Dietary polyamines promote the growth of azoxymethane-induced aberrant crypt foci in rat colon

We have examined whether dietary polyamines influence the formation and initial growth of azoxymethane (AOM)-induced aberrant crypt foci (ACF) in rat colon. Effects of a combination of dietary polyamines at three dose levels (putrescine: 50, 280, 740 nmol/g; spermidine: 10, 261, 763 nmol/g; spermine: 1, 31, 91 nmol/g) in the polyamine-poor AIN-76A diet were studied in animals in two different experimental situations: animals treated with AOM alone and animals treated with AOM + difluoromethylornithine (DFMO), a specific inhibitor of endogenous polyamine synthesis. In both experimental situations, dietary polyamines enhanced the growth of ACF, expressed as the number of large ACF (foci with three or more aberrant crypts, ACF > or = 3), whereas the formation of ACF, expressed as the number of ACF, was apparently not altered. In animals treated with AOM alone, maximal growth enhancing effect on ACF was nearly obtained with the median level of dietary polyamine. In rats fed a low polyamine diet, basic AIN-76A, DFMO reduced the growth of AOM-induced ACF by 83%. This inhibitory effect of DFMO was counteracted by dietary polyamines in a dose- dependent manner, and it was abolished at the highest level of polyamines. In conclusion, it was demonstrated that dietary polyamines are able to enhance the growth of AOM-induced ACF. Further, dietary polyamines reversed the DFMO-caused inhibition of ACF growth, probably by compensating for the DFMO-reduced endogenous polyamine synthesis.      

A brief summary of alcohol intervention research at West Virginia University from 1998-2003

Injury resulting in death and disability and alcohol-related problems are two major problems in West Virginia, yet few effective preventive strategies are available. A relatively simple and effective preventive strategy, appropriate for all health care providers, can help to alter excessive alcohol consumption and its resulting harm and consequences. Over the past five years, a series of alcohol intervention projects have been conducted in the Emergency Department at West Virginia University Hospital and other medical settings. Short motivational counseling sessions, which are referred to as screening and brief intervention (SBI), were tailored to each patient's needs. SBI is a secondary prevention strategy used to help persons identified with alcohol problems to decrease their drinking and reduce the harm caused by alcohol. To date, 90% of the nearly 8,000 eligible patients have consented to participate in these studies. Follow-up rates have ranged between 45% and 61%. This article describes the methodologies and results of our SBI studies and their relevance to West Virginia health care providers.     

Voucher-based incentives for naltrexone treatment attendance in schizophrenia and alcohol use disorders

OBJECTIVE: This study assessed the feasibility of voucher-based incentives for attendance for directly observed naltrexone treatment in a controlled trial for alcohol use disorders in schizophrenia. METHODS: Cash-value voucher-based incentives were contingent on attendance at three research visits per week over 12 weeks for 61 participants. Vouchers increased in value based on consecutive attendance. Missed visits resulted in reduction of voucher value. RESULTS: Participants attended 82% of all research visits. Average value of vouchers earned was $330 (78% of the maximum possible). Psychotic symptom severity at baseline did not affect the utilization of vouchers, and 94% of participants perceived the incentive system as helpful. CONCLUSIONS: The incentive system was well accepted and used despite psychosis severity, and the attendance rate was high, although causality between incentives and attendance could not be examined. A voucher-based incentive system for attendance can be successfully applied in a clinical trial for alcohol dependence treatment in schizophrenia.     

Counselors' reflections on the administration of screening and brief intervention for alcohol problems in the emergency department and 3-month follow-up outcome

Objectives

The purpose of this paper was to explore how events that counselors endorsed occurring during an emergency department–based screening and brief intervention (SBI) for drinking discriminate patients who reported change in Alcohol Use Disorder Identification Test (AUDIT) domains at follow-up from those who did not.

Method

Patients who scored “>5” on the AUDIT were eligible for SBI. At the end of each intervention, counselors completed the questionnaire indicating which parts of the intervention they just used.

Results

Discriminant function analyses indicated that “Referral made” discriminated for alcohol intake change (Wilks' λ = 0.993, P < .05); “Did the patient set goals during intervention?” and “Referral made” discriminated for alcohol dependency change (Wilks' λ = 0.940 and Wilks' λ = 0.919, P < .05, respectively). “Intention to quit” (Wilks' λ = 0.984, P < .05) discriminated for alcohol-related harm change.

Conclusions

Making referrals to addiction treatment during motivational intervention discriminated for alcohol intake and dependency change. Working on intention to quit is an important point in changing alcohol-related harm. When conducting the SBI in ED, counselors may be mindful in making appropriate referrals to address alcohol use and examine intention to quit to maximize the efficacy of the harm-reduction approach.     

Evasin‐3‐like anti‐chemokine activity in salivary gland extracts of ixodid ticks during blood‐feeding: a new target for tick control

Ticks exploit many evasion mechanisms to circumvent the immune control of their hosts including subversion of the communication language between cells of the immune system provided by chemokines and other cytokines. One subversive molecule secreted in the saliva of Rhipicephalus sanguineus is Evasin‐3, a structurally unique 7 kDa protein that selectively binds the neutrophil chemoattractants, CXCL8 and (with lower affinity) CXCL1. We compared anti‐human CXCL8 and anti‐mouse CXCL1/KC activities in salivary gland extracts prepared from adult Amblyomma variegatum, Rhipicephalus appendiculatus and Dermacentor reticulatus ticks during blood‐feeding. Both anti‐CXCL8 activity and anti‐CXCL1 activity were detected in all species and in both adult females and males, with consistently higher activity levels against CXCL8. These results suggest that Evasin‐3‐like activity is common amongst metastriate ixodid tick species, and provide further evidence of the importance to ticks in controlling neutrophils during blood‐feeding. As such, Evasin‐3 offers a new target for anti‐tick vaccine development.     

Dual mTORC1/C2 inhibitors suppress cellular geroconversion (a senescence program)

In proliferating cells, mTOR is active and promotes cell growth. When the cell cycle is arrested, then mTOR converts reversible arrest to senescence (geroconversion). Rapamycin and other rapalogs suppress geroconversion, maintaining quiescence instead. Here we showed that ATP-competitive kinase inhibitors (Torin1 and PP242), which inhibit both mTORC1 and TORC2, also suppressed geroconversion. Despite inhibition of proliferation (in proliferating cells), mTOR inhibitors preserved re-proliferative potential (RP) in arrested cells. In p21-arrested cells, Torin 1 and PP242 detectably suppressed geroconversion at concentrations as low as 1-3 nM and 10-30 nM, reaching maximal gerosuppression at 30 nM and 300 nM, respectively. Near-maximal gerosuppression coincided with inhibition of p-S6K(T389) and p-S6(S235/236). Dual mTOR inhibitors prevented senescent morphology and hypertrophy. Our study warrants investigation into whether low doses of dual mTOR inhibitors will prolong animal life span and delay age-related diseases. A new class of potential anti-aging drugs can be envisioned.     

Hypoxia suppresses conversion from proliferative arrest to cellular senescence

Unlike reversible quiescence, cellular senescence is characterized by a large flat cell morphology, β-gal staining and irreversible loss of regenerative (i.e., replicative) potential. Conversion from proliferative arrest to irreversible senescence, a process named geroconversion, is driven in part by growth-promoting pathways such as mammalian target of rapamycin (mTOR). During cell cycle arrest, mTOR converts reversible arrest into senescence. Inhibitors of mTOR can suppress geroconversion, maintaining quiescence instead. It was shown that hypoxia inhibits mTOR. Therefore, we suggest that hypoxia may suppress geroconversion. Here we tested this hypothesis. In HT-p21-9 cells, expression of inducible p21 caused cell cycle arrest without inhibiting mTOR, leading to senescence. Hypoxia did not prevent p21 induction and proliferative arrest, but instead inhibited the mTOR pathway and geroconversion. Exposure to hypoxia during p21 induction prevented senescent morphology and loss of regenerative potential, thus maintaining reversible quiescence so cells could restart proliferation after switching p21 off. Suppression of geroconversion was p53- and HIF-1-independent, as hypoxia also suppressed geroconversion in cells lacking functional p53 and HIF-1α. Also, in normal fibroblasts and retinal cells, hypoxia inhibited the mTOR pathway and suppressed senescence caused by etoposide without affecting DNA damage response, p53/p21 induction and cell cycle arrest. Also hypoxia suppressed geroconversion in cells treated with nutlin-3a, a nongenotoxic inducer of p53, in cell lines susceptible to nutlin-3a-induced senescence (MEL-10, A172, and NKE). Thus, in normal and cancer cell lines, hypoxia suppresses geroconversion caused by diverse stimuli. Physiological and clinical implications of the present findings are discussed.