Increased Osteopontin Contributes to Inhibition of Bone Mineralization in FGF23‐Deficient Mice

Excessive FGF23 has been identified as a pivotal phosphaturic factor leading to renal phosphate‐wasting and the subsequent development of rickets and osteomalacia. In contrast, loss of FGF23 in mice (Fgf23^?/?) leads to high serum phosphate, calcium, and 1,25‐vitamin D levels, resulting in early lethality attributable to severe ectopic soft‐tissue calcifications and organ failure. Paradoxically, Fgf23^?/? mice exhibit a severe defect in skeletal mineralization despite high levels of systemic mineral ions and abundant ectopic mineralization, an abnormality that remains largely unexplained. Through use of in situ hybridization, immunohistochemistry, and immunogold labeling coupled with electron microscopy of bone samples, we discovered that expression and accumulation of osteopontin (Opn/OPN) was markedly increased in Fgf23^?/? mice. These results were confirmed by qPCR analyses of Fgf23^?/? bones and ELISA measurements of serum OPN. To investigate whether elevated OPN levels were contributing to the bone mineralization defect in Fgf23^?/? mice, we generated Fgf23^?/?/Opn^?/? double‐knockout mice (DKO). Biochemical analyses showed that the hypercalcemia and hyperphosphatemia observed in Fgf23^?/? mice remained unchanged in DKO mice; however, micro‐computed tomography (µCT) and histomorphometric analyses showed a significant improvement in total mineralized bone volume. The severe osteoidosis was markedly reduced and a normal mineral apposition rate was present in DKO mice, indicating that increased OPN levels in Fgf23^?/? mice are at least in part responsible for the osteomalacia. Moreover, the increased OPN levels were significantly decreased upon lowering serum phosphate by feeding a low‐phosphate diet or after deletion of NaPi2a, indicating that phosphate levels contribute in part to the high OPN levels in Fgf23^?/? mice. In summary, our results suggest that increased OPN is an important pathogenic factor mediating the mineralization defect and the alterations in bone metabolism observed in Fgf23^?/? bones. © 2014 American Society for Bone and Mineral Research.     

The health of the Roma people: a review of the published literature

BACKGROUND: The Roma people originated in northern India and have been known in Europe for nearly a thousand years. For much of that time they have been the subjects of discrimination and oppression, culminating in the extermination of half a million Roma in the Nazi death camps. While it is widely believed that the health of Roma people is often poorer than the majority population, these inequalities remain largely unresearched. METHODS: Published literature on the health of the Roma people was identified using Medline. Opinion pieces were excluded, as were papers relating to anthropometry and to genetic markers. The resultant papers were analysed by country of study and by disease type or care group. RESULTS: Some 70% of papers identified related to just three countries; Spain and the Czech and Slovak Republics. Much literature concentrates upon communicable disease or reproductive health. The limited evidence suggests increased morbidity from non-communicable disease, but there is little published on this topic. Evidence on health care, though fragmentary, suggests poorer access to health services and uptake of preventative care. DISCUSSION: Published research on the health needs of the Roma population is sparse. The topics that have received attention suggest a focus on concepts of contagion or social Darwinism, indicating a greater concern with the health needs of the majority populations with which they live. There is a need for both further research into the health of Roma people; with particular emphasis on non-communicable disease; and also for interventions that improve Roma health. Such research must, however, be handled with sensitivity, recognising the social and political context of the society concerned.     

Mechanical ventilation in preterm infants: neurosonographic and developmental studies.

Surviving preterm infants of less than 34 weeks' gestation who were selected on the basis of serial cranial ultrasonographic findings during their nursery course had repeated neurologic and developmental examinations during late infancy and early childhood that established the presence (n = 46) or absence (n = 205) of spastic forms of cerebral palsy. Of the 205 infants without cerebral palsy, 22 scored abnormally low on standardized developmental testing during early childhood. The need for mechanical ventilation beginning on the first day of life (n = 92) was significantly related to gestational age, birth weight, Apgar scores, patent ductus arteriosus, grade III/IV intracranial hemorrhage, large periventricular cysts, and the development of cerebral palsy. In the 192 mechanically ventilated infants, vaginal bleeding during the third trimester, low Apgar scores, and maximally low PCO2 values during the first 3 days of life were significantly related to large periventricular cysts (n = 41) and cerebral palsy (n = 43), but not to developmental delay in the absence of cerebral palsy (n = 18). The severity of intracranial hemorrhage in mechanically ventilated infants was significantly associated with gestational age and maximally low measurements of PCO2 and pH, but not with Apgar scores or maximally low measurements of PO2. Logistic regression analyses controlling for possible confounding variables disclosed that PCO2 values of less than 17 mm Hg during the first 3 days of life in mechanically ventilated infants were associated with a significantly increased risk of moderate to severe periventricular echodensity, large periventricular cysts, grade III/IV intracranial hemorrhage, and cerebral palsy. Neurosonographic abnormalities were highly predictive of cerebral palsy independent of PCO2 measurements.(ABSTRACT TRUNCATED AT 250 WORDS)     

Radiotherapy for melanotic freckles

Five patients who received radiotherapy (RT) for 7 melanotic freckles (MF, also known as Hutchinson's freckles, lentigo maligna) were reviewed 8 to 37 months after their treatment by RT. Local control and a favourable cosmetic result occurred in all patients. Treatment toxicity was minimal. Few reports about the use of RT for MF exist. Many other treatments including observation alone have been associated with high rates of recurrence, and in some cases conversion to invasive melanoma has occurred. RT appears to be a safe and effective treatment for this condition, providing that doses equivalent to 44 Gy in 11 fractions or more are given.     

Health policy-making in central and eastern Europe: lessons from the inaction on injuries?

The burden of disease due to injuries has elicited virtually no public health response in the countries of central and eastern Europe, even though injuries have long been a much greater problem in the east of Europe than in the west, with children especially affected. This paper seeks to identify factors that have inhibited policy development on this topic and to draw lessons for health policy development in this region more generally. Several factors emerge. Deaths from injuries have had low visibility. Data have not been assembled in a way that would facilitate identification of the burden of disease that they constitute. Those organizations responsible for public health, whether within government or at local level, were typically very weak with little capacity either to identify the nature and scale of threats to the health of their populations or to develop strategies to address them. There was uncertainty about ownership, with fragmentation of responsibility but no tradition of intersectoral working. Non-governmental organizations, which have placed injuries on the health policy agenda in the west, are weak or non-existent. International donors, who could have had a role, have focused on issues such as health care reform. This analysis provides a potential framework for examining policy responses, or lack thereof, to other health challenges in this region. It highlights the need for a better understanding of the potential for using available data, which, in turn, requires a major strengthening of capacity. However, in many countries, there is a need for new ways of working, involving a broadening of the sense of ownership, with clearly designated responsibilities but designed in ways that encourage rather than inhibit intersectoral action. There is also a need to develop non-governmental organizations that have sufficient capacity to undertake their own analyses and to place issues on the agenda.     

The use of an implicit standard for measuring discrimination thresholds

We measured thresholds for comparing the separation between lines, using either the method of constant stimuli (MCS) or the method of single stimuli (MSS). In the MCS an explicit standard is presented on each trial, whereas in the MSS the standard is the mean of the set. The thresholds for the MSS procedure were nearly identical to those with the MCS procedure, whether or not feedback was used. A statistical model is presented showing how the threshold error estimated by MSS varies according to the number of past stimuli used by the observer to calculate the mean of the set. If the model is an accurate representation of human processing, our observers were averaging over the last 10-20 trials to estimate the implicit standard. Our results show that the explicit standard in the MCS procedure is generally superfluous. Provided that the test range is small, and that the observer is given some practice trials, thresholds measured with MSS procedure are just as precise as those measured with the traditional MCS procedure.     

Changing mortality patterns in East and West Germany and Poland. II: short-term trends during transition and in the 1990s

OBJECTIVES: To examine trends in life expectancy at birth and age and cause specific patterns of mortality in the former German Democratic Republic (GDR) and Poland during political transition and throughout the 1990s in both parts of Germany and in Poland. METHODS: Decomposition of life expectancy by age and cause of death. Changes in life expectancy during transition by cause of death were examined using data for 1988/89 and 1990/91 for the former GDR and Poland; examination of life expectancy changes after transition were based on 1992-97 data for Germany and 1991-96 data for Poland. RESULTS: In both the former GDR and Poland male life expectancy at birth declined by almost one year during transition, mainly attributable to rising death rates from external causes and circulatory diseases. Female life expectancy in Poland deteriorated by 0.3 years, largely attributable to increasing circulatory mortality among the old, while in East German female rising death rates in children and young adults were nearly outbalanced by declining circulatory mortality among those over 70. Between 1991/92 and 1996/97, male life expectancy at birth increased by 2.4 years in the former GDR, 1.2 years in old Federal Republic, and 2.0 years in Poland (women: 2.3, 0.9, and 1.2 years). In East Germany and Poland, the overall improvement was largely attributable to falling mortality among men aged 40-64, while those over 65 contributed the largest proportion to life expectancy gains in women. The change in deaths among men aged 15-39 accounted for 0.4 of a year to life expectancy at birth in East Germany and Poland, attributable largely to greater decreases from external causes. Among those over 40, absolute contributions to changing life expectancy were greater in the former GDR than in the other two entities in both sexes, largely attributable to circulatory diseases. A persisting East-west life expectancy gap in Germany of 2.1 years in men in 1997 was largely attributable to external causes, diseases of the digestive system and circulatory diseases. Higher death rates from circulatory diseases among the elderly largely explain the female life expectancy gap of approximately one year. CONCLUSIONS: This study provides further insights into the health effects of political transition. Post-transition improvements in life expectancy and mortality have been much steeper in East Germany compared with Poland. Changes in dietary pattern and, in Germany, medical care may have been important factors in shaping post-transition mortality trends.     

Stereo transparency and the disparity gradient limit

Several studies (Vision Research 15 (1975) 583; Perception 9 (1980) 671) have shown that binocular fusion is limited by the disparity gradient (disparity/distance) separating image points, rather than by their absolute disparity values. Points separated by a gradient >1 appear diplopic. These results are sometimes interpreted as a constraint on human stereo matching, rather than a constraint on fusion. Here we have used psychophysical measurements on stereo transparency to show that human stereo matching is not constrained by a gradient of 1. We created transparent surfaces composed of many pairs of dots, in which each member of a pair was assigned a disparity equal and opposite to the disparity of the other member. For example, each pair could be composed of one dot with a crossed disparity of 6' and the other with uncrossed disparity of 6', vertically separated by a parametrically varied distance. When the vertical separation between the paired dots was small, the disparity gradient for each pair was very steep. Nevertheless, these opponent-disparity dot pairs produced a striking appearance of two transparent surfaces for disparity gradients ranging between 0.5 and 3. The apparent depth separating the two transparent planes was correctly matched to an equivalent disparity defined by two opaque surfaces. A test target presented between the two transparent planes was easily detected, indicating robust segregation of the disparities associated with the paired dots into two transparent surfaces with few mismatches in the target plane. Our simulations using the Tsai-Victor model show that the response profiles produced by scaled disparity-energy mechanisms can account for many of our results on the transparency generated by steep gradients.