The pattern of incident fractures according to fracture site in people with T1D.

Higher incidences of fractures are seen in people with type 1 diabetes (T1D), but knowledge on different fracture sites is sparse. We found a higher incidence mainly for distal fracture sites in people with T1D compared to controls. It must be further studied which fractures attributed to the higher incidence rates (IRs) at specific sites. INTRODUCTION: People with T1D have a higher incidence of fractures compared to the general population. However, sparse knowledge exists on the incidence rates of individual fracture sites. Therefore, we examined the incidence of various fracture sites in people with newly treated T1D compared to matched controls. METHODS: All people from the UK Clinical Practice Research Datalink GOLD (1987-2017), of all ages with a T1D diagnosis code (n = 6381), were included. People with T1D were matched by year of birth, sex, and practice to controls (n = 6381). Fracture IRs and incidence rate ratios (IRRs) were calculated. Analyses were stratified by fracture site and sex. RESULTS: The IR of all fractures was significantly higher in people with T1D compared to controls (IRR: 1.39 (CI95%: 1.24-1.55)). Compared to controls, the IRR for people with T1D was higher for several fracture sites including carpal (IRR: 1.41 (CI95%: 1.14-1.75)), clavicle (IRR: 2.10 (CI95%: 1.18-3.74)), foot (IRR: 1.70 (CI95%: 1.23-2.36)), humerus (IRR: 1.46 (CI95%: 1.04-2.05)), and tibia/fibula (IRR: 1.67 CI95%: 1.08-2.59)). In women with T1D, higher IRs were seen at the ankle (IRR: 2.25 (CI95%: 1.10-4.56)) and foot (IRR: 2.11 (CI95%: 1.27-3.50)), whereas in men with T1D, higher IRs were seen for carpal (IRR: 1.45 (CI95%: 1.14-1.86)), clavicle (IRR: 2.13 (CI95%: 1.13-4.02)), and humerus (IRR: 1.77 (CI95%: 1.10-2.83)) fractures. CONCLUSION: The incidence of carpal, clavicle, foot, humerus, and tibia/fibula fractures was higher in newly treated T1D, but there was no difference at other fracture sites compared to controls. Therefore, the higher incidence of fractures in newly treated people with T1D has been found mainly for distal fracture sites.

Diabetes and fractures: new evidence of atypical femoral fractures?

Patients with diabetes have an increased risk of fractures. In this study, subtrochanteric and femoral shaft fractures were increased in patients with type 1 diabetes compared with the general population. In the light of this, more evidence points towards an association between diabetes and atypical femoral fractures. INTRODUCTION: Patients with diabetes have an increased risk of femoral fractures, but little is known about the risk of atypical femoral fractures (AFFs). The aim of this study was to identify the risk of subtrochanteric and femoral shaft (ST/FS) fractures and estimate the risk of AFFs in patients with type 1 (T1D) and type 2 diabetes (T2D). METHODS: From the nationwide Danish National Patient Register, we identified patients with T1D (n = 19,896), T2D (n = 312,188), and sex- and aged-matched controls without diabetes (n = 996,252) from the general population and all ST/FS fractures (n = 7509). Data were analyzed using a Cox proportional-hazards model and the incidence rate and rate ratio of ST/FS fractures were estimated. RESULTS: The incidence rate of ST/FS fractures in T1D was 52.14 events per 100,000 person years and 73.21 per 100,000 person years in T2D. T1D was associated with an increased risk of ST/FS (HR 2.07 (95% CI 1.68-2.56)), whereas T2D was not (HR 0.99 (95% CI 0.94-1.10)). Previous ST/FS fractures were associated with an increased risk of subsequent ST/FS fractures (HR 6.95 (95% CI 6.00-8.05)) and the use of bisphosphonates with an increased risk of ST/FS fractures (HR 1.72 (95% CI 1.54-1.91)). CONCLUSION: Patients with T1D have a higher risk of ST/FS fractures compared with sex- and age-matched controls. Since a proportion of ST/FS fractures are classified as AFFs, this could point towards the fact that AFFs also are increased in patients with T1D, but not T2D.

Twenty years with diabetes and amputations: a retrospective population-based cohort study.

AIM: To investigate the trends in non-traumatic lower limb amputation in people with and without diabetes. METHODS: From the Danish National Patient Register, all people with either type 1 or type 2 diabetes (n = 462 743) as well as a group of people without diabetes from the general population (n = 1 388 886) were identified and separated into three groups based on diabetes type. Among these, 17 265 amputations were identified between 1997 and 2017 and stratified into trans-femoral amputations, trans-tibial amputations and amputations below the ankle using surgical codes. Annual changes were described using least-squares linear regression. RESULTS: The yearly mean decrease in incidence rate of amputation per 1000 person-years was -0.032 [95% CI: -0.062, -0.001], -0.022 [-0.032, -0.012] and -0.006 [-0.009, -0.003] for trans-femoral amputation, -0.072 [-0.093, -0.052], -0.090 [-0.102, -0.078] and -0.015 [-0.016, -0.013] for trans-tibial amputation, and -0.055 [-0.080, -0.020], -0.075 [-0.090, -0.060] and -0.011 [-0.014, -0.007] for amputation below the ankle in people with type 1 diabetes, people with type 2 diabetes and people without diabetes, respectively. CONCLUSIONS: Over recent decades, the incidence of amputation has decreased significantly in people with diabetes and in the general population without diabetes.

Hypoglycaemia and type 1 diabetes are associated with an increased risk of fractures.

People with diabetes have an increased risk of fractures, and in this study, the effect of hypoglycaemia and insulin on this risk was investigated. Type 1 diabetes and hypoglycaemia did increase the fracture risk, and prevention of hypoglycaemia is thus an important focus area in the prevention of fractures. INTRODUCTION: Studies have shown that type 1 diabetes (T1D) and type 2 diabetes (T2D) are associated with increased risk of fractures. Especially, subjects with T1D have an increased risk of fractures. The purpose of this study was to investigate the association of T1D, hypoglycaemia and insulin on fracture risk. METHODS: A cohort study with T1D subjects (n = 19,896) and T2D subjects (n = 312,188) matched with subjects from the general populated (n = 996,252) and a nested case-control study with T1D subjects with fracture (n = 895) as cases and T1D subjects without (n = 2685) as controls were conducted based on subjects from the Danish National Patient Registry (DNPR). RESULTS: T1D (HR = 2.47, 95% CI 2.37 to 2.59), age (HR = 1.05, 95% CI 1.05 to 1.05), previous fracture (HR = 1.95, 95% CI 1.92 to 1.99) and being female (HR = 2.06, 95% CI 2.04 to 2.09) increased the risk of fractures. Also, T2D (HR = 1.14, 95% CI 1.11 to 1.18) increased the risk of proximal upper arm and shoulder fractures. T1D (HR = 2.41, 95% CI 2.20 to 2.65) increased the risk of hip and femoral region fractures. Hypoglycaemia (OR = 1.58, 95% CI 1.27 to 1.97) increased the risk of fractures, whereas insulin use did not change the risk. CONCLUSIONS: Hypoglycaemic episodes are associated with increased fracture risk, and the frequency of hypoglycaemic episodes leading to hospital admission was above 16% for T1D subjects. Prevention of hypoglycaemia is thus an important focus area in the prevention of fractures.

Slow rheological mode in glycerol and glycerol-water mixtures.

Glycerol-water mixtures were studied at molar concentrations ranging from xgly = 1 (neat glycerol) to xgly = 0.3 using shear mechanical spectroscopy. We observed a low frequency mode in neat glycerol, similar to what has been reported for monohydroxy alcohols. This mode has no dielectric counterpart and disappears with increased water concentration. We propose that the hydrogen-bonded network formed between glycerol molecules is responsible for the observed slow mode and that water acts as a plasticizer for the overall dynamics and as a lubricant softening the hydrogen-bonding contribution to the macroscopic viscosity of this binary system.

A systematic study of the isothermal crystallization of the mono-alcohol n-butanol monitored by dielectric spectroscopy.

Isothermal crystallization of the mono-hydroxyl alcohol n-butanol was studied with dielectric spectroscopy in real time. The crystallization was carried out using two different sample cells at 15 temperatures between 120 K and 134 K. Crystallization is characterized by a decrease of the dielectric intensity. In addition, a shift in relaxation times to shorter times was observed during the crystallization process for all studied temperatures. The two different sample environments induced quite different crystallization behaviors, consistent and reproducible over all studied temperatures. An explanation for the difference was proposed on the background of an Avrami analysis and a Maxwell-Wagner analysis. Both types of analysis suggest that the morphology of the crystal growth changes from a higher dimension to a lower at a point during the crystallization. More generally, we conclude that a microscopic interpretation of crystallization measurements requires multiple probes, sample cells, and protocols.

Growth, competition and cooperation in spatial population genetics.

We study an individual based model describing competition in space between two different alleles. Although the model is similar in spirit to classic models of spatial population genetics such as the stepping stone model, here however space is continuous and the total density of competing individuals fluctuates due to demographic stochasticity. By means of analytics and numerical simulations, we study the behavior of fixation probabilities, fixation times, and heterozygosity, in a neutral setting and in cases where the two species can compete or cooperate. By concluding with examples in which individuals are transported by fluid flows, we argue that this model is a natural choice to describe competition in marine environments.

Emergence and decline of scientific paradigms.

Scientific paradigms have a tendency to rise fast and decline slowly. This asymmetry reflects the difficulty in developing a truly original idea, compared to the ease at which a concept can be eroded by numerous modifications. Here we formulate a model for the emergence and spread of ideas which deals with this asymmetry by constraining the ability of agents to return to already abandoned concepts. The model exhibits a fairly regular pattern of global paradigm shifts, where older paradigms are eroded and subsequently replaced by new ones. The model sets the theme for a new class of pattern formation models, where local dynamics breaks the detailed balance in a way that prevents old states from defending themselves against new nucleating or invading states. The model allows for frozen events in terms of the coexistence of multiple metastable states.

Absence of colon as the predominant risk factor for liver fibrosis in adults requiring home parenteral nutrition.

BACKGROUND: Liver fibrosis is a well-known complication of long-term use of parenteral nutrition in patients with intestinal failure associated to the nutrient composition in parenteral nutrition. This study investigates the prevalence of significant liver fibrosis and identifies risk factors for liver fibrosis. METHODS: This was a retrospective study of 35 parenteral nutrition-dependent patients with intestinal failure and 54 patients with intestinal insufficiency and oral nutrition only with a valid liver stiffness measurement obtained with transient elastography from November 2016 to August 2018. Clinical and demographic parameters including age, fat mass index and fat-free mass index, intact colon or colectomy, and nutritional management were analyzed for their association with liver stiffness. RESULTS: A prevalence for liver fibrosis (liver stiffness >7.0 kPa) was established at 37.1% in parenteral nutrition-dependent patients and at 22.2% in patients on oral nutrition. Several factors were significantly and independently associated with liver fibrosis including lipids in home parenteral nutrition (OR 10.66, p = 0.010) and colectomies (OR 3.24, p = 0.036). CONCLUSION: More than a third of patients receiving home parenteral nutrition have liver fibrosis. Several risk factors were demonstrated such as the amount of lipids and performed colectomies despite current international guidelines for lipids are followed. Our findings emphasize suggest a new perspective to prevent significant hepatic complications: colectomies.

Frustrated bistability as a means to engineer oscillations in biological systems.

Oscillations play an important physiological role in a variety of biological systems. For example, respiration and carbohydrate synthesis are coupled to the circadian clock in cyanobacteria (Ishiura et al 1998 Science 281 1519) and ultradian oscillations with time periods of a few hours have been observed in immune response (NF-kappaB, Hoffmann et al 2002 Science 298 1241, Neson et al 2004 Science 306 704), apoptosis (p53, Lahav et al 2004 Nat. Genet. 36 53), development (Hes, Hirata et al 2002 Science 298 840) and growth hormone secretion (Plotsky and Vale 1985 Science 230 461, Zeitler et al 1991 Proc. Natl. Acad. Sci. USA 88 8920). Here we discuss how any bistable system can be 'frustrated' to produce oscillations of a desired nature--we use the term frustration, in analogy to frustrated spins in antiferromagnets, to refer to the addition of a negative feedback loop that destabilizes the bistable system. We show that the molecular implementation can use a wide variety of methods ranging from translation regulation, using small non-coding RNAs, to targeted protein modification to transcriptional regulation. We also introduce a simple graphical method for determining whether a particular implementation will produce oscillations. The shape of the resulting oscillations can be readily tuned to produce spiky and asymmetric oscillations--quite different from the shapes produced by synthetic oscillators (Elowitz and Leibler 2000 Nature 403 335, Fung et al 2005 Nature 435 118). The time period and amplitude can also be manipulated and these oscillators are easy to reset or switch on and off using a tunable external input. The mechanism of frustrated bistability could thus prove to be an easily implementable way to synthesize flexible, designable oscillators.

Oscillations and temporal signalling in cells.

The development of new techniques to quantitatively measure gene expression in cells has shed light on a number of systems that display oscillations in protein concentration. Here we review the different mechanisms which can produce oscillations in gene expression or protein concentration using a framework of simple mathematical models. We focus on three eukaryotic genetic regulatory networks which show 'ultradian' oscillations, with a time period of the order of hours, and involve, respectively, proteins important for development (Hes1), apoptosis (p53) and immune response (NF-kappaB). We argue that underlying all three is a common design consisting of a negative feedback loop with time delay which is responsible for the oscillatory behaviour.

Two subgroups of antipsychotic-naive, first-episode schizophrenia patients identified with a Gaussian mixture model on cognition and electrophysiology.

Deficits in information processing and cognition are among the most robust findings in schizophrenia patients. Previous efforts to translate group-level deficits into clinically relevant and individualized information have, however, been non-successful, which is possibly explained by biologically different disease subgroups. We applied machine learning algorithms on measures of electrophysiology and cognition to identify potential subgroups of schizophrenia. Next, we explored subgroup differences regarding treatment response. Sixty-six antipsychotic-naive first-episode schizophrenia patients and sixty-five healthy controls underwent extensive electrophysiological and neurocognitive test batteries. Patients were assessed on the Positive and Negative Syndrome Scale (PANSS) before and after 6 weeks of monotherapy with the relatively selective D2 receptor antagonist, amisulpride (280.3±159 mg per day). A reduced principal component space based on 19 electrophysiological variables and 26 cognitive variables was used as input for a Gaussian mixture model to identify subgroups of patients. With support vector machines, we explored the relation between PANSS subscores and the identified subgroups. We identified two statistically distinct subgroups of patients. We found no significant baseline psychopathological differences between these subgroups, but the effect of treatment in the groups was predicted with an accuracy of 74.3% (P=0.003). In conclusion, electrophysiology and cognition data may be used to classify subgroups of schizophrenia patients. The two distinct subgroups, which we identified, were psychopathologically inseparable before treatment, yet their response to dopaminergic blockade was predicted with significant accuracy. This proof of principle encourages further endeavors to apply data-driven, multivariate and multimodal models to facilitate progress from symptom-based psychiatry toward individualized treatment regimens.

Dephosphorylation of purine mononucleotides by alkaline phosphatases. Substrate specificity and inhibition patterns.

Three purine mononucleotides, adenosine-, inosine- and guanosine monophosphate, were used as substrates at pH 7.4 and at 10.4 for three alkaline phosphatases (orthophosphoric-monoester phosphohydrolase (acid optimum), EC 3.1.3.1) containing similar phosphate-binding serine groups at their esteratic sites. Substrate specificity was found for the enzymes from calf intestine and bovine liver. Alkaline phosphatase from Escherichia coli was nonspecific. A substrate-dependent and pronounced inhibition with the purine analogue 1,3-dimethyl xanthine was found for the enzymes from intestine and liver, but not for alkaline phosphatase from E. coli. A substrate-independent and pronounced inhibition was found for all three enzymes with the phosphomonoester p-nitrophenol phosphate as the inhibitor. Alkaline phosphatases may play an important role in the regulation of the intracellular content of purine mononucleotides.

Theophylline inhibition of renal and cerebral nucleoside formation.

1 Theophylline inhibits the enzymatic formation of purine nucleosides, among these adenosine (dephosphorylated adenosine 5'-monophosphate), in kidney and brain of the rat. 2 Some pharmacological effects of theophylline on regional blood flow and electrophysiological activity of the nervous system may be caused by inhibition of the endogenous formation of adenosine.

The hazard of acute epiglottitis.

This report is based on a 3 1/2 year's study of 33 cases of acute epiglottitis with 3 child deaths. Suspicion of acute epiglottitis in children with respiratory distress is always an indication for rapid direct laryngoscopy under general anaesthesia with intubation, and preparation for tracheotomy and bronchoscopy. Should the diagnosis of acute epiglottitis not be excluded during this procedure, then a free airway should be ensured by endotracheal intubation, even in cases of apparently less severe character, where the procedure would seem to be more prophylactic than therapeutic. Intubation is often very difficult. It is concluded that the patient should be received at the hospital by an E.N.T.--anaesthetic team conversant with the treatment of this potential killer.

Penetrating peptic ulcer and aortic aneurysm with aortogastric fistula.

The case of a 71-year-old woman with an aortogastric fistula caused by the combination of a penetrating peptic ulcer and an aortic aneurysm is reported. Treatment consisted of excision of the ulcer and primary prosthetic grafting of the aorta. Recovery was uneventful. The possible relationship between aortic aneurysm and peptic ulceration is discussed, as are therapeutic alternatives.

The 5'-nucleotidase complex in sera from patients with gall stones--electrophoretic patterns and substrate specificity.

Various purine and pyrimidine mononucleotides seem to be dephosphorylated by a 5'-nucleotidase complex composed of four fractions in sera from both patients with gall stones and from normal subjects. Agarose gel electrophoresis, with the addition of Triton X-100, demonstrated that the faster (F-) fraction of the enzyme complex and the slower (S-) fraction both consisted of two sub-fractions (termed alpha and beta). The enzyme complex showed a uniform substrate specificity pattern, which was independent of the absolute enzyme activity.

The 5'-nucleotidase activity in normal human serum. Electrophoretic patterns and substrate specificity.

Both the electrophoretic patterns and substrate specificity of the total 5'-nucleotidase activity at pH 7.4 in serum from 10 normal adults (19-49 years) were identical using various purine and pyrimidine mononucleotides as substrates. Different purified alkaline phosphatases were studied at the same time in the same manner. The serum enzymes showed substrate specificity qualitatively similar to that of the bovine liver enzyme. The electrophoretic study showed two fractions for both the liver enzyme and the serum enzymes with the different substrates, indicating that each of these are dephosphorylated by the same two, mutually different, enzyme molecules. Each of the other enzymes showed only a single fraction, which was identical for each enzyme with the various substrates.

Detection of antibodies against porcine parvovirus nonstructural protein NS1 may distinguish between vaccinated and infected pigs.

The humoral antibody response against the nonstructural protein NS1 and the structural protein VP2 of porcine parvovirus (PPV) was evaluated by immuno-peroxidase test (IPT) and enzyme linked immuno sorbent assay (ELISA) using recombinant PPV antigens. The coding sequence for NS1 and VP2 was inserted into the baculovirus. Autographa californica nuclear polyhedrosis virus (AcNPV) genome resulting in two recombinant baculoviruses AcNPV-NS1 and AcNPV-VP2, respectively. Sf9 cells (Spodoptora frugidiperda) inoculated with AcNPV-NS1 producing recombinant nonstructural protein (rNS1) and AcNPV-VP2 producing recombinant virion protein (rVP2) were used in IPT and ELISA to analyse serum antibodies. Pigs vaccinated with an inactivated whole virus vaccine and experimentally infected pigs were studied. Significant titers against rVP2 were obtained in both vaccinated and infected pigs. Specific antibodies against rNS1 could only be detected in infected pigs and NS1 may in this way allow the specific detection of infected animals. Analysis of serum samples collected up to 18 days post infection (p.i.) from four pigs experimentally infected with PPV showed that antibodies against rNS1 and rVP2 could in all cases be detected on day 9 p.i. Two individual pigs were inoculated twice with PPV and the antibody response was followed 89 days after second inoculation. Serum antibodies against both rVP2 and rNS1 could be detected for this period of time.

Thyroid cancer: a computer-assisted review of 5287 cases.

Retrospective computer analysis of all reportable cases of thyroid cancer for the Rocky Mountain Cancer Data Systems between 1973 and 1983 was undertaken. Follow-up data were available for periods of 5 to 10 years. All major histologic findings are reviewed with regard to distribution, prognostic factors, mortality rates, and some treatment modalities. Interesting observations determined by this study include: (1) the significantly greater mortality rates seen in patients with thyroid cancer after 50 years; (2) the lack of increased mortality rates in young patients with differentiated cancer; (3) the poorer prognosis of male patients of equivalent age to female patients in all histologic types of cancer in the first 5 years; (4) the lack of sexual difference in influencing mortality rates after the first 5 years in differentiated cancers and lack of sex as a prognostic indicator in undifferentiated cancers; (5) the excellent prognosis of patients with localized differentiated and medullary cancers and a better-than-expected prognosis in the undifferentiated group; (6) the clear need for combined therapy (surgery and irradiation) in regional medullary cancer; (7) the observation that localized thyroid lymphoma had a higher mortality rate than had regional thyroid lymphoma; and (8) a significantly higher mortality rate in patients older than 79 years with differentiated cancer.