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PubMed2005

Cyclooxygenase-2 in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer related mortality worldwide. The incidence of HCC is rising worldwide, especially in the United States. The overall survival of patients with HCC is grim and currently no efficient secondary prevention or systemic treatments are available. Recent evidence suggests that COX-2 signaling is implicated in hepatocarcinogenesis and COX-2 inhibitors prevent HCC cell growth in vitro and in animal models. However, given the recently reported side effect associated with some of the COX-2 inhibitors, it is imperative to develop chemotherapeutic strategy that simultaneously targets COX-2 and other related key molecules in hepatocarcinogenesis or to utilize agents inhibiting COX-2 signaling in conjunction with other standard chemotherapy or radiation therapy. Such combinational therapeutic approaches are expected to provide synergistic anti-tumor effect with lesser side effect. In this regard, the recently delineated interplay between COX-2-derived PG signaling and other growth-regulatory pathways such as EGFR, Met, iNOS, VEGF and n-3 polyunsaturated fatty acids is expected to provide important therapeutic implications. This review summarizes the recent advances in understanding the mechanisms for COX-2-derived PG signaling in hepatocarcinogenesis and focuses on the newly unveiled interactions between PG cascade and other key signaling pathways that coordinately regulate HCC growth. Understanding these mechanisms and interplays will facilitate the development of more effective chemopreventive and therapeutic strategies.

Animals↗

PubMed2004

Growth factors in the anterior segment: role in tissue maintenance, wound healing and ocular pathology.

A number of growth factors and their associated receptors, including epidermal growth factor, transforming growth factor-beta, keratinocyte growth factor, hepatocyte growth factor, fibroblast growth factor and platelet-derived growth factor have been detected in the anterior segment of the eye. On binding to cellular receptors, these factors activate signalling cascades, which regulate functions including mitosis, differentiation, motility and apoptosis. Production of growth factors by corneal cells and their presence in the tear fluid and aqueous humour is essential for maintenance and renewal of normal tissue in the anterior eye and the prevention of undesirable immune or angiogenic reactions. Growth factors also play a vital role in corneal wound healing, mediating the proliferation of epithelial and stromal tissue and affecting the remodelling of the extracellular matrix (ECM). These functions depend on a complex interplay between growth factors of different types, the ECM, and regulatory mechanisms of the affected cells. Imbalances may lead to deficient wound healing and various ocular pathologies, including edema, neovascularization and glaucoma. Growth factors may be targeted in therapeutic ophthalmic applications, through exogenous application or selective inhibition, and may be used to elicit specific cellular responses to ophthalmic materials. A thorough understanding of the mechanism and function of growth factors and their actions in the complex environment of the anterior eye is required for these purposes. Growth factors, their function and mechanisms of action as well as the interplay between different growth factors based on recent in vitro and in vivo studies are presented.

Animals↗

PubMed2006

Coordinated regulation of endothelial nitric oxide synthase activity by phosphorylation and subcellular localization.

Endothelial nitric oxide synthase (eNOS) is regulated by multiple mechanisms including Ca(2+)/calmodulin binding, protein-protein interactions, phosphorylation, and subcellular locations. Emerging evidence suggests that these seemingly independent mechanisms may be closely correlated. In the present study, the interplay between membrane targeting and phosphorylation of eNOS was investigated by using various mutants designed to target specific subcellular locations or to mimic different phospho states. Phospho-mimicking mutations of wild-type eNOS at S635 and S1179 synergistically activated the enzyme. The targeted eNOS mutants to plasma membrane and Golgi complex exhibited higher NO production activities than that of a myristoylation-deficient cytosolic mutant. Phospho-mimicking mutations at S635 and S1179 rescued the activity of the cytosolic mutant and increased those of the plasma membrane- and Golgi-targeted mutants. In contrast, phospho-deficient mutations at these sites led to inactivation of eNOS. Unlike the other targeted mutants, the cytosolic eNOS mutant was unresponsive to cAMP, indicating that membrane association and phosphorylation are required for eNOS activation. These findings suggest that the coordinated interplay between phosphorylation and subcellular localization of eNOS plays an important role in regulating NO production in endothelial cells.

Amino Acid Sequence↗

PubMed2005

Mosquito immunity against Plasmodium.

Understanding the molecular mechanisms of the innate immune responses of Anopheles gambiae against Plasmodium parasites is of great importance for current efforts to develop novel strategies for malaria disease control. The parasite undergoes substantial stage-specific losses during its development in the mosquito, which in some cases lead to complete refractoriness of the mosquito against the parasite. The underlying genetics of refractoriness are complex and multifactorial. Completion of the genome sequence of An. gambiae 2 years ago, together with the development of DNA microarrays in this species and the extension of the RNAi technique to adult mosquitoes, has allowed comparative and functional genomic approaches of the mosquito innate immune system. A variety of factors were shown to negatively affect the development of Plasmodium parasites in the mosquito, in some cases leading to complete transmission blockage. In addition, mosquito factors have been identified that play positive roles and are required for successful transmission of the parasite. These findings indicate a highly complex interplay between parasite and vector. Research is continuing to identify new factors involved in this interaction and to decipher the interplay of these molecules and their regulation.

Animals↗

PubMed2006

The influence of patient complexity and nurses' experience on haemodynamic decision-making following cardiac surgery.

Critical care nurses' haemodynamic decision-making in the immediate postoperative cardiac surgical context is complex. To optimise patient outcomes, nurses of varying levels of experience are required to make complex decisions rapidly and accurately. In a dynamic clinical context such as critical care, the quality of such decision-making is likely to vary considerably. The aim of this study was to describe variability of nurses' haemodynamic decision-making in the 2-hour period after cardiac surgery as a function of interplay between decision complexity, nurses' levels of experience, and the support provided. A descriptive study based on naturalistic decision-making was used. Data were collected using continuous non-participant observation of clinical practice for a 2-hour period and follow-up interview. Purposive sampling was used to recruit 38 nurses for inclusion in the study. The quality of nurses' decision-making was influenced by interplay between the complexity of patients' haemodynamic presentations, nurses' levels of cardiac surgical intensive care experience, and the form of decision support provided by nursing colleagues. Two factors specifically influenced decision-making quality: nurses' utilisation of evidence for practice and the experience levels of both nurses and their colleagues. The findings have implications for staff resourcing decisions and postoperative patient management, and may be used to inform nurses' professional development and education.

Adult↗

PubMed2006

TLRs, NLRs and RLRs: a trinity of pathogen sensors that co-operate in innate immunity.

Significant advances in our understanding of innate immunity have been made following the identification of three families of pathogen sensors: Toll-like receptors (TLRs), NOD-like receptors (NLRs) and RIG-I-like receptors (RLRs). Members of the TLR family recognize bacteria, viruses, fungi and protozoa; NLRs with known functions detect bacteria, and RLRs are anti-viral. It is likely that interplay between these families ensures the efficient co-ordination of innate immune responses, through either synergistic or co-operative signalling. Important interactions occur between TLRs and certain NLRs for inducing the pro-inflammatory cytokine interleukin (IL)-1beta. TLRs induce pro-IL-1beta production and prime NLR-containing multi-protein complexes, termed "inflammasomes", to respond to bacterial products and products of damaged cells. This results in caspase-1 activation and the subsequent processing of pro-IL-1beta to its active form. In this article, we hypothesize that during the first phase of the host response to infection, an important interplay occurs between these families, providing a substantial combinatorial repertoire in innate immunity.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Synergistic interactions between aqueous and membrane domains of a designed protein determine its fold and stability.

Membrane-spanning proteins contain both aqueous and membrane-spanning regions, both of which contribute to folding and stability. To explore the interplay between these two domains we have designed and studied the assembly of coiled-coil peptides that span from the membrane into the aqueous phase. The membrane-spanning segment is based on MS1, a transmembrane coiled coil that contains a single Asn at a buried a position of a central heptad in its sequence. This Asn has been shown to drive assembly of the monomeric peptide in a membrane environment to a mixture of dimers and trimers. The coiled coil has now been extended into the aqueous phase by addition of water-soluble helical extensions. Although too short to fold in isolation, these helical extensions were expected to interact synergistically with the transmembrane domain and modulate its stability as well as its conformational specificity for forming dimers versus trimers. One design contains Asn at a position of the aqueous helical extension, which was expected to specify a dimeric state; a second peptide, which contains Val at this position, was expected to form trimers. The thermodynamics of assembly of the hybrid peptides were studied in micelles by sedimentation equilibrium ultracentrifugation. The aqueous helical extensions indeed conferred additional stability and conformational specificity to MS1 in the expected manner. These studies highlight the delicate interplay between membrane-spanning and water-soluble regions of proteins, and demonstrate how these different environments define the thermodynamics of a given specific interaction. In this case, an Asn in the transmembrane domain provided a strong driving force for folding but failed to specify a unique oligomerization state, while an Asn in the water-soluble domain was able to define specificity for a specific aggregation state as well as modulate stability.

Amino Acid Sequence↗

PubMed2006

The seeking of baby-feeding information by Canadian women pregnant with twins.

OBJECTIVE: To analyse baby-feeding information needs and seeking described by Canadian women pregnant with twins. DESIGN: Qualitative; data were collected by in-depth semi-structured interviews. Transcripts provided the data for discourse analysis of the use of two interpretative repertoires. SETTING: Ontario, Canada. PARTICIPANTS: 19 women pregnant with twins. MEASUREMENTS AND FINDINGS: The first interpretative repertoire represented caring for twins as fundamentally distinct from caring for singly born babies, and therefore emphasised the commonality of mothers of twins regardless of their background or situation. The second highlighted the uniqueness and individuality of each person. These repertoires intersect with discourses of baby feeding and good mothering, resulting in a complex discursive interplay of similarity and difference, commonality and individuality, information seeking, baby feeding and good mothering. Participants used the two interpretative repertoires to (1) frame information needs; (2) construct complex accounts of the biomedical, experiential and personalised authority of information sources; (3) describe the helpfulness of information sources independent of their authority; and (4) describe the barriers encountered in the finding appropriate sources of baby-feeding information in pregnancy. IMPLICATIONS: Understanding and respecting the discursive constructions of pregnancy and mothering can help practitioners understand the complex discursive interplay underlying participants' baby-feeding decisions, and may facilitate more sensitive support for women's individual needs and understandings.

Adult↗

PubMed2005

Relationships between genomic, cell cycle, and mutagenic responses of TK6 cells exposed to DNA damaging chemicals.

Genotoxic stress causes a variety of cellular and molecular responses in mammalian cells, including cell cycle arrest, DNA repair, and apoptosis. These responses result from the interplay between the genotoxic events themselves, and the biological context in which they occur. To better understand this interplay, we investigated cytotoxicty, mutagenesis, cell cycle profile, and global gene expression in the human TK6 lymphoblastoid cell line exposed to six genotoxicants. The six compounds have broad structural diversity and cause genotoxic stress by many different mechanisms, including covalent modification (methyl methanesulfonate, mitomycin C), reactive oxygen species (hydrogen peroxide, bleomycin), and topoisomerase II inhibition (etoposide and doxorubicin). Cell cycle analysis was performed 4 and 20 h following a 4 h chemical exposure. Cells exposed to all compounds experienced S-phase arrest at the 8h time point, but by 24 h had markedly different cell cycle responses. Cells exposed to compounds that cause covalent modification had a strong G2/M arrest at 24 h. These cells also had a robust (>25-fold) increase in mutant frequency, and had a moderate but sustained p53 response at 4, 8, and 24h, detectable as approximately 2-5-fold increases in transcript levels for p21WAF1/CIP1, GADD45alpha, BTG2, and cyclin G1. In contrast, cells exposed to the reactive oxygen compounds had little or no G2/M arrest at 24 h and no increase in mutant frequency. In addition, these compounds caused a strong but transient induction of the p53 pathway, detectable as 15-25-fold increases in p21WAF1/CIP1 transcription at 4 h that decreased dramatically by 8h and was near control levels at 24 h. Thus, the mutagenic effect of compounds was consistent with G2/M arrest and sustained kinetics of p53 pathway activation. Global gene expression data were also consistent with the mutagenesis data. Activation of genes associated with cell cycle arrest, the p53 and TNF-related pathways, and chemokines and chemokine receptors, were particularly evident for the reactive oxygen compounds. In contrast, the most mutagenic compounds caused fewer and less robust changes in global gene expression. There was therefore an inverse relationship between global gene expression and mutagenic potency.

Cell Cycle↗

PubMed2006

The neural cell adhesion molecule NCAM regulates neuritogenesis by multiple mechanisms of interaction.

The neural cell adhesion molecule NCAM and its glycosylation with polysialic acid (polySia) are crucially involved in proliferation, migration and differentiation of neural progenitors. Modification with polySia, homophilic and heterophilic interactions set the function of NCAM, but little is known on their interplay. We have shown recently that removal of polySia induces neuronal differentiation via heterophilic NCAM interactions at cell contacts between SH-SY5Y neuroblastoma cells. Here we analyze the additional impact of NCAM-positive fibroblasts as a ligand-presenting cellular environment, a model often used to demonstrate the neuritogenic effect of homophilic NCAM interactions. Native SH-SY5Y cells did not respond to interactions with fibroblast NCAM. However, after induction of neuronal differentiation by retinoic acid the previously ineffective NCAM signals activated extracellular signal-regulated kinase (ERK) and promoted neuritogenesis. Removal of polySia increased neuritogenesis in retinoic acid-treated cells additive to the NCAM substrate effect. The change in responsiveness to substrate NCAM was associated with a rearrangement of polysialylated NCAM away from its enrichment at homotypic cell-cell contacts and with the appearance of non-polysialylated NCAM, i.e. changes facilitating NCAM interactions with the substrate. Thus, heterophilic and homophilic NCAM interactions are integrated into the cell's response yet they have the capacity to independently trigger neuritogenesis. The actual occurrence of each of these interactions, however, depends on the cellular context, targeted cell surface presentation of NCAM and the dynamic regulation of its modification by polysialic acid. In summary, this study reveals how the complex interplay of NCAM interactions and polysialylation provides an elaborate system to regulate neuritogenesis.

Animals↗

PubMed2007

Role of the corpus callosum in speech comprehension: interfacing syntax and prosody.

The role of the corpus callosum (CC) in the interhemispheric interaction of prosodic and syntactic information during speech comprehension was investigated in patients with lesions in the CC, and in healthy controls. The event-related brain potential experiment examined the effect of prosodic phrase structure on the processing of a verb whose argument structure matched or did not match the prior prosody-induced syntactic structure. While controls showed an N400-like effect for prosodically mismatching verb argument structures, thus indicating a stable interplay between prosody and syntax, patients with lesions in the posterior third of the CC did not show this effect. Because these patients displayed a prosody-independent semantic N400 effect, the present data indicate that the posterior third of the CC is the crucial neuroanatomical structure for the interhemispheric interplay of suprasegmental prosodic information and syntactic information.

Adult↗

PubMed2005

Molecular interactions of the type 1 human immunodeficiency virus transregulatory protein Tat with N-methyl-d-aspartate receptor subunits.

We investigated the effect of type 1 human immunodeficiency virus (HIV-1) regulatory protein Tat on N-methyl-d-aspartate (NMDA) receptors expressed in Xenopus oocytes by voltage-clamp recording and its role in NMDA-mediated neurotoxicity using cultured rat hippocampal neurons. Tat (0.01-1muM) potentiated NMDA-induced currents of recombinant NMDA receptors. However, in the presence of Zn(2+), the potentiating effect of Tat was much more pronounced, indicating an additional Zn(2+)-related effect on NMDA receptors. Consistently, Tat potentiated currents of the particularly Zn(2+)-sensitive NR1/NR2A NMDA receptor with a higher efficacy, whereas currents from a Zn(2+)-insensitive mutant were only marginally augmented. In addition, chemical-modified Tat, deficient for metal binding, did not reverse Zn(2+)-mediated inhibition of NMDA responses, demonstrating that Tat disinhibits NMDA receptors from Zn(2+)-mediated antagonism by complexing the cation. We therefore investigated the interplay of Tat and Zn(2+) in NMDA-mediated neurotoxicity using cultures of rat hippocampal neurons. Zn(2+) exhibited a prominent rescuing effect when added together with the excitotoxicant NMDA, which could be reverted by the Zn(2+)-chelator tricine. Similar to tricine, Tat enhanced NMDA-mediated neurotoxicity in the presence of neuroprotective Zn(2+) concentrations. Double-staining with antibodies against Tat and the NR1 subunit of the NMDA receptor revealed partial colocalization of the immunoreactivities in membrane patches of hippocampal neurons, supporting the idea of a direct interplay between Tat and glutamatergic transmission. We therefore propose that release of Zn(2+)-mediated inhibition of NMDA receptors by HIV-1 Tat contributes to the neurotoxic effect of glutamate and may participate in the pathogenesis of AIDS-associated dementia.

Animals↗

PubMed2006

The interaction of neuroactive steroids and GABA in the development of neuropsychiatric disorders in women.

A growing literature suggests that hormonal fluctuations occurring across the menstrual cycle, during and after pregnancy, and during the menopausal transition are associated with onset of affective disorders or exacerbation of existing disorders. This influence of the neuroendocrine system on psychiatric disorders is thought to be mediated by an abnormality in central nervous system response to neuroactive steroids such as estradiol, progesterone, and the progesterone derivative allopregnanolone (ALLO). This interplay is considerably complex as neuroactive steroids modulate the function of multiple neurotransmitter systems throughout various stages of development. While one could choose to study any number of steroid-neurotransmitter interactions, our group in addition to others has focused our investigative efforts on unraveling the contribution of neuroactive steroids to psychiatric syndromes and disorders via their modulation of gamma aminobutyric acid (GABA), the brain's major inhibitory neurotransmitter. The goal of this article is two-fold: to synthesize the clinical and preclinical research focusing on the interplay between neuroactive steroids and GABA as they relate to neuropsychiatric and substance use disorders in women and to integrate data from our laboratory using proton magnetic resonance spectroscopy into this context.

Affect↗

PubMed2006

Importing measured field fluences into the treatment planning system to validate a breathing synchronized DMLC-IMRT irradiation technique.

BACKGROUND AND PURPOSE: Recalculating dose distributions using measured IMRT fluence fields imported into the treatment planning system (TPS) to evaluate the technical feasibility of a prototype developed for breathing synchronized irradiation. PATIENTS AND METHODS: DMLC-IMRT fluence patterns acquired on radiographic film, generated by the linac in non-gated and gated mode, have been imported into the TPS. The effect of dose blurring and possible interplay between organ motion and leaf motion, and the efficacy of a breathing synchronized irradiation technique (an adapted version of a commercially available image-guidance system: NOVALIS BODY/ExacTrac4.0, BrainLAB AG) have been evaluated using radiographic film mounted to a simple phantom simulating a breathing pattern of 16 cycles per minute and covering a distance of 4 cm to obtain the resulting fluence maps. Two situations have been investigated to illustrate this principle: (a) a tumor located close to the diaphragm to assess the influence of organ motion on the dose to the target volume as well as to the gastro-intestinal tract that presents a high risk at intersecting with the beam during the breathing cycle. (b) A mediastinal lesion requiring complicated fluence patterns. RESULTS: Importing measured fluence maps yielded highly disturbed reconstructed dose distributions in case of the non-gated delivery with the phantom in motion (both orthogonal and parallel to the leaf direction), whereas the measurements from the static (film fixed in space) and the gated delivery showed good agreement with the original theoretical dose distribution. These findings have been confirmed by the dose-volume histograms, corresponding tumor control probabilities, conformity index and dose heterogeneity values. The normal tissue complication probabilities investigated in this study seem to be affected to a lesser degree, which concurs with the observation that the motion effects result in a dose spread in the direction of motion. The applied breathing synchronization technique introduced an increased treatment time with a factor 3-4. CONCLUSIONS: The use of measured fluence fields, delivered by the linac in non-gated and gated mode, as imported fluence maps for the treatment planning system is an interesting quality assurance tool and revealed the dramatic impact of dose blurring and interplay between DMLC-IMRT dose delivery and organ motion, as well as the potential of breathing synchronization to resolve this issue. The possible advantage of breathing synchronized irradiation is compromised with an increased treatment time.

Artifacts↗

PubMed2005

Caveolin, cholesterol, and lipid bodies.

In mammalian cells a complex interplay regulates the distribution of cholesterol between intracellular membrane compartments. One important aspect of cholesterol regulation is intracellular cholesterol storage in neutral lipid storage organelles called lipid droplets or lipid bodies (LBs). Recent work has thrust the LB into the limelight as a complex and dynamic cellular organelle. LBs play a crucial role in maintaining the cellular levels of cholesterol by regulating the interplay between lipid storage, hydrolysis and trafficking. Studies of caveolins, caveolar membrane proteins linked to lipid regulation, are providing new insights into the role of LBs in regulating cholesterol balance.

3T3 Cells↗

PubMed2005

An explanatory model of health promotion and quality of life for persons with post-polio syndrome.

Although previous studies have examined selected factors influencing health promoting behaviors or quality of life, the complex interplay of these variables in persons with different chronic disabling conditions has not been investigated. This study tested an explanatory model of variables influencing health promotion and quality of life originally developed with a sample of persons with multiple sclerosis in a new sample of persons living with post-polio syndrome (PPS) in the USA. The sample of 1603 persons with PPS (1123 females, 478 males and 2 unknown) completed a battery of instruments including measures of severity of polio-related impairment, barriers to health promoting behaviors, resources, self-efficacy, acceptance, health promoting behaviors and perceived quality of life. A model originally developed in a sample of 786 persons with multiple sclerosis was assessed and modified using the weighted least squares procedure (WLS) which is implemented by LISREL8. The structural equation analyses resulted in a proper solution that exhibited adequate fit: chi2 (8, N = 1549)=84.22, p<0.05; GFI=0.96, IFI=0.90, CFI=0.90. The antecedent variables accounted for 65% of the variance in the frequency of health promoting behaviors and 53% of the variance in perceived quality of life. The model test supports the hypothesis that quality of life is the outcome of a complex interplay between contextual factors (severity of impairment), antecedent variables, and health promoting behaviors. It also suggests that the relationships among these variables are similar in samples of persons with two different chronic conditions. Further research using a qualitative approach is needed to clarify other contributors to quality of life in persons with post-polio syndrome.

Activities of Daily Living↗

PubMed2005

Trustful bonds: a key to "becoming a mother" and to reciprocal breastfeeding. Stories of mothers of very preterm infants at a neonatal unit.

A preterm birth and subsequent hospitalization of an infant at a neonatal unit (NU) implies an extraordinary life situation for mothers, in which the maternal role and breastfeeding begin and evolve in a medical and unfamiliar setting. Descriptions of how women experience "becoming a mother" and breastfeeding in such a situation are sparse and this question was addressed in the present study. In this qualitative study, inspired by the grounded theory approach, in-depth interviews were conducted with 25 mothers whose very preterm infants had been cared for in seven NUs in Sweden. Findings indicated the importance of quality in social bonds with the infant, father, staff and other mothers at the NU, for "becoming mothers" and experiencing mutually satisfying breastfeeding. Three themes comprised a structure for descriptions of experiences, social bonds and mediated emotions: (1) 'loss' of the infant and the emotional chaos--"putting life on hold"; (2) separation--a sign of being unimportant as a person and mother; and (3) critical aspects of becoming more than a physical mother. The qualities were described as trustful or distrustful, characterized by accompanying feelings of pride/trust or shame/distrust. Social bonds were affected not only by the interpersonal interplay but also by the public environment and care routines. In conclusion, the contextual setting and distrustful social bonds impaired the ability to "become mothers" and the sensation of reciprocity i.e. breastfeeding becoming dutiful and not mutually satisfying. As breastfeeding is an intimate interplay and a personal choice it was considered that the best breastfeeding support would seem to be provision of a favorable environment that enhances the mother's confidence in herself. The contextual setting should be modeled such as to create conditions for a trustful and reciprocal mother-infant bond.

Adult↗

PubMed2005

Pathophysiology of gastroesophageal reflux disease.

From a pathophysiologic viewpoint, GERD results from the excessive reflux of gastric contents into the distal esophagus. Under normal conditions, this is prevented as a function of the antireflux barrier at the EGJ, the integrity of which is dependent on the delicate interplay of a host of anatomic and physiologic factors, including the integrity of the LES, TLESR, and anatomic degradation of the EGJ inclusive of but not limited to hiatus hernia. Considerable investigative focus is aimed at describing the subtle aberrations of the EGJ that may contribute to the root causes of GERD. The net result is an increased number of reflux events, an increasing diversity of potential mechanisms of reflux, and a diminished ability of the stomach to selectively vent gas, as opposed to gas and gastric juice, during TLESR. Once reflux occurs, the duration of resultant esophageal acid exposure is determined by the effectiveness of esophageal acid clearance, the dominant determinants of which are peristalsis, salivation, and, again, the anatomic integrity of the EGJ. Approximately half of patients who have GERD have abnormal acid clearance and the major contributor to this is hiatus hernia. Abnormalities of acid clearance probably are the major determining factor influencing which patients who have GERD are most prone to developing esophagitis as opposed to symptomatic GERD. In summary, GERD is a multifactorial process involving physiologic and anatomic abnormalities. These abnormalities exhibit a complicated interplay that degrades the ability of the EGJ to contain gastric juice within the stomach and to clear the esophagus of gastric juice effectively once reflux has occurred.

Disease Progression↗