Myogenic stem cells.

Both skeletal muscle and bone marrow tissue contain myogenic stem cells. The population residing in muscles is heterogenic. Predominant in number are "typical" satellite cells - muscle progenitors migrating from somites during embryonic life. Another population is group of multipotent muscle stem cells which, at least in part, are derived from bone marrow. These cells are tracked by gradient of growth factors releasing from muscle during injury or exercise. Recruited bone marrow-derived cells gradually change their phenotype becoming muscle stem cells and eventually can attain satellite cell position and express Pax7 protein. Mesenchymal stem cells (MSC) isolated directly from bone marrow also display myogenic potential, although methods of induction of myogenic differentiation in vitro have not been optimized yet. Concerning efforts of exploiting myogenic stem cells in cell-mediated therapies it is important to understand the cause of impaired regenerative potential of aged muscle. Up to now, most of research data suggest that majority of age related changes in skeletal muscles are reversible, thus depending on extrinsic factors. However, irreversible intrinsic features of muscle stem cells are also taken into consideration

Machine learning models for predicting patients survival after liver transplantation

In our work we have built models predicting whether a patient will lose an organ after liver transplantation within a specified time horizon. We have used the observations of bilirubin and creatinine in the whole first year after the transplantation to derive predictors capturing not only their static value but also variability. Our models indeed have predictive power which proves the value of incorporating variability of biochemical measurements and it is the first contribution of our paper.The second one is the selection of the best model for the defined problem. We have identified that full-complexity models, such as random forests and gradient boosting, despite having the best predictive power, lack sufficient interpretability which is important in medicine. We have found that generalized additive models (GAM) provide desired interpretability and their predictive power is closer to the predictions of full-complexity models than to the predictions of simple linear models

Concentrations of Transition Metal Ions in Rat Lungs after Tobacco Smoke Exposure and Treatment with His-Leu Dipeptide

Tobacco smoking is deleterious to the lungs because it exposes them to many toxic substances. These include transition metal ions, such as cadmium. However, there is a lack of information about the influence of endogenous metal-binding peptides, such as His-Leu (HL), on the lung distribution of transition metals in smokers. To address this, we administered HL subcutaneously to rats exposed to tobacco smoke for six weeks, then we measured the concentrations of transition metal ions in the lungs. We found that exposure to tobacco smoke elevates the concentrations of Cd(II) and Cu(II). Administration of the HL peptide, whose elevation is a consequence of angiotensin receptor blocker anti-hypertension therapy, increases the concentration of Fe in the lungs of rats exposed to smoke. These findings suggest that smoking is a risk factor for patients receiving angiotensin receptor blockers to treat hypertension

Arteriovenous oscillations of the redox potential: Is the redox state influencing blood flow?

OBJECTIVE Studies on the regulation of human blood flow revealed several modes of oscillations with frequencies ranging from 0.005 to 1 Hz. Several mechanisms were proposed that might influence these oscillations, such as the activity of vascular endothelium, the neurogenic activity of vessel wall, the intrinsic activity of vascular smooth muscle, respiration, and heartbeat. These studies relied typically on non-invasive techniques, for example, laser Doppler flowmetry. Oscillations of biochemical markers were rarely coupled to blood flow. METHODS The redox potential difference between the artery and the vein was measured by platinum electrodes placed in the parallel homonymous femoral artery and the femoral vein of ventilated anesthetized pigs. RESULTS Continuous measurement at 5 Hz sampling rate using a digital nanovoltmeter revealed fluctuating signals with three basic modes of oscillations: ∼ 1, ∼ 0.1 and ∼ 0.01 Hz. These signals clearly overlap with reported modes of oscillations in blood flow, suggesting coupling of the redox potential and blood flow. DISCUSSION The amplitude of the oscillations associated with heart action was significantly smaller than for the other two modes, despite the fact that heart action has the greatest influence on blood flow. This finding suggests that redox potential in blood might be not a derivative but either a mediator or an effector of the blood flow control system

Mycophenolic Acid Metabolites Acyl-Glucuronide and Glucoside Affect the Occurrence of Infectious Complications and Bone Marrow Dysfunction in Liver Transplant Recipients.

BACKGROUND Mycophenolic acid (MPA) prodrugs are anti-proliferative immunosuppressive agents commonly used after organ transplantation. Although they are generally well tolerated by patients, adverse effects may occur. It is postulated that MPA metabolites could also contribute to these adverse effects. MATERIAL AND METHODS The objective of this study was the assessment of concentrations of total MPA and its metabolites, phenyl glucuronide (MPAG), acyl glucuronide (AcMPAG) and glucoside (GluMPA), using liquid chromatography combined with mass spectrometry (LC/MS/MS) in two groups: kidney transplant recipients and liver transplant patients. Associations of MPA and its metabolites with adverse effects were analyzed. RESULTS The study group consisted of 211 recipients of liver or kidney transplants who received immunosuppressive therapy, including MPA prodrugs. Multivariant analysis showed a positive influence of MPA on gastroenterotoxicity in kidney transplant recipients. In liver patients, gastroenterotoxicity was associated with lower MPAG concentrations. A positive influence of AcMPAG on bacterial infections in liver transplant patients was observed. In liver transplant recipients, a positive influence of MPA and a negative influence of GluMPA levels on the PLT count were revealed. MPA and its metabolites did not influence the hemoglobin levels in both groups. There were no significant relationships among MPA, its metabolites and WBC counts. CONCLUSIONS In kidney transplant recipients, total MPA trough concentration is associated with gastroenterotoxicity and its monitoring could have important role in management of gastrointestinal complications. The quantification of AcMPAG in liver recipients receiving MPA may be helpful in avoiding bacterial infections. GluMPA seems to have a toxic effect on thrombopoiesis

Low Content of Cyclosporine A and Its Metabolites in the Colostrum of Post-Transplant Mothers

The rate of post-transplant mothers who breastfeed while on immunosuppression is progressively increasing. Data on breastfeeding while on cyclosporine-based regimens are limited. Therefore, we assessed the amount of cyclosporine and its metabolites that might be ingested by a breastfed infant by measuring the concentration of cyclosporine and its metabolites in the colostrum of seven post-transplant mothers. The mean concentration of cyclosporine in the colostrum was 22.40 ± 9.43 mcg/L, and the estimated mean daily dose of the drug was 1049.22 ± 397.41 ng/kg/24 h. Only three metabolites (AM1, DHCsA, and THCsA) had mean colostrum amounts comparable to or higher than cyclosporine itself, with the daily doses being 468.51 ± 80.37, 2757.79 ± 1926.11, and 1044.76 ± 948.56 ng/kg/24 h, respectively. Our results indicate a low transfer of cyclosporine and its metabolites into the colostrum in the first two days postpartum and confirm the emerging change to the policy on breastfeeding among post-transplant mothers. A full assessment of the safety of immunosuppressant exposure via breastmilk will require further studies with long-term follow-ups of breastfed children

Low Transfer of Tacrolimus and Its Metabolites into Colostrum of Graft Recipient Mothers

Currently, the majority of neonates born to organ recipient mothers on chronic immunosuppressive therapy are formula fed. However, over the past few years, evidence has grown, suggesting that breastfeeding might be possible and beneficial. We designed a study assessing the transfer of tacrolimus into the colostrum of posttransplant mothers. We assessed the amount of tacrolimus and its metabolites, M-1 and M-3, that would be ingested by the breastfed neonates. Concentrations of tacrolimus and its metabolites were measured in colostrum from 14 posttransplant mothers as well as in venous cord blood and venous blood of the neonates. Test material analysis was performed by liquid chromatography coupled with mass spectrometry (LC/MS). The amount of ingested formula was registered, which allowed for estimation of the amount of tacrolimus and its metabolites that would be ingested by breastfed infants. The mean amount of tacrolimus that would be ingested by the neonates in maternal milk was 151.4 ng/kg/24 h (standard deviation SD � 74.39); metabolite M-1: 23.80 ng/kg/24 h (SD � 14.53); and metabolite M-3: 13.25 ng/kg/24 h (SD � 9.05). The peak level of tacrolimus and metabolite M-1 in colostrum was noted 8 h after an oral dose (3.219 ng/mL SD � 2.22 and 0.56 ng/mL SD � 0.60, respectively) and metabolite M-3 after 6 h (0.29 ng/mL SD � 0.22). Low concentrations of tacrolimus and its metabolites, M-1 and M-3, in colostrum show that neonates will ingest trace amounts of the drug. Further studies are required to fully assess the safety of breastfeeding by posttransplant mothers