Putative Pathophysiological Mechanisms Research Articles

Predictors of New-Onset Diabetes After Transplantation: The Overlooked Confounders

To the Editor: The article by Van Laecke et al. (1Van Laecke S Van Biesen W Verbeke F De Bacquer D Peeters P Vanholder R Post-transplantation hypomagnesemia and its relation with immunosuppression as predictors of new-onset diabetes after transplantation.Am J Transplant. 2009; 9: 2140-2149Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar) highlights the relationship between calcineurin inhibitor (CNI) induced hypomagnesemia and development of abnormal glucose metabolism posttransplantation. The authors’ analyses suggest the diabetogenicity of CNIs, primarily considered secondary to pancreatic β-cell dysfunction, is also partially related to hypomagnesemia. Insulin regulates magnesium homeostasis but magnesium itself is reciprocally implicated in both insulin and glucose metabolism (2Barbagallo M Dominguez LJ Magnesium metabolism in type 2 diabetes mellitus, metabolic syndrome and insulin resistance.Arch Biochem Biophys. 2007; 458: 40-47Crossref PubMed Scopus (263) Google Scholar). Use of magnesium replacement, dietary or pharmacological, is associated with attenuation of the risk of diabetes in the general population and therefore the authors’ paradoxical findings of magnesium supplements being associated with new-onset diabetes after transplantation, albeit on univariate analysis alone, is difficult to explicate. The explanations offered by the authors are legitimate but the answer may lie in the multitude of unappreciated confounding factors involved with glucose metabolism. CNIs are associated with numerous biochemical abnormalities, with hypomagnesemia the focus of this paper. CNIs are also well documented as causing hyperuricemia and are implicated in increased rates of gout posttransplantation. Serum uric acid has also been suggested as a risk factor for abnormal glucose metabolism in the general population; Dehghan et al. (3Dehghan A Van Hoek M Sijbrands EJ Hofman A Witteman JC High serum uric acid as a novel risk factor for type 2 diabetes.Diabetes Care. 2008; 31: 361-362Crossref PubMed Scopus (447) Google Scholar) found increasing serum uric acid to be a strong and independent risk factor for the development of diabetes in 4526 nondiabetic individuals aged 55 years and above, over a mean follow up of 10.1 years. This raises the possibility of targeting hyperuricemia posttransplantation as a strategy for attenuation of transplant-associated hyperglycemia. As with hypomagnesemia, it is difficult to extrapolate whether hyperuricemia is a precursor or consequence of abnormal glycemia but hyperuricemia could prove a confounding factor in the analysis by Van Laecke et al. The authors also report the use of active vitamin D therapy for all their patients posttransplantation and thereby add an additional confounding factor. Pittas et al. (4Pittas AG Dawson-Hughes B Li T et al.Vitamin D and calcium intake in relation to type 2 diabetes in women.Diabetes Care. 2006; 29: 650-656Crossref PubMed Scopus (619) Google Scholar) found both calcium and vitamin D intake were inversely associated with development of type 2 diabetes in a prospective study of 83 779 nondiabetic women during 20 years of follow up. Putative pathophysiological mechanisms proposed included vitamin D insufficiency induced insulin resistance and pancreatic β-cell dysfunction—the latter possibly explained by the finding of vitamin D receptors in pancreatic β-cells. Finally, there is a complicated interplay between insulin, glucose and renal graft function (5Sharif A Insulin, glucose, and glomerular filtration rate.Transplantation. 2009; 87: 1592-1593Crossref PubMed Scopus (4) Google Scholar) and the higher creatinine in the NODAT group compared to non-NODAT group (1.60 md/dL vs. 1.38 mg/dL respectively, p = 0.016) is an additional confounding factor. It is unclear whether this has been factored into the multivariate Cox proportional hazard model. In addition, the confounders highlighted above all have a ‘cause and effect’ relationship with renal function, which makes the interplay even more complicated. The work by Van Laecke et al. is a welcome addition to the NODAT literature and provides interesting ‘food for thought’. Further work is required to explore these confounding mechanisms posttransplantation to ensure findings from general population-based data translates to transplantation. Randomized controlled trials or prospectively collated observational data should be designed to address these issues, with all possible confounders acknowledged in data analysis.

Relationship between symptom pattern, assessed by the PAGI‐SYM© questionnaire, and gastric sensorimotor dysfunction in functional dyspepsia

The patient assessment of upper gastrointestinal symptom severity index (PAGI-SYM) questionnaire was recently developed and validated for the evaluation of therapeutic responsiveness in functional dyspepsia (FD). Functional dyspepsia is a heterogeneous disorder, with different pathophysiological mechanisms underlying the symptom pattern. The relationship between PAGI-SYM scores and putative pathophysiological mechanisms has not been studied. The aim of this study was to evaluate the relationship between PAGI-SYM subscales and gastric emptying, gastric sensitivity and gastric accommodation in FD. A total of 161 consecutive FD patients underwent Helicobacter pylori (HP), gastric barostat and standardized gastric emptying testing (n = 126), and completed the PAGI-SYM questionnaire. Relationships between scores for the six subscales (heartburn/regurgitation, nausea/vomiting, fullness/satiety, bloating, upper abdominal pain, lower abdominal pain) and gastric function were analysed using Pearson's linear correlation, multiple regression analysis, chi-square and Student's t-tests. Gastric emptying was significantly correlated with scores for heartburn/regurgitation (r = 0.26), nausea/vomiting (r = 0.19), fullness/satiety (r = 0.20), bloating (r = 0.21) and lower abdominal pain (r = 0.22; all P < 0.05). Patients with delayed emptying had significantly higher scores for each of these subscales (all P < 0.05). Discomfort volume during gastric distension was significantly correlated with scores for fullness/satiety (r = -0.27), bloating (r = -0.23), heartburn/regurgitation (r = -0.21), and upper abdominal pain (r = -0.20). Patients with hypersensitivity to distension had significantly higher scores for fullness/satiety (P < 0.05). At different cut-off levels of symptom severities, consistent associations were found between fullness/satiety and gastric discomfort volume, between preprandial volumes and upper abdominal pain, compliance and upper abdominal pain, and between bloating and gastric discomfort volume. Multiple regression analysis revealed that gastric emptying rate contributed significantly to models for the severity of these subscales. The importance of discomfort volume disappeared in favour of gender when sex was included in the model. No significant correlations were found with HP status or with gastric accommodation. PAGI-SYM scores are mainly correlated with gastric emptying rate and with gastric hypersensitivity. Multivariate analysis suggests that the questionnaire may be useful in the evaluation of gastroprokinetics. Its role in the evaluation of drugs that alter gastric sensitivity is less clear.

A Possible Role of Food Intolerance in the Pathogenesis of Gastroesophageal Reflux Disease

Caselli, Michele MD1; Zeni, Elena PhD2; Cascio, Natalina Lo PhD2; Alvisi, Vittorio MD1; Stanghellini, Vincenzo MD3 Author Information

Review article: Biomarkers of clinical outcomes in advanced chronic kidney disease.

Chronic kidney disease (CKD) is a complex condition, where the decrease in kidney function is accompanied by numerous metabolic changes affecting virtually all the organ systems of the human body. Many of the biomarkers characteristic of the individually affected organ systems have been associated with adverse outcomes including higher mortality in advanced CKD, whereas in persons without CKD these biomarkers may have no bearing on survival. It is believed that the high mortality seen in CKD is a result of several abnormalities conspiring to induce or aggravate a heightened degree of cardiovascular morbidity and predisposition to wasting syndrome. Not all the biomarkers may, however, be causally responsible for the adverse outcomes associated with them. We review various biomarkers of protein-energy wasting, inflammation, oxidative stress, potassium disarrays, acid-base disorders, bone and mineral disorders, glycemic status, and anemia. Although all of these biomarkers have shown associations with worsened outcomes in CKD, markers of protein-energy wasting, especially serum albumin, remain the strongest predictor of survival in CKD patients, especially those undergoing maintenance dialysis treatment. We also review the putative pathophysiologic mechanisms behind these associations, and present potential therapeutic interventions that could result in remedies to improve poor clinical outcomes in CKD, pending the results of current and future controlled trials.

Reconciling neuroimaging and neuropathological findings in schizophrenia and bipolar disorder

Although structural magnetic resonance imaging (sMRI) and neuropathological investigations offer complementary information that can be used to formulate and test hypotheses about pathophysiological mechanisms in psychiatric disorders, the findings from these two fields are seldom integrated in a systematic manner. In this study, we overview recent sMRI findings in schizophrenia and bipolar disorder and consider how they relate to neuropathological data. sMRI research indicates that schizophrenia is associated with volumetric reductions in a network of frontal, temporal, limbic, striatal, and thalamic regions. Some of these abnormalities are apparent prior to psychosis onset and may progress with ongoing illness. sMRI findings in bipolar disorder have been more variable, with both volumetric increases and decreases being reported across several brain regions at different illness stages. Neuropathological studies of both patient groups suggest the cellular changes associated with these volumetric differences affect diverse tissue compartments in a regionally heterogeneous way. These findings suggest that any putative pathophysiological mechanism in schizophrenia or bipolar disorder should account for the dynamic, complex, and regionally heterogeneous brain abnormalities seen in these patients. We contend that greater integration of the findings from these two fields will facilitate more targeted and hypothesis-driven research in the future.

Mutant models for genes associated with schizophrenia

Schizophrenia is a highly complex and heritable psychiatric disorder in which multiple genes and environmental factors interact to cause the schizophrenia phenotype. A new generation of molecular studies has yielded numerous candidate genes with a putative role in risk for schizophrenia, whereas other genes regulate putative pathophysiological mechanisms. Mutant mice having either deletion (knockout) or insertion (knockin/transgenesis) of schizophrenia risk genes now allow the functional role of these genes to be investigated. In the present mini-review, we outline the advantages and limitations of various approaches to phenotypic assessment of mutant mouse models, including ethologically based methods. Thereafter, we consider recent findings, with a particular focus on, first, dopaminergic and glutamatergic pathophysiological models and, secondly, putative roles for DISC1 (disrupted in schizophrenia 1) and NRG1 (neuregulin 1) as susceptibility genes for schizophrenia. Finally, we identify current challenges associated with the use of genetic mutant models and highlight their potential value for exploring gene-gene and gene-environment interactions in relation to schizophrenia.

Van Wyk and Grumbach syndrome revisited: imaging and clinical findings in pre- and postpubertal girls

In 1960 Van Wyk and Grumbach described a syndrome of juvenile hypothyroidism, precocious puberty and ovarian enlargement. These findings undergo complete regression with thyroid hormone replacement therapy. This diagnosis can be made on the basis of imaging findings and thyroid function analysis, avoiding surgery. To relate the distinctive clinical and imaging features and putative pathophysiological mechanism of a series of patients with Van Wyk and Grumbach syndrome (VWGS). Patients with VWGS diagnosed at two large children's hospitals over a 6-year period beginning in 1999 were retrospectively reviewed. A literature review was also conducted. Five female patients were diagnosed with cystic ovarian enlargement and hypothyroidism at ages ranging from 9 to 17 years. Isosexual precocious puberty was found in prepubescent patients. Associated findings included delayed bone age, ascites, and pleural and pericardial effusions. Ovarian cyst involution occurred following treatment of the hypothyroidism. The association of primary hypothyroidism with cystic ovarian enlargement and precocious puberty is important to recognize. In the absence of suspected ovarian torsion, surgery is unnecessary, as cyst regression occurs after appropriate thyroid hormone replacement. Noncompliance with hormone replacement therapy should be considered when cystic ovarian enlargement is noted in patients with a history of hypothyroidism.

Obesity, Inflammation, and the Potential Application of Pharmaconutrition

Obesity is an emerging problem worldwide. Hospitalized obese patients often have a worse outcome than patients of normal weight, particularly in the setting of trauma and critical care. Obesity creates a low-grade systemic inflammatory response syndrome (SIRS) that is similar (but on a much smaller scale) to gram-negative sepsis. This process involves up-regulation of systemic immunity, is characterized clinically by insulin resistance and the metabolic syndrome, and puts the patient at increased risk for organ failure, infectious morbidity, and mortality. Through lipotoxicity and cytokine dysregulation, obesity may act to prime the immune system, predisposing to an exaggerated subsequent immune response when a second clinical insult occurs (such as trauma, burns, or myocardial infarction). Specialized nutrition therapy for such patients currently consists of a hypocaloric, high-protein diet. However, this approach does not address the putative pathophysiologic mechanisms of inflammation and altered metabolism associated with obesity. A number of dietary agents such as arginine, fish oil, and carnitine may correct these problems at the molecular level. Pharmaconutrition formulas may provide exciting innovations for the nutrition therapy of the obese patient.

Sudden sensorineural hearing loss after heroin injection

Sudden sensorineural hearing loss is a symptom of cochlear injury. Potential aetiologies are vascular diseases, viral infections, allergic reactions, autoimmune disorders, and traumatic rupture of the intralabyrinthe membrane. Unlike in unilateral cases bilateral sensorineural hearing loss is often associated with specific disease entities. We report a case of sudden bilateral deafness after intravenous heroin abuse. The putative pathophysiological mechanisms are discussed.

Expression of the local angiotensin II system in gastric cancer may facilitate lymphatic invasion and nodal spread

Purpose: In this study we investigated the putative pathophysiological mechanism, by which angiotensin converting enzyme (ACE), and angiotensin II receptor (ATR) type 1 and 2 might contribute to cancer progression and lymph node metastasis in gastric cancer.Materials and Methods: Local expression of ACE, AT1R, and AT2R was investigated immunohistochemically in non-lesional tissue, primary tumors and lymph node metastases from 45 gastric cancer patients. The distribution of the ACE genotypes was studied in gastric cancer cell lines. In vitro cell proliferation, apoptosis and invasion assays were carried out in the presence of ACE, AT1R and AT2R inhibitors.Results: ACE and AT2R were significantly up-regulated in tumors and metastases, and expressed in the lymph node metastases of 26 (58%) and 40 (89%) gastric cancer patients, respectively. AT1R expression was higher in all tissues of metastatic cancers than in previous investigations. ACE, but not AT1R or AT2R, occasionally exhibited an increased expression in tumor cells directly surrounding lymph follicles. All three possible combinations of the ACE gene insertion/deletion polymorphism were found in gastric cancer cell lines, i.e. the DD- (AGS, MKN28), the II- (MKN45), and the ID-genotype (N87). ACE, AT1R and AT2R inhibition resulted in a significantly increased proliferation and a significant reduction in invasive ability of the N87 and MKN45 cell lines, with N87 exhibiting reduced apoptosis.Conclusions: Our study provides evidence of the expression of the local angiotensin II system in lymph node metastases, and that ACE-, AT1R- and AT2R-activity promotes tumor cell invasion.

Functional dyspepsia: A new Rome III paradigm

Functional dyspepsia (FD) is a condition commonly seen in gastroenterological practice. With the introduction of Rome III criteria in 2006, a new approach for categorizing patients has been recommended. The diagnostic criteria suggest that meal-related and pain-predominant symptom groupings that presumably have distinct pathophysiologic mechanisms and potentially different therapeutic targets exist. The new classification is in the early stages of testing; in the meantime, the umbrella term of FD should continue to be utilized in clinical practice. Treatment of FD remains a major challenge. Unfortunately, most of the agents used in practice have limited or no evidence of efficacy, and the results typically are short-lived once therapy is ceased. Appropriate therapy currently is based on a consideration of putative pathophysiologic mechanisms. Testing for and eradicating Helicobacter pylori is a first-line strategy irrespective of the symptom pattern. In patients who have epigastric pain, antisecretory agents are recommended. Antacids, bismuth, and sucralfate seem to be no better than placebo. For meal-related symptoms such as postprandial fullness or early satiety, prokinetics may confer some benefit. However, few choices are available, and the efficacy for those drugs on the market is limited at best. Antidepressants are of uncertain efficacy but are widely used. Psychological therapies seem promising and may confer benefits on both pain and meal-related symptoms. Efficacy of complementary medicines has been suggested in controlled trials, but more data are needed. Emerging treatments include gastric fundus relaxors and visceral analgesics, although their application in FD is still in the preliminary stages.

Functional dyspepsia: A new Rome III paradigm

Functional dyspepsia (FD) is a condition commonly seen in gastroenterological practice. With the introduction of Rome III criteria in 2006, a new approach for categorizing patients has been recommended. The diagnostic criteria suggest that meal-related and pain-predominant symptom groupings that presumably have distinct pathophysiologic mechanisms and potentially different therapeutic targets exist. The new classification is in the early stages of testing; in the meantime, the umbrella term of FD should continue to be utilized in clinical practice. Treatment of FD remains a major challenge. Unfortunately, most of the agents used in practice have limited or no evidence of efficacy, and the results typically are short-lived once therapy is ceased. Appropriate therapy currently is based on a consideration of putative pathophysiologic mechanisms. Testing for and eradicating Helicobacter pylori is a first-line strategy irrespective of the symptom pattern. In patients who have epigastric pain, antisecretory agents are recommended. Antacids, bismuth, and sucralfate seem to be no better than placebo. For meal-related symptoms such as postprandial fullness or early satiety, prokinetics may confer some benefit. However, few choices are available, and the efficacy for those drugs on the market is limited at best. Antidepressants are of uncertain efficacy but are widely used. Psychological therapies seem promising and may confer benefits on both pain and meal-related symptoms. Efficacy of complementary medicines has been suggested in controlled trials, but more data are needed. Emerging treatments include gastric fundus relaxors and visceral analgesics, although their application in FD is still in the preliminary stages.

Overlap Between GERD and IBS

A substantial proportion of patients seen in gastroenterologic clinics complain of symptoms suggestive of functional derangement of both proximal and distal portions of the alimentary canal. Specifically, many patients with gastro-esophageal reflux disease also complain of the irritable bowel syndrome, but whether this association merely occurs by chance (owing to the high prevalence of these diseases in the general population) or rather reflects a common pathophysiologic basis is unknown. Recent evidence seems to partially support the latter hypothesis, because remarkable similarities have been identified in pathophysiologic studies performed on these apparently different subgroups of patients. This review highlights pathophysiologic features with a potential causative effect in both gastro-esophageal reflux and the irritable bowel syndrome including derangements of mucosal defensive mechanisms, mild inflammation, and visceral hypersensitivity. Indeed, interesting similarities exist in these putative pathophysiologic mechanisms, suggesting that the 2 pathologic conditions may represent different clinical manifestations of similar underlying causes. Ad hoc studies are necessary to prospectively evaluate this hypothesis.

Phantom limb pain: a case of maladaptive CNS plasticity?

Phantom pain refers to pain in a body part that has been amputated or deafferented. It has often been viewed as a type of mental disorder or has been assumed to stem from pathological alterations in the region of the amputation stump. In the past decade, evidence has accumulated that phantom pain might be a phenomenon of the CNS that is related to plastic changes at several levels of the neuraxis and especially the cortex. Here, we discuss the evidence for putative pathophysiological mechanisms with an emphasis on central, and in particular cortical, changes. We cite both animal and human studies and derive suggestions for innovative interventions aimed at alleviating phantom pain.

Association of the Predominant Symptom With Clinical Characteristics and Pathophysiological Mechanisms in Functional Dyspepsia

Functional dyspepsia (FD) is considered a heterogeneous disorder with different pathophysiological mechanisms contributing to the symptom pattern. The Rome II committee proposed that subdividing patients with FD into groups with predominant pain versus discomfort might identify subgroups with homogeneous pathophysiological and clinical properties. The aim of this study was to analyze the relationship of predominant pain or discomfort with pathophysiological mechanisms and to evaluate whether considering individual predominant symptoms yields better results. Consecutive FD patients (n = 720; 489 women; mean age, 41.3 +/- 0.6 years) filled out a dyspepsia questionnaire and identified a single most bothersome symptom. We analyzed the association of this predominant symptom with demographic, clinical, and pathophysiological features (Helicobacter pylori status, gastric emptying in 592 patients, and gastric sensitivity and accommodation testing in 332 patients). According to Rome II criteria, 22% were pain predominant and 78% discomfort predominant. Patients with predominant pain had a higher prevalence of hypersensitivity (44% vs 25%) and delayed gastric emptying was observed less frequently in these patients (16% vs 26%), but there was major overlap. Detailed analysis showed that any of 8 dyspeptic symptoms could be predominant. Predominant early satiety or vomiting was associated with significantly higher prevalences of weight loss (89% and 75%, respectively) and of acute onset (61% and 60%, respectively). Impaired accommodation was found in 79% of patients with predominant early satiety. The highest prevalence of delayed emptying was found in predominant fullness (38%) and of hypersensitivity in predominant pain (44%). Subdividing FD patient groups according to the predominant symptom does not reliably identify subgroups with a homogeneous underlying pathophysiological mechanism.

Are there Differential Symptom Profiles that Improve in Response to Different Pharmacological Treatments of Premenstrual Syndrome/Premenstrual Dysphoric Disorder?

Current evidence suggests that the accepted treatments for premenstrual syndrome (PMS)/premenstrual dysphoric disorder (PMDD) have similar overall efficacy. While these treatments are more effective than placebo, response rates associated with them are far from satisfactory (<60%), such that, irrespective of treatment modality, there remain a significant number of women who are unresponsive to current conventional pharmacological therapy. The available data on response rates of specific types of premenstrual symptoms to, or symptom profiles that are most amenable to, each treatment modality are limited and not well defined because most studies were not designed to assess specific symptom profiles. Those studies that have attempted to evaluate which symptom profiles respond to specific therapies have revealed variations within the individual modalities, as well as between the different modalities. It appears that suppression of ovulation ameliorates a broad range of behavioural as well as physical premenstrual symptoms. SSRIs are most effective for irritability and anxiety symptoms, with lesser efficacy for 'atypical' premenstrual symptoms. GABAergic compounds are most efficacious for anxiety and anxious/depressive symptoms, while dopamine agonists, particularly bromocriptine, are perhaps most efficacious for mastalgia. Overall treatment response rates may improve if treatments are targeted at well-defined subgroups of patients. Re-analysis of available datasets from randomised clinical trials may shed more light on the notion that targeting women with specific premenstrual symptom profiles for specific treatment modalities would improve response rates beyond the current ceiling of approximately 60%. Such information would also improve understanding of the putative pathophysiological mechanisms underlying PMS and PMDD, and may point to a more specific diagnosis of these conditions.

QSART in idiopathic pure sudomotor failure

QSART (quantitative sudomotor axon reflex testing) was performed in a patient with idiopathic pure sudomotor failure. Generalized reduction in thermoregulatory sweating and complete absence of axon reflex sweating were observed, suggesting a deficit of sweat gland cholinergic synaptic transmission or receptors. QSART responded promptly to treatment. Putative pathophysiological mechanisms are discussed.

Treatment of functional dyspepsia

Functional dyspepsia (FD) is a common reason a patient presents with upper gastrointestinal symptoms for medical care. Although treatment of FD remains expensive, the agents are rarely used in a systematic manner; the majority of treatments are empirical and the results short lived once therapy is ceased. This is partly due to the lack of consistent pathophysiologic markers in FD, so therapy is symptom driven. This review appraises the best evidence on available interventions. A structured scheme for deciding on appropriate therapies is to consider the possible putative pathophysiologic mechanisms. Eradicating Helicobacter pylori, if present, is a first-line strategy. In patients who have symptoms suggesting excessive gastric acid secretion, particularly epigastric pain, antisecretory agents are recommended. Prokinetics may confer benefits on symptoms suggestive of upper gastrointestinal dysmotility, like fullness or early satiety. However, their use is limited due to availability issues. The expanding field of psychologic therapies provides a promising avenue of treatment. Complementary medicines are now widely use and their benefits have been suggested in recent controlled trials. Emerging treatments include cholecystokinin 1 blockers, opioid receptor agonists, and serotonergic agents, although their application in FD is in the preliminary stages.

Functional dyspepsia pathogenesis and therapeutic options—Implications for management

Functional dyspepsia is far more common than dyspepsia due to organic disease, both in the community and general practice. Proposed aetiopathogenic factors include gastric acid, Helicobacter pylori infection, delayed emptying, hypersensitivity or impaired accommodation of the stomach, dysfunction of the duodenum or brain–gut axis, psychosocial morbidity and post-infective mucosal damage. More effective therapy will depend on the development of drugs targeted at these putative pathophysiological mechanisms. On current evidence tricyclic antidepressants appear to be more effective than either acid suppressants or H. pylori eradication.

Dural arteriovenous fistulas with aggressive course: clinical and angiographic correlations in two patients

Cranial dural arteriovenous fistulas (DAVFs) usually present with non-aggressive symptoms. We here report two patients who presented a peculiar clinical picture related to DAVFs, with focal neurological signs and haemorrhagic (case 1) or ischaemic lesions (case 2) respectively. The clinical and angiographic findings and putative pathophysiological mechanisms are discussed.