The Role of Maternal Weight in the Hierarchy of Macrosomia Predictors; Overall Effect of Analysis of Three Prediction Indicators

So far it has not been established which maternal features play the most important role in newborn macrosomia. The aim of this study is to provide assessment of a hierarchy of twenty six (26) maternal characteristics in macrosomia prediction. A Polish prospective cohort of women with singleton pregnancy (N = 912) which was recruited in the years 2015–2016 has been studied. Two analyses were performed: for probability of macrosomia > 4000 g (n = 97) (vs. 755 newborns 2500–4000 g); and for birthweight > 90th percentile (n = 99) (vs. 741 newborns 10–90th percentile). A multiple logistic regression was used (with 95% confidence intervals (CI)). A hierarchy of significance of potential predictors was established after summing up of three prediction indicators (NRI, IDI and AUC) calculated for the basic prediction model (maternal age + parity) extended with one (test) predictor. ‘Net reclassification improvement’ (NRI) focuses on the reclassification table describing the number of women in whom an upward or downward shift in the disease probability value occurred after a new factor had been added, including the results for healthy and ill women. ‘Integrated discrimination improvement’ (IDI) shows the difference between the value of mean change in predicted probability between the group of ill and healthy women when a new factor is added to the model. The area under curve (AUC) is a commonly used indicator. Results. The macrosomia risk was the highest for prior macrosomia (AOR = 7.53, 95%CI: 3.15–18.00, p < 0.001). A few maternal characteristics were associated with more than three times higher macrosomia odds ratios, e.g., maternal obesity and gestational age ≥ 38 weeks. A different hierarchy was shown by the prediction study. Compared to the basic prediction model (AUC = 0.564 (0.501–0.627), p = 0.04), AUC increased most when pre-pregnancy weight (kg) was added to the base model (AUC = 0.706 (0.649–0.764), p < 0.001). The values of IDI and NRI were also the highest for the model with maternal weight (IDI = 0.061 (0.039–0.083), p < 0.001), and (NRI = 0.538 (0.33–0.746), p < 0.001). Adding another factor to the base model was connected with significantly weaker prediction, e.g., for gestational age ≥ 38 weeks (AUC = 0.602 (0.543–0.662), p = 0.001), (IDI = 0.009 (0.004; 0.013), p < 0.001), and (NRI = 0.155 (0.073; 0.237), p < 0.001). After summing up the effects of NRI, IDI and AUC, the probability of macrosomia was most strongly improved (in order) by: pre-pregnancy weight, body mass index (BMI), excessive gestational weight gain (GWG) and BMI ≥ 25 kg/m². Maternal height, prior macrosomia, fetal sex-son, and gestational diabetes mellitus (GDM) occupied an intermediate place in the hierarchy. The main conclusions: newer prediction indicators showed that (among 26 features) excessive pre-pregnancy weight/BMI and excessive GWG played a much more important role in macrosomia prediction than other maternal characteristics. These indicators more strongly highlighted the differences between predictors than the results of commonly used odds ratios.     

Luliberin inhibits the release of Oxytocin from hypothalamo-neurohypophysial system in dehydrated but not in euhydrated or haemorrhaged rats

Rats euhydrated, dehydrated for two days or haemorrhaged were given intracerebroventricularly (i.c.v.) luteinizing hormone releasing hormone (LH-RH) in a daily dose of 100 ng dissolved in 10 microl of 0.9 % sodium chloride. In euhydrated rats, a single i.c.v. dose of LH-RH as well as the daily i.c.v. treatment with LH-RH for two days did not affect significantly either the plasma oxytocin concentrations or the hypothalamo-neurohypophysial oxytocin content. In animals dehydrated for two days and treated with LH-RH the increase in plasma oxytocin was almost suppressed and the depletion of neurohypophysial hormone content was significantly less marked. Luliberin treatment had no effect on the hypothalamo-neurohypophysial content of oxytocin as well as on plasma oxytocin concentration in haemorrhaged rats. We suggest that LH-RH may have a regulatory role in the hypothalamo-neurohypophysial oxytocinergic system, especially under hyperosmotic dehydration.     

Cell-type-specific adhesion mechanisms mediated by fibronectin adsorbed to chemically derivatized substrata.

Plasma fibronectin (pFN) adhesion mechanisms on inert substrata were evaluated for murine fibroblasts (3T3) and human neuroblastoma (Platt) cells using glass coverslips chemically derivatized with a self-assembled monolayer of aliphatic chains terminated with a specific endgroup to interact with adsorbed pFN: [CH3], [SH], [SCOCH3], [NH2], [SO3H], or underivatized glass [SiOH]. All surfaces bound similar amounts of pFN and facilitated attachment of both cell types within narrow ranges. However, spreading/differentiation responses of cells differed considerably among the surfaces. While 3T3 cells spread and developed microfilament stress fibers comparably on all surfaces, inclusion of an RGDS-containing synthetic peptide in the medium revealed variation in resistance to stress fiber formation mediated by an RGDS-recognizing integrin: [NH2] greater than [CH3] much greater than [SiOH],[SH],[SCOCH3]. Different patterns of neurite formation were observed for neuroblastoma cells: [SiOH], [SO3H] greater than [SCOCH3],[SH] much greater than [CH3] greater than [NH2]. Similarity in cell responses to both [CH3] and [NH2] surfaces argues against a pattern dependent upon the hydrophobicity of substrata. When pFN was diluted to a subsaturable concentration with albumin for adsorption, neuroblastoma responses changed significantly from those observed on pFN-saturated surfaces, for both spreading and neurite generation: [NH2],[SO3H] much greater than [SH], [SCOCH3] greater than [SiOH],[CH3]. Responses to the pFN: albumin mixture were markedly improved from responses after sequential adsorptions, demonstrating "optimization" of pFN conformation (not merely binding) by coadsorption of albumin molecules. In most cases, the [NH2] surface yielded responses distinctively different from the other surfaces. Overall, these data suggest many variations in the conformation of pFN molecules adsorbed to specific inert surfaces, as well as variations in the responses of cell surface receptors to conformationally specific pFNs. They also reveal cell-type-specific changes in differentiated cell responses on derivatized substrata, mediated by different classes of cell surface receptors for the two cell types, and provide optimism for regulating FN-dependent adhesion mechanisms in either positive or negative contexts on biomaterial surfaces derivatized with one or more of these chemical end-groups.     

Loss of Miro1-directed mitochondrial movement results in a novel murine model for neuron disease

Defective mitochondrial distribution in neurons is proposed to cause ATP depletion and calcium-buffering deficiencies that compromise cell function. However, it is unclear whether aberrant mitochondrial motility and distribution alone are sufficient to cause neurological disease. Calcium-binding mitochondrial Rho (Miro) GTPases attach mitochondria to motor proteins for anterograde and retrograde transport in neurons. Using two new KO mouse models, we demonstrate that Miro1 is essential for development of cranial motor nuclei required for respiratory control and maintenance of upper motor neurons required for ambulation. Neuron-specific loss of Miro1 causes depletion of mitochondria from corticospinal tract axons and progressive neurological deficits mirroring human upper motor neuron disease. Although Miro1-deficient neurons exhibit defects in retrograde axonal mitochondrial transport, mitochondrial respiratory function continues. Moreover, Miro1 is not essential for calcium-mediated inhibition of mitochondrial movement or mitochondrial calcium buffering. Our findings indicate that defects in mitochondrial motility and distribution are sufficient to cause neurological disease.Motor neuron diseases (MNDs), including ALS and spastic paraplegia (SP), are characterized by the progressive, length-dependent degeneration of motor neurons, leading to muscle atrophy, paralysis, and, in some cases, premature death. There are both inherited and sporadic forms of MNDs, which can affect upper motor neurons, lower motor neurons, or both. Although the molecular and cellular causes of most MNDs are unknown, many are associated with defects in axonal transport of cellular components required for neuron function and maintenance (1–6).A subset of MNDs is associated with impaired mitochondrial respiration and mitochondrial distribution. This observation has led to the hypothesis that neurodegeneration results from defects in mitochondrial motility and distribution, which, in turn, cause subcellular ATP depletion and interfere with mitochondrial calcium ([Ca²⁺]_m) buffering at sites of high synaptic activity (reviewed in ref. 7). It is not known, however, whether mitochondrial motility defects are a primary cause or a secondary consequence of MND progression. In addition, it has been difficult to isolate the primary effect of mitochondrial motility defects in MNDs because most mutations that impair mitochondrial motility in neurons also affect transport of other organelles and vesicles (1, 8–11).In mammals, the movement of neuronal mitochondria between the cell body and the synapse is controlled by adaptors called trafficking kinesin proteins (Trak1 and Trak2) and molecular motors (kinesin heavy chain and dynein), which transport the organelle in the anterograde or retrograde direction along axonal microtubule tracks (7, 12–24). Mitochondrial Rho (Miro) GTPase proteins are critical for transport because they are the only known surface receptors that attach mitochondria to these adaptors and motors (12–15, 18, 25, 26). Miro proteins are tail-anchored in the outer mitochondrial membrane with two GTPase domains and two predicted calcium-binding embryonic fibroblast (EF) hand motifs facing the cytoplasm (12, 13, 25, 27, 28). A recent Miro structure revealed two additional EF hands that were not predicted from the primary sequence (29). Studies in cultured cells suggest that Miro proteins also function as calcium sensors (via their EF hands) to regulate kinesin-mediated mitochondrial “stopping” in axons (15, 16, 26). Miro-mediated movement appears to be inhibited when cytoplasmic calcium is elevated in active synapses, effectively recruiting mitochondria to regions where calcium buffering and energy are needed. Despite this progress, the physiological relevance of these findings has not yet been tested in a mammalian animal model. In addition, mammals ubiquitously express two Miro orthologs, Miro1 and Miro2, which are 60% identical (12, 13). However, the individual roles of Miro1 and Miro2 in neuronal development, maintenance, and survival have no been evaluated.We describe two new mouse models that establish the importance of Miro1-mediated mitochondrial motility and distribution in mammalian neuronal function and maintenance. We show that Miro1 is essential for development/maintenance of specific cranial neurons, function of postmitotic motor neurons, and retrograde mitochondrial motility in axons. Loss of Miro1-directed retrograde mitochondrial transport is sufficient to cause MND phenotypes in mice without abrogating mitochondrial respiratory function. Furthermore, Miro1 is not essential for calcium-mediated inhibition of mitochondrial movement or [Ca²⁺]_m buffering. These findings have an impact on current models for Miro1 function and introduce a specific and rapidly progressing mouse model for MND.     

Beta subunit of human chorionic gonadotropin, CA 125 antigen and CA 19-9 antigen with non-trophoblastic malignancy of genital tract. Vulval cancer

Our investigations embraced the group of patients with vulval cancer before surgical treatment (n = 10). We measured in serum of blood the level of the total human chorionic gonadotrophin hCG, beta subunit of human Chorionic Gonadotrophin, CA 125 and CA 19-9 antigen. We ascertained significant elevation the beta subunit of hCG level in the group of women with neoplasms in comparison with control group (n = 96) and significant positive correlation between beta subunit level and degree of cancer cells maturity (r = 0.66, p < 0.05). We also ascertained strong positive correlation among beta subunit of hCG and CA 19-9 antigen level in the serum of the patients with vulval cancer (r = 0.55 and p < 0.05).