Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This review addresses three related bone marrow failure diseases, the study of which has generated important insights in hematopoiesis, red cell biology, and immune-mediated blood cell injury. In Section I, Dr. Young summarizes the current knowledge of acquired aplastic anemia. In most patients, an autoimmune mechanism has been inferred from positive responses to nontransplant therapies and laboratory data. Cytotoxic T cell attack, with production of type I cytokines, leads to hematopoietic stem cell destruction and ultimately pancytopenia; this underlying mechanism is similar to other human disorders of lymphocyte-mediated, tissue-specific organ destruction (diabetes, multiple sclerosis, uveitis, colitis, etc.). The antigen that incites disease is unknown in aplastic anemia as in other autoimmune diseases; post-hepatitis aplasia is an obvious target for virus discovery. Aplastic anemia can be effectively treated by either stem cell transplantation or immunosuppression. Results of recent trials with antilymphocyte globulins and high dose cyclophosphamide are reviewed. Dr. Abkowitz discusses the diagnosis and clinical approach to patients with acquired pure red cell aplasia, both secondary and idiopathic, in Section II. The pathophysiology of various PRCA syndromes including immunologic inhibition of red cell differentiation, viral infection (especially human parvovirus B19), and myelodysplasia are discussed. An animal model of PRCA (secondary to infection with feline leukemia virus [FeLV], subgroup C) is presented. Understanding the mechanisms by which erythropoiesis is impaired provides for insights into the process of normal red cell differentiation, as well as a rational strategy for patient management. Among the acquired cytopenias paroxysmal nocturnal hemoglobinuria (PNH) is relatively rare; however, it can pose formidable management problems. Since its first recognition as a disease, PNH has been correctly classified as a hemolytic anemia; however, the frequent co-existence of other cytopenias has hinted strongly at a more complex pathogenesis. In Section III, Dr. Luzzatto examines recent progress in this area, with special emphasis on the somatic mutations in the PIG-A gene and resulting phenotypes. Animal models of PNH and the association of PNH with bone marrow failure are also reviewed. Expansion of PNH clones must reflect somatic cell selection, probably as part of an autoimmune process. Outstanding issues in treatment are illustrated through clinical cases of PNH. Biologic inferences from PNH may be relevant to our understanding of more common marrow failure syndromes like myelodysplasia.
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PMID:New Insights into the Pathophysiology of Acquired Cytopenias. 1170 33

We report 6 cases of group B streptococcal prosthetic joint infections seen in our institution and review 8 previously reported cases. These 14 patients (6 men and 8 women) had an average age of 69. Seven hip joints and 7 knee joints were affected. Only 4 patients had risk factors for prosthetic joint infection (diabetes mellitus in 2, cancer in 1, and myelodysplasia in 1). The average time from surgery to onset of symptoms was approximately 4 years (range, 5 months to 10 years). Pain in the affected joint was the chief complaint. Six patients had bacteremia. Seven patients had known or suspected foci of infection, which were genitourinary tract (1), skin and soft tissue trauma sites (1), gastrointestinal tract (1), and oropharynx (1). Nine patients required prosthesis removal in addition to antibiotic therapy. Two patients had apparent cure of the infection with retention of the prosthesis. Group B streptococcal prosthetic joint infections appear to be a late complication of prosthetic joint replacement surgery.
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PMID:Group B streptococcal prosthetic joint infections. 1213 19

An international workshop on the noninvasive measurement of iron was conducted by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) on April 17, 2001, to assess the current state of the science and to identify areas needing further investigation. The workshop concluded that a clear clinical need is evident for quantitative, noninvasive, safe, accurate, and readily available means of measuring body storage iron to improve the diagnosis and management of patients with iron overload from such disorders as hereditary hemochromatosis, thalassemia major, sickle cell disease, aplastic anemia, and myelodysplasia, among others. Magnetic resonance imaging (MRI) potentially provides the best available technique for examining the 3-dimensional distribution of excess iron in the body, but further research is needed to develop means of making measurements quantitative. Biomagnetic susceptometry provides the only noninvasive method to measure tissue iron stores that has been calibrated, validated, and used in clinical studies, but the complexity, cost, and technical demands of the liquid-helium-cooled superconducting instruments required at present have restricted clinical access to the method. The workshop identified basic and clinical research opportunities for deepening our understanding of the physical properties of iron and iron toxicity, for further investigation of MRI as a method for quantitative determinations of tissue iron, especially in liver, heart and brain, and for development of improved methods and more widely available instrumentation for biomagnetic susceptometry.
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PMID:Noninvasive measurement of iron: report of an NIDDK workshop. 1239 26

Diabetic neuroarthropathy was observed in four patients; these are the first cases of this nature reported in the Canadian medical literature. The criteria for this diagnosis included: (1) long-standing diabetes; (2) arthropathy, most frequently involving the foot, which shows deformity, shortening and ulceration without evidence of infection or peripheral circulatory failure; (3) abolition or diminution of pain on weight-bearing; (4) diabetic peripheral neuropathy with impaired sense of position or vibration and weak or absent deep tendon reflexes. Radiographic findings were similar to those in patients with Charcot's arthropathy from any cause.Tabes dorsalis, leprosy, syringomyelia, myelodysplasia and the arthropathies of corticosteroid therapy were ruled out in these cases. In addition to conventional medical therapy the patients were treated by means of walking-casts for several months.Diabetic neuroarthropathy is probably more common than the medical literature would indicate. Diminished sensation in the lower limbs in diabetics of long standing appears to be the major factor contributing to this disorder.
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PMID:DIABETIC NEUROARTHROPATHY: REPORT OF FOUR CASES. 1419 8

1alpha,25-Dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)], the active metabolite of vitamin D(3), is known for the maintenance of mineral homeostasis and normal skeletal architecture. However, apart from these traditional calcium-related actions, 1,25-(OH)(2)D(3) and its synthetic analogs are being increasingly recognized for their potent antiproliferative, prodifferentiative, and immunomodulatory activities. These actions of 1,25-(OH)(2)D(3) are mediated through vitamin D receptor (VDR), which belongs to the superfamily of steroid/thyroid hormone nuclear receptors. Physiological and pharmacological actions of 1,25-(OH)(2)D(3) in various systems, along with the detection of VDR in target cells, have indicated potential therapeutic applications of VDR ligands in inflammation (rheumatoid arthritis, psoriatic arthritis), dermatological indications (psoriasis, actinic keratosis, seborrheic dermatitis, photoaging), osteoporosis (postmenopausal and steroid-induced osteoporosis), cancers (prostate, colon, breast, myelodysplasia, leukemia, head and neck squamous cell carcinoma, and basal cell carcinoma), secondary hyperparathyroidism, and autoimmune diseases (systemic lupus erythematosus, type I diabetes, multiple sclerosis, and organ transplantation). As a result, VDR ligands have been developed for the treatment of psoriasis, osteoporosis, and secondary hyperparathyroidism. Furthermore, encouraging results have been obtained with VDR ligands in clinical trials of prostate cancer and hepatocellular carcinoma. This review deals with the molecular aspects of noncalcemic actions of vitamin D analogs that account for the efficacy of VDR ligands in the above-mentioned indications.
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PMID:Noncalcemic actions of vitamin D receptor ligands. 1579 98

Gamma-linolenic acid (GLA, C18:3delta6 ,9,12), an essential polyunsaturated fatty acid, plays an important role in hormone regulation and fatty acid metabolization. Delta6-fatty acid desaturase (D6D) is the rate-limiting enzyme of the desaturation of linoleic acid (C18:2delta9,12) in the production of gamma-linolenic acid. A deficiency of GLA may have occurred when delta6-fatty acid desaturase activity decreases in aging, stress, diabetes, eczema, and some infections. To establish a new expression system for delta6-fatty acid desaturase gene in Pichia pastoris, which is an increasingly popular heterologous gene expression system, a gene encoding delta6-fatty acid desaturase from Mortieralla alpina was isolated by PCR amplification. The PCR product was then digested by EcoR I and Not I and subcloned into the intracellular expression vector pPIC3.5K to generate the recombinant vector pPIC3.5K-MA6. The resulting vector was linearized by Sac I and electroporated into P. pastoris SMD1168 (his- pep-) host cells. After electroporation, aliquots were spreaded on the MDS plates and incubated at 30 degrees C for three days until colonies appeared. Those transformants were subsequently screened for clones with high copy number by using the YPD plates containing G418. To identify the D6D constructs that were produced, chromosomal DNA of the transformants were prepared and used as template for PCR with the primer 5' AOX and 3' AOX. The PCR product of Mut+ recombinants was shown as a band of 1.38 kb of D6D gene and the product of 2.2 kb of AOX1 gene, while the product of Mut(s) transformants only was shown as a band of 1.38 kb of the D6D gene.To further confirm the transformants containing a functional D6D gene, the positive clones were selected and induced by methanol for expression. Those induced cultures were taken for analyses of the intracellular fatty acid composition by GC. The resultant chromatograms of fatty acid methyl esters showed that a novel peak was detected, which was not apparent in the case of control. Comparisons of the retention times of the newly yielded peaks with those of authentic standards have anticipated that the fatty acid is GLA. And this prospects was positively supported by definitive assignments of the compounds by GCMS analyses. Thus, the active delta6-fatty acid desaturase was expressed intracellularly in P. pastoris and gamma-linolenic acid reached 16.26% of the total fatty acid in recombinant P. pastoris strains. It was the first report about the expression of Mortieralla alpina D6D gene in P. pastoris.
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PMID:[Expression of delta6-fatty acid desaturase gene from Mortierella alpina in Pichia pastoris]. 1610 86

A 52-year-old woman with diabetes mellitus (DM) complained of weakness of the arms and legs. She was referred to our hospital in November 2002 because of anemia, thyroid tumor and meningioma including DM. She was short in stature, juvenile bilateral cataract, intractable skin ulcers, clavus on the sole of her foot, a bird-like face and high-pitched voice. Typical physical features led to the final diagnosis of Werner's syndrome. Although the myelogram revealed no abnormal findings except erythroid hypoplasia, cytogenetic analysis of bone marrow cells showed deletion of chromosome 20 in 10% of the analyzed cells, which suggested the possibility of that myelodysplastic syndrome (MDS) or acute myeloblastic leukemia (AML) could occur. She had a thyroidectomy because both lobes of the thyroid gland were enlarged and caused hoarseness, In addition, it is common knowledge that the goiter could become malignant. We need to follow her carefully because she might be vulnerable to malignant disease, including leukemia and malignant meningioma.
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PMID:[A case of Werner syndrome with chromosomal abnormality]. 1707 96

Isotechnika is developing the immunosuppressive drug ISA 247, a calcineurin inhibitor that is undergoing clinical development for the treatment of psoriasis (phase III) and prevention of organ rejection after transplantation (phase II). Preclinical development for uveitis is also underway. Other autoimmune disease indications that could be explored include arthritis, type I diabetes and Crohn's disease. ISA 247 was being co-developed as R 1524 by Isotechnika and Roche. However, Roche is no longer involved in the development of this compound. Based on analysis of previously collected data, the trans-ISA 247 isomer was found to be more bioavailable and it is expected that this isomer can be administered at a lower dose compared with the previous formulation that consisted of an equivalent mixture of the two geometric isomers (cis and trans). Preclinical observations indicate that ISA 247 has the potential to be more potent and less toxic than other marketed immunosuppressants in its class used for the prevention of transplant rejection. Experiments to date suggest that ISA 247 is about three times as potent as ciclosporin, while genotoxicity studies in animals have shown that the compound has a significantly reduced tendency to cause renal toxicity. The combination of reduced toxicity and improved potency would give ISA 247 a therapeutic benefit over existing calcineurin-based treatments. Isotechnika and Roche entered into a co-development and commercialisation agreement in April 2002, with Roche gaining the exclusive worldwide marketing rights for ISA 247; Isotechnika received milestone payments of $US4 million and $CAN21.9 million in September 2002 and May 2003, respectively. The agreement was restructured in April 2004, under which Isotechnika will now solely manage and fund the clinical development of trans-ISA 247. Upon successful completion of these trials, Isotechnika will conduct at its own expense a phase IIb study in renal transplantation and phase III studies in psoriasis. Roche will have the right to opt-in to the development and commercialisation of trans-ISA 247 for transplant indications up to the end of the phase IIb renal transplantation trial. Isotechnika retains all rights to develop and commercialise the product outside of transplant indications. Under an agreement signed with Cellgate Inc. on 25 April 2006, Isotechnika has the option to obtain an exclusive licence to develop and commercialise conjugates consisting of Cellgate's patented transporter technology, for the topical delivery of ISA 247 in patients with mild-to-moderate psoriasis. Cellgate will perform studies to evaluate the feasibility of using their technology to topically deliver ISA 247. In return, Isotechnika will pay Cellgate Inc. a total of $US500 000, with $US100 000 paid upfront, and the remainder at predetermined time points. Upon successful completion of the studies, Isotechnika has the option to further develop and commercialise conjugates for topical delivery of ISA 247. Isotechnika and Atrium Medical Corporation announced an exclusive worldwide licensing agreement for ISA 247 alone and in combination with TAFA 93 with respect to drug-eluting devices, in September 2005. Atrium's implantable products include those for the local, non-systemic treatment of vascular and cardiovascular disorders, soft tissue repair and other disorders. In May 2006, Isotechnika licensed ISA 247 to Lux Biosciences for ophthalmic indications. Under terms of the agreement, Lux Biosciences obtains the exclusive worldwide marketing rights to ISA 247 for treatment and prophylaxis of all ophthalmic indications. The company will be responsible for development, registration and marketing of the drug for ophthalmic indications and will make upfront and milestone payments to Isotechnika in addition to royalties on any sales. Isotechnika formalised a manufacturing agreement with Swiss-based Lonza Ltd in June 2004. Under the terms of the agreement, Lonza will manufacture sufficient quantities of trans-ISA 247 in a GMP environment for use in the company's upcoming clinical trials. Isotechnika completed the phase III SPIRIT trial of ISA 247 for psoriasis in Canada. The randomised, double-blind trial compared the efficacy of three doses of ISA 247 (0.2 mg/kg [low dose], 0.3 mg/kg [mid dose] and 0.4 mg/kg [high dose] twice daily) with placebo, with equal numbers of patients assigned to each of the four groups. Subsequent to the first 12 weeks, those patients who received placebo moved into the mid-dose group for the remaining 12 weeks of the study. Patients already receiving ISA 247 remained in their respective dosing groups for the final 12 weeks of the trial. Patients completing the 24-week SPIRIT trial were given the opportunity to continue therapy for an addditonal 36 weeks or to discontinue therapy. Those patients who chose to enrol in the extension trial were moved from the 0.2 mg/kg bid (low-dose) or 0.4 mg/kg bid (high-dose) groups into the the 0.3 bid mg/kg bid (mid dose) group. Patients who commenced the SPIRIT trial in the mid-dose group remained on the same dosage regimen for the duration of the extension trial. The goal of the extension trial is to demonstrate continued therapeutic benefit to psoriasis patients while gathering long-term safety data. So far, data has been received on 193 patients receiving treatment for a total of 48 weeks. A phase IIa trial investigating the safety and efficacy of ISA 247 in renal transplantation was completed in the US and Canada in January 2003. The trial compared ISA 247 with ciclosporin (Neoral in approximately 130 stable renal transplant patients who underwent transplantation at least 6 months prior to enrolment; patient recruitment was completed in October 2002. Half of the patients were treated with ciclosporin and the other half received ISA 247 over a 90-day period. An extension trial was then initiated in which another 200 patients were treated with ISA 247 for up to 6 months from the time of transplantation. Results from the trial were reported. All endpoints were achieved in a multiple ascending dose study of trans-ISA 247 in November 2004. The study, initiated in June 2004, was conducted by SFBC Anapharm in Montreal, Canada and involved 43 healthy volunteers. Final dosing recommendations are to be determined in phase III trials in patients with psoriasis. Interim results reported in September 2004, of a double-blind, parallel-group, placebo and moxifloxacin controlled, randomised single-dose QTc trial in healthy volunteers, showed no evidence of QTc prolongation when trans-ISA 247 was administered at therapeutic doses. A single ascending dose (SAD) trial for trans-ISA 247 was completed in July 2004. The SAD trial was conducted among healthy volunteers to assess the appropriate dosage of trans-ISA 247 for further clinical evaluations. The trial commenced in March 2004 with approximately 46 subjects enrolled under the supervision of MDS Pharma Services in Phoenix, Arizona, USA. Isotechnika received US FDA approval for the SAD trial in February 2004. A European patent (No. EP 0 991 660) entitled 'Deuterated and Undeuterated Cyclosporine Analgoues and Their Use as Immunomodulating Agents' was issued to Isotechnika for ISA 247, in October 2006. A US patent entitled 'Novel Cyclosporin Analogue Formulations' was issued to Isotechnika (No. 7 060 672) for ISA 247 in June 2006. The patent claims have been filed in 36 countries, and in the US it is the first patent to be issued in this patent family. Isotechnika was issued a US patent (No. 6 998 385, entitled 'Cyclosporine Analogue Mixtures and their use as Immunomodulating Agents') in February 2006 covering mixtures of cis- and trans- isomers of ISA 257. This patent is the first US patent to be issued in this family of patents. These patent claims have been filed in 36 countries. Three patents relating to this claim were previously issued in the following countries; Morocco (No. 26337 issued 1 October 2004); Pakistan (No. 138338 issued 30 September 2004) and South Africa (No. 2004/2270 issued 25 May 2005). A US patent (No 6 686 454) was issued in February 2004 entitled 'Antibodies to Specific Regions of Cyclosporine Related Compounds'. This patent covers a novel, simple and cost-effective assay used in the use and management of ISA 247. It also received another US patent entitled 'Deuterated Cyclosporine Analogs and their Use as Immunomodulating Agents'. Isotechnika has received patents for chemical composition of ISA 247 in New Zealand (November 2001; New Zealand Patent No. 502362), Canada (December 2001; Canadian Patent No. 2 298 572), South Korea (June 2006; South Korean Patent No. 585348) and Australia (November 2002; Australian Patent No. 750245). In addition, Isotechnika announced in August 2003 that it had been granted US patent No. 6 605 593, entitled 'Deuterated Ciclosporine Analogs and their use as Immunomodulating Agents'. An additional US patent covering ISA 247 was granted in September 2003.
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PMID:ISA 247: trans-ISA 247, trans-R 1524, ISA(TX)247, ISAtx 247, ISATx247, LX 211, LX211, R 1524, R-1524. 1732 8

The objective of this study was to investigate the occurrence of daily pain, its associates and impact on work load in institutional long-term care (LTC) in a geriatric hospital responsible for all the hospital-based LTC-services in one health district (population 71,000) in Helsinki, Finland. All LTC-patients (n=656, females 81%, mean age=83 years) treated during 1 week were examined. Minimum Data Set (MDS 1.0), measurement of patient-related time according to Resource Utilization Groups (RUG-III)-studies, and Mini-Mental State Examination test (MMSE) were performed. If the patients complained or showed verbal or non-verbal evidence of pain at least once per day, they were considered to suffer from daily pain. Daily pain was present in 23% of the patients studied and its occurrence associated significantly with severity of illnesses, dehydration, vomiting, swallowing problems, weight loss, dyspnea, edema and terminal prognosis. It also related to frailty, poor functional capacity, contracture and the lack of body control. The occurrence of pain was increased in patients needing wound care, pressure relieving tools and mechanically altered diet. According to multivariate analysis dehydration, dyspnea, edema, diabetes mellitus, depression, wound care and dependency in locomotion emerged as independent associates of pain. The distribution of daily pain is heterogenic, even though it is accumulated in the sickest and frailest patients. The nursing staff addressed 14% more time to patients with pain than to those with out pain (P<0.05).
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PMID:Daily pain, its associates and impact on work load in institutional long-term care. 1865 55

Mycobacterium avium complex (MAC) pulmonary infection is usually seen in elderly persons. We encountered a rare case of MAC pulmonary disease seen in a 19-year-old adolescent. The patient had received bone marrow transplantation at the age of 16 for myelodysplastic syndrome. Subsequently, he developed constrictive bronchiolitis and has been treated with corticosteroid and taclorimus. At age 19, small or fine nodules and a cavitary nodule in right lung were detected on the chest radiograph and computed tomography. Afterwards, Mycobacterium avium was detected by bronchoscopic examination and sputum examination and he was diagnosed as MAC pulmonary infection. MAC pulmonary infection in a young person at the age of 19 is an extremely rare case, in which constrictive bronchiolitis, immunosuppression by corticosteroid and tacrolimus, and diabetes mellitus were considered as critical predisposing factors.
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PMID:[An adolescent case of pulmonary MAC infection, found 3 years later from bone marrow transplantation for myelodysplastic syndrome]. 1880 Jun 51


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