Calcineurin Inhibition Rescues Early Synaptic Plasticity Deficits in a Mouse Model of Alzheimer’s Disease

Functional and ultrastructural investigations support the concept that altered brain connectivity, exhausted neural plasticity, and synaptic loss are the strongest correlates of cognitive decline in age-related neurodegenerative dementia of Alzheimer’s type. We have previously demonstrated that in transgenic mice, expressing amyloid-β precursor protein-Swedish mutation active caspase-3 accumulates in hippocampal postsynaptic compartments leading to altered postsynaptic density (PSD) composition, increased long-term depression (LTD), and dendritic spine loss. Furthermore, we found strong evidence that dendritic spine alteration is mediated by calcineurin activation, a calcium-dependent phosphatase involved in synapse signaling. In the present work, we analyzed the molecular mechanism linking alteration of synaptic plasticity to the increase of calcineurin activity. We found that acute treatment of young and plaque-free transgenic mice with the calcineurin inhibitor FK506 leads to a complete rescue of LTD and PSD composition. Our findings are in agreement with other results reporting that calcineurin inhibition improves memory function and restores dendritic spine density, confirming that calcineurin inhibition may be explored as a neuroprotective treatment to stop or slowdown synaptic alterations in Alzheimer’s disease.     

Bumping to a rollator walker: How pretibial hematomas create more costs than pretibial lacerations

Pretibial lacerations (PL) and pretibial hematomas (PH) are debilitating traumas among the elderly and infirm. The injuries are frequently grouped together despite differences in treatment and symptoms. Patients are known to have multiple contacts in health care, perhaps because of inadequate treatment. Despite the burden, financial costs have not been assessed. Calculate and compare the treatment costs of PLs and PHs for differences and provide economic incentives to treat and diagnose patients optimally. From linkage to ICD10 diagnoses, we analysed NordDRG product invoices generated by the treatment of the patients. We calculated and compared the costs of treatment in both cohorts from the invoices. This method has not been previously used for analysing wound care costs. Mean treatment costs were 1800€ (PL) and 3300€ (PH). The total costs, emergency room, surgical treatment, and inpatient care of PHs were higher than PLs (P = .0486, P = .0002, P = .0058, P = .6526). PLs generate more costs from the outpatient clinic but were not statistically significant (P = .6533). PHs cause a higher economic burden than PLs. Costs arise from repeat ER visits and the need for surgeries because of delayed treatment. PLs have multiple contacts in the wound clinic. Improvement in the diagnosis and treatment of both injuries is needed.     

Similar effects of leucine rich and regular dairy products on muscle mass and functions of older polymyalgia rheumatica patients: A randomized crossover trial

Objectives  

Leucine-rich milk and whey proteins have been suggested for prevention of age related loss of muscle mass and strength i.e. sarcopenia. The effects of milk protein supplementation and low intensity home based physical exercise on body composition and muscle functions were investigated.     

Spontaneous human combustion in the light of the 21st century

The term "spontaneous human combustion" refers to a situation when a human body is found with significant portions of the middle parts of the body reduced to ashes, much less damage to the head and extremities, and minimal damage to the direct surroundings of the body. Typically, no observable source of ignition is found in the vicinity of the victim and a bad smelling oily substance is noted. In the past, such a situation was erroneously attributed to supernatural powers, as such phenomenon occurs in the absence of any witness. The purpose of this review article was to analyze articles published from January 1, 2000, on this unique type of burn injury. Further aims were to gather and present data on the causes and events leading to this situation. The literature was reviewed with PubMed interface using the key words spontaneous human combustion and preternatural combustion. Specific inclusion criteria resulted in 12 patients. A unique sequence of events takes place for the human body to incinerate to ashes. The flame burn victim has to die for the body fat to start melting. A tear in the skin has to occur for the melted fat to impregnate the charred clothes, igniting a wick effect that produces localized heat for extended period. A phenomenon called spontaneous human combustion is reality. The term "spontaneous human combustion" has nuances which are not applicable to this situation or to these modern times, therefore we suggest a new term "fat wick burns."     

Multi-detector computed tomography demonstrates smoke inhalation injury at early stage

A multitrauma victim was transported to our trauma centre. Smoke inhalation injury was suspected based on trauma history and clinical examination. The first trauma computer tomography (CT) obtained 2.8 h after the injury revealed subtle ground-glass opacifications with mainly peribronchial distribution and patchy peribronchial consolidations centrally in the left lung. A repeated scan showed a more distinctive demarcation of the peribronchial opacities, further substantiating the clinically verified smoke inhalation injury. The golden standard for diagnosing smoke inhalation injury still is fibroptic bronchoscopy examination. This paper shows that lesions typical to smoke inhalation injury appear much earlier than previously reported. Whether assessment of smoke inhalation injury severity using CT could clinically benefit patients is controversial and still requires further research. Multi-detector computed tomography is readily available in trauma centres and to simply neglect its potential as a diagnostic tool in some inhalation injury would be unwise.     

Metabolomic approaches to phenotype characterization and applications to complex diseases

Metabolites are the key regulators of systems homeostasis. As such, concentration changes of specific groups of metabolites may reflect systemic responses to environmental, therapeutic or genetic interventions. Thus, the study of metabolites is a powerful tool for the characterization of complex phenotypes as well as for the development of biomarkers for specific physiological responses. Therefore, metabolomics is a valuable platform for studies of complex diseases and the development of new therapies, both in nonclinical disease model characterization and clinical settings.     

GAD Antibody Positivity Predicts Type 2 Diabetes in an Adult Population

OBJECTIVE

To evaluate the significance of GAD antibodies (GADAs) and family history for type 1 diabetes (FH_T1) or type 2 diabetes (FH_T2) in nondiabetic subjects.

RESEARCH DESIGN AND METHODS

GADAs were analyzed in 4,976 nondiabetic relatives of type 2 diabetic patients or control subjects from Finland. Altogether, 289 (5.9%) were GADA⁺—a total of 253 GADA⁺ and 2,511 GADA⁻ subjects participated in repeated oral glucose tolerance tests during a median time of 8.1 years. The risk of progression to diabetes was assessed using Cox regression analysis.

RESULTS

Subjects within the highest quartile of GADA⁺ (GADA⁺_high) had more often first-degree FH_T1 (29.2 vs. 7.9%, P < 0.00001) and GADA⁺ type 2 diabetic (21.3 vs. 13.7%, P = 0.002) or nondiabetic (26.4 vs. 13.3%, P = 0.010) relatives than GADA⁻ subjects. During the follow-up, the GADA⁺ subjects developed diabetes significantly more often than the GADA⁻ subjects (36/253 [14.2%] vs. 134/2,511 [5.3%], P < 0.00001). GADA⁺_high conferred a 4.9-fold increased risk of diabetes (95% CI 2.8–8.5) compared with GADA⁻—seroconversion to positive during the follow-up was associated with 6.5-fold (2.8–15.2) and first-degree FH_T1 with 2.2-fold (1.2–4.1) risk of diabetes. Only three subjects developed type 1 diabetes, and others had a non–insulin-dependent phenotype 1 year after diagnosis. GADA⁺ and GADA⁻ subjects did not clinically differ at baseline, but they were leaner and less insulin resistant after the diagnosis of diabetes.

CONCLUSIONS

GADA positivity clusters in families with type 1 diabetes or latent autoimmune diabetes in adults. GADA positivity predicts diabetes independently of family history of diabetes, and this risk was further increased with high GADA concentrations.Latent autoimmune diabetes in adults (LADA) was introduced nearly 2 decades ago to separate a GAD antibody (GADA)-positive subgroup of adult patients initially diagnosed with type 2 diabetes (1,2). Using this definition with the add-on criteria of no exogenous insulin during the first 6–12 months, the prevalence of LADA among unselected “type 2 diabetic patients” is ∼25% in subjects younger than 35 years and between 4 and 13% in subjects older than 35 years at diagnosis in populations of European origin (3–9). In follow-up studies, a progressive defect in insulin secretion was observed in ∼50–60% of LADA patients within 6–10 years (3,10), which led to the inclusion of these patients as a slowly progressing form of type 1 diabetes in the last World Health Organization (WHO) classification of diabetes (11). However, both the existence of LADA as a distinct subgroup of diabetes and the criteria that should be used to diagnose it have been challenged (e.g., (12,13). The LADA group is heterogeneous, and most studies have been cross-sectional, whereas prospective studies including patients at or before diagnosis and population-based studies are few (3,4,14–16). Genetic background, especially for type 1 diabetes, may be a confounding factor, and we have shown that LADA was more frequent in families with both type 1 and type 2 diabetes than in families with type 2 diabetes only (17). Moreover, some data support that type 1 and type 2 diabetes cluster in same families (17–20), although this has been contradicted in a large U.K. study on parents of type 1 diabetic patients (21).In children, progression to diabetes has been associated with high antibody levels and early development of multiple autoantibodies, whereas subjects with a later appearance of antibodies had a slower progression (22–25). We have previously hypothesized that GADAs would be a marker of a subclinical autoimmune process and showed that GADA positivity was associated with a decrease in maximal insulin secretory capacity in nondiabetic subjects (26). If that is the case, GADAs should also be a predictor of future diabetes in adults. This was not supported by two studies on the general population (16,27), but a Swedish study reported a sixfold increased risk for diabetes in GADA⁺ subjects (15).In a prospective follow-up study of a large cohort of relatives of type 2 diabetic patients and population control subjects from Finland, we have now evaluated the predictive value of GADAs and family history for type 1 or type 2 diabetes in conjunction with the traditional risk factors for diabetes.