous structure localised in the cytoplasm in association with normal mitochondria and other organelles. Larger inclusions were surrounded by reactive microglia. The main inorganic components in these deposits were Ca and P, frequently accompanied by S. Al, Si and K. The shape and Ca/P molar ratio of the large deposits (>10 microm) indicate that they may be biological apatites. Aluminosilicates were detected as small deposits (<4 microm) free of other mineral constituents. To our knowledge this is the first report showing that IBO lesion induces brain accumulation of aluminosilicates similar to that described in Alzheimer's or Fahr's patients. Our data indicate that precipitation of Ca and Al may reduce their IBO-induced increased concentration. In conclusion, the experimental model and the improved efficiency of X-ray analysis described may help us to understand the pathogenesis of BGC.

Aluminum Silicates↗