Effect of standing frames used in real life on bone remodeling in non-walking children with cerebral palsy.

Children with severe cerebral palsy are prone to low bone mineral density. No clear recommendation exists for an optimal use of standing frame to enhance bone health in this context. Used in real life, this study suggests for the first time that standing practice improved bone mineralization by limiting bone resorption. INTRODUCTION: To compare the bone health of children with severe cerebral palsy who use a static standing frame in real life to that of children who do not. METHODS: A total of 24 children with severe cerebral palsy GMFCS IV & V were included in the study and were divided into two groups: 13 were using a passive standing frame and 11 were not. We performed a single center retrospective cross-sectional study comparing the two groups using dual X-ray absorptiometry data and tests on biological samples, including bone remodeling factors. RESULTS: Total body (less head) bone mineral content was significantly higher in children who used a standing frame for an average of 30 min/day. This was confirmed in the lumbar spine. Although the total body bone mineral density (less head and proximal femur) densitometric data were not significantly higher, a positive trend favored the use of a standing frame in the children. Bone resorptive factors (CTX) were higher in the non-standing-frame group, whereas there was no difference among osteoformation factors. No difference in fracture history was found. CONCLUSIONS: We show that non-ambulant children with cerebral palsy who use a static standing frame in real life have better bone health, with lower bone resorption, than children who do not. Further studies are needed to determine how standing practice could impact bone mineralization over time in real life and to explore more bone remodeling factors.

Glycaemic variabilities: Key questions in pursuit of clarity.

After years of intensive investigation, the definition of glycaemic variability remains unclear and the term variability in glucose homoeostasis might be more appropriate covering both short and long-term glycaemic variability. For the latter, we remain in the search of an accurate definition and related targets. Recent work leads us to consider that the within-subject variability of HbA1c calculated from consecutive determinations of HbA1c at regular time-intervals could be the most relevant index for assessing the long-term variability with a threshold value of 5% (%CV = SD of HbA1c/mean HbA1c) to separate stability from lability of HbA1c. Presently, no one can deny that short- and long-term glucose variability should be maintained within their lower ranges to limit the incidence of hypoglycaemia. Usually, therapeutic strategies aimed at reducing post-meal glucose excursions, i.e. the major contributor to daily glucose fluctuations, exert a beneficial effect on the short-term glucose variability. This explains the effectiveness of adjunct therapies with either GLP- receptor agonists or SGLT inhibitors in type 2 diabetes. In type 1 diabetes, the application of a CGM device alone reduces the short-term glycaemic variability. In contrast, sophisticated insulin delivery does not necessarily lead to such reductions despite marked downward shifts of 24-hour glycaemic profiles. Such contrasting observations raise the question as to whether the prolonged wear of CGM devices is or not the major causative factor for improvement in glucose variability among intensively insulin-treated persons with type 1 diabetes.

Application of medium-term metrics for assessing glucose homoeostasis: Usefulness, strengths and weaknesses.

This review aims to address the issue of whether or not the newer metrics, developed for continuous glucose monitoring [real-time CGM (rtCGM), intermittently scanned CGM (isCGM)], enhance assessment of the "glucose tetrad": Ambient hyperglycaemia, short-term glycaemic variability, postprandial glucose excursions and hypoglycaemia. The ever-increasing number of metrics offered with rtCGM and isCGM includes intermediate-term indicators referred to as "time in range" (TIR), the time spent in the range of 70-180mg/dL (TIR 70-180); time spent above the range of 180mg/dL (TAR>180); and time spent below the range of 70mg/dL or 54mg/dL (TBR<70 or TBR<54). The former two values are strongly correlated with HbA1c levels and can therefore serve as short- or medium-term markers of ambient hyperglycaemia, depending on whether glucose sensors are worn over periods of several days or weeks, respectively, whereas the latter indices (TBR<70 or<54) are more relevant for capturing hypoglycaemic events and quantifying their magnitude and duration, in contrast to random spot testing with self-monitoring of blood glucose. Nevertheless, although analyses of 24h glucose profiles by CGM provide a highly valuable method for quantifying postprandial glucose excursions and short-term glycaemic variability, neither of these factors can be fully represented by such TIR metrics. Thus, other metrics are clearly needed for more comprehensive assessment of glucose homoeostasis.

Outcomes of vaginal squamous cell carcinoma of patients treated with radiation therapy: a series of 37 patients from a single expert center.

INTRODUCTION: The aim is to assess the outcome of patients treated for vaginal carcinoma with radiation therapy in terms of long-term tolerance and survival. MATERIALS AND METHODS: This single-center retrospective study included patients with squamous cell carcinoma of the vagina treated with pelvic external beam radiation therapy (EBRT) with or without vaginal brachytherapy (VB) between 1990 and 2013. RESULTS: Thirty-seven patients were included with stage I (24%), II (60%), III (8%), or IV (8%) vaginal tumors. Median age was 66 years (range 27-86 years). Median tumor size was 4 cm (range 0.7-12 cm). Seven patients underwent first intention surgery. The 37 patients received pelvic EBRT (45 Gy) with inguinal irradiation in 57% of cases. Fifteen (41%) received concurrent chemotherapy. Low-dose supplemental VB was performed in 31 patients (84%) (median dose: 20 Gy). Median follow-up was 59 months (range 7-322 months). Four patients (11%) had late grade 3-4 complications. Relapse occurred in 11 patients (30%), five of them locally. The 5-year relapse-free and cancer-specific survival rates were 68% and 76%, respectively. Surgery and concurrent chemotherapy did not seem to have an impact on the course of the disease. CONCLUSION: In our experience, pelvic EBRT leads to prolonged survival with acceptable long-term toxicity in patients with squamous cell carcinoma of the vagina.

Glucocentric risk factors for macrovascular complications in diabetes: Glucose 'legacy' and 'variability'-what we see, know and try to comprehend.

Recognizing the role of dysglycaemia, 'ambient' hyperglycaemia, 'metabolic memory' and glycaemic variability as risk factors for macrovascular diseases is mandatory for effective diabetes management. Chronic hyperglycaemia, also referred to as 'ambient hyperglycaemia', was only fully acknowledged as a risk factor for adverse cardiovascular events when the beneficial effects of intensive glucose-lowering strategies were consolidated in the extended follow-up (> 10 years) of patients included in the United Kingdom Prospective Diabetes Study (UKPDS) and Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Study. These studies led to the concept of the glucose-lowering 'legacy effect' (metabolic memory), which depends on the duration and magnitude of glucose-lowering, and is not a 'forever' phenomenon, as demonstrated in the 15-year follow-up of the Veterans Affairs Diabetes Trial (VADT). The relatively weak evidence for linking long- and short-term glycaemic variability to vascular complications in patients with diabetes is mainly due to a reliance on observational and retrospective studies, and the lack of randomized interventional trials. However, hypoglycaemia may play an intermediary role in accentuating the link between glycaemic variability and vascular events.

The application of simple metrics in the assessment of glycaemic variability.

The assessment of glycaemic variability (GV) remains a subject of debate with many indices proposed to represent either short- (acute glucose fluctuations) or long-term GV (variations of HbA1c). For the assessment of short-term within-day GV, the coefficient of variation for glucose (%CV) defined as the standard deviation adjusted on the 24-h mean glucose concentration is easy to perform and with a threshold of 36%, recently adopted by the international consensus on use of continuous glucose monitoring, separating stable from labile glycaemic states. More complex metrics such as the Low Blood Glucose Index (LBGI) or High Blood Glucose Index (HBGI) allow the risk of hypo or hyperglycaemic episodes, respectively to be assessed although in clinical practice its application is limited due to the need for more complex computation. This also applies to other indices of short-term intraday GV including the mean amplitude of glycemic excursions (MAGE), Shlichtkrull's M-value and CONGA. GV is important clinically as exaggerated glucose fluctuations are associated with an enhanced risk of adverse cardiovascular outcomes due primarily to hypoglycaemia. In contrast, there is at present no compelling evidence that elevated short-term GV is an independent risk factor of microvascular complications of diabetes. Concerning long-term GV there are numerous studies supporting its association with an enhanced risk of cardiovascular events. However, this association raises the question as to whether the impact of long-term variability is not simply the consequence of repeated exposure to short-term GV or ambient chronic hyperglycaemia. The renewed emphasis on glucose monitoring with the introduction of continuous glucose monitoring technologies can benefit from the introduction and application of simple metrics for describing GV along with supporting recommendations.

Two phases of aging separated by the Smurf transition as a public path to death.

Aging's most obvious characteristic is the time dependent increase of an individual's probability to die. This lifelong process is accompanied by a large number of molecular and physiological changes. Although numerous genes involved in aging have been identified in the past decades its leading factors have yet to be determined. To identify the very processes driving aging we have developed in the past years an assay to identify physiologically old individuals in a synchronized population of Drosophila melanogaster. Those individuals show an age-dependent increase of intestinal permeability followed by a high risk of death. Here we show that this physiological marker of aging is conserved in 3 invertebrate species Drosophila mojavensis, Drosophila virilis, Caenorhabditis elegans as well as in 1 vertebrate species Danio rerio. Our findings suggest that intestinal barrier dysfunction may be an important event in the aging process conserved across a broad range of species, thus raising the possibility that it may also be the case in Homo sapiens.

Near normal HbA1c with stable glucose homeostasis: the ultimate target/aim of diabetes therapy.

Achieving near normal glucose homeostasis implies that all components of dysglycemia that are present in diabetes states be eliminated. Reducing ambient/overall hyperglycemia is a pre-requisite to eliminate the risk of development and progression of diabetes complications. More controversially however, are the relative and related contributions of postprandial glucose excursions, glucose variability, hypoglycemia and the dawn phenomenon across the spectrum of dysglycemia. For instance, it is likely that the dawn phenomenon contributes to ambient hyperglycemia and that postprandial glucose excursions are at the cross road of ambient hyperglycemia and glucose variability with glucose fluctuations as causative risk factors for hypoglycemia. Proof-of-concept trials such as the ongoing FLAT-SUGAR study are necessary for gaining further insight into the possible harmful effects of some of these features such as excessive glycemic variability and glucose excursions, still considered to be of minor relevance by several diabetologists. Whether their role will be more thoroughly proven through further intervention trials with "hard" endpoints, remains to be seen. In the meantime more consideration should be given to medications aimed at concomitantly reducing ambient/overall hyperglycemia and those additional abnormal glycemic features of dysglycemia.

Ramadan and diabetes: What we see, learn and understand from continuous glucose monitoring.

Abstinence from eating and drinking from dawn to sunset characterizes the holy month of Ramadan. For the 50 million Muslims worldwide with diabetes who adhere to this religious fast, the practice results in marked changes in glucose homoeostasis. The sunset meal (Iftar) that breaks the fasting state is followed by exaggerated surges in blood glucose and sustained overnight hyperglycaemia in cases of nocturnal overfeeding. The predawn meal (Suhoor) frequently results in prolonged glucose decay over the daylight hours. These glycaemic disturbances are particularly marked in insulin-treated patients, in those with unsatisfactory diabetes control during the pre-Ramadan period and in patients who are poorly compliant with lifestyle recommendations. Whether such patients should be exempt from the Islamic fast remains an open debate, which might be partially resolved by long-term controlled studies using the technology of continuous glucose monitoring in large populations of patients with diabetes.

[Ductal carcinoma in situ treated with radiation therapy and additional boost]. / Carcinomes canalaires in situ du sein traités par chirurgie conservatrice et irradiation avec complément dans le lit opératoire.

PURPOSE: Women with ductal carcinoma in situ are treated with breast-conserving surgery and radiation therapy. The impact of an additive boost radiation is under evaluation. PATIENTS AND METHODS: All women treated for ductal carcinoma in situ with breast-conserving surgery and whole breast radiation therapy at a total dose of 45Gy with a boost radiation from 1990 to 2008 have been included in this retrospective monocentric retrospective study. RESULTS: We included 171 patients. Boost radiation to the surgical bed was delivered by brachytherapy in 66 patients (39%), by direct en-face electron beam in 86 patients (50%), and by tangential fields using photon beams in 19 patients (11%). Median follow-up was 95.1months. Eight local relapses (4.6%) have occurred. The 10-year local recurrence-free survival rate was 97%. The 10-year overall survival rate was 98%. On multivariable analysis, brachytherapy (P=0.05; HR=5.15; IC=1-26.3) was associated with a reduction risk of local recurrence-free survival. CONCLUSION: In our experience, women treated for a ductal carcinoma in situ with breast-conserving surgery and whole breast radiation therapy with a boost radiation have a high 10-year local recurrence-free survival rate.

The dawn phenomenon in type 2 diabetes: how to assess it in clinical practice?

AIM: The study was aimed at determining whether the dawn phenomenon in type 2 diabetes (T2D) can be predicted and quantified using simple and easily accessible glucose determinations. METHODS: A total of 210 non-insulin-treated persons with T2D underwent continuous glucose monitoring (CGM). The dawn phenomenon was quantified as the absolute increment from the nocturnal glucose nadir to the pre-breakfast value (Δdawn, mg/dL). Pre-lunch (preL) and pre-dinner (preD) glucose, and their averaged values (preLD), were compared with the nocturnal nadir. These pre-meal values were subtracted from the pre-breakfast values. The differences obtained (Δpre-mealL, Δpre-meal D and Δpre-meal LD) were correlated with Δdawn values. The receiver operating characteristic (ROC) curve was used to select the optimal Δpre-meal value that best predicted a dawn phenomenon, set at a threshold of 20mg/dL. RESULTS: All pre-meal glucose levels and differences from pre-breakfast values (Δpre-meal) significantly correlated (P<0.0001) with the nocturnal nadir and Δdawn values, respectively. The strongest correlations were observed for the parameters averaged at preL and preD time points: r=0.83 for preLD and r=0.58 for Δpre-meal LD. ROC curve analysis indicated that the dawn phenomenon at a threshold of 20mg/dL can be significantly predicted by a Δpre-meal LD cut off value of 10mg/dL. The relationship between Δdawn (Y, mg/dL) and Δpre-meal LD (X, mg/dL) was Y=0.49 X+15. CONCLUSION: The self-monitoring of preprandial glucose values at the three main mealtimes can predict the presence/absence of the dawn phenomenon, and permits reliable assessment of its magnitude without requiring continuous overnight glucose monitoring.