Kerstin Brismar

Nutritional Status Using Mini Nutritional Assessment and Subjective Global Assessment Predict Mortality in Geriatric Patients

OBJECTIVES: To evaluate the clinical assessment of nutritional status and mortality in geriatric patients.

Stabilization of HIF-1α is critical to improve wound healing in diabetic mice

Relative hypoxia is essential in wound healing since it normally plays a pivotal role in regulation of all the critical processes involved in tissue repair. Hypoxia-inducible factor (HIF) 1α is the critical transcription factor that regulates adaptive responses to hypoxia. HIF-1α stability and function is regulated by oxygen-dependent soluble hydroxylases targeting critical proline and asparaginyl residues. Here we show that hyperglycemia complexly affects both HIF-1α stability and activation, resulting in suppression of expression of HIF-1 target genes essential for wound healing both in vitro and in vivo. However, by blocking HIF-1α hydroxylation through chemical inhibition, it is possible to reverse this negative effect of hyperglycemia and to improve the wound healing process (i.e., granulation, vascularization, epidermal regeneration, and recruitment of endothelial precursors). Local adenovirus-mediated transfer of two stable HIF constructs demonstrated that stabilization of HIF-1α is necessary and sufficient for promoting wound healing in a diabetic environment. Our findings outline the necessity to develop specific hydroxylase inhibitors as therapeutic agents for chronic diabetes wounds. In conclusion, we demonstrate that impaired regulation of HIF-1α is essential for the development of diabetic wounds, and we provide evidence that stabilization of HIF-1α is critical to reverse the pathological process.

Diabetes mellitus and risk of bladder cancer: a meta-analysis

Aims/hypothesisEpidemiological evidence indicates that individuals with diabetes mellitus have an increased risk of several cancers. We performed a systematic review with meta-analysis to evaluate the association between diabetes and risk of bladder cancer.MethodsPertinent studies were identified by searching MEDLINE (from January 1966 to July 2006) and by reviewing the reference lists of retrieved articles. We included case–control and cohort studies reporting relative risk (RR) estimates with 95% CIs (or data to calculate them) of bladder cancer associated with diabetes. Studies of type 1 diabetes were not included. Summary RRs were calculated using a random-effects model.ResultsA total of 16 studies (seven case–control studies, three cohort studies and six cohort studies of diabetic patients) fulfilled the inclusion criteria. Analysis of all studies showed that diabetes was associated with an increased risk of bladder cancer, compared with no diabetes (RR = 1.24, 95% CI 1.08–1.42). There was strong evidence of heterogeneity among these studies (p < 0.0001). Stratification by study design found that diabetes was associated with an increased risk of bladder cancer in case–control studies (RR = 1.37, 95% CI 1.04–1.80, pheterogeneity = 0.005) and cohort studies (RR = 1.43, 95% CI 1.18–1.74, pheterogeneity = 0.17), but not in cohort studies of diabetic patients (RR = 1.01, 95% CI 0.91–1.12, pheterogeneity = 0.35).Conclusions/interpretationFindings from this meta-analysis suggest that individuals with diabetes may have a modestly increased risk of bladder cancer.

Interaction with factor inhibiting HIF-1 defines an additional mode of cross-coupling between the Notch and hypoxia signaling pathways

Cells adapt to hypoxia by a cellular response, where hypoxia-inducible factor 1α (HIF-1α) becomes stabilized and directly activates transcription of downstream genes. In addition to this “canonical” response, certain aspects of the pathway require integration with Notch signaling, i.e., HIF-1α can interact with the Notch intracellular domain (ICD) to augment the Notch downstream response. In this work, we demonstrate an additional level of complexity in this cross-talk: factor-inhibiting HIF-1 (FIH-1) regulates not only HIF activity, but also the Notch signaling output and, in addition, plays a role in how Notch signaling modulates the hypoxic response. We show that FIH-1 hydroxylates Notch ICD at two residues (N1945 and N2012) that are critical for the function of Notch ICD as a transactivator within cells and during neurogenesis and myogenesis in vivo. FIH-1 negatively regulates Notch activity and accelerates myogenic differentiation. In its modulation of the hypoxic response, Notch ICD enhances recruitment of HIF-1α to its target promoters and derepresses HIF-1α function. Addition of FIH-1, which has a higher affinity for Notch ICD than for HIF-1α, abrogates the derepression, suggesting that Notch ICD sequesters FIH-1 away from HIF-1α. In conclusion, the data reveal posttranslational modification of the activated form of the Notch receptor and an intricate mode of cross-coupling between the Notch and hypoxia signaling pathways.

Hyperbaric oxygen (HBO) therapy in treatment of diabetic foot ulcers. Long-term follow-up

BACKGROUND The cause of diabetic foot ulcers is multifactorial, e.g., neuropathy and angiopathy, leading to functional disturbances in the macrocirculation and skin microcirculation. Adequate tissue oxygen tension is an essential factor in infection control and wound healing. Hyperbaric oxygen (HBO) therapy, daily sessions of oxygen breathing at 2.5-bar increased pressure in a hyperbaric chamber, has beneficial actions on wound healing including antimicrobial action, prevention of edema and stimulation of fibroblasts. The aim of the present study was to investigate the long-term effect of HBO in treatment of diabetic foot ulcers. METHODS Thirty-eight diabetic patients (30 males) with chronic foot ulcers were investigated in a prospective study. The mean age was 60+/-13 years and the mean diabetes duration 27+/-14 years. All patients were evaluated with measurements of transcutaneous oxygen tension (tcPO(2)), peripheral blood pressure, and HbA(1c). All patients had a basal tcPO(2) value lower than 40 mmHg, which increased to >/=100 mmHg, or at least three times the basic value, during inhalation of pure oxygen. Seventeen patients underwent 40-60 sessions of HBO therapy, while 21 patients were treated conventionally. The follow-up time was 3 years. RESULTS 76% of the patients treated with HBO (Group A) had healed with intact skin at a follow-up time of 3 years. The corresponding value for patients treated conventionally (Group B) was 48%. Seven patients (33%) in Group B compared to two patients (12%) in Group A went to amputation. Peripheral blood pressure, HbA(1c), diabetes duration, and basal values of tcPO(2) were similar in both groups. CONCLUSIONS Adjunctive HBO therapy can be valuable for treating selected cases of hypoxic diabetic foot ulcers. It seems to accelerate the rate of healing, reduce the need for amputation, and increase the number of wounds that are completely healed on long-term follow-up. Additional studies are needed to further define the role of HBO, as part of a multidisciplinary program, to preserve a functional extremity, and reduce the short- and long-term costs of amputation and disability.

New susceptibility loci associated with kidney disease in Type 1 diabetes

Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genome-wide association studies (GWAS) of T1D DN comprising ∼2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2×10−8) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0×10−9). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-β1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1×10−7), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.

Inhibited proliferation of fibroblasts derived from chronic diabetic wounds and normal dermal fibroblasts treated with high glucose is associated with increased formation of L-lactate

Diabetes is accompanied by delayed wound healing and insufficient granulation tissue formation, possibly because of a defect in fibroblast function. We have previously shown that fibroblasts derived from chronic diabetic foot ulcers have lower proliferation compared with those from uninjured skin. The aim of this study was to investigate possible mechanisms explaining the impaired fibroblast proliferation observed in fibroblasts from non‐insulin‐dependent diabetes mellitus chronic wounds and normal fibroblasts cultured in high glucose. Fibroblasts from two groups of patients were studied: nondiabetic patients with chronic venous stasis ulcers and non‐insulin‐dependent diabetes mellitus patients with chronic diabetic wounds. Biopsies from both uninjured skin and wounds were taken from the same patients to serve as sources of fibroblasts. A fluorometric method was used to determine DNA content, and a spectrophotometric lactate oxidase method was used for lactate level analysis. We found a dose‐dependent inhibition of normal fibroblast proliferation when adding conditioned media from non‐insulin‐dependent diabetes mellitus wound fibroblasts. The conditioned medium, from these cells showed elevated L‐lactate levels, 6.3 ± 0.7 mmol/L, compared with media derived from nondiabetic, 2.1 ± 0.3 mmol/L (p < 0.01), and diabetic uninjured skin fibroblasts, 3.5 ± 0.6 mmol/L, and from chronic nondiabetic wound fibroblasts 2.9 ± 0.3 mmol/L. Addition of 6 mmol/L L‐lactate to uninjured normal fibroblasts resulted in decreased DNA content (58 ± 7%, p < 0.01). Previously we have shown that high glucose concentrations inhibit fibroblast proliferation and induce growth factor resistance. When increasing the amount of D‐glucose in the media, L‐lactate levels increased in all cell types. When the uninjured normal cells were treated with β‐hydroxybutyrate, the total DNA content decreased by 42 ± 5% (p < 0.05), with no significant increase in the L‐lactate levels. These observations indicate that L‐lactate production may be of importance for fibroblast proliferation in vitro and may play a role in fibroblast proliferation in vivo.

Elevated Hip Fracture Risk in Type 1 Diabetic Patients: A Population-Based Cohort Study in Sweden

OBJECTIVE Patients with type 1 diabetes often have low bone mineral density, but epidemiological data on fracture risk are sparse and imprecise, particularly for men. RESEARCH DESIGN AND METHODS In the Swedish Inpatient Register, we identified a population-based cohort of 24,605 patients (12,551 men and 12,054 women) who were hospitalized for diabetes before age 31 years during 1975 through 1998. Follow-up for hip fracture was accomplished through cross-linkage in the Inpatient Register until the end of 1998. Censoring information was obtained from the registers of Death and Migration. Using the Kaplan-Meier method, we calculated the cumulative probability of getting a hip fracture. Standardized hospitalization ratios and their 95% CIs estimated relative risks with the age-, sex-, and calendar period-matched Swedish general population as reference. RESULTS In total, 70 and 51 first hip fractures were ascertained in men and women, respectively, corresponding to a cumulative probability (both sexes) of 65.8/1,000 until age 65 years. Markedly elevated risks were observed in both men and women (standardized hospitalization ratios = 7.6 [95% CI 5.9-9.6] and 9.8 [7.3-12.9], respectively), increasing with follow-up time. Ophthalmic, nephropathic, neurological, and cardiovascular complications were indicators of particularly high risks. CONCLUSIONS Both male and female type 1 diabetic patients are at increased risk for hip fracture. Although optimal preventive measures still need to be defined, the co-occurrence with other diabetes complications suggests that tighter metabolic control might reduce the risk.

Altered properties of the fibrin gel structure in patients with IDDM.

Summary High plasma fibrinogen levels are associated with vascular complications in the general population. Fibrin, the structural element in a clot, is derived from fibrinogen by activation of thrombin. An abnormal fibrin gel structure has been demonstrated in patients with myocardial infarction and in diabetic patients during poor metabolic control. In the present study the properties of fibrin gel structure were investigated in 20 patients with insulin-dependent diabetes mellitus (IDDM): 10 patients without (age: 30 ± 8; diabetes duration: 7 ± 6 years), and 10 patients (age: 44 ± 7; diabetes duration: 27 ± 9 years) with microangiopathy. Fifteen healthy subjects served as controls (age: 40 ± 8 years). The glycosylated haemoglobin level (HbA1c) was elevated (p < 0.001) in the patients: 6.5 ± 1.5 % in diabetic patients without, and 7.1 ± 1.0 % in diabetic patients with microangiopathy. C-reactive protein and plasma fibrinogen were similar as compared to healthy control subjects. The properties of the fibrin gel structure; i. e. the permeability coefficient (Ks) and the fibre mass length ratio (μ) formed in recalcified plasma on addition of thrombin were investigated. Ks was decreased in the diabetic patients, with (6.5 ± 2.0 cm2; p < 0.01) and without microangiopathy (6.5 ± 2.7 cm2; p < 0.05), as compared to healthy subjects (10.0 ± 3.4 cm2), while μ was not significantly (p = 0.14) altered. The results indicate a lower fibrin gel porosity in patients with IDDM, despite normal plasma fibrinogen and irrespective of microangiopathy. The abnormal fibrin gel structure may be due to an increased glycosylation of the fibrin (-ogen) molecule caused by long-term hyperglycaemia and may be of importance for the development of angiopathy in diabetic patients. [Diabetologia (1996) 39: 1519–1523]

Nutritional status, insulin-like growth factor-1 and quality of life in elderly women with hip fractures

AIM To evaluate nutritional status and its relation to cognitive and physical function and quality of life in elderly female patients with hip fractures. METHODS Nutritional status was assessed in 42 women (80+/-7 years old) using the body mass index (BMI), triceps skin fold, arm muscle circumference and serum levels of insulin-like growth factor (IGF-1) and its binding protein (BP) IGFBP-1. Handgrip strength was measured. The Short Portable Mental Status Questionnaire was used to assess cognitive function and the Nottingham Health Profile to asses quality of life. RESULTS Low BMI (<== 20) and reduced IGF-1 and IGFBP-1 levels were detected in 50% of the patients. BMI correlated with IGF-1 (p<< 0.02) and with hand grip strength (P<< 0.001). Hand grip strength correlated with arm muscle circumference (P<< 0.05). Cognitive dysfunction was detected in 18% of the patients, and a correlation was found between cognitive function and BMI (P<< 0.01). The Nottingham Health Profile assessment indicated a lower quality of life in underweight patients as compared to others (P<< 0.05). CONCLUSIONS Half of the elderly women with hip fractures displayed signs of protein-energy malnutrition. Underweight was associated with reduced serum levels of IGF-1, muscle fatigue, cognitive dysfunction and a low quality of life rating, i.e. a cluster of factors which may unfavourably influence the postoperative course in a large proportion of hip fracture patients.