Sequential intramedullary nailing of open tibial shaft fractures after external fixation

Abstracts: We reviewed 32 tibial shaft fractures in 31 patients treated with sequential intramedullary nailing after primary external fixation. There were 30 open fractures and 2 closed injuries with severe blunt trauma requiring fasciotomy. Fifty per cent of the fractures were classified as Gustilo type III A and B injuries [13]. The mean external fixation treatment averaged 6.6 weeks, and secondary intramedullary nailing was done on average 7.4 weeks after injury. In 50% of the fractures, secondary nailing was done at the same procedure as removal of the external fixation. Overall, the incidence of osteomyelitis and nonunion was 3.1% each and of malunion 19%. The time to full weight-bearing averaged 31.2 weeks. The results were separately analyzed according to Gustilo types and subtypes. In the Gustilo type III B injuries, the incidence of osteomyelitis and non-union was 11 %, while malunion occurred in 33%. The time to full weight-bearing averaged 53 weeks. These results support the conclusion that this treatment modality is a valid alternative to other treatment options. However, previous pintract infections should be regarded as a contraindication for secondary nailin

Differential interaction of glimepiride and glibenclamide with the β-cell sulfonylurea receptor I. Binding characteristics

Glimepiride is a novel sulfonylurea drug for treatment of non-insulin-dependent diabetes mellitus with higher blood sugar lowering efficacy in diabetic patients than glibenclamide raising the question whether this characteristics is in line with different binding of glimepiride and glibenclamide to the β-cell sulfonylurea receptor. Scatchard plot analysis of [3H]sulfonylurea binding to membranes isolated from rat β-cell tumors and (RINm5F) insulinoma cells and to RINm5F cells demonstrated that glimepiride has a 2.5–3-fold lower affinity than glibenclamide. This corresponded well to the 8–9-fold higher koff and 2.5–3-fold higher kon rates of glimepiride compared to glibenclamide as revealed by the dissociation and association kinetics of [3H]sulfonylurea binding and the Kd values calculated thereof. In agreement, the concentrations required for half-maximal displacement of [3H]sulfonylurea bound to β-cell membranes were significantly higher for glimepiride compared to glibenclamide. However, the binding affinity of glimepiride measured by both equilibrium binding and kinetic binding studies upon solubilization of β-cell tumor membranes and RINm5F cell membranes increased up to the value for glibenclamide. This was primarily based on a drastic decrease of the dissociation rate constant of glimepiride whereas the kinetics of glibenclamide binding remained largely unaffected upon solubilization. These data suggest that the Kd value alone is not sufficient for characterization of a sulfonylurea drug, since the kinetic binding parameters may also determine its acute blood sugar lowering efficacy

Diagnostic accuracy of calculated serum osmolarity to predict dehydration in older people: adding value to pathology lab reports

Objectives: To assess which osmolarity equation best predicts directly measured serum/plasma osmolality and whether its use could add value to routine blood test results through screening for dehydration in older people. Design: Diagnostic accuracy study Participants: Older people (≥65 years) in 5 cohorts: Dietary Strategies for Healthy Ageing in Europe (NU-AGE, living in the community), Dehydration Recognition In our Elders (DRIE, living in residential care), Fortes (admitted to acute medical care), Sjöstrand (emergency room) or Pfortmueller cohorts (hospitalised with liver cirrhosis). Reference standard for hydration status: Directly measured serum/plasma osmolality: current dehydration (serum osmolality >300mOsm/kg), impending/current dehydration (≥295mOsm/kg). Index tests: 39 osmolarity equations calculated using serum indices from the same blood draw as directly measured osmolality. Results: Across five cohorts 595 older people were included, of whom 19% were dehydrated (directly measured osmolality >300mOsm/kg). Of 39 osmolarity equations, five showed reasonable agreement with directly measured osmolality and three had good predictive accuracy in subgroups with diabetes and poor renal function. Two equations were characterized by narrower limits of agreement, low levels of differential bias and good diagnostic accuracy in ROC plots (areas under the curve >0.8). The best equation was osmolarity =1.86 × (Na+ + K+) + 1.15 × glucose + urea + 14 (all measured in mmol/L). It appeared useful in people aged ≥65 years with and without diabetes, poor renal function, dehydration, in men and women, with a range of ages, health, cognitive and functional status. Conclusions: Some commonly used osmolarity equations work poorly, and should not be used. Given costs and prevalence of dehydration in older people we suggest use of the best formula by pathology laboratories using a cutpoint of 295mOsm/L (sensitivity 85%, specificity 59%), to report dehydration risk opportunistically when serum glucose, urea and electrolytes are measured for other reasons in older adults

Saxagliptin co-therapy in C-peptide negative Type 1 diabetes does not improve counter-regulatory responses to hypoglycaemia

Aims: To test the hypothesis that dipeptidyl peptidase-4 inhibition in C-peptide negative Type 1 diabetes would reduce glucose variability and exposure to hypoglycaemia and therefore may indirectly enhance counter-regulatory responses to subsequent hypoglycaemia.Methods: We conducted a 12-week double-blind, randomized, placebo-controlled crossover study. The study was conducted in a tertiary hospital outpatient clinic, with additional studies performed in a clinical research centre. After obtaining informed consent, we recruited 14 subjects with moderately well controlled Type 1 diabetes (HbA1c 64 ` 2 mmol/mol) of long duration (20.5 ` 2.7 years). The subjects received 12 weeks’ therapy with oral saxagliptin (5 mg) or placebo. Glucose variability, assessed via continuous glucose monitoring, together with frequency of hypoglycaemia, hypoglycaemia awareness and symptomatic, cognitive and counter-regulatory hormone responses to experimental hypoglycaemia, were assessed. Additional outcome measures included HbA1c level, weight, total daily insulin dose and adverse events.Results: Saxagliptin co-therapy did not reduce glucose variability (low blood glucose index, average daily risk range), hypoglycaemia frequency or awareness and did not improve counter-regulatory hormonal responses during experimental hypoglycaemia (area under the curve for adrenaline 25 775 vs. 24 454, for placebo vs saxagliptin, respectively; P = 0.76).Conclusions: No additional benefit of dipeptidyl peptidase-4 inhibition co-therapy with saxagliptin in the management of Type 1 diabetes was observed

The Genetic Basis of Type 2 Diabetes Mellitus: Impaired Insulin Secretion versus Impaired Insulin Sensitivity

A. General considerations B. Diabetogenic vs. diabetes-related genes C. Secondary impairment of insulin secretion and in-sulin sensitivit

Inhibition of microsomal cortisol production by (–)-epigallocatechin-3-gallate through a redox shift in the endoplasmic reticulum — A potential new target for treating obesity-related diseases

Conversion of cortisone to cortisol by 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) in the endoplasmic reticulum (ER) of the target cells is a major determinant of glucocorticoid action, and plays an important role in the development of obesity-related diseases. Inhibition of 11βHSD1 activity is, therefore, considered as a promising novel strategy for the treatment of metabolic syndrome and diabetes. Tea flavanols and their major representative, epigallocatechin gallate are known as antiobesity and antidiabetic agents. Their impacts on blood glucose level, hepatic glucose production, and insulin responsiveness resemble those observed on inhibition or depletion of 11βHSD1. We aimed to study the effect of epigallocatechin gallate on 11βHSD1 activity in ER-derived rat liver microsomes by measuring cortisone and cortisol with HPLC. Cortisol production was efficiently suppressed in a concentration dependent manner in intact microsomal vesicles. However, this effect was abolished by membrane permeabilization; and the three proteins involved in the overall process (11βHSD1, hexose 6-phosphate dehydrogenase, and glucose 6-phosphate transporter) were not or only mildly affected. Further investigation revealed the oxidation of luminal NADPH to NADP+, which attenuates cortisone reduction and favors cortisol oxidation in this compartment. Such a redox shift in the ER lumen might contribute to the beneficial health effects of tea flavanols and should be regarded as a promising strategy for the development of novel selective 11βHSD1 inhibitors to treat obesity-related diseases. © 2013 BioFactors 39(5):534–541, 201

Становлення та розвиток ідеї свободи як принципу права

Вказується, непересічна важливість досліджу­ваного питання підтверджується також змістом Угоди про асоціацію між Україною, з однієї сторо­ни, та Європейським Союзом, Європейським спів­товариством з атомної енергії і їхніми держава­ми-членами, з іншої сторони, де закріплено важ­ливість спільного управління свободи пересуван­ня (міграційними потоками) між територіями та всеохоплюючий діалог щодо всіх питань у сфері міграції, зокрема нелегальної міграції, легальної міграції, незаконного переправлення осіб через державний кордон та торгівлі людьми, а також включення проблемних питань у сфері міграції до національних стратегій економічного та соціаль­ного розвитку регіонів, звідки походять мігранти. Особлива вага проблем свободи пересування в рамках міграційного контролю відображається та­кож у національному законодавстві тим фактом, що у відповідності до положень Конституції Укра­їни виключно законами України визначаються за­сади регулювання демографічних та міграційних процесів, а також порядок утворення і функціо­нування вільних та інших спеціальних зон, що ма­ють економічний чи міграційний режим, відмінний від загального. Автори відзначають, становлення та розвиток ідей свободи як принципу права - це постійний процес, що відображає виклики різних епох. Су­часний світ вимагає не лише утримання цих ідей, але і їхнє активне вдосконалення відповідно до нових реалій та прогресу суспільства. Забезпе­чення свободи залишається головним завданням для правозахисників, законодавців та громадян. Звернення уваги до нових викликів, таких як гло­бальні проблеми, технологічний прогрес, соціокультурні трансформації, дозволяє вдосконалю­вати існуючі концепції свободи та пристосовувати їх до нових умов. Спільні зусилля, ефективне міжнародне спів­робітництво та взаємне повага до прав людини є ключовими елементами для розвитку ідей свобо­ди. Глобальне співтовариство повинне активно працювати над створенням інклюзивних та ефек­тивних механізмів захисту прав людини на всіх рівнях. У світлі нових викликів, що стоять перед люд­ством, збереження та розвиток ідей свободи ста­ють не лише завданням законодавців, а й питан­ням громадської свідомості та активного участі кожного члена суспільства. Тільки спільні зусилля та постійна готовність вдосконалювати наші уяв­лення про свободу можуть забезпечити сталість цього важливого принципу права в сучасному та майбутньому світі

Type 2 diabetes: postprandial hyperglycemia and increased cardiovascular risk

Hyperglycemia is a major risk factor for both the microvascular and macrovascular complications in patients with type 2 diabetes. This review summarizes the cardiovascular results of large outcomes trials in diabetes and presents new evidence on the role of hyperglycemia, with particular emphasis on postprandial hyperglycemia, in adverse cardiovascular outcomes in patients with type 2 diabetes. Treatment options, including the new dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 mimetics that primarily target postprandial hyperglycemia, are also discussed. Hyperglycemia increases cardiovascular mortality, and reducing hyperglycemia lowers cardiovascular risk parameters. Control of both fasting and postprandial hyperglycemia is necessary to achieve optimal glycated hemoglobin control. Therefore, anti-hyperglycemic agents that preferentially target postprandial hyperglycemia, along with those that preferentially target fasting hyperglycemia, are strongly suggested to optimize individual diabetes treatment strategies and reduce complications

Tendinopathy—from basic science to treatment

Chronic tendon pathology (tendinopathy), although common, is difficult to treat. Tendons possess a highly organized fibrillar matrix, consisting of type I collagen and various 'minor' collagens, proteoglycans and glycoproteins. The tendon matrix is maintained by the resident tenocytes, and there is evidence of a continuous process of matrix remodeling, although the rate of turnover varies at different sites. A change in remodeling activity is associated with the onset of tendinopathy. Major molecular changes include increased expression of type III collagen, fibronectin, tenascin C, aggrecan and biglycan. These changes are consistent with repair, but they might also be an adaptive response to changes in mechanical loading. Repeated minor strain is thought to be the major precipitating factor in tendinopathy, although further work is required to determine whether it is mechanical overstimulation or understimulation that leads to the change in tenocyte activity. Metalloproteinase enzymes have an important role in the tendon matrix, being responsible for the degradation of collagen and proteoglycan in both healthy patients and those with disease. Metalloproteinases that show increased expression in painful tendinopathy include ADAM (a disintegrin and metalloproteinase)-12 and MMP (matrix metalloproteinase)-23. The role of these enzymes in tendon pathology is unknown, and further work is required to identify novel and specific molecular targets for therapy

<i>RD Lawrence Lecture 2015</i>. Old habits are hard to break:lessons from the study of hypoglycaemia

Despite the introduction of newer technologies and improved insulin formulations, recurrent hypoglycaemia continues to affect the lives of many people with Type 1 and Type 2 diabetes. Developing strategies or therapies designed to prevent or minimize hypoglycaemia risk is of utmost importance to help individuals safely achieve glycaemic targets. Novel, educational or behavioural approaches need to be based on a clear understanding of the mechanisms underpinning both the detection of hypoglycaemia and why repeated exposure to hypoglycaemia leads to the development of a clinical syndrome referred to as impaired awareness of hypoglycaemia. In the present review, I propose that impaired awareness of hypoglycaemia may represent a form of learning called habituation, a response that, at a cellular level, represents a biological adaptation designed to protect the organism from future exposure to that stressor. In diabetes, this survival response to low glucose is, however, overwhelmed by high systemic insulin levels resulting from exogenous insulin therapy, leading to progressively more severe hypoglycaemia. A recognition of the underlying mechanism means that the development of impaired awareness of hypoglycaemia can perhaps be better understood and explained to individuals with diabetes, and novel therapeutic approaches such as dishabituation or cognitive behavioural therapies can be considered. This article is protected by copyright. All rights reserved.</p