Computed tomography scanning of implanted hypoglossal nerve stimulators and approach to device malfunction: case series.

OBJECTIVE: Serious device-related complications for hypoglossal nerve stimulators are rare, but surgeons should implement a prompt and systematic approach to quickly troubleshoot a non-functioning device. METHOD: Records were queried at a single academic tertiary referral centre between January 2019 and June 2021. RESULTS: The authors present four cases of non-functioning hypoglossal nerve stimulator devices: one case in which migration of the stimulation lead required a revision implantation, one in which the implantable pulse generator was found to be non-functional intra-operatively, one case of an intramuscular sensory lead tract causing pain and one case of implantable pulse generator failure that was probably triggered by implantable cardiac device discharge. In this study, computed tomography imaging was critical to the diagnosis for the first and third cases. CONCLUSION: Given the limited complication reporting available for hypoglossal nerve stimulators, these cases highlight management and unique imaging findings. The authors present an algorithm to work-up non-functioning hypoglossal nerve stimulator devices.

Predictors of oral bisphosphonate prescriptions in post-menopausal women with osteoporosis in a real-world setting in the USA.

SUMMARY: We identified factors associated with oral bisphosphonate treatment in 50+-year-old female patients with a first fracture, osteoporosis diagnosis, or BMD < or =-2.5 in the Geisinger Health System electronic health record database. Treatment was positively associated with age, oral corticosteroids, and smoking, and negatively associated with body mass index and bone mineral density scores. INTRODUCTION: To identify factors associated with oral bisphosphonate treatment in patients with an indicator for post-menopausal osteoporosis. METHODS: Females age 50+ years with a first fracture, osteoporosis diagnosis, or bone mineral density (BMD) < or =-2.5 (index date) were identified in the Geisinger Health System electronic health record database. Treatment was defined as an oral bisphosphonate prescription order (risedronate sodium, ibandronate sodium, or alendronate) < or =90 days post-index date. Treatment rates were assessed and a multivariate logistic model was used to identify predictors of treatment separately for patients with fracture (FRAC) and with diagnosis or low BMD (ICD-9-BMD). RESULTS: The FRAC group had 2,003 female patients with a mean (SD) age of 69.0 (+/-11.3) years and the ICD-9-BMD group had 12,976 female patients with a mean (SD) age of 66.9 (+/-10.0) years. Within 90 days of the index date of fracture, diagnosis, or low BMD score, 188 (9.4%) patients in the FRAC group and 5,395 (41.6%) in the ICD-9-BMD group received treatment. Treatment was positively associated with age and oral corticosteroids and negatively associated with body mass index and subsequent BMD in both groups. Smoking currently was positively associated with treatment in the ICD-9-BMD group. CONCLUSION: Certain patient characteristics are predictors of physicians prescribing oral bisphosphonates. However, many patients remain untreated.

Evidence for a novel functional role of cannabinoid CB(2) receptors in the thalamus of neuropathic rats.

Cannabinoid CB(1) receptors have analgesic effects in models of neuropathic pain, but can also produce psychoactive side-effects. A supraspinal location of CB(2) receptors has recently been described. CB(2) agonists are also antinociceptive, although the functional role of supraspinal CB(2) receptors in the control of nociception is unknown. Herein, we provide evidence that CB(2) receptors in the thalamus play a functional role in the modulation of responses of neurons in the ventral posterior nucleus (VPL) of the thalamus in neuropathic, but not sham-operated, rats. Spontaneous and mechanically evoked activity of VPL neurons was recorded with a multichannel electrode array in anaesthetized spinal nerve-ligated (SNL) rats and compared to sham-operated rats. Intra-VPL administration of the CB(2) agonist JWH-133 (30 ng in 500 nL) significantly reduced spontaneous (P < 0.05), non-noxious (P < 0.001) and noxious (P < 0.01) mechanically evoked responses of VPL neurons in SNL rats, but not in sham-operated rats. Inhibitory effects of JWH-133 on spontaneous (P < 0.01) and noxious-evoked (P < 0.001) responses of neurons were blocked by the CB(2) antagonist SR144528. Local administration of SR144528 alone did not alter spontaneous or evoked responses of VPL neurons, but increased burst activity of VPL neurons in SNL rats. There were, however, no differences in levels of the endocannabinoids anandamide and 2AG in the thalamus of SNL and sham-operated rats. These data suggest that supraspinal CB(2) receptors in the thalamus may contribute to the modulation of neuropathic pain responses.

Baseline differences between vascular cognitive impairment no dementia reverters and non-reverters.

BACKGROUND: The underlying factors of reversion from cognitive impairment to normal cognitive functioning in stroke are not well understood. We compare demographic, cognitive and imaging factors in Vascular Cognitive Impairment, No Dementia (Vascular CIND) patients who revert to normal cognitive functioning to Vascular CIND patients who do not revert. METHODS: Thirty-one ischaemic stroke patients, who met classification criteria for Vascular CIND, were >49.5 years old, met NINDS stroke criteria, and were free from additional neurological illness, completed baseline and 1-year examinations. Forty-five per cent of the Vascular CIND participants reverted to no cognitive impairment at 1-year follow-up examination. RESULTS: There was greater cognitive impairment in non-reverters on a summary score spanning several neuropsychological domains and on psychomotor and working memory summary scores. There were no differences on demographic factors or in stroke severity between reverters and non-reverters. Structural MRI analyses revealed no baseline differences in number of strokes, stroke volume or stroke location. However, there was greater frontal white matter hyperintensity load in the non-reverter group. CONCLUSIONS: These results suggest that Vascular CIND reversion may be a function of a combination of baseline neuropsychological function and location of cerebrovascular disease.

Endocannabinoid metabolism and uptake: novel targets for neuropathic and inflammatory pain.

Cannabinoid CB1 and CB2 receptors are located at key sites involved in the relaying and processing of noxious inputs. Both CB1 and CB2 receptor agonists have analgesic effects in a range of models of inflammatory and neuropathic pain. Importantly, clinical trials of cannabis-based medicines indicate that the pre-clinical effects of cannabinoid agonists may translate into therapeutic potential in humans. One of the areas of concern with this pharmacological approach is that CB1 receptors have a widespread distribution in the brain and that global activation of CB1 receptors is associated with adverse side effects. Studies of the endogenous cannabinoids (endocannabinoids) have demonstrated that they are present in most tissues and that in some pain states, such as neuropathic pain, levels of endocannabinoids are elevated at key sites involved in pain processing. An alternative approach that can be used to harness the potential therapeutic effects of cannabinoids is to maximise the effects of the endocannabinoids, the actions of which are terminated by re-uptake and metabolism by various enzymes, including fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL) and cyclooxygenase type 2 (COX2). Preventing the metabolism, or uptake, of endocannabinoids elevates levels of these lipid compounds in tissue and produces behavioural analgesia in models of acute pain. Herein we review recent studies of the effects of inhibition of metabolism of endocannabinoids versus uptake of endocannabinoids on nociceptive processing in models of inflammatory and neuropathic pain.

Behavioral, central monoaminergic and hypothalamo-pituitary-adrenal axis correlates of fear-conditioned analgesia in rats.

Fear-conditioned analgesia is an important survival response which is expressed upon re-exposure to a context previously paired with a noxious stimulus. The aim of the present study was to characterize further the behavioral, monoaminergic and hypothalamo-pituitary-adrenal axis alterations associated with expression of fear-conditioned analgesia. Rats which had received footshock conditioning 24 h earlier, exhibited reduced formalin-evoked nociceptive behavior upon re-exposure to the footshock chamber, compared with non-footshocked formalin-treated rats. Intra-plantar injection of formalin reduced the duration of contextually-induced freezing and 20-40 kHz ultrasound emission. Intra-plantar injection of formalin to non-footshocked, non-conditioned rats did not induce ultrasonic vocalizations. Intra-plantar injection of formalin to footshock-conditioned rats, significantly increased tissue levels of 3,4-dihydroxyphenylacetic acid and the 3,4-dihydroxyphenylacetic acid:dopamine ratio in the periaqueductal gray and reduced levels of dopamine in the thalamus, compared with saline-treated footshocked controls. Non-footshocked, non-conditioned rats were capable of mounting a robust formalin-evoked increase in plasma corticosterone levels. Moreover, plasma corticosterone levels were significantly higher in saline-treated, footshock conditioned rats compared with saline-treated non-footshocked rats and levels did not differ between saline- and formalin-treated footshock conditioned rats. Assessment of the effects of the intra-plantar injection procedure revealed an attenuation of short-term extinction of contextually-induced freezing in rats anesthetized for intra-plantar injection of saline compared with non-anesthetized, non-injected rats as well as discrete effects on monoamines, their metabolites and plasma corticosterone levels. These data extend behavioral characterization of the phenomenon of fear-conditioned analgesia and suggest that measurement of ultrasound emission may be used as an ethologically relevant index of the defense response during fear-conditioned analgesia. Ultrasonic vocalization may also be a useful behavioral output to aid separation of nociception and aversion. The data provide evidence for discrete alterations in dopaminergic activity in the periaqueductal gray and thalamus and for altered hypothalamo-pituitary-adrenal axis activity following expression of defensive behavior.

Contribution of proximal promoter elements to the regulation of basal and differential glutathione S-transferase P1 gene expression in human breast cancer cells.

Glutathione S-transferase P1 (GST P1-1) is normally expressed exclusively in estrogen receptor negative (ER-) but not receptor positive (ER+) cultured breast cancer cells. We examined the role of proximal promoter elements in GST P1 gene expression in MCF7 (ER+, GST P1-) and HS578T (ER-, GST P1+) breast cancer cells. Transient transfection of GST P1 promoter-CAT reporter genes confirmed that the GST P1 TRE (-69 to -60) and the adjacent distal GC box (-56 to -51) are required for basal promoter activity in both cell lines. Other studies identified differences in the GST P1 promoter activity and DNA-protein interactions between the two cell lines. Electrophoretic mobility shift assay revealed a protein-TRE interaction that is unique to nuclear proteins derived from GST P1 expressing HS578T cells. Furthermore, a putative silencer region contained within sequences -130 to -70 selectively reduced GST P1 promoter-CAT reporter gene expression in MCF7 but not HS578T cells. While this cell-line specific silencer contributed to the level of GST P1 promoter activity observed in the two cell lines, analysis of cells stably transfected with a novel genomic GST P1 minigene vector established that the silencer is insufficient to completely repress GST P1 transcription in ER+, MCF7 cells that do not normally express endogenous GST P1.

Methylation-mediated regulation of the glutathione S-transferase P1 gene in human breast cancer cells.

Understanding the mechanisms that regulate the human pi class GST (GSTP1) gene expression in breast cancer cells is of particular importance to the study of breast cancer biology. In cultured human breast cancer cell lines, GSTP1 is exclusively expressed in estrogen receptor-negative (ER-) cells but is undetectable in receptor-positive (ER+) cells. Previously, we examined transiently transfected GSTP1 promoter activities, in vitro GSTP1 promoter-DNA interactions, and GSTP1 mRNA stability. These studies indicated that transiently transfected GSTP1 promoter elements and GSTP1 mRNA stability could only partially explain cell line-specific expression of endogenous GSTP1. In the present study, we examined whether the methylation status of the GSTP1 CpG island plays an important role in GSTP1 regulation. Southern blot analysis revealed that the GSTP1 CpG island is hypermethlyated in ER+, GSTP1 non-expressing cell lines but is undermethylated in ER-, GSTP1 expressing cell lines. Moreover, partial demethylation of the GSTP1 CpG island by treatment with 5-aza-2'-deoxycytidine resulted in de novo gene expression in ER+ cell lines, as detected by RT-PCR, Northern blot and Western blot analyses. Our data strongly indicate that methylation status of the promoter contributes significantly to the levels of GSTP1 expressed in ER- and ER+ breast cancer cell lines.

Effects of direct periaqueductal grey administration of a cannabinoid receptor agonist on nociceptive and aversive responses in rats.

The analgesic potential of cannabinoids may be hampered by their ability to produce aversive emotion when administered systemically. We investigated the hypothesis that the midbrain periaqueductal grey (PAG) is a common substrate mediating the anti-nociceptive and potential aversive effects of cannabinoids. The rat formalin test was used to model nociceptive behaviour. Intra-PAG microinjection of the excitatory amino acid D,L-homocysteic acid (DLH) was used to induce an aversive, panic-like reaction characteristic of the defensive "fight or flight" response. Administration of the cannabinoid receptor agonist HU210 (5 microg/rat) into the dorsal PAG significantly reduced the second phase of formalin-evoked nociceptive behaviour, an effect which was blocked by co-administration of the CB(1) receptor antagonist SR141716A (50 microg/rat). This anti-nociceptive effect was accompanied by an HU210-induced attenuation of the formalin-evoked increase in Fos protein expression in the caudal lateral PAG. Intra-dorsal PAG administration of HU210 (0.1, 1 or 5 microg/rat) significantly reduced the aversive DLH-induced explosive locomotor response. The anti-nociceptive effect of HU210 is likely to result from activation of the descending inhibitory pain pathway. Mechanisms mediating the anti-aversive effects of cannabinoids in the PAG remain to be elucidated. These data implicate a role for the PAG in both cannabinoid-mediated anti-nociceptive and anti-aversive responses.

Passage of the first stool in very low birth weight infants.

Times of first stool passage were studied in 171 infants who weighed less than 1,500 g at birth. Delayed passage (greater than 48 hours) was noted in 20.4% of this group. Significant differences were noted between the delayed and nondelayed groups for gestational age, presence of severe respiratory distress syndrome, and the time of the first enteral feeding. In very low birth weight infants, delay in the passage of the first stool is a common occurrence. This delay is probably due to physiologic immaturity of the motor mechanisms of the gut, lack of triggering effect of enteral feeds on gut hormones, and the presence of severe respiratory distress syndrome, which may singly or in concert adversely affect gastrointestinal motility.

Paternal uniparental disomy for chromosome 14: a case report and review.

Uniparental disomy (UPD) for several chromosomes has been associated with disease phenotypes. Maternal UPD for chromosome 14 has been described and has a characteristic abnormal phenotype. Paternal UPD14 is rare and only three previous cases have been reported. We describe a new case of paternal UPD for chromosome 14 in an infant with a 45,XX,der(13q;14q) karyotype, which was confirmed by molecular analysis. The proposita had findings similar to those of the previous cases of patUPD14 and we conclude that there is a characteristic patUPD14 syndrome most likely due to imprinting effects. Couples with Robertsonian translocations involving chromosome 14 should be counseled as to the possibility of UPD14 and the option of prenatal diagnosis when indicated.

Infantile hemangioendothelioma of heterotopic intrathoracic liver associated with diaphragmatic hernia.

An autopsy of a six-hour-old term neonate, who died during surgery for repair of a left diaphragmatic hernia, revealed an infantile hemangioendothelioma type I arising in a heterotopic lobe of liver in the left thorax. The upper pole of the tumor was attached by fibrovascular tissue to the lower lobe of the left hypoplastic lung. A pedicle attached to the lower pole of the heterotopic liver pierced through the diaphragm to the left lobe of the normal liver. This case is an example of an unusual association of congenital malformation and putative neoplasm.

Crossed renal ectopia associated with maternal alkaloid cocaine abuse: a case report.

Although cocaine abuse has declined in popularity in the United States, certain groups continue to use the drug at high rates. The teratogenicity of cocaine has been widely investigated in the newborn. We report a case of crossed renal ectopia in a term neonate whose mother practiced alkaloid cocaine abuse in the first trimester of pregnancy. We propose that this anomaly was caused by cocaine's direct pharmacologic effect, leading to vasoconstriction that affected the developing fetal kidney by compromising the blood vessels that supply the organ or by causing hemorrhages and infarctions with fibrosis, causing disruption during a crucial period of morphogenesis.

Evaluation of a metal artifacts reduction algorithm applied to postinterventional flat panel detector CT imaging.

BACKGROUND AND PURPOSE: Flat panel detector CT images are degraded by streak artifacts caused by radiodense implanted materials such as coils or clips. A new metal artifacts reduction prototype algorithm has been used to minimize these artifacts. The application of this new metal artifacts reduction algorithm was evaluated for flat panel detector CT imaging performed in a routine clinical setting. MATERIALS AND METHODS: Flat panel detector CT images were obtained from 59 patients immediately following cerebral endovascular procedures or as surveillance imaging for cerebral endovascular or surgical procedures previously performed. The images were independently evaluated by 7 physicians for metal artifacts reduction on a 3-point scale at 2 locations: immediately adjacent to the metallic implant and 3 cm away from it. The number of visible vessels before and after metal artifacts reduction correction was also evaluated within a 3-cm radius around the metallic implant. RESULTS: The metal artifacts reduction algorithm was applied to the 59 flat panel detector CT datasets without complications. The metal artifacts in the reduction-corrected flat panel detector CT images were significantly reduced in the area immediately adjacent to the implanted metal object (P = .05) and in the area 3 cm away from the metal object (P = .03). The average number of visible vessel segments increased from 4.07 to 5.29 (P = .1235) after application of the metal artifacts reduction algorithm to the flat panel detector CT images. CONCLUSIONS: Metal artifacts reduction is an effective method to improve flat panel detector CT images degraded by metal artifacts. Metal artifacts are significantly decreased by the metal artifacts reduction algorithm, and there was a trend toward increased vessel-segment visualization.

Will insomnia treatments produce overall cost savings to commercial managed-care plans? A predictive analysis in the United States.

OBJECTIVE: Research indicates that insomnia may contribute significantly to healthcare costs; however, information on the effects of treatments on costs has not been thoroughly published. This study presents predictive models that forecast, from the perspective of commercial managed care, the effects of insomnia medications in reducing overall medical costs. The main objectives of this study were to predict the level of cost savings associated with insomnia treatments, illustrate the variation in outcomes given underlying model assumptions, and assist managed-care policy-makers with the evaluation of medications routinely administered for insomnia. METHODS: Data on four primary-efficacy measures: wake after sleep onset (WASO), sleep efficiency (SE), sleep onset latency (SOL) and total sleep time (TST) were abstracted from published clinical trial data for eszopiclone, indiplon, low-dose trazodone, ramelteon, zaleplon, zolpidem and zolpidem extended-release. Change in per-patient per-year (PPPY) healthcare costs in a single claims database was calculated for subjects taking zolpidem, zaleplon and low-dose trazodone using generalized linear model (GLM) techniques, controlling for baseline demographics and baseline costs. Change in costs for emerging insomnia medications was forecasted by imputing efficacy values for these drugs into the regressions. RESULTS: Using the accepted efficacy measure, WASO, zolpidem extended-release had the overall forecasted savings of -$1253 (CI: -$1404 to -$1404) PPPY compared to remaining treatments, whereas ramelteon cost an additional $348 (-$1280 to $584) PPPY. In three out of four cost-efficacy models, zolpidem extended-release had higher mean forecasted PPPY savings. CONCLUSION: This study examined cost effects of existing and emerging insomnia medications using models integrating clinical literature and medical claims within a statistical framework. The use of a single database may limit generalizability and models only address a 1-year period. Results suggest treatments can offer health plans direct cost savings, with amounts sensitive to variable and efficacy measures, potentially limited by those variables available in the claims database. Compared to other evaluated treatments, zolpidem extended-release produced consistently higher predicted cost savings.

Role of posttranscriptional processes in the regulation of glutathione S-transferase P1 gene expression in human breast cancer cells.

Human glutathione S-transferase P1 (GSTP1) is normally expressed in estrogen receptor negative (ER-) but not receptor positive (ER+) cultured breast cancer cells. Previous results indicated that posttranscriptional mechanisms may contribute to this differential expression of GSTP1 (J. Biol. Chem. 267, 10544-10550, 1992). Here, we have tested the hypothesis that differences in posttranscriptional processing of primary transcripts to mature mRNA or differences in mRNA stability influence the levels of GSTP1 in ER- versus ER+ breast cancer cells. We examined the expression both of the endogenous GSTP1 gene and of uniquely designed GSTP1 minigenes that were stably transfected into HS578T (ER-) and MCF7 (ER+) cells. In both cell lines, GSTP1 transcripts are processed to mature, functional mRNAs. However, GSTP1 mRNA is considerably less stable in MCF7 than in HS578T cells. These results indicate that for a given level of GSTP1 gene transcription, differential mRNA stability will result in higher steady state levels of GSTP1 mRNA in ER-, HS578T than in ER+, MCF7 cells.

Impact of extracellular folate levels on global gene expression.

Methylation of DNA is associated with gene silencing. DNA methylation uses S-adenosylmethionine (SAM) as the methyl donor and the formation of SAM requires a continuous supply of folate from the extracellular milieu. Low extracellular folate levels are known to result in induction of expression of the human alpha folate receptor in nasopharyngeal epidermoid carcinoma cells. Low folate levels have been implicated in global activation of gene expression. We have investigated the impact of lowering the level of extracellular folate by performing cDNA microarray analysis of global gene expression in human nasopharyngeal carcinoma KB cells grown in folate-deplete and folate-replete medium. We found that expression of only eight genes reproducibly responded to variation of folate levels. Among those, three were up-regulated and five were down-regulated. Examination of one gene, H-cadherin, demonstrated down-regulation in response to folate depletion. Despite the low level of extracellular folate, there was hypermethylation of H-cadherin 5' sequences. These data indicate that low extracellular folate positively and negatively influences the expression levels of a small cohort of genes. The data suggest that folate deficiency is associated with gene-specific methylation/demethylation, rather than global DNA demethylation and transcriptional activation.

Evaluation of oxygen saturation monitoring by pulse oximetry in neonates in the delivery system.

The pulse oximeter was evaluated for use in neonates in the delivery room. One hundred neonates, delivered vaginally or by Caesarean section with general or epidural anaesthesia, were studied. After delivery, pulse oximetry probes were placed simultaneously on the ulnar side of the right hand and on the right Achilles tendon to determine whether there was a difference in arterial oxygenation (SpO2). Measurements of SpO2 were taken at 1, 5, 10 min, and 24 hr after delivery. At one and five minutes, SpO2 recorded from the right hand was higher than that recorded from the lower extremities (71.9% +/- 6.5% vs 63.4% +/- 4.3% and 83.3% +/- 4.2% vs 76% +/- 4.1%, mean +/- SD, respectively). At ten minutes these differences diminished, and had almost completely disappeared after 24 hr. These results can be explained by the presence of R-L shunting at the ductus arteriosus level, producing reduced SaO2 in the lower extremities. Oxygen saturation did not differ between neonates delivered vaginally or by Caesarean section, regardless of the presence or type of anaesthesia. We concluded that neonates remain relatively desaturated in the immediate postpartum period and that the SpO2 obtained from the right hand is a better index of neonatal oxygenation than that obtained from the heel.