Evolution of Modeled Cortisol Is Prognostic of Death in Hospitalized Patients With COVID-19 Syndrome.

Introduction: Patients hospitalized with SARS-CoV-2 have an elevated risk of mortality related to a severe inflammatory response. We hypothesized that biological modeling with a complete blood count (CBC) would be predictive of mortality. Method: In 2020, 81 patients were randomly selected from La Rochelle Hospital, France for a simple blinded retrospective study. Demographic, vital signs, CBC and CRP were obtained on admission, at days 2-3 and 3-5. From a CBC, two biological modeling indexes were resulted: the neutrophil-to-lymphocyte ratio (NLR) and cortisol index adjusted (CA). Results: By ANOVA, in survivors vs. non-survivors there was statistical different at p < 0.01 for age (66.2 vs. 80), CRP (92 vs. 179 mg/dL, normal < 10), cortisol index adjusted (323 vs. 698, normal 3-7) and genito-thyroid indexes (7.5 vs. 18.2, normal 1.5-2.5), and at p = 0.02 creatinine (1.03 vs. 1.48, normal 0.73-1.8 mg/dL). By mixed model analysis, CA and NLR improved in those who survived across all three time points, but worsened again after 3-5 days in non-survivors. CRP continued to improve over time in survivors and non-survivors. Positive vs. Negative predictive value were: CRP (91.1%, 30.4%), NLR (94.5%, 22.7%), CA (100%, 0%). Discussion: Cortisol modeling and the neutrophil-to-lymphocyte ratio were more accurate in describing the course of non-survivors than CRP. Conclusion: In patients admitted for SARS CoV-2 infection, biological modeling with a CBC predicted risk of death better than CRP. This approach is inexpensive and easily repeated.

Magnesium sulfate, chorioamnionitis, and neurodevelopment after preterm birth.

OBJECTIVE: To assess the neuroprotective effect of magnesium sulfate (MgSO4 ) in preterm children exposed to chorioamnionitis. DESIGN: A secondary analysis of a multicentre randomised controlled trial of antenatal MgSO4 administered to women at risk of preterm birth for the prevention of cerebral palsy (CP). Singleton, non-anomalous pregnancies with clinical chorioamnionitis, delivering at ≥24 weeks of gestation, were selected. Cases were exposed to antepartum MgSO4 ; controls received placebo. SETTING: Multicentre randomised controlled trial. POPULATION: Singleton, non-anomalous pregnancies with clinical chorioamnionitis, delivering at ≥24 weeks of gestation. METHODS: All data were analysed by intention to treat. Univariate and multivariate analyses were performed. MAIN OUTCOME MEASURES: Primary outcome was a composite of stillbirth, death by the age of 1 year, or moderate or severe CP by the age of 2 years. Secondary outcomes included a composite neonatal outcome as well as neurodevelopmental delay, defined as Bayley II mental and psychomotor developmental indices <70 at the age of 2 years. Subgroup analysis assessed these outcomes in children born at <28 weeks of gestation. RESULTS: A total of 396 children were included, with 192 (48.5%) randomised to MgSO4 . Maternal and delivery characteristics were similar between the groups. The primary outcome occurred in 14.1% of children exposed to MgSO4 and 12.7% of children exposed to placebo (relative risk, RR 1.29; 95% CI 0.70-2.38). Rates of stillbirth, death, moderate-severe CP, and neurodevelopmental delay did not differ between groups. In the subgroup analysis of children born at <28 weeks of gestation, there was no difference in the rates of the primary outcome, nor in the secondary outcomes assessed. [Correction added on 02 March 2016 after online publication: There were errors in statistical data analysis and these have been corrected throughout the article.] CONCLUSIONS: Among children at risk for early preterm delivery exposed to chorioamnionitis, antenatal administration of MgSO4 was not associated with improved neurodevelopmental outcome. We do not recommend any change in the guidelines on the administration of MgSO4 for neuroprotection based on this study. TWEETABLE ABSTRACT: MgSO4 was not associated with improved neurodevelopmental outcome in setting of chorioamnionitis.

A novel use of biomarkers in the modeling of cancer activity based on the theory of endobiogeny.

INTRODUCTION: Cancer is a complex disorder whose detection and monitoring remains challenging. A biological modeling system, the biology of functions (BoF), claims to be able to evaluate physiologic elements related to carcinogenic activity. A pilot study was undertaken to evaluate the accuracy of the BoF in detecting differences between cancer cases and matched controls. MATERIALS AND METHODS: A retrospective case control study was performed using the BoF analyses of 46 patients with all types of solid and hematgenous cancers, active and inactive (total cases), and 46 controls from a private practice. The standard BoF panel of 17 biomarkers was evaluated. Sixty-two of 150 BoF indices derived from these biomarkers were pre-selected for analysis based on their relationship to cancer physiology. The data was analyzed with the Wilcoxon Signed Ranks Test using SPSS software. RESULTS: Of the 62 indices, 7 were found to be statistically significant in comparing total cancer cases to controls: ßMSH/αMSH, Estrogen Fraction #5, Comparative Genital Androgeny, Thyroid, Genito-thyroid, Catabolism/Anabolism and Pro-inflammatory. CONCLUSIONS: In a small retrospective case control study, statistically significant differences were found between cancer cases and controls in 7 BoF indices. These indices are indicators of physiological conditions consistent with cancer growth. These results warrant further study of this biological modeling system in cancer patients.

Endobiogeny: a global approach to systems biology (part 2 of 2).

ENDOBIOGENY AND THE BIOLOGY OF FUNCTIONS ARE BASED ON FOUR SCIENTIFIC CONCEPTS THAT ARE KNOWN AND GENERALLY ACCEPTED: (1) human physiology is complex and multifactorial and exhibits the properties of a system; (2) the endocrine system manages metabolism, which is the basis of the continuity of life; (3) the metabolic activity managed by the endocrine system results in the output of biomarkers that reflect the functional achievement of specific aspects of metabolism; and (4) when biomarkers are related to each other in ratios, it contextualizes one type of function relative to another to which is it linked anatomically, sequentially, chronologically, biochemically, etc.

Endobiogeny: a global approach to systems biology (part 1 of 2).

Endobiogeny is a global systems approach to human biology that may offer an advancement in clinical medicine based in scientific principles of rigor and experimentation and the humanistic principles of individualization of care and alleviation of suffering with minimization of harm. Endobiogeny is neither a movement away from modern science nor an uncritical embracing of pre-rational methods of inquiry but a synthesis of quantitative and qualitative relationships reflected in a systems-approach to life and based on new mathematical paradigms of pattern recognition.

ZnO nanoparticles enhanced antibacterial activity of ciprofloxacin against Staphylococcus aureus and Escherichia coli.

Nanoparticle metal oxides offer a wide variety of potential applications in medicine due to the unprecedented advances in nanobiotechnology research. In this work, the effect of zinc oxide (ZnO) nanoparticles prepared by mechano-chemical method on the antibacterial activity of different antibiotics was evaluated using disk diffusion method against Staphylococcus aureus and Escherichia coli. The average size of ZnO nanoparticles was between 20 nm and 45 nm. Although ZnO nanoparticles (500 microg/disk) decreased the antibacterial activity of amoxicillin, penicillin G, and nitrofurantoin in S. aureus, the antibacterial activity of ciprofloxacin increased in the presence of ZnO nanoparticles in both test strains. A total of 27% and 22% increase in inhibition zone areas was observed for ciprofloxacin in the presence of ZnO nanoparticles in S. aureus and E. coli, respectively. The enhancing effect of this nanomaterial on the antibacterial activity of ciprofloxacin was further investigated at three different contents (500, 1000, and 2000 microg/disk) against various clinical isolates of S. aureus and E. coli The enhancing effect of ZnO nanoparticles on the antibacterial activity of ciprofloxacin was concentration-dependent against all test strains. The most enhancing activities were observed in the contents of the 2000 microg/disk.

Effects of the anthelmintic drug PF1022A on mammalian tissue and cells.

Nematode infections cause human morbidity and enormous economic loss in livestock. Since resistance against currently available anthelmintics is a worldwide problem, there is a continuous need for new compounds. The cyclooctadepsipeptide PF1022A is a novel anthelmintic that binds to the latrophilin-like transmembrane receptor important for pharyngeal pumping in nematodes. Furthermore, PF1022A binds to GABA receptors, which might contribute to the anthelmintic effect. Like other cyclodepsipeptides, PF1022A acts as an ionophore. However, no correlation between ionophoric activity and anthelmintic properties was found. This is the first study describing the effect of PF1022A on mammalian cells and tissues. While channel-forming activity was observed already at very low concentrations, changes in intracellular ion concentrations and reduction of contractility in isolated guinea pig ileum occurred at multiples of anthelmintically active concentrations. PF1022A did not induce necrotic cell death indicated by complete lack of cellular lactate dehydrogenase release. In contrast, apoptosis induction via the mitochondrial pathway was suggested for long-term drug treatment at high concentrations due to numerous apoptotic morphological changes as well as mitochondrial membrane depolarisation. Short time effects were based on cell cycle blockade in G(0)/G(1) phase. Additionally, the cell cycle and apoptosis regulating proteins p53, p21 and bax, but not Bcl-2 were shown to impact on PF1022A-induced cytotoxicity. However, since PF1022A-induced cytotoxicity was found at drug concentrations higher than those used in anthelmintic treatment, it can be suggested that PF1022A intake might not impair human or animal health. Thus, PF1022A seems to be a safe alternative to other anthelmintic drugs.

Cyclodepsipeptides - potential drugs and lead compounds in the drug development process.

Cyclodepsipeptides show an interesting spectrum of biological activity. Members of this new class of potential drugs may also serve as lead compounds for more pharmacologically potent and toxicologically safe derivatives. Some of these natural products and (semi-)synthetic derivatives have already been evaluated in clinical trials. A common feature of cyclodepsipeptides is their ionophoric properties. However, their pharmacologically relevant action does not seem to correlate with this feature; rather it is based on interactions with distinct cellular compartments and signal transduction pathways. Cyclodepsipeptides, which are currently being evaluated in clinical trials, are used in refractory cancer therapy, usually in combination with other cytotoxic drugs. A series of cyclooctadepsipeptides, however, shows a completely different spectrum of biological activity, namely, potent anthelmintic properties. A number of cyclodepsipeptides have been well characterized in vitro and in vivo, and interesting modes of action, such as antiplasmodial, antiviral, insecticidal, cytotoxic, and antiproliferative properties have been observed. Whether these natural products will be of benefit for patients must be evaluated in clinical trials. Recently, a number of cyclodepsipeptides from marine sponges, bacteria and fungi have been identified. Subsequent structural determination revealed unique structural features within some of these compounds. It was suggested that the cyclic depsipeptide structure is important for the biological activity because the linear homologues were inactive. The scope of activity of these newly isolated natural products spans a range from cytoprotective activity against HIV-1 infection, growth inhibitory effects toward cancer cells, and antimycobacterial, and antimalarial activity.

[Pharmacology and clinical relevance of vasopressin antagonists]. / Pharmakologie und klinische Bedeutung von Vasopressinantagonisten.

As vasopressin receptors are found in many different tissues, vasopressin antagonists may benefit the treatment of numerous disorders. Effects of vasopressin via V1(a) and V2 receptors are closely implicated in a variety of water-retaining diseases and cardiovascular diseases, including heart failure, hyponatremia, hypertension, renal diseases, syndrome of inappropriate antidiuretic hormone secretion, cirrhosis, and ocular hypertension. Furthermore, V1(a) vasopressin antagonists might be useful in cerebral ischemia and stroke, Raynaud's disease, dysmenorrhoea and tocolytic treatment. V1(b) selective vasopressin antagonists are discussed in terms of their usefulness in the treatment of emotional and psychiatric disorders. The vaptans are vasopressin receptor antagonists with V1(a) (relcovaptan) or V2 (tolvaptan, lixivaptan, satavaptan) selectivity or non-selective activity (conivaptan). Conivaptan is the first vaptan which has been approved by the FDA for the treatment of euvolemic hyponatremia. For further indications such as congenital heart failure, studies are going on.

Clinical practice guidelines for support of the family in the patient-centered intensive care unit: American College of Critical Care Medicine Task Force 2004-2005.

OBJECTIVE: To develop clinical practice guidelines for the support of the patient and family in the adult, pediatric, or neonatal patient-centered ICU. PARTICIPANTS: A multidisciplinary task force of experts in critical care practice was convened from the membership of the American College of Critical Care Medicine (ACCM) and the Society of Critical Care Medicine (SCCM) to include representation from adult, pediatric, and neonatal intensive care units. EVIDENCE: The task force members reviewed the published literature. The Cochrane library, Cinahl, and MedLine were queried for articles published between 1980 and 2003. Studies were scored according to Cochrane methodology. Where evidence did not exist or was of a low level, consensus was derived from expert opinion. CONSENSUS PROCESS: The topic was divided into subheadings: decision making, family coping, staff stress related to family interactions, cultural support, spiritual/religious support, family visitation, family presence on rounds, family presence at resuscitation, family environment of care, and palliative care. Each section was led by one task force member. Each section draft was reviewed by the group and debated until consensus was achieved. The draft document was reviewed by a committee of the Board of Regents of the ACCM. After steering committee approval, the draft was approved by the SCCM Council and was again subjected to peer review by this journal. CONCLUSIONS: More than 300 related studies were reviewed. However, the level of evidence in most cases is at Cochrane level 4 or 5, indicating the need for further research. Forty-three recommendations are presented that include, but are not limited to, endorsement of a shared decision-making model, early and repeated care conferencing to reduce family stress and improve consistency in communication, honoring culturally appropriate requests for truth-telling and informed refusal, spiritual support, staff education and debriefing to minimize the impact of family interactions on staff health, family presence at both rounds and resuscitation, open flexible visitation, way-finding and family-friendly signage, and family support before, during, and after a death.

Vasopressin antagonists.

Effects of vasopressin via V1a- and V2-receptors are closely implicated in a variety of water-retaining diseases and cardiovascular diseases, including heart failure, hyponatraemia, hypertension, renal diseases, syndrome of inappropriate antidiuretic hormone secretion, cirrhosis and ocular hypertension. As vasopressin receptors are found in many different tissues, vasopressin antagonists may benefit the treatment of disorders such as cerebral ischaemia and stroke, Raynaud's disease, dysmenorrhoea and tocolytic treatment. V1b selective vasopressin antagonists are discussed in terms of their usefulness in the treatment of emotional and psychiatric disorders. The vaptans are vasopressin receptor antagonists with V1a (relcovaptan) or V2 (tolvaptan, lixivaptan) selectivity or non-selective activity (conivaptan) which may be advantageous in some disorders. The V1a/V2 non-selective vasopressin antagonist conivaptan is the first vaptan which is approved by the FDA for the treatment of euvolaemic hyponatraemia.

Effects of moniliformin in presence of cyclohexadepsipeptides on isolated mammalian tissue and cells.

Secondary metabolites produced by Fusarium spp. including beauvericin, enniatin and moniliformin are mycotoxins identified in cereal samples. The two cyclohexadepsipeptide mycotoxins beauvericin and enniatin have cytotoxic, antibiotic, insecticidal and ionophoric properties, while moniliformin primarily acts as a cardiotoxic mycotoxin. In this study, we examined the electromechanical and electrophysiological effects of moniliformin and moniliformin with ionophoric mycotoxins on cells (ventricular myocytes, Caco-2 cells) and in multicellular preparations (papillary muscles and terminal ilea of the guinea pig). Additionally, we investigated the influence of moniliformin on cell homeostasis in absence and presence of the cyclodepsipeptide mycotoxins (ventricular myocytes, Caco-2 cells). Experiments were performed using isometric measurements of contractility, intracellular microelectrode and patch-clamp techniques, and fluorescence imaging. While ionophoric cyclohexadepsipeptides affect action potential parameters and cell homeostasis, moniliformin did not change spontaneous rates of activity or cardiac action potentials. Furthermore, moniliformin had no effect on intracellular concentrations of ions and ATP, and did not affect pH. Moniliformin reduced contractility in papillary muscle, terminal ileum, the aorta and the pulmonary artery. However, moniliformin did not alter beauvericin and enniatin induced effects. From our studies, we conclude that moniliformin is not solely a cardiotoxic secondary metabolite, but also exerts its effects on smooth muscle. Moreover, there is no synergistic relationship between moniliformin and the concurrently produced cyclohexadepsipeptide mycotoxins beauvericin and enniatin.

Transplantation ethics from the Islamic point of view.

Organ transplantation has been transformed from an experimental procedure at Western academic centers to an increasingly common procedure in private and public hospitals throughout the world. Attendant with advancements in organ harvesting, preservation, and transplantation come moral issues. Islam is a holistic religion that takes into account social affairs of man as well as spiritual ones. Islam has a long history of ethics literature including the subgenre of medical ethics. Historical considerations are discussed as to why Muslim thinkers were late to consider contemporary medical issues such as organ donation. Islam respects life and values the needs of the living over the dead, thus allowing organ donation to be considered in certain circumstances. The sources of Islamic law are discussed in brief in order for non-Muslims to appreciate how the parameters of organ transplantation are derived. The Islamic viewpoint, both Shiite and Sunni, is examined in relation to organ donation and its various sources. The advantages and disadvantages of brain dead and cadaveric donation is reviewed with technical and ethical considerations. The Islamic concept of brain death, informed and proxy consent are also discussed. We discuss the concept of rewarded donation as a way to alleviate the current shortage of organs available for transplantation and consider secular and religious support for such a program. Suggestions are made for greater discussion and exchange of ideas between secular and religious thinkers in the Islamic world and between the Islamic world and secular Western countries.