The implantation effect: delay in seizure occurrence with implantation of intracranial electrodes.

OBJECTIVE: A transient decrease in seizure frequency has been identified during therapeutic brain stimulation trials with stimulator in patients in the inactive sham group. This study was performed to examine whether the implantation of intracranial electrodes decreases seizure occurrence and explores factors that may be associated. METHODS: A retrospective review of 193 patients was performed, all evaluated with both scalp video EEG monitoring and intracranial EEG (iEEG) monitoring. Data about the number of seizures per day during the monitoring period, the number of days until the first seizure, anti-epileptic drugs (AEDs), pain medications, types of implanted electrodes, and anesthetic agents were reviewed. We conducted a repeated measure analysis for counted data using generalized estimating equations with a log-link function and adjustment for number of days and anti-epileptic medication load on the previous day to compare seizure frequencies between scalp and iEEG monitoring. RESULTS: The time to the first seizure was significantly prolonged during iEEG monitoring as compared to scalp monitoring after correction for AED withdrawal (hazard ratio: 0.81, CI 0.69-0.96). During scalp video EEG monitoring, patients experienced an average of 1.09 seizures/day vs 1.27 seizures/day during iEEG monitoring (P=.066). There was no significant difference in seizure frequency in patients that received craniotomy vs burr holes only for intracranial implantation. An increasing number of electrodes implanted increased the delay to seizures (P=.01). Of all anesthetic agents used, desflurane seemed to have an anticonvulsive effect compared to other anesthetics (P=.006). Pain medication did not influence delay to seizures. SIGNIFICANCE: Seizures are delayed during iEEG as opposed to scalp monitoring illustrating the "implantation effect" previously observed. Surgical planning should account for longer monitoring periods, particularly when using larger intracranial arrays.

High-risk antimicrobial prescriptions among ambulatory patients on warfarin.

WHAT IS KNOWN AND OBJECTIVE: Warfarin is a potent anticoagulant with many drug-drug interactions, including antimicrobials. There is limited data on the frequency of prescription of high-risk antimicrobials to patients on warfarin. To examine the frequency of prescriptions for potentially interacting antimicrobials in ambulatory patients on warfarin and the impact of warfarin on the prescription of high-risk antimicrobials. METHODS: A retrospective cohort study of patients with pharmacy benefits who had ≥1 claim for an oral antimicrobial between 1 January 2008 and 31 December 2008 was conducted, utilizing a pharmacy benefits database. Demographic data including age, gender, chronic disease score (CDS) and geographic location were determined. Warfarin users were defined as any patient with ≥1 claim for warfarin during the follow-up period. Antimicrobials considered high risk for potential interaction with warfarin based on existing literature included trimethoprim/sulfamethoxazole, levofloxacin, ciprofloxacin, metronidazole and fluconazole. Multivariate analysis was used to determine the impact of warfarin use and other factors on high-risk antimicrobial prescription. RESULTS AND DISCUSSION: A total of 4,568,150 patients with ≥1 claim for antimicrobials during 2008 were analysed. Of them, 110,192 (2·4%) also had one or more claims for warfarin. Among all antimicrobial prescriptions in warfarin users, 42·6% were for high-risk antimicrobials. The mean number of antimicrobial prescriptions was 3·0 in warfarin users versus 2·4 in warfarin non-users (P-value <0·001). After adjusting for age, gender, CDS and geography, the odds of exposure to high-risk antimicrobials was 42% lower (OR 0·58; P-value <0·001) in warfarin users compared with warfarin non-users. WHAT IS NEW AND CONCLUSIONS: A high percentage (42·6%) of antimicrobial prescriptions among warfarin users were for high-risk antimicrobials that carry excess bleeding risk. Although clinicians were somewhat less likely to prescribe high-risk antimicrobials to warfarin users compared with non-users, the incidence of co-prescription remains high.

Pharmacological disinhibition enhances paced breathing following complete spinal cord injury in rats.

Respiratory dysfunction is one of the most devastating and life-threatening deficits that occurs following cervical spinal cord injury (SCI). Assisted breathing with mechanical ventilators is a necessary part of care for many cervical injured individuals, but it is also associated with increased risk of secondary complications such as infection, muscle atrophy and maladaptive plasticity. Pre-clinical studies with epidural stimulation (EDS) have identified it as an alternative/additional method to support adequate lung ventilation without mechanical assistance. The full potential of EDS, however, may be limited by spinal inhibitory mechanisms within the injured spinal cord. The goal of the present work is to assess the potential improvement for EDS in combination with pharmacological disinhibition of spinal circuits following complete high cervical SCI. All experiments were performed in decerebrate, unanesthetized, non-paralyzed (n = 13) and paralyzed (n = 8) adult Sprague-Dawley rats 6 h following a complete C1 transection. The combination of high-frequency EDS (HF-EDS) at the C4 spinal segment with intrathecal delivery of GABA and glycine receptors antagonists (GABAzine and strychnine, respectively) resulted in significantly increased phrenic motor output, tidal volume and amplitude of diaphragm electrical activity compared to HF-EDS alone. Thus, it appears that spinal fast inhibitory mechanisms limit phrenic motor output and present a new neuropharmacological target to improve paced breathing in individuals with cervical SCI.

Efficient choice of colored noise in the stochastic dynamics of open quantum systems.

The stochastic Liouville-von Neumann (SLN) equation describes the dynamics of an open quantum system reduced density matrix coupled to a non-Markovian harmonic environment. The interaction with the environment is represented by complex colored noises which drive the system, and whose correlation functions are set by the properties of the environment. We present a number of schemes capable of generating colored noises of this kind that are built on a noise amplitude reduction procedure [Imai et al., Chem. Phys. 446, 134 (2015)CMPHC20301-010410.1016/j.chemphys.2014.11.014], including two analytically optimized schemes. In doing so, we pay close attention to the properties of the correlation functions in Fourier space, which we derive in full. For some schemes the method of Wiener filtering for deconvolutions leads to the realization that weakening causality in one of the noise correlation functions improves numerical convergence considerably, allowing us to introduce a well-controlled method for doing so. We compare the ability of these schemes, along with an alternative optimized scheme [Schmitz and Stockburger, Eur. Phys. J.: Spec. Top. 227, 1929 (2019)1951-635510.1140/epjst/e2018-800094-y], to reduce the growth in the mean and variance of the trace of the reduced density matrix, and their ability to extend the region in which the dynamics is stable and well converged for a range of temperatures. By numerically optimizing an additional noise scaling freedom, we identify the scheme which performs best for the parameters used, improving convergence by orders of magnitude and increasing the time accessible by simulation.

Interoperability of biodiversity databases: biodiversity information on every desktop.

Data about biodiversity are either scattered in many databases or reside on paper or other media not amenable to interactive searching. The Global Biodiversity Information Facility (GBIF) is a framework for facilitating the digitization of biodiversity data and for making interoperable an as-yet-unknown number of biodiversity databases that are distributed around the globe. In concert with other existing efforts, GBIF will catalyze the completion of a Catalog of the Names of Known Organisms and will develop search engines to mine the vast quantities of biodiversity data. It will be an outstanding tool for scientists, natural resource managers, and policy-makers.

Mapping of the human Blym-1 transforming gene activated in Burkitt lymphomas to chromosome 1.

Blym-1, a transforming gene detected by transfection of NIH 3T3 cells with DNA from Burkitt lymphomas, was mapped to the short arm of chromosome 1 (1p32) by chromosomal in situ hybridization. The Blym-1 gene was not physically linked to the cellular myc oncogene or to any of the immunoglobulin gene loci implicated in the characteristic chromosomal translocations in Burkitt lymphoma.

Graded unilateral cervical spinal cord injury and respiratory motor recovery.

We examined the potential contribution of ventromedial (VM) tissue sparing to respiratory recovery following chronic (1 mo) unilateral C2 spinal cord injury (SCI) in rats. Preserved white matter ipsilateral to the injury was quantitatively expressed relative to contralateral white matter. The ipsilateral-to-contralateral white matter ratio was 0 after complete C2 hemisection (C2HS) and 0.23+/-0.04 with minimal VM sparing. Inspiratory (breath min(-1)) and phrenic frequency (burst min(-1)), measured by plethysmography (conscious rats) and phrenic neurograms (anesthetized rats) respectively, were both lower with minimal VM sparing (p<0.05 vs. C2HS). Tidal volume also was greater in minimal VM sparing rats during a hypercapnic challenge (p<0.05 vs. C2HS). In other C2 hemilesioned rats with more extensive VM matter sparing (ipsilateral-to-contralateral white matter ratio=0.55+/-0.05), respiratory deficits were indicated at 1 mo post-injury by reduced ventilation during hypercapnic challenge (p<0.05 vs. uninjured). Anterograde (ventral respiratory column-to-spinal cord) neuroanatomical tracing studies showed that descending respiratory projections from the brainstem are present in VM tissue. We conclude that even relatively minimal sparing of VM tissue after C2 hemilesion can alter respiratory outcomes. In addition, respiratory deficits can emerge in the adult rat after high cervical SCI even when relatively extensive VM sparing occurs.

Transformation of NIH 3T3 cells by DNA of the MCF-7 human mammary carcinoma cell line induces expression of an endogenous murine leukemia provirus.

Previous studies identified two glycoproteins of 86 (gp86) and 72 (gp72) kilodaltons and two nonglycosylated proteins of 70 (p70) and 19 (p19) kilodaltons which were specifically expressed in NIH cells transformed by DNA of the MCF-7 human mammary carcinoma cell line. Pulse-chase experiments and the use of tunicamycin to inhibit glycosylation suggested that gp86, gp72, and p19 were related as precursor products. Characteristics of the four transformation-associated proteins resembled those of murine leukemia virus (MuLV) proteins. Sera raised against disrupted MuLV immunoprecipitated the same four proteins in extracts of NIH(MCF-7) cells and MuLV-infected NIH 3T3 cells. In addition, a monoclonal antibody against MuLV gp70 immunoprecipitated proteins gp86 and gp72, whereas a monoclonal antibody against MuLV p15(E) immunoprecipitated gp86 and p19. These results indicate that proteins gp86, gp72, and p19 expressed in NIH(MCF-7) transformants correspond to MuLV envelope proteins gp80env, gp70, and p15(E), respectively. The transformation-associated protein p70 appears to be a non-envelope MuLV protein, most likely p65gag. Northern blot analysis confirmed that transformation of NIH cells by MCF-7 mammary carcinoma DNA led to the induction of an endogenous MuLV provirus.

Muscarinic cholinergic activation of mouse spleen cells cytotoxic to tumor cells in vitro.

Carbamylcholine, acting via a pharmacologically specific receptor, had the ability to activate effector populations of spleen cells from female BALB/cfC3H and BALB/c mice; those cell populations were then significantly reactive in vitro against syngeneic tumor target cells but were only minimally reactive to normal syngeneic target tissues. The induced reactivity was inhibited by the muscarinic cholinergic antagonists atropine, scopolamine, and isopropamide, but not by the nicotinic antagonist d-tubocurare, and it appeared to involve both T-cell and non-T-cell effectors.

Effect of immune manipulation on natural immune responses to murine mammary tumor antigens.

The virus-host relationship in BALB/cfC3H virgin female mice neonatally infected with an oncogenic virus (mammary tumor virus) (MuMTV) was significantly altered by a brief immunosuppressive treatment during young adult life. Natural immune responses were augmented and changed. The ability of lymphoid cells to attack target cells expressing MuMTV-associated antigens was significantly increased, and a new component, a non-T-cell reactivity, was added to the T-cell reactivity found in normal females. Serum blocking factors were both quantitatively and qualitatively altered.

In situ dephosphorylation of p53 protein by calf intestinal alkaline phosphatase treatment.

The monoclonal antibody (mAb) 1801 has been reported to identify an N-terminal determinant within the tumor-suppressor protein p53 located between amino acids 32 and 79. This region contains two potential sites for serine phosphorylation at amino acids 33 and 46. Using a novel technique which dephosphorylates proteins in situ in fixed permeabilized cells, we have unmasked determinants in p53 recognized by mAb 1801, allowing additional sites of p53 protein to be detected in immunohistochemically reacted cells. This result indicates that phosphorylation at one or both sites within the determinant recognized by mAb 1801 previously blocked antibody-ligand interaction. It further suggests that in situ dephosphorylation may be of more general use in identifying antibodies which can only bind to epitopes in a particular phosphorylation state.

Mouse liver plasma membrane redox system activity is altered by aging and modulated by calorie restriction.

Caloric restriction (CR) is known as the only non-genetic method proven to slow the rate of aging and extend lifespan in animals. Free radicals production emerges from normal metabolic activity and generates the accumulation of oxidized macromolecules, one of the main characteristics of aging. Due to its central role in cell bioenergetics, a great interest has been paid to CR-induced modifications in mitochondria, where CR has been suggested to decrease reactive oxygen species production. The plasma membrane contains a trans-membrane redox system (PMRS) that provides electrons to recycle lipophilic antioxidants, such as α-tocopherol and coenzyme Q (CoQ), and to modulate cytosolic redox homeostasis. In the present study, we have investigated age differences in the PMRS in mouse liver and their modulation by CR. Aging induced a decrease in the ratio of CoQ10/CoQ9 and α-tocopherol in liver PM from AL-fed mice that was attenuated by CR. CoQ-dependent NAD(P)H dehydrogenases highly increased in CR old mice liver PMs. On the other hand, the CoQ-independent NADH-FCN reductase activity increased in AL-fed animals; whereas, in mice under CR this activity did not change during aging. Our results suggest that liver PMRS activity changes during aging and that CR modulates these changes. By this mechanism CR maintains a higher antioxidant capacity in liver PM of old animals by increasing the activity of CoQ-dependent reductases. Also, the putative role of PMRS in the modulation of redox homeostasis of cytosol is implicated.

Accommodative function in rhesus monkeys: effects of aging and calorie restriction.

Numerous degenerative changes in the visual system occur with age, including a loss of accommodative function possibly related to hardening of the lens or loss of ciliary muscle mobility. The rhesus monkey is a reliable animal model for studying age-related changes in ocular function, including loss of accommodation. Calorie restriction (CR) is the only consistent intervention to slow aging and extend lifespan in rodents, and more recently the beneficial effects of CR have been reported in nonhuman primates. The goal of the present study was to evaluate age-related changes in ocular accommodation and the potential effect of long-term (>8 years) CR on accommodation in male and female rhesus monkeys. Refraction, accommodation (Hartinger coincidence refractometer), and lens thickness (A-scan ultrasound) were measured in 97 male and female rhesus monkeys age 8-36 years under Telazol/acepromazine anesthesia. Refraction and accommodation measurements were taken before and after 40% carbachol corneal iontophoresis to induce maximum accommodation. Half the animals were in the control (CON) group and were fed ad libitum. The CR group received 30% fewer calories than age- and weight-matched controls. Males were on CR for 12 years and females for eight years. With increasing age, accommodative ability declined in both CON and CR monkeys by 1.03 ± 0.12 (P = 0.001) and 1.18 ± 0.12 (P = 0.001) diopters/year, respectively. The age-related decline did not differ significantly between the groups (P = 0.374). Baseline lens thickness increased with age in both groups by 0.03 ± 0.005 mm/year (P = 0.001) and 0.02 ± 0.005 mm/year (P = 0.001) for the CON and CR groups, respectively. The tendency for the for the lens to thicken with age occurred at a slower rate in the CR group vs. the CON group but the difference was not statistically significant (P = 0.086). Baseline refraction was -2.8 ± 0.55 and -3.0 ± 0.62 diopters for CON and CR, respectively. Baseline refraction tended to become slightly more negative with age (P = 0.070), but this trend did not differ significantly between the groups (P = 0.587). In summary, there was no difference in the slope of the age-related changes in accommodation, lens thickness, or refraction in the carbachol-treated eyes due to diet. These data are consistent with previous findings of decreased accommodative ability in aging rhesus monkeys, comparable to the age-dependent decrease in accommodative ability in humans. This study is the first to indicate that the accommodative system may not benefit from calorie restriction.

Cellular immunity in aging.

Our study of the aging process in human beings and in mice is complicated by our need to know whether we are observing diseases of aging or natural nondisease state processes. Results from studies on inbred strains of mice and retrospective studies on HLA types in aging human populations suggest that genetic effects play a significant role in predetermining the life span of an individual. It is clear that in such mouse strains genetic defects that affect cell regulatory mechanisms result in the production of autoimmune reactivity, tumor development, and a shortened life span. In human beings, although results are less clear-cut, strong associations exist between some disease states and the HLA type. Also, the disappearance of HLA-B8 from older women suggests that this HLA type does not confer longevity. Cellular immune reactivity declines with age in all populations studied to date, and cell cooperative or regulatory mechanisms function less well. We need to characterize the specific nature of the cells directly responsible for these alterations and to attempt to correct deficiencies by dietary manipulation or transfer techniques.

Dehydroepiandrosterone sulfate: a biomarker of primate aging slowed by calorie restriction.

The adrenal steroids, dehydroepiandrosterone (DHEA) and its sulfate (DHEAS), have attracted attention for their possible antiaging effects. DHEAS levels in humans decline markedly with age, suggesting the potential importance of this parameter as a biomarker of aging. Here we report that, as seen in humans, male and female rhesus monkeys exhibit a steady, age-related decline in serum DHEAS. This decline meets several criteria for a biomarker of aging, including cross-sectional and longitudinal linear decreases with age and significant stability of individual differences over time. In addition, the proportional age-related loss of DHEAS in rhesus monkeys is over twice the rate of decline observed in humans. Most important is the finding that, in rhesus monkeys, calorie restriction, which extends life span and retards aging in laboratory rodents, slows the postmaturational decline in serum DHEAS levels. This represents the first evidence that this nutritional intervention has the potential to alter aspects of postmaturational aging in a long-lived species.

Dietary caloric restriction prevents the age-related decline in plasma melatonin levels of rhesus monkeys.

Rhesus monkeys exhibit an age-associated decrease in peak plasma melatonin levels analogous to that reported for humans. This decrease is essentially abolished in monkeys subjected to a 30% reduction in caloric intake over a 12-yr period. The caloric restriction (CR) effect does not seem to be a reversal, but rather a long-term prevention, of the age-related decline in hormone concentrations. The age effect does not seem to be due to a phase shift in the peak of melatonin secretions, as has been observed in some populations of aged humans. It is also extremely unlikely that the CR effect simply reflects a phase shift, since old monkeys on the diet have nocturnal melatonin levels equal to or greater than adult fully fed controls. Thus, if peak times (approximately 0200 h) were actually shifted, maximal levels in old CR monkeys would be even higher. These findings, coupled with previous observations in humans, suggest that peak plasma melatonin levels may represent a possible candidate "biomarker of aging" in primates. Moreover, this index of age-associated physiological decrement seems to be inhibited by dietary CR.

Skeletal effects of aging and menopausal status in female rhesus macaques.

To further define the nonhuman primate as a model of the adult human skeleton, we explored the impact of growth, natural menopause, and osteoarthritis on bone mass, serum markers of bone turnover (osteocalcin and C-terminal telopeptide of type I collagen) and measures of skeletal relevance (PTH, 25-hydroxyvitamin D, total alkaline phosphatase, calcium, phosphorus, creatinine, and albumin). Fifty-eight female (aged 4-30 yr) rhesus macaques were defined as growing (G; n = 12; < or = 10 yr old), adult premenopausal (APre; n = 30; > 10 yr old; eumenorrheic, high serum estradiol and low FSH), or postmenopausal (Post; n = 16; amenorrheic for at least 1 yr, with low serum estradiol and high FSH). Total body and posterior-anterior spinal bone masses were lower in G than APre animals (P < 0.05). Post females had lower total body, distal radius, and spinal bone mass than premenopausal animals (P < 0.05). Osteocalcin was higher in Post than APre animals (P < 0.01). Other measures showed no relationship with menopausal status. In older monkeys, spinal osteoarthritis became common, causing increased dual-energy x-ray absorptiometry-measured bone mass in the lumbar spinal posterior-anterior projection. In conclusion, after natural menopause, rhesus monkeys have lower bone mass and higher skeletal turnover without alteration of the calcium-vitamin D axis. As such, they are an excellent model of human estrogen-depletion bone loss.

Loss of D2 receptor binding with age in rhesus monkeys: importance of correction for differences in striatal size.

The relation between striatal dopamine D2 receptor binding and aging was investigated in rhesus monkeys with PET. Monkeys (n = 18, 39 to 360 months of age) were scanned with 11C-raclopride; binding potential in the striatum was estimated graphically. Because our magnetic resonance imaging analysis revealed a concomitant relation between size of striatum and age, the dynamic positron emission tomography (PET) data were corrected for possible partial volume (PV) artifacts before parameter estimation. The age-related decline in binding potential was 1% per year and was smaller than the apparent effect if the age-related change in size was ignored. This is the first in vivo demonstration of a decline in dopamine receptor binding in nonhuman primates. The rate of decline in binding potential is consistent with in vitro findings in monkeys but smaller than what has been measured previously in humans using PET. Previous PET studies in humans, however, have not corrected for PV error, although a decline in striatal size with age has been demonstrated. The results of this study suggest that PV correction must be applied to PET data to accurately detect small changes in receptor binding that may occur in parallel with structural changes in the brain.

Age-related decline in striatal volume in monkeys as measured by magnetic resonance imaging.

Age-related declines in striatal markers for the dopamine system have been demonstrated in several species. The current study investigated structural changes during aging in the rhesus monkey striatum. Male monkeys were studied using a volumetric spoiled gradient recall (SPGR) magnetic resonance imaging protocol. The caudate nucleus and putamen were segmented by manual tracing using landmarks made in the orthogonal planes. The whole brain volume (defined as volume of gray and white matter plus cerebrospinal fluid in ventricles and sulci) was measured using a semi-automated algorithm. There was no correlation between age and whole brain volume. There were age-related declines in normalized (i.e. brain region/whole brain volume) caudate nucleus and putamen volumes. Monkeys in the young group (n = 7, 39-45 months old) had larger volumes of both the caudate nucleus and putamen than animals in the middle-age (n = 5, 120-180 months) or old (n = 7, 291-360 months) groups. The current results provide normative data to assess potential interventions (e.g. caloric restriction) in the aging process.