Leptin and its receptor, obese receptor (OB-R), comprise an important signaling system for the regulation of body weight. Splice variants of OB-R mRNA encode proteins that differ in the length of their cytoplasmic domains. We cloned a long isoform of the wild-type leptin receptor that is preferentially expressed in the hypothalamus and show that it can activate signal transducers and activators of transcription (STAT)-3, and . A point mutation within the OB-R gene of diabetic (db) mice generates a new splice donor site that dramatically reduces expression of this long isoform in homozygous db/db mice. In contrast, an OB-R protein with a shorter cytoplasmic domain is present in both db/db and wild-type mice. We show that this short isoform is unable to activate the STAT pathway. These data provide further evidence that the mutation in OB-R causes the db/db phenotype and identify three STAT proteins as potential mediators of the anti-obesity effects of leptin.Leptin, the product of the obese (ob) gene, is a 16-kDa secreted protein primarily produced by adipocytes (1). There is a good correlation between the percentage of body fat and serum leptin levels suggesting that leptin production is regulated by the mass of adipocytes (2, 3). Leptin levels were normal or elevated in obese individuals (2, 4) arguing against a simple leptin deficiency as the cause of obesity in the majority of humans (5). Serum leptin concentrations increased under a fatty diet but failed to prevent weight gain (3). Therefore, insensitivity to the action of leptin appears to be a common mechanism in obese individuals and in several rodent models. This suggests that dysregulation at the level of the leptin receptor, the downstream signaling pathway, or an unknown modifying mechanism may constitute the basis for weight disorders. The crucial role of leptin and its receptor in obesity is well illustrated by two phenotypically very similar mutants obese (ob) and diabetes (db) (6). Mice homozygous for a loss of function mutation of ob display obesity, hyperglycemia, and insulin resistance resembling type II diabetes. Administration of recombinant leptin to ob mice corrected these abnormalities (7-9). Based on early parabiosis experiments it was expected that db would be caused by a mutation in the ob receptor (OB-R) (6).OB-R was cloned by virtue of its high affinity to leptin through an expression cloning strategy (10). The OB-R gene was mapped to the same 5-centimorgan interval on mouse chromosome 4 to which db had been localized (10). Surprisingly, no mutation in the coding region of OB-R cDNA of db/db mice was found and leptin binding sites were unaltered in db/db mice (10). However, the cloned mouse OB-R cDNA encoded a protein with a much shorter cytoplasmic domain than the human homologue, suggesting that a longer mouse isoform exists. We cloned this longer form of OB-R from wild-type mice and found that the mRNA for this isoform is dramatically reduced in db/db mice. A G to T mutation in db mice generates a new splice donor and su...

Background Health monitoring in Germany falls short on generating timely, reliable and representative data among migrants, especially transient and marginalized groups such as asylum seekers and refugees (ASR). We aim to advance current health monitoring approaches and obtain reliable estimates on health status and access to essential healthcare services among ASR in Germany’s third largest federal state, Baden-Württemberg. Methods We conducted a state-wide, cross-sectional, population-based health monitoring survey in nine languages among ASR and their children in collective accommodation centres in 44 districts. Questionnaire items capturing health status, access to care, and sociodemographic variables were taken from established surveys and translated using a team approach. Random sampling on the level of 1938 accommodation centres with 70,634 ASR was employed to draw a balanced sample of 65 centres with a net sample of 1% of the state’s ASR population. Multilingual field teams recruited eligible participants using a “door-to-door” approach. Parents completed an additional questionnaire on behalf of their children. Results The final sample comprised 58 centres with 1843 ASR. Of the total sample expected eligible (N = 987), 41.7% (n = 412) participated in the survey. Overall, 157 households had children and received a children’s questionnaire; 61% (n = 95) of these were returned. Age, sex, and nationality of the included sample were comparable to the total population of asylum applicants in Germany. Adults reported longstanding limitations (16%), bad/very bad general health (19%), pain (25%), chronic illness (40%), depression (46%), and anxiety (45%). 52% utilised primary and 37% specialist care services in the previous 12 months, while reporting unmet needs for primary (31%) and specialist care (32%). Younger and male participants had above-average health status and below-average utilisation compared to older and female ASR. Conclusions Our health monitoring survey yielded reliable estimates on health status and health care access among ASR, revealing relevant morbidities and patterns of care. Applying rigorous epidemiological methods in linguistically diverse, transient and marginalized populations is challenging, but feasible. Integration of this approach into state- and nation-wide health monitoring strategies is needed in order to sustain this approach as a health planning tool. Electronic supplementary material The online version of this article (10.1186/s12982-019-0085-2) contains supplementary material, which is available to authorized users.

We generated mice expressing a fulllength Mpl transgene under the control of a 2-kb Mpl promoter in an Mpl Ϫ/Ϫ background, effectively obtaining mice that express full-length Mpl in the absence of other Mpl isoforms. These mice developed thrombocytosis with platelet levels approximately 5-fold higher than wildtype controls and markedly increased megakaryocyte numbers. The reintroduction of one wild-type Mpl allele restored normal platelet counts. We excluded the deletion of Mpl-tr, a dominant-negative isoform, as the underlying molecular cause for thrombocytosis. Instead, we found that transgene expression driven by the 2-kb Mpl promoter fragment was decreased during late megakaryocyte maturation, resulting in strongly diminished Mpl protein expression in platelets. Because platelets exert a negative feedback on thrombopoiesis by binding and consuming Tpo in the circulation through Mpl, we propose that the severe reduction of Mpl protein in platelets in Mpltransgenic Mpl ؊/؊ mice shifts the equilibrium of this feedback loop, resulting in markedly elevated levels of megakaryocytes and platelets at steady state. Although the mechanism causing decreased expression of Mpl protein in platelets from patients with myeloproliferative disorders differs from this transgenic model, our results suggest that lowering Mpl protein in platelets could contribute to raising the platelet count. IntroductionThrombopoietin (Tpo) and its receptor Mpl are the principal regulators of megakaryopoiesis. 1,2 Mice deficient in Tpo or Mpl continue to produce functional platelets, albeit at much lower levels, 3,4 suggesting that Mpl mainly controls quantitative aspects of thrombopoiesis. Tpo serum levels are controlled by the platelet mass through Mpl-mediated Tpo uptake and degradation. 5,6 Consequently, Mpl Ϫ/Ϫ mice show increased Tpo levels. 3 Although an important function of Mpl is to regulate platelet numbers, it is also expressed on hematopoietic stem cells (HSCs) and early progenitors. 7,8 Consistently, Mpl-deficient mice show markedly decreased numbers of hematopoietic progenitors, and competitive repopulation assays indicate that the numbers of murine HSCs is reduced by 7-to 8-fold. 7,8 In humans, loss-of-function mutations in Mpl lead to congenital amegakaryocytic thrombocytopenia, a disorder that frequently leads to bone marrow failure. [9][10][11] The reason for the more severe phenotype in humans remains unknown.Mutant versions of Mpl can lead to uncontrolled proliferation and survival signals as exemplified by the retroviral fusion oncogene v-Mpl, which can immortalize hematopoietic progenitors. 12 An autosomal-dominant point mutation in the transmembrane domain of Mpl (S505N) was identified as the cause of thrombocytosis in families with hereditary thrombocytosis. 13,14 Recently, point mutations in the cytoplasmic domain of Mpl (W515L, W515K) were identified in patients with primary myelofibrosis and essential thrombocythemia, and W515L was shown in mouse models to elicit myeloproliferative disease (MPD) with marked thromboc...

A superiority of LMWH is suggested but heterogeneity might make generalizability to future patients questionable. A meta-analysis on individual patient data should be the next step before randomizing additional patients in future trials.