bluuebunny/crossref_metadata_2025 huggingface dataset:
Beneficial Effect of Supplemental Lipoic Acid on Diabetes‐Induced Pregnancy Loss in the Mouse
Authors: PADMANABHAN RENGASAMY , MOHAMED SHAFIULLAH , SINGH SARABJIT
Published: December 2006

Abstract:  Uncontrolled diabetes mellitus (DM) is an etiological factor for recurrent pregnancy loss, fetal growth disorders, and major congenital malformations in the offspring. Antioxidant therapy has been advocated to overcome the oxidant–antioxidant disequilibrium inherent in diabetes. The objective of this article was to evaluate the beneficial effects of α‐lipoic acid (LA) on fetal outcome in a mouse model of streptozotocin (STZ)‐induced DM. Timed pregnant mice were made diabetic by intraperitoneal (IP) injection of a single dose of STZ (200 mg/kg) on gestation day (GD) 2. Diabetic animals were supplemented daily with an IP injection of 15 mg/kg of LA starting on GD 4 and continued through GD 12. Fetuses were examined on GD 18 for malformations and growth restriction. Some diabetic mice injected with Evans blue were examined on GD 3.5 and GD 6.5 to evaluate frequency of implantations. STZ‐treated mice had all cardinal signs of DM. LA treatment did not normalize blood glucose levels of DM mice. Rates of pregnancy in saline control, DM, and DM + LA groups were 90%, 28%, and 64%, respectively, indicating that LA promotes pregnancy in DM animals. However, postimplantation resorption showed a threefold increase in the DM + LA group. Rates of intrauterine growth restriction and major congenital malformations were also augmented thus indicating that the interaction between DM and LA has deleterious effects on postimplantation embryos.
Effects of Streptozotocin‐Induced Type 1 Diabetes Mellitus on Total Protein Concentrations and Cation Contents in the Isolated Pancreas, Parotid, Submandibular, and Lacrimal Glands of Rats
Authors: CHANGRANI NAVIN R. , CHONKAR APURVA , ADEGHATE ERNEST , SINGH JAIPAUL
Published: December 2006

Abstract:  This study investigated the effect of streptozotocin (STZ)‐induced type 1 diabetes mellitus (DM) on total protein concentration and levels of sodium (Na+), potassium (K+), magnesium (Mg2+), zinc (Zn2+), copper (Cu2+), calcium (Ca2+), and iron (Fe2+) in the pancreas, parotid, submandibular, and lacrimal glands of the rat, compared to age‐matched control animals. Protein concentrations were measured by the Bradford Assay, whereas levels of Na+, K+, Mg2+, Zn2+, Cu2+, Ca2+, and Fe2+ were measured by flame photometry and atomic absorbance spectrophotometry. The results show marked changes in the characteristics of diabetic and control animals. Diabetic rats and their different glands weighed significantly (P < 0.05) less compared to age‐matched controls. Diabetic rats also have significantly elevated blood glucose and significantly reduced plasma insulin, compared to controls. The results also show that the concentrations of proteins and levels of cations were significantly (P < 0.05) reduced in the pancreas, parotid, submandibular and lacrimal glands of diabetic rats, compared to glands from age‐matched animals. These differences in the cation contents and protein levels in STZ‐induced DM in this study, along with supporting evidences from previous studies, may provide evidence for the development of long‐term complications of DM including exocrine gland deficiencies.
Lipid Peroxidation and Serum Antioxidant Enzymes in Patients with Type 2 Diabetes Mellitus
Authors: AHMED FEROZA N. , NAQVI FARZANA N. , SHAFIQ FAKHRA
Published: December 2006

Abstract:  Diabetes mellitus is characterized by fasting hyperglycemia, with both type 1 and type 2 diabetes. Persons are also known to be prone to develop complications related to elevated blood glucose concentrations, including atherosclerosis, retinal damage, cataract, and neuropathy. Hyperglycemia may also result in increased production of the reactive oxygen species within numerous biochemical pathways that have the potential to initiate changes in endothelial function. This article demonstrates the presence of lipid peroxidation products in the red cell membranes of type 2 diabetic patients compared to the normal subjects. These membranes are more susceptible to exogenous oxidative stress than those of normal healthy individuals. Significantly higher activities of antioxidant enzymes, namely, serum peroxidase, superoxide dismutase (SOD), and catalase (CAT) were found in type 2 diabetic patients as compared to control. This study led us to conclude that elevated levels of glucose induce oxidative stress that is ultimately reflected by the increased malondialdehyde (MDA) levels in erythrocyte ghost membranes of diabetic patients. Hyperglycemia also induced an increase in antioxidant enzymes and a relationship seems to exist between diabetic complications and elevated levels of these enzymes. It is suggested that these antioxidant enzymes may be considered as markers for vascular injury.
Effect of Psychological Intervention on Exercise Adherence in Type 2 Diabetic Subjects
Authors: MARTINUS ROBERT , CORBAN ROD , WACKERHAGE HENNING , ATKINS STEVE , SINGH JAIPAUL
Published: December 2006

Abstract:  Previous research has pointed to the efficacy of physical activity in individuals suffering from type 2 diabetes mellitus (type 2 DM). However, as with other populations, adherence to exercise programs is often problematic. This study assessed the effectiveness of a combination of exercise and psychological interventions in type 2 diabetics in terms of disease management and exercise adherence. Forty newly diagnosed type 2 diabetic subjects (54 ± 6.5 years) took part in the study. Subjects were allocated to an exercise‐only intervention (EO) or a combined exercise and psychological adherence intervention (EP) group. Adherence to the program was also monitored at a 6‐month follow‐up. The results confirmed a significant improvement in physiological parameters (total mass, fat mass, grip strength, peak flow, flexibility, and VO2 max) after the 12‐week program in both groups (P < 0.001). The EP group had significant changes in body fat, grip strength, and peak flow (P < 0.05) in comparison to the EO group. Components of the visual analog mood scale (VAMS) were positively influenced in both groups from the therapy program (P < 0.001). The directed psychological intervention had a significant influence on attendance to the 12‐week program (P < 0.001). This also resulted in significantly better adherence 6 months later (P < 0.05). In conclusion, the results have demonstrated that psychological intervention is of paramount importance for ensuring high adherence rates during exercise therapy for type 2 diabetic subjects.
Signaling Proteins Associated with Diabetic‐Induced Exocrine Pancreatic Insufficiency in Rats
Authors: PATEL REKHA , ATHERTON PHILIP , WACKERHAGE HENNING , SINGH JAIPAUL
Published: December 2006

Abstract:  Diabetes mellitus (DM) is associated with pancreatic atrophy and compromised digestion of carbohydrates as a result of exocrine pancreatic insufficiency and lower alpha‐amylase synthesis and secretion. The reduced production of digestive enzymes is likely to be caused by deregulated protein metabolism. The relative concentrations and phosphorylation of signaling proteins associated with protein translation, such as PKB, p70S6K1, 4E‐BP1, ERK1/2, and also some of those implicated in protein breakdown, such as ubiquitin and NF‐κB, in the pancreas of streptozotocin (STZ)‐induced type I diabetic pancreas were measured using Western blotting. There were significant decreases in the levels of total PKB, p70S6K, 4E‐BP1, ERK1/2, and NF‐κB in the diabetic pancreas compared to control. In contrast, the phosphorylation of p70S6K1, 4E‐BP1, ERK1/2, and protein ubiquitination increased significantly compared to controls. Together, these results indicate that STZ‐induced DM leads to reduced levels of enzymes mediating protein synthesis while their phosphorylation is actually increased, perhaps in an attempt to maintain protein homeostasis, which is further compromised by heightened ubiquitin‐dependent protein breakdown. It is likely that these factors are responsible for pancreatic atrophy, enzyme synthesis, and net protein loss in DM.
Effect of Insulin on Acetylcholine‐Evoked Amylase Release and Calcium Mobilization in Streptozotocin‐Induced Diabetic Rat Pancreatic Acinar Cells
Authors: PATEL REKHA , PARIENTE JOSÉ A. , MARTINEZ MARIA A. , SALIDO GINÉS M. , SINGH JAIPAUL
Published: December 2006

Abstract:  This article investigated the effect of acetylcholine (ACh) on amylase secretion and cellular calcium homeostasis [Ca2+]i in streptozotocin (STZ; 60 mg kg−1, intraperitoneally)‐induced diabetic rats compared to age‐matched controls in an attempt to understand the cellular mechanism of exocrine pancreatic insufficiency. ACh‐evoked marked dose‐dependent increases in amylase release from isolated pancreatic acini and acinar cells in healthy control rats. In diabetic acini and acinar cells, the ACh‐evoked amylase release was significantly (P < 0.05) reduced compared to healthy acini and acinar cells. Insulin (10−6M) stimulated amylase release in both control and diabetic acini and acinar cells but with a much reduced effect in diabetic tissues. Combining insulin with ACh had no significant effect on amylase release compared to the effect of ACh alone. In fura‐2 loaded pancreatic acinar cells of normal rats, ACh (10−5M) evoked a large initial rise (peak) in [Ca2+]i followed by a decline into a plateau phase. This effect of ACh was significantly (P < 0.05) reduced in fura‐2 loaded diabetic acinar cells. In control cells, insulin had no significant effect on either basal or ACh evoked [Ca2+]i compared to the effect of ACh alone. In contrast, in diabetic acinar cells, insulin significantly (P < 0.05) attenuated the effect of ACh. In a normally free extracellular Ca2+ medium [Ca2+]o containing 1 mM EGTA, the ACh‐evoked [Ca2+]i in normal healthy fura‐2 loaded acini was similar to the response obtained with ACh in fura‐2 loaded diabetic acini. Together, the results indicated that exocrine pancreatic insufficiency is associated with decreased [Ca2+]i due to less Ca2+ released from internal stores and less Ca2+ entering the cell from the extracellular medium.
Effect of Streptozotocin‐Induced Type 1 Diabetes Mellitus on Contraction, Calcium Transient, and Cation Contents in the Isolated Rat Heart
Authors: SINGH JAIPAUL , CHONKAR APURVA , BRACKEN NICHOLAS , ADEGHATE ERNEST , LATT ZAY , HUSSAIN MUNIR
Published: December 2006

Abstract:  Cations play major physiological and biochemical roles in the excitation–contraction coupling processes in the heart. This study investigated the effect of streptozotocin (STZ)‐induced type I diabetes mellitus (DM) on contraction, calcium transient [Ca2+]i, and cation contents in the isolated rat heart compared to age‐matched control. Diabetes rats weighed significantly (P < 0.05) less compared to control. They also had significantly (P < 0.05) elevated blood glucose compared to control. The whole heart, as well as the atria, right and left ventricles of the diabetic heart weighed significantly (P < 0.05) less compared to hearts from age control rats. The force of contraction and time to peak (t‐pk) contraction in diabetic ventricular myocytes increased significantly (P < 0.05) compared to control. By contrast, these parameters did not change for the Ca2+ transient except for the time to half (t½) relaxation. The levels of sodium (Na+), potassium (K+), calcium (Ca2+), magnesium (Mg2+), iron (Fe2+), copper (Cu2+), and zinc (Zn2+) in the hearts varied from diabetic compared to control animals. The results indicate that 6–8 weeks of STZ‐induced DM is associated with marked changes in contraction and in cation contents of the heart. The delay in the t½ relaxation of the Ca2+ transient may be responsible for the elevated contraction seen in the diabetic heart. Moreover, the changes in cation contents in the heart may be responsible for abnormal cardiac rhythms and activity during DM.
An Update on the Etiology and Epidemiology of Diabetes Mellitus
Authors: ADEGHATE ERNEST , SCHATTNER PETER , DUNN EARL
Published: December 2006

Abstract: Diabetes mellitus is one of the most common endocrine disorders affecting almost 6% of the world's population. The number of diabetic patients will reach 300 million in 2025 (International Diabetes Federation, 2001). More than 97% of these patients will have type II diabetes. The projected increase in the number of diabetic patients will strain the capabilities of healthcare providers the world over. Thus it is of paramount importance to revisit the causes and epidemiology of diabetes mellitus. Diabetes mellitus is caused by both environmental and genetic factors. The environmental factors that may lead to the development of diabetes mellitus include physical inactivity, drugs and toxic agents, obesity, viral infection, and location. While type I diabetes is not a genetically predestined disease, an increased susceptibility can be inherited. Genetic susceptibility plays a crucial role in the etiology and manifestation of type II diabetes, with concordance in monozygotic twins approaching 100%. Genetic factors may have to be modified by environmental factors for diabetes mellitus to become overt. An individual with a susceptible gene may become diabetic if environmental factors modify the expression of these genes. Since there is an increase in the trend at which diabetes prevail, it is evident that environmental factors are playing a more increasing role in the cause of diabetes mellitus. The incidence of type I diabetes ranged from 1.9 to 7.0/100,000/yr in Africa, 0.13 to 10/100,000/yr in Asia, ∼4.4/100,000/yr in Australasia, 3.4 to 36/100,000/yr in Europe, 2.62 to 20.18/100,000/yr in the Middle East, 7.61 to 25.7/100,000/yr in North America, and 1.27 to 18/100,000/yr in South America. The epidemiology of type II diabetes is equally bleak. The prevalence of type II diabetes ranged from 0.3 to 17.9% in Africa, 1.2 to 14.6% in Asia, 0.7 to 11.6% in Europe, 4.6 to 40% in the Middle East, 6.69 to 28.2% in North America, and 2.01 to 17.4% in South America.
Vitamin E Ameliorates Some Biochemical Parameters in Normal and Diabetic Rats
Authors: AL SHAMSI MARIAM , AMIN AMR , ADEGHATE ERNEST
Published: December 2006

Abstract:  Diabetes is associated with hyperglycemia, one of the most important causes of oxidative stress. Endogenous antioxidants are able to destroy the reactive species and create a balance between antioxidant and free radicals. In diabetes, the oxidative stress is increased due to the deficiency in the antioxidant defense. The intake of antioxidants, such as vitamin E, may reduce the oxidative stress associated with diabetes and hence help to restore the antioxidant defense system. The aim of this article was to investigate the effect of different doses of vitamin E on the biochemical parameters of normal and streptozotocin (STZ)‐induced diabetic rats. Biochemical analysis was used to study the effect of this vitamin on the biochemical parameters of normal and diabetic rats. The plasma levels of alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactic dehydrogenase (LDH), and gamma‐glutamyl transferase (γ‐GT) were significantly increased after the onset of diabetes. In addition, STZ‐induced diabetes also caused an increase in the level of blood urea nitrogen (BUN) and creatinine. Oral administration of vitamin E (0.2–0.4 mg daily) significantly (P < 0.05) decreased the plasma level of ALT, AST, and γ‐GT. In addition, there was a slight but not significant reduction in the plasma level of ALP. Parameters of kidney function, such as BUN and creatinine, were slightly reduced after the oral administration of vitamin E. The plasma level of electrolytes, such as calcium and sodium, also changed significantly (P < 0.00001) after the oral administration of vitamin E. Vitamin E ameliorates the metabolic and biochemical parameters of diabetic rats.
Cardiovascular Risk Factors Predicting the Development of Distal Symmetrical Polyneuropathy in People with Type 1 Diabetes
Authors: SIBAL LATIKA , LAW HUONG NAI , GEBBIE JANICE , HOME PHILIP
Published: December 2006

Abstract:  The aim of the article was to use prospectively collected data on people with type 1 diabetes to examine which routinely collected clinical measures predict the development of peripheral neuropathy in people with type 1 diabetes. Within the Newcastle Diabetes Services, structured data collection at an annual review has been collected since 1985. This includes metabolic measures, cardiovascular risk factors, and markers of complications. From 1990 data collection was standardized and computerized. For this study, all people with type 1 diabetes in the database in both 1992 and 2001 were ascertained. Data were extracted for a diagnosis of peripheral neuropathy (based on neuropathic symptoms, absence of pinprick sensation, and abnormal biothesiometer measurements and/or monofilament sensation) and for the other metabolic and cardiovascular risk measures, as well as markers of other microvascular complications. Associations with the development of neuropathy were sought. Eighteen of 404 people already had peripheral neuropathy in 1992, and 38 others developed neuropathy during follow‐up. People who developed neuropathy were older (47 ± 14 [SD] versus 36 ± 11 years; P= 0.000), had longer‐duration of diabetes (27 ± 13 versus 18 ± 10 years; P= 0.001), higher baseline serum cholesterol (5.8 ± 1.3 versus 5.2 ± 1.2 mmol/L, P= 0.017), and higher systolic (139 ± 18 versus 129 ± 20 mmHg; P= 0.003) and diastolic BP (82 ± 12 versus 76 ± 11 mmHg; P= 0.009) than those who remained free of neuropathy. We found no significant difference for BMI and glycated hemoglobin. The multivariate model showed that diastolic BP, duration of diabetes, serum cholesterol, and history of callus/ulcers on the feet predicted the development of peripheral neuropathy. Neuropathy developed in 11.4% of people with type 1 diabetes over a 9‐year follow‐up, and was predicted by factors normally associated with cardiovascular rather than microvascular disease.
Mechanism of Exocrine Pancreatic Insufficiency in Streptozotocin‐Induced Type 1 Diabetes Mellitus
Authors: PATEL REKHA , SHERVINGTON AMIL , PARIENTE JOSE A. , MARTINEZ‐BURGOS MARIA A. , SALIDO GINES M. , ADEGHATE ERNEST , SINGH JAIPAUL
Published: December 2006

Abstract:  Diabetes mellitus (DM) is a major health problem at present affecting about 180 million people worldwide. DM is associated with many metabolic abnormalities in the body including the indigestion of carbohydrates leading to malnutrition and weight loss. In this article we investigate the cellular and molecular mechanisms of exocrine pancreatic insufficiency in streptozotocin (STZ, 60 mg kg−1, i.p.)‐induced DM in male rats compared to healthy age‐matched controls. Either electrical field stimulation (EFS) or cholecystokinin octapeptide (CCK‐8, 10−8 M) can elicit large and significant (P < 0.05) increases in amylase output from pancreatic segments compared to basal secretion. Insulin (10−6 M) alone has no significant effect on amylase output compared to basal but it enhanced the secretory responses to either EFS or CCK‐8. When rats were rendered diabetic with STZ, either EFS or CCK‐8‐evoked amylase output was significantly (P < 0.01) decreased compared to the responses obtained with either EFS or CCK‐8 alone in healthy age‐matched control pancreas. In addition, CCK‐8 can elicit large dose‐dependent release of amylase in age‐matched control and diabetic acinar cells with significantly (P < 0.05) reduced responses in diabetic acinar cells. CCK‐8 evoked a large rapid increase in peak cytosolic free calcium concentration ([Ca2+]c) followed by a decrease to a plateau phase in age‐matched control fura‐2‐loaded pancreatic acinar cells. These responses were significantly (P < 0.05) decreased in STZ‐induced diabetic acinar cells. In the presence of 10−6 M insulin, CCK‐8 evoked a much larger increase in the Ca2+ transient compared to the response obtained with CCK‐8 alone. These effects were significantly (P < 0.01) inhibited in STZ‐induced diabetic acinar cells. Similarly, in zero extracellular Ca2+[Ca2+]ĉ, the CCK‐8‐evoked [Ca2+]c was significantly (P < 0.05) reduced in both diabetic and age‐matched control acinar cells, but with more pronounced reduction in diabetic acinar cells. CCKA receptor mRNA levels remained unchanged in diabetic rat acinar cells compared to age‐matched healthy control. In contrast, amylase mRNA was significantly (P < 0.05) reduced in diabetic acinar cells compared to control. The results indicate that reduced amylase secretion in response to either EFS or CCK‐8 in the diabetic pancreas may be due to reduced [Ca2+]c and gene expression for amylase and not to the gene expression of CCKA receptor in pancreatic acinar cells.
Inflammatory Process in Type 2 Diabetes
Authors: ALEXANDRAKI KRYSTALLENIA , PIPERI CHRISTINA , KALOFOUTIS CHRISTOS , SINGH JAIPAUL , ALAVERAS ANTONIS , KALOFOUTIS ANASTASIOS
Published: December 2006

Abstract:  Population‐based studies have shown strong relationship between inflammatory markers and metabolic disturbances, obesity, and atherosclerosis, whereas inflammation has been considered as a “common soil” between these clinical entities and type 2 diabetes (T2D). The accumulation of macrophages in adipose tissue (AT), the common origin of macrophages and adipocytes, the prevalent presence of peripheral mononuclear cells, and apoptotic β cells by themselves seem to be the sources of inflammation present in T2D, since they generate the mediators of the inflammatory processes, namely cytokines. The main cytokines involved in the pathogenesis of T2D are interleukin‐1β (IL‐1β), with an action similar to the one present in type 1 diabetes, tumor necrosis factor‐α (TNF‐α), and IL‐6, considered as the main regulators of inflammation, leptin, more recently introduced, and several others, such as monocyte chemoattractant protein‐1, resistin, adiponectin, with either deleterious or beneficial effects in diabetic pathogenesis. The characterization of these molecules targeted diabetes treatment beyond the classical interventions with lifestyle changes and pharmaceutical agents, and toward the determination of specific molecular pathways that lead to low grade chronic inflammatory state mainly due to an immune system's unbalance.
Peroxisome Proliferator-Activated Receptor γ and Adipose Tissue—Understanding Obesity-Related Changes in Regulation of Lipid and Glucose Metabolism
Authors: Sharma Arya M. , Staels Bart
Published: December 2006

Context: Adipose tissue is a metabolically dynamic organ, serving as a buffer to control fatty acid flux and a regulator of endocrine function. In obese subjects, and those with type 2 diabetes or the metabolic syndrome, adipose tissue function is altered (i.e. adipocytes display morphological differences alongside aberrant endocrine and metabolic function and low-grade inflammation).

Evidence Acquisition: Articles on the role of peroxisome proliferator-activated receptor γ (PPARγ) in adipose tissue of healthy individuals and those with obesity, metabolic syndrome, or type 2 diabetes were sourced using MEDLINE (1990–2006).

Evidence Synthesis: Articles were assessed to provide a comprehensive overview of how PPARγ-activating ligands improve adipose tissue function, and how this links to improvements in insulin resistance and the progression to type 2 diabetes and atherosclerosis.

Conclusions: PPARγ is highly expressed in adipose tissue, where its activation with thiazolidinediones alters fat topography and adipocyte phenotype and up-regulates genes involved in fatty acid metabolism and triglyceride storage. Furthermore, PPARγ activation is associated with potentially beneficial effects on the expression and secretion of a range of factors, including adiponectin, resistin, IL-6, TNFα, plasminogen activator inhibitor-1, monocyte chemoattractant protein-1, and angiotensinogen, as well as a reduction in plasma nonesterified fatty acid supply. The effects of PPARγ also extend to macrophages, where they suppress production of inflammatory mediators. As such, PPARγ activation appears to have a beneficial effect on the relationship between the macrophage and adipocyte that is distorted in obesity. Thus, PPARγ-activating ligands improve adipose tissue function and may have a role in preventing progression of insulin resistance to diabetes and endothelial dysfunction to atherosclerosis.
Glycodelin-A interacts with fucosyltransferase on human sperm plasma membrane to inhibit spermatozoa-zona pellucida binding
Authors: Chiu Philip C. N. , Chung Man-Kin , Koistinen Riitta , Koistinen Hannu , Seppala Markku , Ho Pak-Chung , Ng Ernest H. Y. , Lee Kai-Fai , Yeung William S. B.
Published: December 2006

Fertilization depends on successful binding of the spermatozoa to the zona pellucida of the oocyte. Glycodelin-A inhibits spermatozoa-zona pellucida binding. Previous data showed that glycodelin-A receptor(s) and zona pellucida protein receptor(s) on human spermatozoa are closely related. Using a chemical cross-linking approach, the glycodelin-A-sperm receptor complex was isolated. The receptor was identified to be fucosyltransferase-5 (FUT5) by mass spectrometry and confirmed with the use of anti-FUT5 antibodies. Sperm FUT5 was an externally oriented integral membrane protein in the acrosomal region of human spermatozoa. Biologically active FUT5 was purified from spermatozoa. Co-immunoprecipitation confirmed the interaction between glycodelin-A and sperm FUT5. Solubilized zona pellucida reduced the binding of glycodelin-A to sperm FUT5. An anti-FUT5 antibody and FUT5 acceptor blocked the binding of glycodelin-A to spermatozoa and the zona binding inhibitory activity of glycodelin-A. Sperm FUT5 bound strongly to intact and solubilized human zona pellucida. The equilibrium dissociation constant of sperm FUT5 binding to solubilized zona pellucida was 42.82 pmol/ml. These observations suggest that human sperm FUT5 is a receptor of glycodelin-A and zona pellucida proteins, and that glycodelin-A inhibits spermatozoa-zona binding by blocking the binding of sperm FUT5 to the zona pellucida.
A loss-of-function screen reveals SNX5 and SNX6 as potential components of the mammalian retromer
Authors: Wassmer Thomas , Attar Naomi , Bujny Miriam V. , Oakley Jacqueline , Traer Colin J. , Cullen Peter J.
Published: December 2006

The mammalian retromer is a multimeric protein complex involved in mediating endosome-to-trans-Golgi-network retrograde transport of the cation-independent mannose-6-phosphate receptor. The retromer is composed of two subcomplexes, one containing SNX1 and forming a membrane-bound coat, the other comprising VPS26, VPS29 and VPS35 and being cargo-selective. In yeast, an additional sorting nexin - Vps17p - is a component of the membrane bound coat. It remains unclear whether the mammalian retromer requires a functional equivalent of Vps17p. Here, we have used an RNAi loss-of-function screen to examine whether any of the other 30 mammalian sorting nexins are required for retromer-mediated endosome-to-trans-Golgi-network retrieval of the cation-independent mannose-6-phosphate receptor. Using this screen, we identified two proteins, SNX5 and SNX6, that, when suppressed, induced a phenotype similar to that observed upon suppression of known retromer components. Whereas SNX5 and SNX6 colocalised with SNX1 on early endosomes, in immunoprecipitation experiments only SNX6 appeared to exist in a complex with SNX1. Interestingly, suppression of SNX5 and/or SNX6 resulted in a significant loss of SNX1, an effect that seemed to result from post-translational regulation of the SNX1 level. Such data suggest that SNX1 and SNX6 exist in a stable, endosomally associated complex that is required for retromer-mediated retrieval of the cation-independent mannose-6-phosphate receptor. SNX5 and SNX6 may therefore constitute functional equivalents of Vps17p in mammals.
Counseling the Oncology Patient
Authors: Vall Emily Du , Lash Stephen D. , Grabenstein John D. , Watson Ralph R.
Published: December 2006

The clinical pharmacist of today has developed a broad knowledge base in the areas of cancer chemotherapy and the associated ancillary therapies. In spite of this expertise, most are ill-prepared for a face-to-face interaction with the cancer patient. Difficult situations may tempt the pharmacist to avoid contact with the cancer patient and confine his talents to areas in which he feels more comfortable. However, the pharmacist is in a unique situation in that he is accessible, informed, and respected by the patient. Pharmacists must assume the responsibility of ensuring that the cancer patient receives the full benefit of this expertise, which can only be accomplished through appropriate communication skills. This editorial explores some of the techniques and common pitfalls that await the pharmacist in his day-to-day practice.
Inhaled Amphotericin B for Prophylaxis Against Invasive Aspergillus Infections
Authors: Mohammad Rima A , Klein Kristin C
Published: December 2006

Objective:

To evaluate the available literature describing the use of inhaled amphotericin B for prophylaxis of invasive Aspergillus spp. infections.

Data Sources:

A MEDLINE search was conducted (1966–July 2006) using the key terms amphotericin B, inhaled amphotericin B, Aspergillus spp., invasive aspergillosis, solid-organ transplant, neutropenia, and inhalation. Review of the reference lists of the identified articles was also performed.

Study Selection And Data Extraction:

Study selection included published trials, case reports, and case series of humans with hematologic disease and solid-organ transplant who used inhaled amphotericin B in the prevention of invasive Aspergillus infections.

Data Synthesis:

Inhaled amphotericin B has been evaluated for the prevention of invasive aspergillosis (IA) infections in neutropenic patients and certain solid-organ transplant recipients. Use of inhaled amphotericin B seems to reduce the incidence of IA in these patients; however, some of the clinical evidence was limited by factors such as small sample sizes, lack of statistical analyses, and lack of power to detect a difference between prophylaxis and control groups. Although the clinical evidence supporting the use of inhaled amphotericin B has some limitations, its use still may be beneficial for the prophylaxis of invasive Aspergillus infections, especially in solid-organ transplant recipients where the evidence is strongest.

Conclusions:

Invasive Aspergillus infections are becoming more prevalent in high-risk populations (eg, patients with malignancies, following bone marrow transplantation, or following solid-organ transplantation). The mortality rates associated with IA are great in these populations, making prophylaxis an important consideration. Inhaled amphotericin B has recently come into vogue as an option for prophylaxis against IA. Some of the data available supports the use of inhaled amphotericin B for the prevention of IA while providing evidence of fewer drug interactions and toxicities associated with other antifungal agents.
Community Pharmacy Services in Portugal
Authors: Costa Suzete , Santos Cristina , Silveira João
Published: December 2006

Objective:

To describe the status and outline the trends of community pharmacy services in the Portuguese healthcare system.

Findings:

The legal framework for Portuguese pharmacies includes geographic and demographic criteria for opening pharmacies and restricting ownership to pharmacists. Since 1975, pharmacy owners have been organized under one association, the Portuguese National Pharmacy Association, which has dealt with pharmacy development over the past 20 years. Securing the economic sustainability of pharmacies was the first milestone. Investing in information software and communication technologies and modernizing the architecture of pharmacies was the next step. Then, professional services such as point-of-care measurements, drug waste management, and needle exchange services were developed. The methadone substitution program was introduced at a later date. Finally, major comprehensive services, including disease management/pharmaceutical care programs, were implemented.

Discussion:

All Portuguese pharmacies are independent, which means that the decision to provide different services and the extent to which they are attained vary from pharmacy to pharmacy. Recent political changes seem to reinforce the need to pursue the strategies already defined—to expand the traditional scope of pharmacy business to a wider range of health services.

Conclusions:

Achievements that have been accomplished and strategies that are in place reflect a high level of organization and unity among Portuguese pharmacies. From a global perspective, pharmacies are reorganizing to be able to compete against other possible agents and are preparing to expand their scope of intervention.
Combined Organ Failure with Combination Antihyperlipidemic Treatment: A Case of Hepatic Injury and Acute Renal Failure
Authors: Akoglu Hadim , Yilmaz Rahmi , Kirkpantur Alper , Arici Mustafa , Altun Bulent , Turgan Cetin
Published: December 2006

Objective:

To report a case of acute hepatic injury and acute renal failure secondary to rhabdomyolysis associated with fluvastatin–gemfibrozil combination therapy for hyperlipidemia.

Case Summary:

A 56-year-old woman with a history of hyperlipidemia presented with fatigue, weakness in her lower extremities, and red-colored urine. One month prior, she had started combination therapy of fluvastatin 80 mg/day and gemfibrozil 1200 mg/day. On physical examination, she had a serious loss of motor function in the upper and lower extremities. Her laboratory tests revealed severe liver enzyme elevation and abnormal renal function. Abdominal ultrasound did not show hepatic cholestasis, renal parenchymal abnormality, or obstruction.

Discussion:

Statins and fibric acid derivatives have complementary effects on mixed hyperlipidemia. However, such combination therapy increases the risk of myopathy, which may result in life-threatening rhabdomyolysis. Several reports have suggested that combination fluvastatin–gemfibrozil therapy is both effective and safe in mixed lipid disorders. In our patient, severe rhabdomyolysis with serious hepatocellular injury was observed one month after the combination antihyperlipidemic therapy was started. Assessment with the Naranjo probability scale determined that an adverse drug reaction was probable. The mechanism of this combined toxicity is difficult to clarify, although in vivo and in vitro studies to date have reported considerable data concerning antihyperlipidemic drug interactions.

Conclusions:

Clinicians should carefully consider the risks and benefits of treating dyslipidemia with fluvastatin–gemlibrozil combination therapy.
Past, Present, and Future Therapies for Clostridium difficile–Associated Disease
Authors: Surowiec Dorothy , Kuyumjian Arpi G , Wynd Michael A , Cicogna Cristina E
Published: December 2006

Objective:

To describe and examine the past, present, and potential future treatment options for Clostridium difficile–associated disease (CDAD).

Data Sources:

A PubMed search, restricted to English-language articles concerning CDAD, was conducted (1965–October 2006) using the key words Clostridium difficile, diarrhea, vancomycin, metronidazole, immunoglobulin, and recurrence. Additional references were located through review of the bibliographies of cited articles and by visiting www.clinicaltrials.gov .

Study Selection and Data Extraction:

Articles related to the clinical manifestations, diagnosis, and treatment of CDAD, as well as articles addressing current issues related to CDAD, were included.

Data Synthesis:

There have been many investigations into CDAD because of the recent increased incidence and morbidity and mortality of the disease. Various studies examining the changing epidemiology and pathogenicity of C. difficile, as well as new therapies for CDAD with agents such as tolevamer and nitazoxanide, are ongoing. In addition, researchers are investigating probiotics and vaccines to evaluate their effectiveness in preventing CDAD and/or preventing recurrences of CDAD. Studies assessing therapies for refractory CDAD are lacking, although case reports have been published citing treatment strategies using vancomycin enemas, intravenous metronidazole, colestipol and cholestyramine, fecal enemas, bowel irrigation, and immunoglobulin. Furthermore, judicious use of antimicrobials, contact precautions, and adequate environmental cleaning are being evaluated in healthcare institutions as methods for controlling and preventing the spread of C. difficile.

Conclusions:

Oral metronidazole is the drug of choice for an initial CDAD episode. Oral vancomycin is an option for patients who cannot take or fail treatment with oral metronidazole. Clinical trials are necessary to define the therapy for initial CDAD that is most appropriate and produces lower recurrence rates compared with oral metronidazole or vancomycin treatment. Moreover, appropriate treatment for patients with multiple recurrences of or refractory CDAD needs to be determined. More studies are also needed assessing prevention of recurrences of CDAD.
Clinical Pharmacy Practice 30 Years Later
Authors: Tse CS Ted
Published: December 2006

2006 marked the 40th year of publication for The Annals. Throughout its history, The Annals has provided important contributions to the development of clinical pharmacy. In 2007, we are continuing to publish articles reflecting on the history of clinical pharmacy through the eyes of practitioners, including those pioneering clinical pharmacy, as well as those who have more recently entered the profession and a well-established specialty. In addition, we are also presenting articles and editorials from the early history of The Annals that have given direction and shape to the practice of clinical pharmacy (see page 121).
Musical versus Visual Graphs: Cross-Modal Equivalence in Perception of Time Series Data
Authors: Flowers John H. , Hauer Terry A.
Published: December 2006

By applying multidimensional scaling procedures and other quantitative analyses to perceptual dissimilarity judgments, we compared the perceptual structure of visual line graphs depicting simulated time series data with that of auditory displays (musical graphs) presenting the same data. Highly similar and meaningful perceptual structures were demonstrated for both auditory and visual modalities, showing that important data characteristics (function slope, shape, and level) were perceptually salient in either presentation mode. Auditory graphics may be a highly useful alternative to traditional visual graphics for a variety of data presentation applications.
Mixed versus Pure Display Format in Integration and Nonintegration Visual Display Monitoring Tasks
Authors: Payne David G. , Lang Virginia A. , Blackwell Jason M.
Published: December 2006

In four experiments we examined the effect of varying the types of display coding (analog, verbal, digital) used in a visual monitoring task. In pure display conditions all indicators within a display were of the same type, and in mixed conditions display type varied across indicators. Subjects performed either integration tasks, which required responses based on information contained in two indicators, or nonintegration tasks, in which responses could be made based on a single indicator value. Results replicated previous findings of the superiority of analog indicators in tasks of this type and also indicated that the integration/nonintegration task distinction is not an important variable to take into account when designing displays. It is suggested that detailed analyses of decision task demands are required in designing visual displays.
Taxonomy of Scheduling Systems as a Basis for the Study of Strategic Behavior
Authors: Dessouky M. I. , Moray Neville , Kijowski Brian
Published: December 2006

Strategic behavior is frequently characterized by the need to decide among several courses of action, each of which may lead to a desired goal, subject to time constraints. Often strategic behavior can be regarded as a series of answers to the question, "In what sequence should I perform the set of actions required, and when should I start and stop each of them?" Scheduling theory, which is usually used to determine the sequencing of operations in such situations as transportation and manufacturing, provides normative answers to such a question. We introduce the concepts and terminology of scheduling theory and show how these can be identified with aspects of human operator behavior. Scheduling theory can provide a systematic conceptual framework for planning research on behavior in complex human-machine settings, both in and beyond laboratory contexts. It can be used to discover optimal or satisficing strategies and to provide norms against which to measure the quality of strategic decision making and performance in complex systems. The use of scheduling theory is one example of the many well-developed quantitative models available in operations research that are applicable to the analysis of behavior, well beyond the discrete trials paradigm that often characterizes human factors laboratory research.
Naive Judgments of Stimulus-Response Compatibility
Authors: Payne Stephen J.
Published: December 2006

Subjects were asked to rate the usability of interface designs that varied in compatibility of stimulus-response mappings. In Study 1 subjects rated light-button layouts. In Study 2, the same subjects rated stove burner control designs. In Study 3, different subjects ranked fragments of computer command languages. In all three judgment tasks, subjects showed limited sensitivity to stimulus-response compatibility. A theory of naive stimulus-response judgments is put forward to explain the patterns of judgments in the three tasks. According to this theory, naive judges use an item-summing heuristic: Where possible, designs are compared by summing the presumed goodness of individual stimulus-response mappings. The upshot of this heuristic is that the usability benefits of configural, rule-based mappings are systematically undervalued.
Effects of Pictorial Relative Size and Ground-Intercept Information on Judgments about Potential Collisions in Perspective Displays
Authors: Delucia Patricia R.
Published: December 2006

Using perspective displays, observers judged whether two objects that approached each other in midair would collide. When objects were different sizes, observers often did not detect imminent collisions. Errors decreased with equal-sized objects or ground-intercept information. Results from these limited conditions suggest that judgments about collision in perspective displays (e.g., three-dimensional displays of aircraft) can be enhanced by minimizing ambiguities created by pictorial relative size cues. Results are consistent with studies of judgments about object-self collisions.
Effects of Back Support on Intra-Abdominal Pressure and Lumbar Kinetics during Heavy Lifting
Authors: Woodhouse Michael L. , McCoy Raymond W. , Redondo Diego R. , Shall Lawrence M.
Published: December 2006

Lumbosacral supports (LSSs) have been used to minimize the risk of lower back injuries. Theoretically, an LSS will raise intra-abdominal pressure (IAP) and reduce loads in the lower back region. This investigation compared three different LSSs with an unsupported condition. Nine males lifted a weighted box four times, once per condition, at 90% of their one-repetition maximum. Conditions were compared in terms of effects on IAP and its relieving force on L5-S1 kinetics. A multivariate analysis of covariance revealed no statistically significant differences among the three LSSs and the nonsupport conditions on the aforementioned dependent variables. This suggests that there is no difference among LSSs in terms of their biomechanical effects on the lower back region and that the use of any LSS does not necessarily afford more protection than a proper lift without one.
An Experimental Investigation of Configural, Digital, and Temporal Information on Process Displays
Authors: Hansen John Paulin
Published: December 2006

The detection of a temporal event was investigated in two experiments comparing perceptual performance in terms of reaction time, hit rate, and number of false alarms on four separated and integrated display formats with and without historical information. In addition, the importance of supplementary digital information was examined. Experiment 1 showed that instantaneous displays were perceived faster than historical displays on high-rate events but not on low-rate events. The hit rate and the number of false alarms was higher on integrated displays than on separated displays. Experiment 2 used data with random noise added. Graphical integration across time and across the eight variables both had significant importance for the ability to see trends in the presence of noise. Adding digital information to graphical displays was found to decrease reaction time in general, but the hit rate may be reduced by adding numbers on integrated displays without a temporal dimension.
Situation Awareness Is Adaptive, Externally Directed Consciousness
Authors: Smith Kip , Hancock P. A.
Published: December 2006

We define situation awareness (SA) as adaptive, externally directed consciousness. This definition dispels the artificial and contentious division evident in the literature, according to which SA is either exclusively knowledge or exclusively process. This misdirected rivalry has more to do with general perspectives on the study of human behavior than with SA itself. Through defining SA as an aspect of consciousness, we hope to clarify two key issues. (1) The source of goals with respect to SA is a normative arbiter in the task environment; that is, the behavior that SA generates must be directed at an external goal. (2) SA is the invariant at the core of the agent's perception-action cycle that supports skilled performance; that is, relationships among factors or dimensions in the environment determine what the agent must know and do to achieve the goals specified by the external arbiter. We introduce a construct we call the risk space to represent the invariant relations in the environment that enable the agent to adapt to novel situations and to attain prespecified goals. We articulate this concept of a risk space through use of a specific example in commercial aircraft operations. The risk space structures information about the physical airspace in a manner that captures the momentary knowledge that drives action and that satisfies the goals and performance criteria for safe and efficient flight. We note that the risk space may be generalized to many different means of navigation.
Situation Awareness and the Cognitive Management of Complex Systems
Authors: Adams Marilyn Jager , Tenney Yvette J. , Pew Richard W.
Published: December 2006

The issue of how to support situation awareness among operators of complex systems or vehicles is a growing concern in a number of industries, especially when automation takes the operators partly "out of the loop." Cognitive theory suggests that comprehension of the flow of events is an active process, constrained by the dynamics and modularity of attention and memory. Focusing on issues of commercial aviation, we review the meaning of the term situation awareness both definition ally and by way of examples. We then discuss the cognitive factors involved in achieving and maintaining situation awareness, drawing on recent cognitive theory to clarify their interactions. Finally, having emphasized the need for a more analytic and precise understanding of situation awareness, we discuss strengths and weaknesses of various empirical approaches that might be used toward that end.