Thalidomide and the immunomodulatory drug, lenalidomide, are therapeutically active in hematological malignancies. The ubiquitously expressed E3 ligase protein cereblon (CRBN) has been identified as ...the primary teratogenic target of thalidomide. Our studies demonstrate that thalidomide, lenalidomide and another immunomodulatory drug, pomalidomide, bound endogenous CRBN and recombinant CRBN-DNA damage binding protein-1 (DDB1) complexes. CRBN mediated antiproliferative activities of lenalidomide and pomalidomide in myeloma cells, as well as lenalidomide- and pomalidomide-induced cytokine production in T cells. Lenalidomide and pomalidomide inhibited autoubiquitination of CRBN in HEK293T cells expressing thalidomide-binding competent wild-type CRBN, but not thalidomide-binding defective CRBN(YW/AA). Overexpression of CRBN wild-type protein, but not CRBN(YW/AA) mutant protein, in KMS12 myeloma cells, amplified pomalidomide-mediated reductions in c-myc and IRF4 expression and increases in p21(WAF-1) expression. Long-term selection for lenalidomide resistance in H929 myeloma cell lines was accompanied by a reduction in CRBN, while in DF15R myeloma cells resistant to both pomalidomide and lenalidomide, CRBN protein was undetectable. Our biophysical, biochemical and gene silencing studies show that CRBN is a proximate, therapeutically important molecular target of lenalidomide and pomalidomide.
To determine the effect of dexamethasone on the antimyeloma effects of lenalidomide, we tested in vitro proliferation, tumor suppressor gene expression, caspase activity, cell cycling, and apoptosis ...levels in a series of multiple myeloma (MM) and plasma cell leukemia cell lines treated with lenalidomide and dexamethasone, alone or in combination. The effect of dexamethasone on the immunomodulatory activities of lenalidomide such as T cell and natural killer (NK) cell activation was measured via interleukin IL-2 production, and interferon-gamma and granzyme B production respectively. Lenalidomide inhibited proliferation in most cell lines tested, and this effect was enhanced by dexamethasone. This effect was observed in MM cells containing the high-risk cytogenetic abnormalities t(4;14), t(14;16), del17p, del13, and hypodiploidy. Mechanistically, lenalidomide plus dexamethasone synergistically induced expression of the tumor suppressor genes Egr1, Egr2, Egr3, p15, p21, and p27 in MM cell lines and MM patient cells. The combination activated caspases 3, 8, and 9; and induced cell cycle arrest and apoptosis. Lenalidomide alone increased T cell production of IL-2, and NK cell production of interferon-gamma and granzyme B. Notably, dexamethasone antagonized these immunostimulatory effects of lenalidomide in a dose-dependent manner. These data further elucidate the mechanism of action of lenalidomide and dexamethasone in MM, and suggest that use of low-dose dexamethasone with lenalidomide may retain the antiproliferative effect of lenalidomide while permitting greater immunomodulatory effects of this combination regimen.
The measures adopted to control the spread of the COVID-19 pandemic in several countries included mobility and social restrictions that produced an immediate impact on the lifestyle of their ...inhabitants.
We assessed the association between the consequences of these measures and depressive symptomatology using a population-based sample of 692 individuals aged 18 or over from an ongoing study in the province of Girona (Catalonia, Spain). Participants responded to a telephone-based survey that included questions related to the consequences of confinement and the Patient Health Questionnaire-9 (PHQ-9) was used to assess depressive symptomatology. Multivariate logistic and linear regressions were used to identify which changes in lifestyle resulting from confinement were independently associated with a possible depression episode and depressive symptomatology.
The prevalence of a possible depressive episode during the confinement was 12.7% (95% CI = 10.3–15.4). An adverse work situation, expected economic distress, self-reported worsening of the mental health and of the dietary pattern, and worries about a relative's potential infection were variables related to an increased risk of having a possible depressive episode. The changes in lifestyle accounted for 32% of the variance of the PHQ-9 score.
The findings indicate an association of the job situation, the expected negative economic consequences, the perceived worsening of health and habits, and the worries about COVID-19 infection with depressive symptomatology during the confinement.
•The prevalence of depressive episode during the confinement among individuals aged 18 years or over was 12.7%.•Work status, expected economic distress, health worsening, and reduction of activities were related to depressive symptoms.•Affective symptoms were related to the length of confinement and somatic symptoms with physical activity restrictions.
To estimate the incidence of early-onset dementia (EOD) and to compare the clinical characteristics of EOD vs late-onset dementia (LOD) in a geographically defined area.
We used data from the ...Registry of Dementia of Girona (ReDeGi), an epidemiologic surveillance system of dementia. The ReDeGi is a standardized clinical registry of new dementia cases diagnosed in the 7 hospitals of the Health Region of Girona (Catalonia, Spain), which encompasses an area of 5,517 km(2) and 690,207 inhabitants. EOD cases were defined as those patients residing in the target area at the time of diagnosis who were diagnosed with dementia with an age at onset of symptoms before 65 years.
The ReDeGi registered 2,083 patients between January 1, 2007, and December 31, 2009 (6.9% EOD). The incidence rate of EOD for the age range 30-64 was 13.4 cases per 100,000 person-years (95% confidence interval 11.3-15.8). Alzheimer disease was the most frequent cause of EOD (42.4%), followed by secondary dementia (18.1%), vascular dementia (13.8%), and frontotemporal dementia (9.7%). EOD cases at the time of diagnosis were less impaired on the Mini-Mental State Examination and had a greater score on the Blessed Dementia Rating Scale behavior subscale than LOD cases. The frequency of a personal history of depression was higher in EOD cases.
The incidence of EOD was less than 6 cases per 100,000 person-years in the age group 30-49 years; in the age group 50-64 years, the incidence rate was 3-fold higher and doubled with each 5-year increase.
OBJECTIVES: To assess the prevalence of suspected elder abuse subtypes and to identify related factors.
DESIGN: Cross‐sectional, population‐based, descriptive study.
SETTING: Eight rural villages in ...Girona, Spain.
PARTICIPANTS: Six hundred seventy‐six inhabitants aged 75 and older.
MEASUREMENTS: All participants were interviewed in their homes using the study protocol, which includes an abuse screen used in previous elder abuse studies and questions about demographic, social, physical, psychiatric, cognitive, and social services variables.
RESULTS: The mean age of the participants was 81.7 ± 4.8; 58.2% were female. Prevalence of suspected neglect abuse was 16.0% (95% confidence interval (CI)=13.2–18.9), prevalence of psychosocial abuse was 15.2% (95% CI=12.8–18.2), prevalence of financial abuse was 4.7% (95% CI=3.0–6.4) and prevalence of physical abuse was 0.1% (95% CI=0.004–0.8). Psychosocial abuse was positively associated with depressive symptoms (odds ratio (OR)=1.65, 95% CI=1.01–2.72), social isolation (OR=0.35, 95% CI=0.18–0.69), and frequent bladder incontinence (OR=2.44, 95% CI=1.23–4.86). Neglect abuse was positively associated with social isolation (OR=0.52, 95% CI=0.27–0.99), use of social services (OR=1.83, 95% CI=1.05–3.20), and living arrangements (OR=5.29, 95% CI=2.65–10.56). Financial abuse was associated with marital status (OR=0.15, 95% CI=0.04–0.59), age 85 and older, (OR=3.84, 95% CI=1.70–8.68), and Mini‐Mental State Examination score (OR=0.85, 95% CI=0.78–0.94).
CONCLUSION: After adjustment for confounding factors, each subtype of suspected elder abuse was associated with different variables. The results of this study suggest that elder abuse cannot be analyzed as a unitary concept and that risk factors must be assessed for each abuse subtype.
Abstract Transcutaneous electrical nerve stimulation (TENS) is a noninvasive alternative to traditional pain treatments. TENS has been studied in the past as a pain reduction modality in colonoscopy ...with limited success. Reviews and meta-analysis have shown that the inconclusive results of TENS may be due to the lack of randomized controlled trials and the difficulty in defining precise output parameters. The objective of this double-blind randomized placebo-controlled trial was to investigate the pain-relieving effect of a new application of TENS in unsedated screening colonoscopy. Ninety patients undergoing unsedated screening colonoscopy were randomly allocated to one of three groups: a control group ( n = 30), a group to receive active TENS ( n = 30), or a group to receive placebo TENS ( n = 30). A visual analogue scale (VAS) and a five-point Likert scale were used to assess pain 5 min into the procedure and at the end of the procedure. The patient’s bloating sensation during colonoscopy and the effect on the duration of the procedure were also evaluated. Throughout the procedure, the active TENS group experienced a VAS pain score reduction ⩾50% compared to the placebo TENS group ( P < 0.001) and the control group ( P < 0.001). On the five-point Likert scale, there was also a significant reduction in pain score in the active TENS group compared to the placebo TENS and control groups ( P = 0.009). No significant differences were found between the study groups as to the bloating sensation and the duration of the procedure. We conclude that TENS can be used as a pain relief therapy in unsedated screening colonoscopy.
Acetylcholinesterase inhibitors (AChEIs) and the N-methyl D-aspartate-antagonist memantine are indicated for the symptomatic treatment of Alzheimer's disease (AD).
Our aims were to describe the ...baseline characteristics of patients with AD according to prescription of these treatments after the diagnostic work-up to describe long-term trends in the use of these medications and to identify baseline characteristics associated with the frequency of use of each treatment.
This was a cohort study with a sample of 2992 patients with AD recorded in the Registry of Dementias of Girona (ReDeGi) between 2007 and 2014. Consumption of AChEIs and memantine was assessed using the Pharmacy Unit database from the Public Catalan Healthcare Service. We used generalized estimating equation analyses to identify the baseline characteristics associated with the consumption of AChEIs and memantine over time.
Most of the patients (70.4%; 95% confidence interval CI 68.7-72.0) were prescribed antidementia medication at the time of diagnosis. Of these, 75.0% (95% CI 73.1-76.8) were prescribed AChEIs, 14.7% (95% CI 13.2-16.3) were prescribed an AChEI plus memantine, and 10.3% (95% CI 9.0-11.6) were prescribed memantine. Advanced age reduced the likelihood of AChEI consumption. Mild dementia severity increased the use of AChEIs, and moderate-advanced dementia increased the likelihood of memantine consumption. After diagnosis, the likelihood of AChEI consumption decreased from the first year until the fifth, whereas the likelihood of memantine consumption, either alone or in combination with AChEIs, increased.
Antidementia drug use in this study showed the initial use of AChEIs alone with later use of AChEIs in combination with memantine and memantine alone in older patients with severe AD. Our findings are in agreement with current clinical practice guidelines for the pharmacological treatment of AD.
PDF
