Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial.

The geroscience hypothesis proposes that therapy to slow or reverse molecular changes that occur with aging can delay or prevent multiple chronic diseases and extend healthy lifespan1-3. Caloric restriction (CR), defined as lessening caloric intake without depriving essential nutrients4, results in changes in molecular processes that have been associated with aging, including DNA methylation (DNAm)5-7, and is established to increase healthy lifespan in multiple species8,9. Here we report the results of a post hoc analysis of the influence of CR on DNAm measures of aging in blood samples from the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trial, a randomized controlled trial in which n = 220 adults without obesity were randomized to 25% CR or ad libitum control diet for 2 yr (ref. 10). We found that CALERIE intervention slowed the pace of aging, as measured by the DunedinPACE DNAm algorithm, but did not lead to significant changes in biological age estimates measured by various DNAm clocks including PhenoAge and GrimAge. Treatment effect sizes were small. Nevertheless, modest slowing of the pace of aging can have profound effects on population health11-13. The finding that CR modified DunedinPACE in a randomized controlled trial supports the geroscience hypothesis, building on evidence from small and uncontrolled studies14-16 and contrasting with reports that biological aging may not be modifiable17. Ultimately, a conclusive test of the geroscience hypothesis will require trials with long-term follow-up to establish effects of intervention on primary healthy-aging endpoints, including incidence of chronic disease and mortality18-20.

Biological aging in maltreated children followed up into middle adulthood.

BACKGROUND: Childhood adversity has been linked to many indicators of shorter healthy lifespan, including earlier onset of disease and disability as well as early mortality. These observations suggest the hypothesis that childhood maltreatment may accelerate aging. OBJECTIVE: To characterize the relationship between childhood maltreatment and accelerated biological aging in a prospective cohort of 357 individuals with documented cases of childhood maltreatment and 250 controls matched on demographic and socioeconomic factors. METHODS: Cases were drawn from juvenile and adult court records from the years 1967 through 1971 in a large Midwest metropolitan geographic area. Cases were defined as having court-substantiated cases of childhood physical or sexual abuse, or neglect occurring at age 11 or younger. Controls were selected from the same schools and hospitals of birth and matched on age, sex, race, and approximate socioeconomic status. We compared biological aging in these two groups using two blood-chemistry algorithms, the Klemera-Doubal method Biological Age (KDM BA) and the PhenoAge. Algorithms were developed and validated in data from the National Health and Nutrition Examination Surveys (NHANES) using published methods and publicly available software. RESULTS: Participants (55% women, 49% non-White) had mean age of 41 years (SD=4). Those with court substantiated childhood maltreatment history exhibited more advanced biological aging as compared with matched controls, although this difference was statistically different for only the KDM BA measure (KDM BA Cohen's D=0.20, 95% CI=[0.03,0.36], p = 0.02; PhenoAge Cohen's D=0.09 95% CI=[-0.08,0.25], p = 0.296). In subgroup analyses, maltreatment effect sizes were larger for women as compared to men and for White participants as compared to non-White participants, although these differences were not statistically significant at the α= 0.05 level. CONCLUSIONS AND RELEVANCE: As of midlife, effects of childhood maltreatment on biological aging are small in magnitude but discernible. Interventions to treat psychological and behavioral sequelae of exposure to childhood maltreatment, including in midlife adults, have potential to protect survivors from excess burden of disease, disability, and mortality in later life.

Reduced Neural Satiety Responses in Women Affected by Obesity.

Overweight and obesity are major risk factors for a number of chronic diseases, including diabetes, cardiovascular diseases, and cancer. Obesity rates are on the rise worldwide with women more frequently affected than men. Hedonic responses to food seem to play a key role in obesity, but the exact mechanisms and relationships are still poorly understood. In this study, we investigate the perceived pleasantness of food rewards in relation to satiety and calories consumed during an ad libitum meal in women. Using functional magnetic resonance imaging (fMRI) and a milkshake consumption task, we studied how experienced food values are encoded in women with healthy weight, overweight or obesity. Participants rated the pleasantness and intensity of high and low caloric milkshakes in the fMRI scanner during both the fasted and fed states. We found differences in the neural responses and experienced pleasantness of high and low caloric milkshakes depending on satiety and Body Mass Index (BMI). Women with both high ad libitum consumption levels and high BMI reported greater experienced pleasantness for milkshakes. In contrast, among women with low ad libitum consumption levels, greater BMI was associated with less experienced pleasantness. At the neural level, satiety affected women with obesity to a lesser degree than women with healthy weight. Thus, having obesity was associated with altered relationships between food consumption and the hedonic responses to food rewards as well as reduced satiety effects in women.

Primary and secondary parasitoids (Hymenoptera) of aphids (Hemiptera: Aphididae) on blueberry and other Vaccinium in the Pacific Northwest.

Blueberry scorch virus, a commercially important Carlavirus in highbush blueberry, Vaccinium corymbosum L., is vectored by aphids (Hemiptera: Aphididae). We surveyed the aphids, primary parasitoids (Hymenoptera: Aphelinidae, Braconidae), and associated secondary parasitoids (Hymenoptera: Charipidae, Megaspilidae, Pteromalidae) on highbush blueberry and other Vaccinium in the Pacific Northwest from 1995 to 2006, with samples concentrated in 2005 and 2006, to lay the groundwork for augmentative biological control. Ericaphis fimbriata (Richards) was the principal aphid. The dominant parasitoid species were Praon unicum Smith, Aphidius n. sp., A. sp., and Aphidius ervi Haliday. Their frequency in relation to the other primary parasitoids varied significantly with geographical area; P. unicum dominated the frequency distribution in southwestern British Columbia, A. n. sp., west of the Cascades, and A. sp. and A. ervi east of the Cascades. Among the secondary parasitoids, pteromalids dominated, and their frequency in relation to the other secondary parasitoids was lowest in southwestern British Columbia. The parasitization rate for P. unicum and A. n. sp. in southwestern British Columbia increased from May or June to a maximum of 0.080 +/- 0.024 and 0.090 +/- 0.084 (SD), respectively, in late July or early August. P. unicum emerged in the spring 4 wk before A. n. sp. The parasitization rate for P. unicum was lower in conventional than organic fields. Whereas aphid density increased monotonically, P. unicum had two spring peaks. A simulation model showed that these peaks could reflect discrete generations. Releases of insectary-reared P. unicum at 150 or 450 DD above 5.6 degrees C, summing from 1 January, may effectively augment the natural spring populations by creating overlapping generations.

[Spinal epidural abscess after long-term epidural catheterization]. / Spinaler Epiduralabszess nach rückenmarknaher Langzeitanalgesie.

This case report describes a 63-year-old male patient with considerably impaired postoperative wound healing in the region of the lower extremities. After initial drug therapy for the pain was ineffectual, the patient was treated repeatedly through an epidural catheter. In the further course, an extensive spinal epidural abscess was diagnosed as an incidental finding without neurological symptoms. After taking into consideration the patient's age and the risk factors present as well as inclusion of the subspecialties involved for an interdisciplinary assessment, the patient was successfully treated with a conservative approach. Our contribution concludes with a detailed discussion and comparison of the literature.

Idiopathic systemic granulomatous disease with encephalitis in a horse.

A 14-year-old standardbred mare with clinically suspected acute bronchitis was killed because of rapidly progressing central nervous disturbances. Necropsy revealed systemic granulomatous inflammation and vasculitis involving the lungs, thoracic lymph nodes, ribs, and liver. In the cerebrum there was a severe subacute bilateral encephalitis and malacia predominately affecting the white matter, and vasculitis with perivascular infiltration of lymphocytes, macrophages, and giant cells. A causative infectious agent could not be detected by Ziehl-Neelsen, Grocott, or Giemsa stains, by periodic acid-Schiff reaction of tissue sections, nor by bacterial and fungal cultures. Therefore, idiopathic systemic granulomatous disease (ISGD) was diagnosed and an immune-mediated pathogenesis was suspected. Inflammatory involvement of the brain has hitherto not been reported in cases of equine ISGD. This case seems to be an uncommon variant of ISGD with encephalitis and lack of dermal involvement.

Effect of estrogen on scavenger receptor BI expression in the rat.

High-dose 17alpha-ethinyl estradiol treatment is associated with increased adrenal and decreased hepatic levels of scavenger receptor class B type 1 (SR-BI) in rats. In this paper we explored the mechanisms responsible for the differential regulation of SR-BI by estrogen in these two tIssues. Previously it was shown that estrogen-treated rats are profoundly hypolipidemic due to increased hepatic low density lipoprotein receptor (LDLR) activity, and that this effect is not maintained with hypophysectomy. To determine if the reduction in hepatic SR-BI was a direct or indirect effect of estrogen, we treated hypophysectomized rats with high-dose estrogen; the levels of SR-BI expression did not change in the livers or adrenals of these animals. To determine if the absence of response to estrogen in the adrenals of hypophysectomized animals was due to the absence of adrenocorticotropic hormone (ACTH), we examined the effect of estrogen treatment on SR-BI expression in animals treated with dexamethasone, which inhibits endogenous ACTH production. The administration of dexamethasone completely inhibited the increase in SR-BI expression in the adrenals of estrogen-treated rats. From these studies we conclude that estrogen does not have a direct effect on SR-BI expression in either the liver or the adrenals. In the liver, the decrease in SR-BI is dependent on the estrogen-induced increase in LDLR activity, and in the adrenal glands, ACTH is required for the estrogen-associated increase in expression of SR-BI.

Complications of burr-hole craniostomy and closed-system drainage for chronic subdural hematomas: a retrospective analysis of 376 patients.

OBJECTIVE: Burr-hole craniostomy with closed-system drainage (BCD) is the most frequently used neurosurgical treatment of chronic subdural hematomas (cSDH). The surgical and medical complications of BCD have seldom been investigated systematically. The objective of this study was to define the frequency of surgical and medical complications following BCD for cSDH. METHODS: The medical records of 376 patients managed by BCD were reviewed with respect to complications during the hospital stay. RESULTS: Seventy-seven surgical complications (20.5%) were encountered. The most frequent minor complication after surgery was seizures (n 51, 13.6%). The most frequent major surgical complications were intracerebral hemorrhage and subdural empyema (n 8, 2.1% each). Four patients with intracerebral hemorrhage died, accounting for a surgical mortality rate of 1.1%. Fifty-nine medical complications (15.7%) occurred during the hospital stay. Pneumonia was the most frequent medical complication (n 29, 7.7%). Medical complications were fatal in 24 patients, accounting for a mortality rate of 6.4%. In 22 patients (5.8%), death was not related to a complication, but to the initial brain damage. The overall mortality rate was 13.3%. CONCLUSION: The rate of complications in patients with cSDH who underwent the BCD is high. The clinical relevance of medical complications has to be emphasized because of their substantial contribution to overall mortality.

Optimal quantum pumps.

We study adiabatic quantum pumps on time scales that are short relative to the cycle of the pump. In this regime the pump is characterized by the matrix of energy shift which we introduce as the dual to Wigner's time delay. The energy shift determines the charge transport, the dissipation, the noise, and the entropy production. We prove a general lower bound on dissipation in a quantum channel and define optimal pumps as those that saturate the bound. We give a geometric characterization of optimal pumps and show that they are noiseless and transport integral charge in a cycle. Finally we discuss an example of an optimal pump related to the Hall effect.

17beta-Estradiol promotes the up-regulation of SR-BII in HepG2 cells and in rat livers.

The scavenger receptor class B type I (SR-BI) binds to HDL and mediates the selective uptake of cholesterol esters from HDL to cells. SR-BII is an alternatively spliced product of the SR-BI gene that only differs in the C-terminal cytoplasmic domain. Previous studies with male mice demonstrated that SR-BII comprises about 12% of the total SR-BI/SR-BII present in liver. In the current studies we used a liver cell line, HepG2, and a rat estrogen replacement model to examine the effects of estrogen on the expression of SR-BII. HepG2 cells express SR-BI but not SR-BII. SR-BI/SR-BII - blocking antibodies demonstrated that HepG2 cells selectively internalize cholesterol esters in a SR-BI - dependent manner. Incubation of HepG2 cells with 10 pM of 17beta-estradiol for 12 h eliminated the expression of SR-BI and promoted the up-regulation of SR-BII. Radiolabeled HDL-binding studies demonstrated that 17beta-estradiol increased the number of HDL binding sites by 3-fold in HepG2 cells. However, 17beta-estradiol - treated cell internalized approximately 25% less cholesterol ester than vehicle-only-treated cells. The livers obtained from male rats and ovariectomized female rats contained SR-BI and a small amount of SR-BII. In contrast, the livers obtained from intact female rats and ovariectomized female rats receiving estrogen replacement contained SR-BII and a small amount of SR-BI. The amount of SR-BI and SR-BII in adrenal tissue was not affected by any of the experimental treatments. We conclude that estrogen up-regulates SR-BII in HepG2 cells and rat liver.

Effect of oxytocin on expression of cytosolic phospholipase A2 mRNA and protein in ovine endometrial tissue in vivo.

The induction of endometrial prostaglandin (PG) F2alpha synthesis by oxytocin is dependent upon activation of phospholipase (PL) A2 and mobilization of arachidonic acid. The objective of this study was to determine if oxytocin stimulates PGF2alpha synthesis by inducing synthesis of cytosolic PLA2 (cPLA2). In Experiment 1, 15 ovariectomized ewes were given progesterone and estradiol to simulate an estrous cycle. Ewes were then given an injection of oxytocin on Day 14 of the simulated estrous cycle. Jugular blood samples were collected and assayed for 13,14-dihydro-15-keto-prostaglandin F2alpha (PGFM). Uteri were collected at 0, 7.5, 25, 90, or 240 min postinjection (n = 3 ewes/time point). Total RNA was isolated from caruncular endometrium and subjected to dot-blot analysis. Oxytocin induced a rapid and transient increase in serum PGFM (P < 0.01). However, endometrial concentrations of cPLA2 mRNA did not change following oxytocin administration (P > 0.10). In Experiment 2, 11 ovary-intact ewes were given oxytocin (n = 5) or saline (n = 6) on Day 15 after estrus. Jugular blood samples were collected and assayed for serum concentrations of PGFM. Uteri were collected at 15 min postinjection. Homogenates were prepared from caruncular endometrium and subjected to Western blot analysis. Concentrations of PGFM were higher in oxytocin treated ewes compared to saline treated ewes at 15 min postinjection (P < 0.01). Endometrial concentrations of cPLA2 protein were greater in the cytosolic than in the microsomal fraction (P < 0.01). Oxytocin did not affect the amount of cPLA2 protein in either fraction (P > 0.10). In conclusion, oxytocin did not effect expression of either cPLA2 mRNA or protein in ovine endometrium. Oxytocin may stimulate PGF2alpha synthesis by activating cPLA2 protein that is already present in an inactive form.

Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters.

In healthy individuals, acute changes in cholesterol intake produce modest changes in plasma cholesterol levels. A striking exception occurs in sitosterolemia, an autosomal recessive disorder characterized by increased intestinal absorption and decreased biliary excretion of dietary sterols, hypercholesterolemia, and premature coronary atherosclerosis. We identified seven different mutations in two adjacent, oppositely oriented genes that encode new members of the adenosine triphosphate (ATP)-binding cassette (ABC) transporter family (six mutations in ABCG8 and one in ABCG5) in nine patients with sitosterolemia. The two genes are expressed at highest levels in liver and intestine and, in mice, cholesterol feeding up-regulates expressions of both genes. These data suggest that ABCG5 and ABCG8 normally cooperate to limit intestinal absorption and to promote biliary excretion of sterols, and that mutated forms of these transporters predispose to sterol accumulation and atherosclerosis.

Expression of a cytosolic phospholipase A2 by ovine endometrium on days 11-14 of a simulated oestrous cycle.

Oxytocin stimulates the synthesis and secretion of PGF2 alpha from uterine tissues in vivo and in vitro late in the ovine oestrous cycle. The synthesis of eicosanoids is dependent upon the availability of free arachidonic acid which is released through the activity of arachidonate releasing phospholipases. In the present study, the following hypothesis was tested: the ovine endometrium expresses a cytosolic phospholipase A2 (cPLA2) and expression or activity of cPLA2 increases as uterine secretory responsiveness to oxytocin develops late in the oestrous cycle. Endometrial tissue was collected from cyclic ewes on day 15 of the oestrous cycle for the preparation of tissue homogenates and isolation of mRNA to determine whether ovine endometrium expressed a cPLA2. A 110 kDa band was detected by western blotting, indicating the presence of a putative ovine cPLA2. A 834 bp fragment of the ovine cPLA2 shared 87% homology with human and mouse cDNA, and northern blot hybridization analysis indicated a single 3.4 kb transcript. A total of 20 ewes were ovariectomized and treated with progesterone and oestrogen to simulate the oestrous cycle to determine whether the expression or activity of ovine cPLA2 changed during the onset of uterine secretory responsiveness to oxytocin in vivo. On days 11-14 (n = 5 per day) of a simulated oestrous cycle, caruncular endometrium was evaluated for expression of ovine cPLA2 mRNA and protein and the synthesis of PGF2 alpha in response to melittin (a potent stimulator of PLA2 activity). Immunoreactive cPLA2 and cPLA2 mRNA were observed on all days and did not increase during the development of uterine responsiveness to oxytocin in vivo. Similarly, melittin increased the synthesis of PGF2 alpha irrespective of day, indicating the presence of a functional cPLA2 on all days examined. These data indicate that the ovine endometrium expresses a functional cPLA2 and that ample concentrations of cPLA2 are present by day 11 of a simulated oestrous cycle.

The class B, type I scavenger receptor promotes the selective uptake of high density lipoprotein cholesterol ethers into caveolae.

The uptake of cholesterol esters from high density lipoproteins (HDLs) is characterized by the initial movement of cholesterol esters into a reversible plasma membrane pool. Cholesterol esters are subsequently internalized to a nonreversible pool. Unlike the uptake of cholesterol from low density lipoproteins, cholesterol ester uptake from HDL does not involve the internalization and degradation of the particle and is therefore termed selective. The class B, type I scavenger receptor (SR-BI) has been identified as an HDL receptor and shown to mediate selective cholesterol ester uptake. SR-BI is localized to cholesterol- and sphingomyelin-rich microdomains called caveolae. Caveolae are directly involved in cholesterol trafficking. Therefore, we tested the hypothesis that caveolae are acceptors for HDL-derived cholesterol ether (CE). Our studies demonstrate that in Chinese hamster ovary cells expressing SR-BI, >80% of the plasma membrane associated CE is present in caveolae after 7.5 min of selective cholesterol ether uptake. We also show that excess, unlabeled HDL can extract the radiolabeled CE from caveolae, demonstrating that caveolae constitute a reversible plasma membrane pool of CE. Furthermore, 50% of the caveolae-associated CE can be chased into a nonreversible pool. We conclude that caveolae are acceptors for HDL-derived cholesterol ethers, and that caveolae constitute a reversible, plasma membrane pool of cholesterol ethers.

Class B scavenger receptors, caveolae and cholesterol homeostasis.

Class B scavenger receptors are predominantly localized to cholesterol and sphingomyelin-enriched domains within the plasma membrane, called caveolae. Caveolae and their associated protein, caveolin, have been implicated in cholesterol trafficking and in the regulation of cellular cholesterol homeostasis. Recent studies indicate that scavenger receptor, class B, type I (SR-BI) mediates cholesterol flux between cells and lipoproteins. Caveolae appear to be the sites within the plasma membrane where such exchange occurs, suggesting that the regulation of caveolae and caveolins may be pivotal to the net flux of cholesterol between cells and lipoproteins when they are bound to SR-BI.

Promoting skin cancer prevention counseling by pharmacists.

OBJECTIVES: This study evaluated the effects of an intervention on rates of skin cancer prevention counseling by pharmacists. METHODS: Fifty-four pharmacies were randomly assigned to intervention or control conditions. Intervention consisted of training, feedback, and prompts. Counseling rates before and after the intervention were obtained from study confederates. RESULTS: At pretest, the proportions of control and intervention sites providing counseling at least once were 7.4% and 0%, respectively (NS). At posttest, these proportions were 3.7% and 66.7%, respectively (P < .001). CONCLUSIONS: The results indicated that the intervention was successful and that pharmacists can play an important role in educating the public about skin cancer prevention strategies.

Skin cancer prevention counseling by pharmacists: specific outcomes of an intervention trial.

The purpose of this study was to evaluate the effects of an intervention on pharmacists' behaviors, knowledge, and attitudes related to skin cancer prevention counseling. Fifty-four pharmacy sites (N = 178 pharmacists) were randomly assigned to the intervention or control condition. Intervention consisted of video-based training, prompts installed in the pharmacy to promote pharmacist-patient discussions on the topic, and group-based feedback on previous week's counseling rates. Outcomes were measured using a mailed survey. The proportion of patients counseled at post-test was significantly higher among intervention subjects, adjusting for pretest values. Similar results were found for pharmacists' skin cancer knowledge and self-rated expertise, but not for counseling-related attitudes. The intervention was successful. If implemented on a wide scale, large segments of the U.S. population would be exposed to skin cancer prevention advice.