Research Papers
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Item In transition: current health challenges and priorities in Sudan(BMJ Global Health, 2019) Charani,Esmita; Cunnington,Aubrey J; Yousif,AlaEldin H A; Ahmed,Mohammed Seed; Ahmed,Ammar E M; Babiker,Souad; Badri,Shahinaz; Buytaert,Wouter; Crawford,Michael A; Elbashir,Mustafa I; Elhag,Kamal; Elsiddig,Kamal E; Hakim,Nadey; Johnson,Mark R; Miras,Alexander D; Swar,Mohamed O; Templeton,Michael R; Taylor-Robinson,Simon DavidA recent symposium and workshop in Khartoum, the capital of the Republic of Sudan, brought together broad expertise from three universities to address the current burden of communicable and non-communicable diseases facing the Sudanese healthcare system. These meetings identified common challenges that impact the burden of diseases in the country, most notably gaps in data and infrastructure which are essential to inform and deliver effective interventions. Non-communicable diseases, including obesity, type 2 diabetes, renal disease and cancer are increasing dramatically, contributing to multimorbidity. At the same time, progress against communicable diseases has been slow, and the burden of chronic and endemic infections remains considerable, with parasitic diseases (such as malaria, leishmaniasis and schistosomiasis) causing substantial morbidity and mortality. Antimicrobial resistance has become a major threat throughout the healthcare system, with an emerging impact on maternal, neonatal and paediatric populations. Meanwhile, malnutrition, micronutrient deficiency and poor perinatal outcomes remain common and contribute to a lifelong burden of disease. These challenges echo the United Nations (UN) sustainable development goals and concentrating on them in a unified strategy will be necessary to address the national burden of disease. At a time when the country is going through societal and political transition, we draw focus on the country and the need for resolution of its healthcare needs.Item Lower succinyl-CoA:3-ketoacid-CoA transferase (SCOT) and ATP citrate lyase in pancreatic islets of a rat model of type 2 diabetes: Knockdown of SCOT inhibits insulin release in rat insulinoma cells(journal homepage: www.elsevier.com/locate/yabbi, 2010) Hasan,Noaman M; Longacre,Melissa J; Ahmed,Mohammed Seed; Kendrick,Mindy A; Gu,Harvest; Ostenson,Claes-Goran; Fukao,Toshiyuki; MacDonald,Michael JSuccinyl-CoA:3-ketoacid-CoA transferase (SCOT) is a mitochondrial enzyme that catalyzes the reversible transfer of coenzyme-A from acetoacetyl-CoA to succinate to form acetoacetate and succinyl-CoA. mRNAs of SCOT and ATP citrate lyase were decreased 55% and 58% and enzyme activities were decreased >70% in pancreatic islets of the GK rat, a model of type 2 diabetes. INS-1 832/13 cells were transfected with shR- NAs targeting SCOT mRNA to generate cell lines with reduced SCOT activity. Two cell lines with >70% knockdown of SCOT activity showed >70% reduction in glucose- or methyl succinate-plus-b-hydroxybu- tyrate-stimulated insulin release. Less inhibition of insulin release was observed with two cell lines with less knockdown of SCOT. Previous studies showed knockdown of ATP citrate lyase in INS-1 832/13 cells does not lower insulin release. The results further support work that suggests mitochondrial pathways involving SCOT which supply acetoacetate for export to the cytosol are important for insulin secretion.Item Association of Platelet Serotonin Levels in Alzheimer’s Disease with Clinical and Cerebrospinal Fluid Markers(Journal of Alzheimer’s Disease, 2016) Tajeddinna,Walid; Fereshtehnejad,Seyed-Mohammad; Ahmed,Mohammed Seed; Yoshitaked,Takashi; Kehr,Jan; Shahnaz,Tasmin; Milovanovic,Micha; Behbahani,Homira; Hoglund ,Kina; Winblad,Bengt; Cedazo-Minguez,Angel; Jelic,Vesna; Jaremo,Petter; Aarsland,DagIntroduction: Serotonin (5-HT) is involved in the pathology of Alzheimer’s disease (AD). Objective: We aimed to measure 5-HT level in platelets in AD and explore its association with cerebrospinal fluid (CSF), AD biomarkers (amyloid- 1-42 (A42), total tau (t-tau), and phosphorylated tau (p-tau)), and clinical symptoms. Methods: 15 patients with AD and 20 patients with subjective cognitive impairment (SCI) were included. 5-HT metabolites were measured, in a specific fraction, using high performance liquid chromatography with electrochemical detection (HPLC- ECD). Results: Significantly lower 5-HT concentrations were observed in AD patients compared to SCI patients both after normal- ization against total protein (p = 0.008) or platelet count (p = 0.019). SCI patients with lower 5-HT level have higher AD CSF biomarkers, total tau (p = 0.026) and tau/A42 ratio (p = 0.001), compared to those with high 5-HT levels. Conclusion: AD patients have reduced platelet 5-HT levels. In SCI, lower 5-HT content was associated with a higher AD-CSF biomarker burden.Item Genetic Association of Adrenergic Receptor Alpha 2a with Obesity and Type 2 Diabetes(Original Article EPIDEMIOLOGY/GENETICS, 2013) La ̊ ngberg,Ewa-Carin; Ahmed,Mohammed Seed; Efendic,Suad; Gu,Harvest F; Ostenson,Claes-GoranObjective: The sympathetic nervous system (SNS) is linked to glucose, lipid, and protein metabolism. The a2A-adrenergic receptor (ADRA2A) is involved in the SNS and mediates inhibition of insulin secretion and lipolysis. The association of ADRA2A single-nucleotide polymorphisms (SNPs) with obesity and/or type 2 diabetes (T2D) was investigated. Design and Methods: Genotyping was performed in a case–control study of 1,177 Swedish individuals, including lean and obese subjects with normal glucose tolerance (NGT) and T2D patients. ADRA2A mRNA expression was measured in pancreatic islets isolated from T2D patients and nondiabetic subjects. Results: SNP rs553668 was associated with T2D in men (odds ratio [OR] 1⁄4 1.47; 95% confidence interval [CI] 1⁄4 1.08–2.01; P 1⁄4 0.015) but this association was lost after adjusting for age and for body mass index (BMI). Associations were also detected when comparing obese NGT and lean NGT subjects (OR 1⁄4 1.49; 95% CI 1⁄4 1.07–2.07; P 1⁄4 0.017), and in obese (OR 1⁄4 1.62; 95% CI 1⁄4 1.06–2.49; P 1⁄4 0.026), but not in lean T2D. In women, multiple logistic regression regarding SNP rs521674 demonstrated an increased OR of 7.61 (95% CI 1⁄4 1.70–34.17; P 1⁄4 0.008) for T2D when including age as a covariant. Correcting for BMI removed the significant association. When age was included in the model, association also found when obese T2D patients were compared with lean NGT subjects (P 1⁄4 0.041). ADRA2A mRNA expression in human pancreatic islets was detectable, but with no statistically significant difference between the diabetic and the control groups. Conclusions: ADRA2A genetic polymorphisms are mainly associated with obesity and possibly with T2D in a Swedish population.Item Expression of Protein Kinase C Isoforms in Pancreatic Islets and Liver of Male Goto- Kakizaki Rats, a Model of Type 2 Diabetes(PLOS ONE journal, 2015) Ahmed,Mohammed Seed; Pelletier,Julien; Leumann,Hannes; Gu,Harvest F; Östenson,Claes-GöranProtein kinase C (PKC) is a family of protein kinases controlling protein phosphorylation and playing important roles in the regulation of metabolism. We have investigated expres- sion levels of PKC isoforms in pancreatic islets and liver of diabetic Goto-Kakizaki (GK) rats with and without insulin treatment to evaluate their association with glucose homeostasis. mRNA and protein expression levels of PKC isoforms were assessed in pancreatic islets and liver of Wistar rats and GK rats with or without insulin treatment. PKCα and PKCζ mRNA expressions were down-regulated in islets of GK compared with Wistar rats. PKCα and phosphorylated PKCα (p-PKCα) protein expressions were decreased in islets of GK compared with insulin-treated GK and Wistar rats. PKCζ protein expression in islets was reduced in GK and insulin-treated GK compared with Wistar rats, but p-PKCζ was decreased only in GK rats. Islet PKCε mRNA and protein expressions were lower in GK compared with insulin-treated GK and Wistar rats. In liver, PKCδ and PKCζ mRNA expres- sions were decreased in both GK and insulin-treated GK compared with Wistar rats. Hepatic PKCζ protein expression was diminished in both GK rats with and without insulin treatment compared with Wistar rats. Hepatic PKCε mRNA expression was down-regulated in insulin- treated GK compared with GK and Wistar rats. PKCα, PKCε, and p-PKCζ expressions were secondary to hyperglycaemia in GK rat islets. Hepatic PKCδ and PKCζ mRNA expressions were primarily linked to hyperglycaemia. Additionally, hepatic PKCε mRNA expression could be under control of insulin.Item Non-specific Detection of a Major Western Blotting Band in Human Brain Homogenates by a Multitude of Amyloid Precursor Protein Antibodies(Frontiers in Aging Neuroscience, 2019) Haytural,Hazal; Lundgren,Jolanta L; Köse,Tansu B; Siquier,Tomàs Jordà; Kalcheva,Marinela; Ahmed,Mohammed Seed; Winblad,Bengt; Sundström,Erik; Barthet ,Gaël; Tjernberg,Lars O; Frykman,SusanneThe use of human post-mortem brain material is of great value when investigating which pathological mechanisms occur in human brain, and to avoid translational problems which have for example been evident when translating animal research into Alzheimer disease (AD) clinical trials. The amyloid β (Aβ)-peptide, its amyloid precursor protein (APP) and the intermediate APP-c-terminal fragments (APP-CTFs) are all important players in AD pathogenesis. In order to elucidate which APP CTF that are the most common in brain tissue of different species and developmental stages, and whether there are any differences in these fragments between AD and control brain, we investigated the occurrence of these fragments using different APP c-terminal antibodies. We noticed that whereas the conventional APP-CTFα and CTFβ fragments were most prominent in rat and mouse brain tissue, the major western blotting band detected in human, macaque and guinea pig was of approximately 20 kDa in size, possibly corresponding to the newly discovered APP-CTFη. However, this band was also intensely stained with a total protein stain, as well as by several other antibodies. The staining intensity of the 20 kDa band by the APP antibodies varied considerably between samples and correlated with the staining intensity of this band by the total protein stain. This could potentially be due to non-specific binding of the antibodies to another protein of this size. In-gel digestion and mass spectrometry confirmed that small amounts of APP were present in this band, but many other proteins were identified as well. The major hit of the mass spectrometry analysis was myelin basic protein (MBP) and a myelin removal protocol removed proportionally more of the 20 kDa APP band than the full-length APP and APP-CTFα/β bands. However, the signal could not be immunodepleted with an MBP antibody. In summary, we report on a potentially non-specific western blotting band of approximately 20 kDa and call for precaution when analyzing proteins of this size in human brain tissue.Item Increased expression of adenylyl cyclase 3 in pancreatic islets and central nervous system of diabetic Goto-Kakizaki rats(Journaltandfonline, 2012) Ahmed,Mohammed Seed; Kovoor,Abraham; Nordman,Sofia; Abu Seman,Norhashimah; Gu,Tianwei; Efendic,Suad; Brismar,Kerstin; Östenson,Claes-Göran; Gu,Harvest FAdenylyl cyclase 3 (AC3) is expressed in pancreatic islets of the Goto-Kakizaki (GK) rat, a spontaneous animal model of type 2 diabetes (T2D), and also exerts genetic effects on the regulation of body weight in man. In addition to pancreatic islets, the central nervous system (CNS) plays an important role in the pathogenesis of T2D and obesity by regulating feeding behavior, body weight and glucose metabolism. In the present study, we have investigated AC3 expression in pancreatic islets, striatum and hypothalamus of GK rats to evaluate its role in the regulation of glucose homeostasis. GK and Wistar rats at the age of 2.5 mo were used. A group of GK rats were implanted with sustained insulin release chips for 15 d. Plasma glucose and serum insulin levels were measured. AC3 gene expression levels in pancreatic islets, striatum and hypothalamus were determined by using real-time RT-PCR. Results indicated that plasma glucose levels in Wistar rats were found to be similar to insulin-treated GK rats, and significantly lower compared with non-treated GK rats. AC3 expression levels in pancreatic islets, striatum and hypothalamus of GK rats were higher compared with Wistar rats, while the levels were intermediate in insulin-treated GK rats. The AC3 expression display patterns between pancreatic islets and striatum-hypothalamus were similar. The present study thus provides the first evidence that AC3 is overexpressed in the regions of striatum and hypothalamus of brain, and similarly in pancreatic islets of GK rats suggesting that AC3 plays a role in regulation of glucose homeostasis via CNS and insulin secretion.Item Pharmacological Modulations of the Serotonergic System in a Cell-Model of Familial Alzheimer’s Disease(Journal of Alzheimer’s Disease, 2016) Tajeddinna,Walid; Persson,Torbjorn; Garridoa,Javier Calvo; Ahmed,Mohammed Seed; Maiolia,Silvia; Vijayaraghavan,Swetha; Kazokoglua,Mehmet Selim; Fernandez,Cristina Parrado; Yoshitaked,Takashi; Kehrd,Jan; Francisb,Paul; Winblada,Bengt; Hoglund ,Kina; Mingueza,Angel Cedazo; Aarsland,DagSerotonin (5-HT) plays a central role in the integrity of different brain functions. The 5-HT homeostasis is regulated by many factors, including serotonin transporter (SERT), monoamine oxidase enzyme (MAO), and several 5-HT receptors, including the 5-HT1B. There is little knowledge how the dynamics of this system is affected by the amyloid- (A) burden of Alzheimer’s disease (AD) pathology. SH-SY5Y neuroblastoma cells transfected with the amyloid precursor protein (APP) gene containing the Swedish mutations causing familial AD (APPswe), were used as a model to explore the effect of A pathology on 5-HT1B and related molecules including the receptor adaptor protein (p11), SERT and MAOA gene expression, and MAOA activity after treatment with selective serotonin reuptake inhibitor (SSRI) (sertraline), and a 5-HT1B receptor antagonist. Sertraline led more than 70 fold increase of 5-HT1B gene expression (p < 0.001), an increased serotonin turnover in both APPswe and control cells and reduced intracellular serotonin levels by 75% in APPswe cells but not in controls (p > 0.05). Treatment with the 5-HT1B receptor antagonist increased SERT gene-expression in control cells but not in the APPswe cells. 5-HT and 5-HT1B antagonist treatment resulted in different p11 expression patterns in APPswe cells compared to controls. Although MAOA gene expression was not changed by APPswe overexpression, adding 5-HT lead to a significant increase in MAOA gene expression in APPswe but not control cells. These findings suggest that the sensitivity of the 5-HT1B receptor and related systems is affected by APPswe overexpression, with potential relevance for pharmacologic intervention in AD. This may at least partly explain the lack of effect of SSRIs in patients with AD and depression.