The Role of Epigenetics and Contributing Impact of Stress, Multigenerational, and Developmental Factors in Opiate Addiction.

Drug addiction is characterized by maladaptive neural plasticity, particularly in vulnerable individuals exposed to drugs of abuse. Epigenetic factors include environmental influences, events during development, and stress adaptations, which seem to play an important role in the neuropathogenesis of drug addiction. This critical review hypothesizes that epigenetic modulation increases an individual's susceptibility to opiate addiction in three key areas of epigenetic study: developmental, stress-related, and transgenerational effects. The widespread use of opioids for clinical and recreational purposes raises significant societal and scientific concerns. Despite the increasing prevalence of opioid abuse, there is limited comprehensive knowledge about the impact of epigenetic factors on opiate addiction manifestation. This review hypothesizes that epigenetic modulation increases susceptibility to opiate addiction, exploring three key areas of epigenetic study: developmental, stress-related, and transgenerational effects. Current literature reveals a correlation between epigenetic influences and vulnerability to drug addiction, specifically in the context of opioid use. Epigenetics, the modulation of genetic expression beyond genotypic predisposition, plays a crucial role in an individual's susceptibility to drug addiction. Studies suggest that epigenetic mechanisms, once considered static in the adult brain, continue to influence synaptic plasticity and long-term memory, particularly in the endogenous opioid system. This review examines the effects of opioids and stress on epigenetic modifications, providing evidence of increased vulnerability to opiate addiction. Animal studies demonstrate how developmental adversities and adolescent exposure to substances can induce persistent epigenetic changes, predisposing individuals to opiate addiction in adulthood. Moreover, the review explores the transgenerational effects of opioid exposure during adolescence, suggesting that functional epigenetic neuroadaptations within the nucleus accumbens can persist for multiple generations. The examination of DNA methylation patterns in opioid addicts reveals potential markers for identifying susceptibility to opiate vulnerability. A critical analysis of research reports supports the hypothesis that developmental, transgenerational, and stress-related epigenetic mechanisms have a profound role in increasing the risk of opioid addiction susceptibility. Each study confirmed that developmental, stress-related, or transgenerational epigenetic regulations have a correlation to increased opiate sensitization and vulnerability. Unfortunately, every study reviewed was unable to elucidate an epigenetic mechanism to explain a specific neuropathogenesis of opiate drug addiction vulnerability, emphasizing our lack of knowledge in the complex pathology of epigenetics.

Atraumatic Spontaneous Splenic Rupture With Unknown Etiology.

Splenic rupture of all causes is a potentially life-threatening event for patients. The infrequency of atraumatic splenic rupture (ASR) poses a significant diagnostic challenge due to atypical findings. ASR is commonly due to a spleen with an underlying disease process such as malignancy, infection, coagulopathies, or neoplasms. However, ASR without an identifiable cause is rare and poses further complexity. In this case, a 57-year-old woman with a history of hypertension presented to the emergency department complaining of chest pain and was found to have a splenic hematoma. She underwent splenic artery embolization due to her continued hemodynamic instability. The patient was ultimately treated with a splenectomy, as embolization was unsuccessful. Gross pathology revealed no underlying disease processes, nodules, or masses. Splenic hemorrhage due to atraumatic rupture of the spleen is rare and without known pathology. The case illustrates the need for providers to have high clinical suspicion of such a diagnosis to stabilize and surgically manage these patients. Few instances of ASR without an identifiable cause are found in medical literature, and further knowledge of the subject is needed.

A pilot study of adalimumab in infliximab-allergic patients.

The anti-TNF-alpha antibody infliximab (Remicade) is highly effective in the treatment of Crohn's disease. A subset of patients experience allergic reactions as a result of antibodies to infliximab (ATIs). The purpose of the current study is to describe the safety and efficacy of adalimumab (Humira) in patients previously allergic or intolerant to infliximab. Adalimumab is an anti-TNF-alpha agent containing only human peptide sequences. Seven patients have been treated with adalimumab who had experienced immediate- or delayed-hypersensitivity reactions to infliximab and one with infliximab-induced lupus. Except for injection site discomfort, adalimumab was well tolerated without signs or symptoms of allergic reactions. One patient who had previously received pooled human immunoglobulin developed a pruritic rash after each dose of adalimumab. Patients with active disease who had previously experienced a robust response to infliximab responded to adalimumab as reflected by an improvement in Harvey-Bradshaw index and inflammatory markers. Based on these preliminary data, adalimumab may be a safe and effective substitute for infliximab-allergic patients. Individuals who have been exposed to human antibodies may be sensitized to other human antibodies such as adalimumab.

Effect of age on biochemical disease-free outcome in patients with T1-T3 prostate cancer treated with definitive radiotherapy in an equal-access health care system: a radiation oncology report of the Department of Defense Center for Prostate Disease Research.

PURPOSE: It has traditionally been a common perception that young age is a negative prognostic factor in prostate cancer (CaP). Furthermore, many urologists believe that younger patients are better suited to surgery rather than radiotherapy (RT) because of this perception. However, the data on the effect of age on outcome in patients with CaP are unclear. The records of the Department of Defense Center for Prostate Disease Research were queried for the biochemical disease-free results of patients after definitive RT and analyzed by age. MATERIALS AND METHODS: The records of 1018 patients with T1-T3 CaP treated with definitive RT between 1988 and 2000 were reviewed. The records of patients receiving adjuvant hormonal therapy or adjuvant or salvage RT postoperatively were excluded. Biochemical failure was calculated by the American Society for Therapeutic Radiology and Oncology criteria. The median potential follow-up was 85.3 months as of December 31, 2001. RESULTS: Age did not affect biochemical disease-free survival significantly when considered as <60 vs. >/=60 years (p = 0.646), by decade (p = 0.329), or as a continuous variable (correlation coefficient r = 0.017, regression slope = 0.007, with p = 0.588 and R(2) < 0.001). Using multiple regression analysis, age was still not significant (p = 0.408). Other variables analyzed were pretreatment prostate-specific antigen level (p < 0.001), Gleason sum (p = 0.023), stage (p = 0.828), and RT dose (p = 0.033). CONCLUSIONS: Age and biochemical disease-free survival after RT for CaP are not related. Age may not be a valid factor in choosing between primary treatment options for CaP.

Effect of race on biochemical disease-free outcome in patients with prostate cancer treated with definitive radiation therapy in an equal-access health care system: radiation oncology report of the Department of Defense Center for Prostate Disease Research.

PURPOSE: To report on the first collaboration of the Department of Defense Center for Prostate Disease Research concerned with the relationship between African American race and biochemical disease-free outcomes after definitive radiation therapy. MATERIALS AND METHODS: Information from the medical records of 1,806 patients (1,349 white, 343 African American, 42 of "other" races, and 72 of "unknown" races) treated with definitive radiation therapy between 1973 and 2000 was reviewed. Patients receiving adjuvant hormonal therapy or postoperative adjuvant or salvage radiation therapy were excluded. Biochemical failure was calculated in over 96% of cases by using ASTRO criteria; patients with fewer than three follow-up visits were considered to have biochemical failure with a prostate-specific antigen (PSA) value more than 10-fold the previous value or with any value greater than 50.0 ng/mL. Median radiation therapy doses were similar. The median follow-up was 58.4 months. Kaplan-Meier tests, Cox proportional hazards regression analysis, and log-rank tests were used for data analysis. RESULTS: There was no statistically significant difference in biochemical disease-free survival according to race when patients were stratified according to T stage. African American race conferred a negative prognosis for patients with lesions of Gleason biopsy score 7 (P =.004) but not for patients with lesions of Gleason score 2-4 (P =.14), 5-6 (P =.79), or 8-10 (P =.86). Similarly, African American race conferred a negative prognosis in patients with PSA values of 20.1-50.0 ng/mL (P =.01) at presentation but not in patients with PSA values less than or equal to 4.0 ng/mL (P =.84), 4.1-10.0 ng/mL (P =.71), 10.1-20.0 ng/mL (P =.75), or above 50.0 ng/mL (P =.15) at presentation. At multivariate analysis, race was not a statistically significant predictor of outcome. CONCLUSION: In the equal-access health care system of the Department of Defense, African American race is not associated with a consistently negative prognosis in patients treated with definitive radiation therapy for prostate cancer. Race appears to confer a negative prognosis only in patients with advanced disease at presentation.