A translational neuroscience perspective on loneliness: Narrative review focusing on social interaction, illness and oxytocin.

This review addresses key findings on loneliness from the social, neurobiological and clinical fields. From a translational perspective, results from studies in humans and animals are included, with a focus on social interaction, mental and physical illness and the role of oxytocin in loneliness. In terms of social interactions, lonely individuals tend to exhibit a range of abnormal behaviors based on dysfunctional social cognitions that make it difficult for them to form meaningful relationships. Neurobiologically, a link has been established between loneliness and the hypothalamic peptide hormone oxytocin. Since social interactions and especially social touch regulate oxytocin signaling, lonely individuals may have an oxytocin imbalance, which in turn affects their health and well-being. Clinically, loneliness is a predictor of physical and mental illness and leads to increased morbidity and mortality. There is evidence that psychopathology is both a cause and a consequence of loneliness. The final section of this review summarizes the findings from social, neurobiological and clinical perspectives to present a new model of the complex construct of loneliness.

New Assessment Tool-Postpartum Functional Assessment Questionnaire.

Background and Objectives: Functional status of the mother after delivery is crucial for performing activities of daily living and caring for the newborn. It is important to assess functional abilities after childbirth in order to improve the quality of postpartum care. The aim of this study is to determine the psychometric properties of the questionnaire and assess the functional abilities after childbirth. Materials and Methods: This study is observational. Postpartum Functional Assessment Questionnaire includes eleven items. 301 women after childbirth, 234 after vaginal birth and 67 after caesarean section participated in the study. An assessment of pain intensity and functional abilities was performed on the first and third day after childbirth. The Factor and Cronbach's alpha analyses were performed to determine the factor structure and internal consistency. Results: The analysis reveals two factors, with seven items loading on factor 1 and four on factor 2. Cronbach's alpha for construct I (Mobility) at the first day was 0.927 and at the third day was 0.913; and for Factor II (Self-care) at the first day was 0.846 and at the third day was 0.894. All between-group differences in pain intensity and functional abilities were highly statistically significant (p < 0.001). Differences between the first and third postpartum day were statistically significant for all variables and all subgroups (p < 0.001). Conclusions: Postpartum Functional Assessment Questionnaire has good psychometric properties and is a valuable tool for use in clinical practice.

IFNγ directly counteracts imatinib-induced apoptosis of primary human CD34+ CML stem/progenitor cells potentially through the upregulation of multiple key survival factors.

Tyrosine kinase inhibitors (TKIs) have dramatically improved the survival in chronic myeloid leukemia (CML), but residual disease typically persists even after prolonged treatment. Several lines of evidence suggest that TKIs administered to CML patients upregulate interferon γ (IFNγ) production, which may counteract the anti-tumorigenic effects of the therapy. We now show that activated T cell-conditioned medium (TCM) enhanced proliferation and counteracted imatinib-induced apoptosis of CML cells, and addition of a neutralizing anti-IFNγ antibody at least partially inhibited the anti-apoptotic effect. Likewise, recombinant IFNγ also reduced imatinib-induced apoptosis of CML cells. This anti-apoptotic effect of IFNγ was independent of alternative IFNγ signaling pathways, but could be notably diminished by STAT1-knockdown. Furthermore, IFNγ upregulated the expression of several anti-apoptotic proteins, including MCL1, PARP9, and PARP14, both in untreated and imatinib-treated primary human CD34+ CML stem/progenitor cells. Our results suggest that activated T cells in imatinib-treated CML patients can directly rescue CML cells from imatinib-induced apoptosis at least partially through the secretion of IFNγ, which exerts a rapid, STAT1-dependent anti-apoptotic effect potentially through the simultaneous upregulation of several key hematopoietic survival factors. These mechanisms may have a major clinical impact, when targeting residual leukemic stem/progenitor cells in CML.

Cytotoxic Alkylynols of the Sponge Cribrochalina vasculum: Structure, Synthetic Analogs and SAR Studies.

A series of twenty-three linear and branched chain mono acetylene lipids were isolated from the Caribbean Sea sponge Cribrochalina vasculum. Seventeen of the compounds, 1-17, are new, while six, 18-23, were previously characterized from the same sponge. Some of the new acetylene-3-hydroxy alkanes 1, 6, 7, 8, 10 were tested for selective cytotoxicity in non-small cell lung carcinoma (NSCLC) cells over WI-38 normal diploid lung fibroblasts. Compound 7, presented clear tumor selective activity while, 1 and 8, showed selectivity at lower doses and 6 and 10, were not active towards NSCLC cells at all. The earlier reported selective cytotoxicity of some acetylene-3-hydroxy alkanes (scal-18 and 23), in NSCLC cells and/or other tumor cell types were also confirmed for 19, 20 and 22. To further study the structure activity relationships (SAR) of this group of compounds, we synthesized several derivatives of acetylene-3-hydroxy alkanes, rac-18, scal-S-18, R-18, rac-27, rac-32, R-32, S-32, rac-33, rac-41, rac-42, rac-43, rac-45, rac-48 and rac-49, along with other 3-substituted derivatives, rac-35, rac-36, rac-37, rac-38, rac-39 and rac-40, and assessed their cytotoxic activity against NSCLC cells and diploid fibroblasts. SAR studies revealed that the alcohol moiety at position 3 and its absolute R configuration both were essential for the tumor cell line selective activity while for its cytotoxic magnitude the alkyl chain length and branching were of less significance.

Combination of tyrosine kinase inhibitors and the MCL1 inhibitor S63845 exerts synergistic antitumorigenic effects on CML cells.

Tyrosine kinase inhibitor (TKI) treatment has dramatically improved the survival of chronic myeloid leukemia (CML) patients, but measurable residual disease typically persists. To more effectively eradicate leukemia cells, simultaneous targeting of BCR-ABL1 and additional CML-related survival proteins has been proposed. Notably, several highly specific myeloid cell leukemia 1 (MCL1) inhibitors have recently entered clinical trials for various hematologic malignancies, although not for CML, reflecting the insensitivity of CML cell lines to single MCL1 inhibition. Here, we show that combining TKI (imatinib, nilotinib, dasatinib, or asciminib) treatment with the small-molecule MCL1 inhibitor S63845 exerted strong synergistic antiviability and proapoptotic effects on CML lines and CD34+ stem/progenitor cells isolated from untreated CML patients in chronic phase. Using wild-type BCR-ABL1-harboring CML lines and their T315I-mutated sublines (generated by CRISPR/Cas9-mediated homologous recombination), we prove that the synergistic proapoptotic effect of the drug combination depended on TKI-mediated BCR-ABL1 inhibition, but not on TKI-related off-target mechanisms. Moreover, we demonstrate that colony formation of CML but not normal hematopoietic stem/progenitor cells became markedly reduced upon combination treatment compared to imatinib monotherapy. Our results suggest that dual targeting of MCL1 and BCR-ABL1 activity may efficiently eradicate residual CML cells without affecting normal hematopoietic stem/progenitors.

Montelukast, a cysteinyl leukotriene receptor antagonist, inhibits the growth of chronic myeloid leukemia cells through apoptosis.

The clinical outcome for patients with chronic myeloid leukemia (CML) has improved significantly with the introduction of tyrosine kinase inhibitors (TKIs). However, their curative potential appears limited, probably as a consequence of TKI-resistant leukemic stem cells (LSCs) that persist as a result of aberrant pathways independent of the well-established oncoprotein Bcr-Abl. One such pathway involves signaling through leukotrienes (LTs), bioactive compounds that have been suggested to play a role in several other malignancies. Cysteinyl LT1 receptor (CysLT1R) has been reported to be overexpressed in a number of solid cancers, and blocking of this receptor with the antagonist montelukast (treatment approved for bronchial asthma) has resulted in the killing of cancer cells. We recently demonstrated that montelukast, alone or in combination with imatinib, can effectively reduce the growth of CML cells, while normal bone marrow cells were left unaffected. Herein, we further investigated the importance of CysLT1R for the survival of CML cells and the mechanisms by which montelukast induces cell death. Knockdown of the CysLT1R of K562 cells with siRNA reduced their growth by 25%. Montelukast had no effect on these cells, while it killed more than 50% of CysLT1R-expressing cells. Growth inhibition exerted by imatinib was unaffected by CysLT1R status. Montelukast-induced killing of K562/JURL-MK1 CML cells was paralleled by Bax overexpression, cytochrome c release, PARP-1 cleavage, and caspase-3 activation, an event further increased in a setting where montelukast was added to imatinib. Wnt/ß-catenin signaling was activated by CysLT1R and we observed that montelukast could induce proteins in this pathway, a finding of relevance for LSC survival. Thus, montelukast, employed at in vivo-like concentrations, induces the killing of CML cells through apoptotic pathways and may provide an additional, novel therapeutic possibility in CML.

Parental Socioeconomic Status as a Predictor of Physical and Mental Health Outcomes in Children - Literature Review.

Parental socioeconomic status is a multidimensional concept of special importance for the growth, development, health outcomes and education of children. Its definition generally refers to the amount of parents' income, their employment status and level of education. Hence, lack of economic resources and poverty of parents affect all aspects of the child's life, health outcomes and education, as well as his/her social inclusion. Accordingly, the consequences of a reduced parental socioeconomic status leave long-term effects on their children. Therefore, in order to create interventional programs for children of parents with low income and lower socioeconomic status, as well as with lower level of education, it is important to address the direct aspects of poverty. This review contributes to the evidence indicating that the parental socioeconomic status is highly influential in determining the child's physical and mental health and future outcomes including his/her academic achievements and education, as well as the parameters of his/her physical abilities, cognitive function and fundamental neurobiology affecting brain development.

Modulation of leukotriene signaling inhibiting cell growth in chronic myeloid leukemia.

Although tyrosine kinase inhibitors (TKIs) have dramatically improved clinical outcome in chronic myeloid leukemia (CML), cure rarely occurs. This may be due to BCR-ABL-independent, aberrant signaling pathways, one of which leads to leukotriene (LT) formation. Well-recognized as inflammatory mediators, LT can also affect oncogenic mechanisms of several tumors. We have previously discovered elevated LT-synthesis and up-regulated cysteinyl-LT-inducing enzyme in CML. Here we report on dose-dependent inhibition of CML cell growth exerted by specific blockers of LT-signaling. Thus, the cysteinyl-LT1-receptor-antagonist montelukast significantly reduced the growth of K562, KCL22, and KU812 cells, as well as primary CD34+ blood cells from two CML patients. Adding montelukast to the TKI imatinib caused combined inhibition. No effect was seen on normal bone marrow cells. Similarly, growth inhibition was also observed with the 5-lipoxygenase (LO)-inhibitor BWA4C, the 5-LO-activating-protein-(FLAP)-inhibitor licofelone and the LTB4(BLT1)-receptor-antagonist LY293111. Thus, blocking of aberrant LT-signaling may provide an additional, novel therapeutic possibility in CML.

Antibiotic prophylaxis for premature rupture of membranes and perinatal outcome.

AIM: To evaluate the perinatal outcomes of newborns after premature rupture of membranes (PROM) at the term according to the timing of initial antibiotic administration. MATERIAL AND METHODS: This is a retrospective, cohort study investigating perinatal outcomes of newborns in pregnant women with PROM at the term who were treated with ampicillin within or after 6 h from the PROM. Statistical analysis was performed using Student's t-test for continuous variables test and chi-square or for categorical data. RESULTS: The study involved 144 pregnant women with PROM and their newborns, a lower number received antibiotics after birth were in the group who received antibiotics within 6 h of PROM (26.4% versus 73.6%), the mediane values of C-reactive protein were lower (3.0 ± 2.9 mg/l versus 6.1 ± 7.3 mg/l; p < 0.001), their newborns remained shorter in hospital after birth (4.13 versus 4.94; p =0.023) and time between PROM and delivery was shorter (p < 0.001). In group who received prophylactic antibiotics after 6 h of the PROM had significantly higher frequency of infection in newborns (45.3% versus 15.4%), and higher number of chorioamnionitis (9.72% versus 3,47%) compared to group who received antibiotics within 6h. CONCLUSION: Timely usage of antibiotic prophylaxis and shorter time between PROM and delivery improve perinatal outcomes.

Compounds from the marine sponge Cribrochalina vasculum offer a way to target IGF-1R mediated signaling in tumor cells.

In this work two acetylene alcohols, compound 1 and compound 2, which were isolated and identified from the sponge Cribrochalina vasculum, and which showed anti-tumor effects were further studied with respect to targets and action mechanisms. Gene expression analyses suggested insulin like growth factor receptor (IGF-1R) signaling to be instrumental in controlling anti-tumor efficacy of these compounds in non-small cell lung cancer (NSCLC). Indeed compounds 1 and 2 inhibited phosphorylation of IGF-1Rß as well as reduced its target signaling molecules IRS-1 and PDK1 allowing inhibition of pro-survival signaling. In silico docking indicated that compound 1 binds to the kinase domain of IGF-1R at the same binding site as the well known tyrosine kinase inhibitor AG1024. Indeed, cellular thermal shift assay (CETSA) confirmed that C. vasculum compound 1 binds to IGF-1R but not to the membrane localized tyrosine kinase receptor EGFR. Importantly, we demonstrate that compound 1 causes IGF-1Rß but not Insulin Receptor degradation specifically in tumor cells with no effects seen in normal diploid fibroblasts. Thus, these compounds hold potential as novel therapeutic agents targeting IGF-1R signaling for anti-tumor treatment.

Croatian clinical epidemiological study (2008-2011): the use of standardised risk scores in paediatric congenital cardiac surgery for a case complexity selection and gradual progress of cardiosurgical model in developing countries.

OBJECTIVE: By employing the widely used and accepted methodologies of case-mix complexity adjustment in congenital cardiac surgery, we tried to evaluate our performance and use the ABC scores for a case complexity selection that may have different outcomes in various centres. METHODS: We analysed outcomes of cardiac surgical procedures - with or without cardiopulmonary bypass - performed in our institution between January, 2008 and December, 2011. Data were collected from the European Association for Cardio-Thoracic Surgery database. Together with prospective collection of these data, the data of all patients sent abroad to foreign cardiosurgical centres were recorded. RESULTS: During the period of study, 634 operations were performed; among them, 60% were performed in Croatia and 40% in foreign cardiosurgical centres. The number of operations performed in Croatia showed a linear increase: 55, 78, 121, and 126 operations performed in the years 2008, 2009, 2010, and 2011, respectively. Early mortality rates were 1.82%, 5.41%, 3.64%, and 3.48% in 2008, 2009, 2010, and 2011, respectively. The increase in the number of operations was followed by a satisfactory low average mortality rate of 3.85%. The mean ABC score complexity for operations performed in Croatia was 5.77. We determined a linear correlation between ABC score and early mortality, especially for the more complex operations. CONCLUSION: The use of standardised risk scores allows selection of complex cardiac diseases, which may have very different outcomes in various centres. In our case, those with higher ABC scores were correctly identified and referred for treatment abroad. In this way, we allowed gradual progress of the cardiosurgical model in Croatia and maintained an enviably low mortality rate.

Epidemiological characteristics of children born with Down syndrome in western Herzegovina in the period of the last twenty years (1994-2013).

BACKGROUND: Children with Down syndrome (DS) are an everyday casuistry of pediatric clinical medicine. The prevalence of DS is dependent on socio-demographic and cultural conditions of a community. Antenatal screening is not carried out mainly due to religious views, and the prevalence of DS in our region is really considered a "natural phenomenon". The aim of the study was to analyze some epidemiological characteristics of infants with Down syndrome in the western region of Herzegovina in the period between year 1994-2013. SUBJECTS AND METHODS: We performed a retrospective analysis of hospital records of children who were supervised and treated at Children's Hospital through the twenty-year period. RESULTS: In this period there were 44,100 liveborn infants. Down syndrome was detected in 78 children (54 male and 24 female). The prevalence is estimated at 1.8/1,000 of live births. Aborted fetuses and stillbirths were not analyzed. 37 (47%) of the parent couples were over 35 years of age. Out of that 65 cytogenetic analysis, a regular type of trisomy 21 was found in 94% of cases, and the translocation in 6%. From major malformations (MM) heart failure was more often present (47%), then the anomaly of the gastrointestinal and genitourinary systems. Ten children (12%) died, most often in the early period of infancy due to complications of the cardiovascular system. CONCLUSION: The prevalence of DS throughout these two decades has been uniform in the region of western Herzegovina. Improvement in perinatal care in recent years caused higher survival and a better quality of life for the children with DS and thus their families. DS is less a desirable family tragedy, and increasingly a tolerable family fate.

Marine sponge Cribrochalina vasculum compounds activate intrinsic apoptotic signaling and inhibit growth factor signaling cascades in non-small cell lung carcinoma.

Marine-derived compounds have been explored and considered as possible antitumor agents. In this study, we analyzed extracts of the sponge Cribrochalina vasculum for their ability to inhibit tumor cell proliferation. Screening identified two acetylenic compounds of similar structure that showed strong tumor-specific toxicity in non-small cell lung carcinoma (NSCLC) cells and small-cell lung carcinoma cells, and less prominent toxicity in ovarian carcinoma, while having no effect on normal cells. These acetylenic compounds were found to cause a time-dependent increase in activation of apoptotic signaling involving cleavage of caspase-9, caspase-3, and PARP, as well as apoptotic cell morphology in NSCLC cells, but not in normal fibroblasts. Further analysis demonstrated that these compounds caused conformational change in Bak and Bax, and resulted in loss of mitochondrial potential and cytochrome c release in NSCLC cells. Moreover, a decreased phosphorylation of the growth factor signaling kinases Akt, mTOR, and ERK was evident and an increased phosphorylation of JNK was observed. Thus, these acetylenic compounds hold potential as novel therapeutic agents that should be further explored for NSCLC and other tumor malignancies.

miRNA-214 is related to invasiveness of human non-small cell lung cancer and directly regulates alpha protein kinase 2 expression.

The prognosis of non-small cell lung cancer (NSCLC) is poor, since it has often metastasized to distant organs by the time of diagnosis. Therefore, biomarkers predicting metastasis are crucial. miRNAs play important roles in the regulation of different tumor cell processes, including metastasis. We recently showed that miRNA-214 is linked to a radioresistant phenotype of NSCLC. miRNA-214 has been linked to metastasis in other tumor types. Therefore, we examined the role of miRNA-214 in the metastatic potential of NSCLC. We showed that downregulation of miRNA-214 increased invasive potential, and conversely, overexpression of miRNA-214 decreased invasiveness of NSCLC cells in vitro. Gene expression and bioinformatic analyses of NSCLC cells with ablated miRNA-214, identified a number of metastasis-related target genes, including pregnancy-associated plasma protein A (PAPP-A), alpha protein kinase 2 (ALPK2), cyclin-dependent kinase 6 (CDK6) and tumor necrosis-factor alpha-induced protein 3 (TNFAIP3). These were validated on mRNA and protein level to be regulated by miRNA-214. Through immunoprecipitation we showed that only ALPK2 is directly regulated by miRNA-214. We also examined the protein expression of these four genes in NSCLC tumors with respect to metastatic potential. These results showed that NSCLC tumors express these proteins at moderate-high levels in the nucleus, cytoplasm and/or plasma membrane although with no significant correlation to the overall survival or the metastatic potential of the patients. However, we also showed that the membrane-localized PAPP-A had a higher expression level compared to the cytoplasm-localized. In conclusion, we show that low miRNA-214 expression is linked to a higher invasive potential of NSCLC cells.

APS8, a polymeric alkylpyridinium salt blocks α7 nAChR and induces apoptosis in non-small cell lung carcinoma.

Naturally occurring 3-alkylpyridinium polymers (poly-APS) from the marine sponge Reniera sarai, consisting of monomers containing polar pyridinium and nonpolar alkyl chain moieties, have been demonstrated to exert a wide range of biological activities, including a selective cytotoxicity against non-small cell lung cancer (NSCLC) cells. APS8, an analog of poly-APS with defined alkyl chain length and molecular size, non-competitively inhibits α7 nicotinic acetylcholine receptors (nAChRs) at nanomolar concentrations that are too low to be acetylcholinesterase (AChE) inhibitory or generally cytotoxic. In the present study we show that APS8 inhibits NSCLC tumor cell growth and activates apoptotic pathways. APS8 was not toxic for normal lung fibroblasts. Furthermore, in NSCLC cells, APS8 reduced the adverse anti-apoptotic, proliferative effects of nicotine. Our results suggest that APS8 or similar compounds might be considered as lead compounds to develop antitumor therapeutic agents for at least certain types of lung cancer.

Binding and permeabilization of lipid bilayers by natural and synthetic 3-alkylpyridinium polymers.

Naturally occurring 3-alkylpyridinium polymers from the marine sponge Reniera sarai are membrane-active compounds exerting a selective cytotoxicity towards non small cell lung cancer cells, and stable transfection of nucleated mammalian cells. In view of their possible use as chemotherapeutics and/or transfection tools, three poly-APS based synthetic compounds were tested on their activity using natural and artificial lipid membranes. The tested compounds were found to be very stable over a wide range of temperature, ionic strength, and pH, and to prefer the solid-ordered membrane state. Their membrane-damaging activity increases with the length of their alkyl chains and the degree of polymerization.

Chemical synthesis and biological activities of 3-alkyl pyridinium polymeric analogues of marine toxins.

UNLABELLED: Two new large poly-1,3-dodecylpyridinium salts, APS12 and APS12-2 of 12.5- and 14.7-kDa size, respectively, were synthesised and tested for their pore-forming and transfection capabilities in HEK 293 and undifferentiated mouse ES cells using patch-clamp recording, Ca(2+) imaging and flow cytometry. Polymerisation reactions were enhanced by microwaves, and the product sizes were controlled by altering the irradiation time. This method can also be applied to obtain polymers with variable linking chains as shown by the preparation of poly-(1,3-octylpyridinium) salt of 11.9-kDa size. Molecular weights of the final products were determined using ESIMS analysis, which also indicated the products to be amongst the largest macro-cycles ever recorded, up to a 900-membered ring. Anti-bacterial, haemolytic and anti-acetylcholinesterase activities were also reported for the two dodecyl pyridinium polymers. These biological activities are characteristic to the structurally related marine toxin, poly-APS. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12154-010-0036-4) contains supplementary material, which is available to authorized users.