Drug Burden Index and physical function in older Australian men

AIMS

This study evaluated the associations of physical performance and functional status measures with the Drug Burden Index in older Australian men. The Drug Burden Index is a measure of total exposure to anticholinergic and sedative medications that incorporates the principles of dose–response and maximal effect.

METHODS

A cross-sectional survey was performed on community-dwelling older men enrolled in The Concord Health and Ageing in Men Project, Sydney, Australia. Outcomes included chair stands, walking speed over 6 m, 20-cm narrow walk speed, balance, grip strength and Instrumental Activities of Daily Living score (IADLs).

RESULTS

The study population consisted of 1705 men (age 76.9 ± 5.5 years). Of the 1527 (90%) participants who reported taking medications, 21% were exposed to anticholinergic and 13% to sedative drugs. The average Drug Burden Index in the study population was 0.18 ± 0.35. After adjusting for confounders (sociodemographics, comorbidities, cognitive impairment, depression), Drug Burden Index was associated with slower walking speed (P < 0.05), slower narrow walk speed (P < 0.05), balance difficulty (P < 0.01), grip weakness (P < 0.01) and poorer performance on IADLs (P < 0.05). Associations with physical performance and function were stronger for the sedative than for the anticholinergic component of the Drug Burden Index.

CONCLUSIONS

Higher Drug Burden Index is associated with poorer physical performance and functional status in community-dwelling older Australian men. The Drug Burden Index has broad applicability as a tool for assessing the impact of medications on functions that determine independence in older people.     

Stereospecific ligands and their complexes. Part VII. Synthesis, characterization and in vitro antitumoral activity of platinum(II) complexes with O,O'-dialkyl esters of (S,S)-ethylenediamine-N,N'-di-2-(4-methyl)pentanoic acid

Platinum(II) complexes (1-4) with bidentate N,N'-ligands, O,O'-dialkyl esters (alkyl = ethyl, n-propyl, n-butyl and n-pentyl), of (S,S)-ethylenediamine-N,N'-di-2-(4-methyl)pentanoic acid were synthesized and characterized by IR, (1)H NMR and (13)C NMR spectroscopy and elemental analysis. DFT calculations were performed for the complexes and it was found that only one diastereoisomer could be formed. Cytotoxic activity of complexes 1-4 was determined against chronic lymphocytic leukemia cells (CLL) and compared to the activity of ligand precursors L1 · 2HCl-L4·2HCl and corresponding palladium(II) complexes, [PdCl(2)L] (L = L1-L4). The complexes were found to exhibit significantly higher antitumor activities than cisplatin on CLL cells. Cytotoxic effect of platinum(II) complexes on CLL cells was higher compared to corresponding palladium(II) complexes. In addition the mode of cell death induced by platinum(II) complexes was determined.     

Abrupt cessation of one-year clopidogrel treatment is not associated with thrombotic events

We aimed to examine the rate of thrombotic events after discontinuation of one year clopidogrel therapy in patients with implanted coronary stent, and to determine platelet aggregability by multiple electrode analyzer after cessation of clopidogrel. This prospective, multicenter study enrolled 200 patients subjected to coronary stent implantation and treated with aspirin + clopidogrel one year after the stent placement. Platelet aggregation was measured using 3 agonists [adenosine diphosphate with PGE(1) (ADPHS), arachidonic-acid (ASPI), and thrombin receptor activating peptide (TRAP)] on the day of cessation of clopidogrel and at 10, 45, and 90 days after clopidogrel was stopped. Two thrombotic events were registered during the 6-months follow up (one ischemic stroke and one myocardial infarction; incidence of 1%). The mean values of ADP + PGE(1)- and ASPI-induced aggregation 10 - 90 days after the cessation of clopidogrel were significantly higher than values obtained before the termination of the drug (P < 0.001, all). Cessation of clopidogrel did not influence the TRAP-induced aggregation, which reached the plateau in all measurements. In conclusion, the incidence of thrombotic events after the cessation of one-year clopidogrel treatment might be lower than expected in patients with implanted coronary stent.     

Targeting the cancer initiating cell: the ultimate target for cancer therapy

An area of therapeutic interest in cancer biology and treatment is targeting the cancer stem cell, more appropriately referred to as the cancer initiating cell (CIC). CICs comprise a subset of hierarchically organized, rare cancer cells with the ability to initiate cancer in xenografts in genetically modified murine models. CICs are thought to be responsible for tumor onset, self-renewal/maintenance, mutation accumulation and metastasis. CICs may lay dormant after various cancer therapies which eliminate the more rapidly proliferating bulk cancer (BC) mass. However, CICs may remerge after therapy is discontinued as they may represent cells which were either intrinsically resistant to the original therapeutic approach or they have acquired mutations which confer resistance to the primary therapy. In experimental mouse tumor transplant models, CICs have the ability to transfer the tumor to immunocompromised mice very efficiently while the BCs are not able to do so as effectively. Often CICs display increased expression of proteins involved in drug resistance and hence they are intrinsically resistant to many chemotherapeutic approaches. Furthermore, the CICs may be in a suspended state of proliferation and not sensitive to common chemotherapeutic and radiological approaches often employed to eliminate the rapidly proliferating BCs. Promising therapeutic approaches include the targeting of certain signal transduction pathways (e.g., RAC, WNT, PI3K, PML) with small molecule inhibitors or targeting specific cell-surface molecules (e.g., CD44), with effective cytotoxic antibodies. The existence of CICs could explain the high frequency of relapse and resistance to many currently used cancer therapies. New approaches should be developed to effectively target the CIC which could vastly improve cancer therapies and outcomes. This review will discuss recent concepts of targeting CICs in certain leukemia models.     

Negative symptoms in individuals at clinical high risk of psychosis

Negative symptoms are present in the psychosis prodrome. However, the extent to which these symptoms are present prior to the onset of the first episode of psychosis remains under-researched. The goal of this study is to examine negative symptoms in a sample of individuals at clinical high risk (CHR) for psychosis and to determine if they are predictive of conversion to psychosis. Participants (n=138) were all participants in the North American Prodrome Longitudinal Study (NAPLS 1) project. Negative symptoms were assessed longitudinally using the Scale of Prodromal Symptoms. The mean total negative symptom score at baseline was 11.0, with 82.0% of the sample scoring at moderate severity or above on at least one negative symptom. Over the course of 12 months, the symptoms remained in the above moderate severity range for 54.0% of participants. Associations between individual symptoms were moderate, and a factor analysis confirmed that all negative symptoms loaded heavily on one factor. Negative symptoms were more severe and persistent overtime in those who converted to psychosis, significantly predicting the likelihood of conversion. Thus, early and persistent negative symptoms may represent a vulnerability for risk of developing psychosis.     

Affect recognition in people at clinical high risk of psychosis

Individuals with schizophrenia demonstrate stable deficits in affect recognition. Similar deficits in affect recognition have been observed in those who are at clinical high risk (CHR) of developing psychosis. The current project aimed to longitudinally examine affect processing in CHR individuals, to determine if affect processing predicted later conversion to psychosis and if affect processing deficits were unique to those who met established criteria for prodromal syndromes. The sample consisted of 172 CHR and 100 help-seeking individuals (HS) who were followed for up to 24 months. All CHR individuals met the Criteria of Prodromal Syndromes (COPS) based on the Structured Interview for Prodromal Symptoms (SIPS). The SIPS was used to determine conversion to psychosis. Affect recognition was assessed using two facial affect recognition tasks and a measure of affective prosody. In comparison to previously published data from non-psychiatric controls, both CHR and HS groups demonstrated deficits in affect recognition. By 2 years 25 CHR participants converted to psychosis. Interestingly, there were no differences between converters and non-converters on any affect recognition tasks. This is one of the first studies to longitudinally examine affect processing and its relationship to later conversion to psychosis in individuals at-risk for psychosis. While poorer affect recognition may be associated with vulnerability for psychosis, the current results suggest that it may not be a marker of developing a psychotic illness.     

Advanced and prospective technologies for potential use in craniofacial tissues regeneration by stem cells and growth factors

The processes of craniofacial tissues development and regeneration are largely dependent on sequential and reciprocal interactions between mesenchymal and epithelial components. These processes involve a series of inductive and permissive interactions that result in the determination, differentiation, and organization of craniofacial tissues. Stem cells and growth factors represent a very interesting research field for craniofacial tissues regeneration. They represent a potential key component in autologous graft for craniofacial tissues regeneration. An ideal goal of oral-craniofacial dental reconstructive therapy is to establish treatment modalities that predictably restore functional tissues. One major area of focus has been that of dental materials with marked improvements in the design of materials used to restore teeth/periodontium/bone lost as a consequence of disease or disorders. Interest in these technologies continues to increase in dental application as a substitute for traditional treatments and artificial components. Recent progress in the studies of molecular basis of tooth development, adult stem cell biology, and regeneration will provide fundamental knowledge for the realization of human craniofacial tissues regeneration in the near future.     

The onset of labor alters corticotropin-releasing hormone type 1 receptor variant expression in human myometrium: putative role of interleukin-1beta

CRH targets the human myometrium during pregnancy. The efficiency of CRH actions is determined by expression of functional receptors (CRH-R), which are dynamically regulated. Studies in myometrial tissue biopsies using quantitative RT-PCR demonstrated that the onset of labor, term or preterm, is associated with a significant 2- to 3-fold increase in CRH-R1 mRNA levels. Detailed analysis of myometrial CRH-R1 mRNA variants showed a decline of the pro-CRH-R1 mRNA encoding the CRH-R1beta variant during labor and increased mRNA levels of CRH-R1d mRNA. Studies in myometrial cells identified IL-1beta as an important regulator of myometrial CRH-R1 gene expression because prolonged treatment of myometrial cells with IL-1beta (1 ng/ml) for 18 h induced expression of CRH-R1 mRNA levels by 1.5- to 2-fold but significantly attenuated CRH-R1beta mRNA expression by 70%. In contrast, IL-1beta had no effect on CRH-R1d mRNA expression. Studies using specific inhibitors suggest that ERK1/2, p38 MAPK, and downstream nuclear translocation of nuclear factor-kappaB mediate IL-1beta effects on myometrial CRH-R1 gene. However, the increased CRH-R1 mRNA expression was associated with a dampening of the receptor efficacy to activate the adenylyl cyclase/cAMP signaling cascade. Thus, our findings suggest that IL-1beta is an important regulator of CRH-R1 expression and functional activity, and this interaction might play a role in the transition of the uterus from quiescence to active contractions necessary for the onset of parturition.     

Anticancer Potential of Xanthohumol and Isoxanthohumol Loaded into SBA-15 Mesoporous Silica Particles against B16F10 Melanoma Cells

Xanthohumol (XN) and isoxanthohumol (IXN), prenylated flavonoids from Humulus lupulus, have been shown to possess antitumor/cancerprotective, antioxidant, antiinflammatory, and antiangiogenic properties. In this study, mesoporous silica (SBA-15) was loaded with different amounts of xanthohumol and isoxanthohumol and characterized by standard analytical methods. The anticancer potential of XN and IXN loaded into SBA-15 has been evaluated against malignant mouse melanoma B16F10 cells. When these cells were treated with SBA-15 containing xanthohumol, an increase of the activity correlated with a higher immobilization rate of XN was observed. Considering the amount of XN loaded into SBA-15 (calculated from TGA), an improved antitumor potential of XN was observed (IC₅₀ = 10.8 ± 0.4 and 11.8 ± 0.5 µM for SBA-15|XN2 and SBA-15|XN3, respectively; vs. IC₅₀ = 18.5 ± 1.5 µM for free XN). The main mechanism against tumor cells of immobilized XN includes inhibition of proliferation and autophagic cell death. The MC₅₀ values for SBA-15 loaded with isoxanthohumol were over 300 µg/mL in all cases investigated.