Does Drug Holiday Affect Jaw Trabeculation in Medication Related Osteonecrosis of the Jaw? - A Pilot Study

The role of drug holiday in long term antiresorptive drug users to prevent MRONJ is debated for quite some time. We aimed to compare jawbone trabeculation between patients on drug holiday with those not on drug holiday among Medication Related Osteonecro

Loss of Temporal Inhibition of Nociceptive Information Is Associated With Aging and Bodily Pain

An age-related decline in endogenous pain inhibitory processes likely places older adults at an increased risk for chronic pain. Limited research indicates that older adults may be characterized by deficient offset analgesia, an inhibitory temporal sharpening mechanism that increases the detectability of minor decreases in noxious stimulus intensity. The primary purpose of the study was to examine age differences in offset analgesia in community-dwelling younger, middle-aged, and older adults. An additional aim of the study was to determine whether the magnitude of offset analgesia predicted self-reported bodily pain. Eighty-seven younger adults, 42 middle-aged adults, and 60 older adults completed 4 offset analgesia trials and 3 constant temperature trials in which a noxious heat stimulus was applied to the volar forearm for 40 seconds. The offset trials consisted of 3 continuous phases: an initial 10-second painful stimulus, either a 1.0°C or .4°C increase in temperature from the initial 10-second painful stimulus for 10 seconds, and either a 1.0°C or .4°C decrease back to the initial testing temperature for 20 seconds. During each trial, subjects rated pain intensity continuously using an electronic visual analog scale (0–100). All subjects also completed the Short-Form Health Survey-36 including the Bodily Pain subscale. The results indicated that older and middle-aged adults showed reduced offset analgesia compared with younger adults in the 1.0°C and .4°C offset trials. Furthermore, the magnitude of offset analgesia predicted self-reported bodily pain, with those exhibiting reduced offset analgesia reporting greater bodily pain. Dysfunction of this endogenous inhibitory system could increase the risk of developing chronic pain for middle-aged and older adults. Perspective Older and middle-aged adults showed reduced offset analgesia compared with younger adults. The significant association between reduced offset analgesia and pain in daily life supports the notion that pain modulatory deficits are associated with not just a chronic pain condition but with the experience of pain in general

Novel method for assessing age-related differences in the temporal summation of pain

Temporal summation (TS) of pain protocols typically involve the delivery of brief repetitive noxious stimuli held at a constant intensity and measuring the consequent increase in the perceived intensity of pain sensations. To date, no studies have examined the effect of a TS protocol on the perceived spatial dimensions of the pain experience and its interaction with age. This study used a new TS protocol that examined changes in the perceived size of the painful area in 22 younger adults and 20 older adults. Four trials of ten brief heat pulses delivered at a constant intensity were administered on the volar forearm. Interpulse intervals (IPIs) were 2.5 seconds or 3.5 seconds. Subjects rated the peak pain intensity (trials 1 and 3) or the size of the painful area (trials 2 and 4) after each pulse on a 0-100 scale. The magnitude of summation was calculated for each trial. Three seconds and 6 seconds after delivering the last heat pulse, the subjects rated the intensity or the size of any remaining pain (aftersensations). The results indicated that older adults compared to younger adults exhibited significantly greater summation of size ratings for the 2.5-second and 3.5-second IPI trials and size of pain aftersensations at 3 seconds following the 2.5-second IPI TS trial. These results suggest that aging is associated with enhanced endogenous facilitation of the perceived size of pain. The potential clinical and mechanistic implications of enhanced TS of size of pain remain unknown and warrant further investigation

Reliability of pain intensity clamping using response-dependent thermal stimulation in healthy volunteers

BACKGROUND: Pain intensity clamping uses the REsponse-Dependent Stimulation (REDSTIM) methodology to automatically adjust stimulus intensity to maintain a desired pain rating set-point which is continuously monitored from a subject's real-time pain ratings. REDSTIM blinds subjects regarding the pain intensity set-point, supporting its use for assessing intervention efficacy. By maintaining the pain intensity at a constant level, a potential decrease in pain sensitivity can be detected by an increase in thermode temperature (unknown to the subject) and not by pain ratings alone. Further, previously described sensitizing and desensitizing trends within REDSTIM provide a novel insight into human pain mechanisms overcoming limitations of conventional testing methods. The purpose of the present study was to assess the test-retest reliability of pain intensity clamping using REDSTIM during three separate sessions. METHODS: We used a method for testing changes in pain sensitivity of human subjects (REDSTIM) where the stimulus temperature is modulated to clamp pain intensity near a desired set-point. Temperature serves as the response variable and is used to infer pain sensitivity. Several measures were analyzed for reliability including average temperature and area under the curve (AUC). Intraclass correlation coefficients were calculated for each measure at pain rating set-points of 20/100 and 35/100. RESULTS: Sixteen healthy individuals (mean age = 21.6 ± 3.9) participated in three experiments two days apart at both pain rating set-points. Most reliability coefficients were in the moderate to substantial range (r's = 0.79 to 0.94) except for the negative AUC (r = 0.52), but only at the 20/100 pain rating set-point. CONCLUSIONS: The present study supports the test-retest reliability of pain intensity clamping using the REDSTIM methodology while providing a novel tool to examine human pain modulatory mechanisms and overcoming common shortcomings of conventional quantitative sensory testing methods

Increased spatial dimensions of repetitive heat and cold stimuli in older women

Protocols of temporal summation (TS) of pain typically involve the delivery of brief repetitive noxious pulses of a constant intensity while measuring the perceived intensity of pain after each pulse. The size percept of noxious repetitive stimulation has been poorly characterized. Furthermore, no studies have investigated age differences in TS of cold pain. The current study examined TS of pain intensity and the perceived size of the painful area during repetitive noxious heat and cold pulses in healthy younger (n = 104) and older adults (n = 40). Trials of 10 brief repetitive noxious heat or cold pulses were delivered to the upper extremities. Participants rated the perceived size of the painful area or intensity of pain after each pulse. The magnitude of change for the size percept and intensity for pain were calculated for each trial. The results indicated that older adults experienced greater TS of the size percept of cold stimuli compared with younger adults. Additionally, older women experienced greater TS of the size percept of heat stimuli compared with older men and all younger participants. No overall age or sex differences were found in the TS of pain intensity for cold or heat trials. These results suggest dysfunctional modulation of the spatial percept of the painful stimuli by older adults, and in particular older women, during repetitive noxious thermal pulses

Steric Shielding of Surface Epitopes and Impaired Immune Recognition Induced by the Ebola Virus Glycoprotein

Many viruses alter expression of proteins on the surface of infected cells including molecules important for immune recognition, such as the major histocompatibility complex (MHC) class I and II molecules. Virus-induced downregulation of surface proteins has been observed to occur by a variety of mechanisms including impaired transcription, blocks to synthesis, and increased turnover. Viral infection or transient expression of the Ebola virus (EBOV) glycoprotein (GP) was previously shown to result in loss of staining of various host cell surface proteins including MHC1 and β1 integrin; however, the mechanism responsible for this effect has not been delineated. In the present study we demonstrate that EBOV GP does not decrease surface levels of β1 integrin or MHC1, but rather impedes recognition by steric occlusion of these proteins on the cell surface. Furthermore, steric occlusion also occurs for epitopes on the EBOV glycoprotein itself. The occluded epitopes in host proteins and EBOV GP can be revealed by removal of the surface subunit of GP or by removal of surface N- and O- linked glycans, resulting in increased surface staining by flow cytometry. Importantly, expression of EBOV GP impairs CD8 T-cell recognition of MHC1 on antigen presenting cells. Glycan-mediated steric shielding of host cell surface proteins by EBOV GP represents a novel mechanism for a virus to affect host cell function, thereby escaping immune detection

Age-related differences in conditioned pain modulation of sensitizing and desensitizing trends during response dependent stimulation

The current study evaluated age differences in conditioned pain modulation using a test stimulus that provided the opportunity to evaluate changes in heat pain sensitivity, sensitization, and desensitization within the same paradigm. During this psychophysical test, pain intensity clamping uses REsponse Dependent STIMulation (REDSTIM) methodology to automatically adjust stimulus intensity to maintain a desired pain rating set-point. Specifically, stimulus intensity increases until a pre-defined pain rating (the setpoint) is exceeded, and then decreases until pain ratings fall below the setpoint, with continued increases and decreases dictated by ratings. The subjects are blinded in terms of the setpoint and stimulus intensities. Younger and older subjects completed two test sessions of two REDSTIM trials, with presentation of conditioning cold stimulation between the trials of one session but not the other. The results indicated that conditioning cold stimulation similarly decreased the overall sensitivity of younger and older subjects, as measured by the average temperature that maintained a setpoint rating of 20 (on a scale of 0-100). The conditioning stimulus also significantly enhanced sensitization following ascending stimulus progressions and desensitization following descending stimulus progressions in older subjects relative to younger subjects. Thus, older subjects experienced greater swings in sensitivity in response to varying levels of painful stimulation. These results are discussed in terms of control over pain intensity by descending central modulatory systems. These findings potentially shed new light on the central control over descending inhibition and facilitation of pain

Using Cerebrospinal Fluid Biomarker Testing to Target Treatment to Patients with Mild Cognitive Impairment: A Cost-Effectiveness Analysis

Objective Cerebrospinal fluid (CSF) biomarkers are shown to facilitate a risk identification of patients with mild cognitive impairment (MCI) into different risk levels of progression to Alzheimer’s disease (AD). Knowing a patient’s risk level provides an opportunity for earlier interventions, which could result in potential greater benefits. We assessed the cost effectiveness of the use of CSF biomarkers in MCI patients where the treatment decision was based on patients’ risk level. Methods We developed a state-transition model to project lifetime quality-adjusted life-years (QALYs) and costs for a cohort of 65-year-old MCI patients from a US societal perspective. We compared four test-and-treat strategies where the decision to treat was based on a patient’s risk level (low, intermediate, high) of progressing to AD with two strategies without testing, one where no patients were treated during the MCI phase and in the other all patients were treated. We performed deterministic and probabilistic sensitivity analyses to evaluate parameter uncertainty. Results Testing and treating low-risk MCI patients was the most cost-effective strategy with an incremental cost-effectiveness ratio (ICER) of US$37,700 per QALY. Our results were most sensitive to the level of treatment effectiveness for patients with mild AD and for MCI patients. Moreover, the ICERs for this strategy at the 2.5th and 97.5th percentiles were US$18,900 and US$50,100 per QALY, respectively. Conclusion Based on the best available evidence regarding the treatment effectiveness for MCI, this study suggests the potential value of performing CSF biomarker testing for early targeted treatments among MCI patients with a narrow range for the ICER

New syntheses of (±)-tashiromine and (±)-epitashiromine via enaminone intermediates

The syntheses of the naturally occurring indolizidine alkaloid (±)-tashiromine and its unnatural epimer (±)-epitashiromine are demonstrated through the use of enaminone chemistry. The impact of various electron-withdrawing substituents at the C-8 position of the indolizidine core on the preparation of the bicyclic system is described.Supporting Information File 1 Experimental procedures and copies of NMR spectra.This work is based on research supported by the National Research Foundation of South Africa, Pretoria (grant numbers 85964 and 93447), and by the University of the WitwatersrandThe National Research Foundation of South Africa, Pretoria (grant numbers 85964 and 93447), and by the University of the Witwatersrand.http://www.sherpa.ac.uk/romeo/issn/1860-5397/am2017Chemistr

New syntheses of (±)-tashiromine and (±)-epitashiromine via enaminone intermediates

The syntheses of the naturally occurring indolizidine alkaloid (±)-tashiromine and its unnatural epimer (±)-epitashiromine are demonstrated through the use of enaminone chemistry. The impact of various electron-withdrawing substituents at the C-8 position of the indolizidine core on the preparation of the bicyclic system is described.Supporting Information File 1 Experimental procedures and copies of NMR spectra.This work is based on research supported by the National Research Foundation of South Africa, Pretoria (grant numbers 85964 and 93447), and by the University of the WitwatersrandThe National Research Foundation of South Africa, Pretoria (grant numbers 85964 and 93447), and by the University of the Witwatersrand.http://www.sherpa.ac.uk/romeo/issn/1860-5397/am2017Chemistr