BrainGENIE: The Brain Gene Expression and Network Imputation Engine.

In vivo experimental analysis of human brain tissue poses substantial challenges and ethical concerns. To address this problem, we developed a computational method called the Brain Gene Expression and Network-Imputation Engine (BrainGENIE) that leverages peripheral-blood transcriptomes to predict brain tissue-specific gene-expression levels. Paired blood-brain transcriptomic data collected by the Genotype-Tissue Expression (GTEx) Project was used to train BrainGENIE models to predict gene-expression levels in ten distinct brain regions using whole-blood gene-expression profiles. The performance of BrainGENIE was compared to PrediXcan, a popular method for imputing gene expression levels from genotypes. BrainGENIE significantly predicted brain tissue-specific expression levels for 2947-11,816 genes (false-discovery rate-adjusted p < 0.05), including many transcripts that cannot be predicted significantly by a transcriptome-imputation method such as PrediXcan. BrainGENIE recapitulated measured diagnosis-related gene-expression changes in the brain for autism, bipolar disorder, and schizophrenia better than direct correlations from blood and predictions from PrediXcan. We developed a convenient software toolset for deploying BrainGENIE, and provide recommendations for how best to implement models. BrainGENIE complements and, in some ways, outperforms existing transcriptome-imputation tools, providing biologically meaningful predictions and opening new research avenues.

A Case for the Use of the 5-Item Modified Frailty Index in Preoperative Risk Assessment for Tissue Expander Placement in Breast Reconstruction.

BACKGROUND: Preoperative risk assessment is essential in determining which surgical candidates will have the most to gain from an operation. The 5-item modified frailty index (mFI-5) has been validated as an effective way to determine this risk. This study sought to evaluate the performance of the mFI-5 as a predictor of postoperative complications after tissue expander placement. METHODS: Patients who underwent placement of a tissue expander were identified using the 2012 to 2018 American College of Surgeons National Surgical Quality Improvement Project database. Univariate and multivariate regression analysis models were used to assess how mFI-5, the components of the mFI-5 (functional status, diabetes, chronic obstructive pulmonary disease, chronic heart failure, and hypertension), and other factors commonly used to risk stratify (age, body mass index [BMI], American Society of Anesthesiologists (ASA) classification, and history of smoking) were associated with complications. RESULTS: In 44,728 tissue expander placement cases, the overall complication rate was 10.5% (n = 4674). The mFI-5 score was significantly higher in the group that experienced complications (0.08 vs 0.06, P < 0.001). Compared with the mFI-5 individual components and other common variables used preoperatively to risk stratify patients, univariate analysis demonstrated that mFI-5 had the largest effect size (odds ratio [OR], 5.46; confidence interval [CI], 4.29-6.94; P < 0.001). After controlling for age, BMI, ASA classification, and history of smoking, the mFI-5 still remained the predictor of complications with the largest effect size (OR, 2.25; CI, 1.70-2.97; P < 0.001). In assessing specific complications, the mFI-5 is the independent predictor with the largest significant effect size for surgical dehiscence (OR, 12.76; CI, 5.58-28.18; P < 0.001), surgical site infection (OR, 6.68; CI, 4.53-9.78; P < 0.001), reoperation (OR, 5.23; CI, 3.90-6.99; P < 0.001), and readmission (OR, 4.59; CI, 3.25-6.45; P < 0.001) when compared with age, BMI, ASA class, and/or history of smoking alone. CONCLUSIONS: The mFI-5 can be used as an effective preoperative predictor of postoperative complications in patients undergoing tissue expander placement. Not only does it have the largest effect size compared with other historical perioperative risk factors, it is more predictive than each of its individual components.

Elective surgery resource utilization.

PURPOSE: Cessation of elective surgery during COVID-19 was partly driven by concern for consumption of hospital resources required by critically ill patients. We aim to determine the extent of resource utilization by elective outpatient surgery to assist in ensuring future resource conservation decisions are data driven. METHODS: The study utilized a retrospective cohort gathered from the American College of Surgeons National Surgical Quality Improvement Program database. Participants were adult patients who underwent elective or non-elective surgery between 2017 and 2018. Outcomes included patient characteristics and post-operative outcomes for elective and non-elective surgeries. Post-operative outcomes were used as a surrogate for the consumption of hospital resources. RESULTS: A total of 1,558,938 (79.8%) elective and 393,339 (20.2%) non-elective surgeries were identified. Elective surgery patients were more likely to be outpatient status, have an ASA class < 3, and exhibited lower rates of prolonged ventilation, 30-day reoperation, and 30-day readmissions, and averaged 5 days less of inpatient stay. Elective outpatient surgery (vs. elective inpatient surgery) averaged shorter operative times and exhibited lower rates of readmissions (2.1% vs. 5.5%; p < 0.001), reoperations (1.1% vs. 2.8%; p < 0.001), prolonged ventilation (0.0% vs. 0.3%; p < 0.001), and 30-day mortality (0.1% vs. 0.5%; p < 0.001) and accounted for 30.2% of the overall relative value units ($339,815,038). CONCLUSION: We evaluated utilization of hospital resources by patients undergoing elective outpatient surgery by identifying surgeries performed in 2017-2018 then stratifying them by outpatient status. Elective outpatient surgeries consumed negligible amounts of hospital resources and should not be considered a threat to resources in the setting of high demand by critically ill COVID-19 patients.

National Trends in Length of Stay for Microvascular Breast Reconstruction: An Evaluation of 10,465 Cases Using the American College of Surgeons National Surgical Quality Improvement Program Database.

BACKGROUND: Decreasing length of stay benefits patients and hospital systems alike. This should be accomplished safely without negatively impacting patient outcomes. The authors hypothesize that in the United States, the average length of stay for patients undergoing microsurgical breast reconstruction has decreased since 2012 without a concurrent increase in complication and readmission rates. METHODS: The authors identified female patients who underwent microvascular breast reconstruction (CPT 19364) from the 2012 to 2018 National Surgical Quality Improvement Program database. Trends in complication and readmission rates and length of stay were examined over 7 years. Multivariable logistic regression models and Mann-Kendall trend tests were used to evaluate associations between length of stay and complication and readmission rates. RESULTS: A total of 10,465 cases were identified. The number of autologous microvascular breast reconstruction procedures performed increased annually between 2012 and 2018. Length of stay decreased significantly from 2012 to 2018 (from 4.47 days to 3.90 days) (p < 0.01). Minor and major complication rates remained constant, although major complications showed a decreasing trend (from 27 percent to 21 percent) (p = 0.07). Thirty-day readmission, surgical-site infection, and wound dehiscence rates remained consistent over the study period, whereas rates of blood transfusion or bleeding decreased (p = 0.02). CONCLUSIONS: Using a national sample from 2012 to 2018, the authors observed a significant decrease in length of stay for patients undergoing microvascular breast reconstruction without a concurrent increase in complication and readmission rates. Current efforts to reduce length of stay have been successful without increasing complication or readmission rates. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

An Analysis of the Modified Five-Item Frailty Index for Predicting Complications following Free Flap Breast Reconstruction.

BACKGROUND: The modified five-item frailty index is a validated and effective tool for assessing risk in surgical candidates. The authors sought to compare the predictive ability of the modified five-item frailty index to established risk factors for complications in free flap breast reconstruction. METHODS: The 2012 to 2018 American College of Surgeons National Surgical Quality Improvement Program database was queried for free flap breast reconstructive procedures. Univariate and multivariate regression analysis models were used to assess how modified five-item frailty index and factors commonly used to risk stratify (age, body mass index, American Society of Anesthesiologists classification, and history of smoking) were associated with complications. RESULTS: Of the total 10,550 cases, 24.1 percent experienced complications. A high modified five-item frailty index score is associated with a higher overall rate of postoperative complications (p < 0.001). This significant trend was demonstrated in both surgical (p < 0.001) and medical (p < 0.001) complications. When controlling for other risk factors commonly used for risk stratification such as age, body mass index, American Society of Anesthesiologists classification, and history of smoking, the modified five-item frailty index was significantly associated with medical (OR, 1.75; 95 percent CI, 1.37 to 2.22; p = 0.001) and any complications (OR, 1.58; 95 percent CI, 1.29 to 1.93; p < 0.001) and had the largest effect size. Assessing for specific complications, the modified five-item frailty index is the strongest independent predictor of reoperation (OR, 1.41; 95 percent CI, 1.08 to 1.81; p = 0.009). CONCLUSION: The modified five-item frailty index is a useful predictor of postoperative outcomes in patients undergoing free flap breast reconstruction when compared to other historically considered risk factors for surgical complications. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

A population-based study of breast implant illness.

BACKGROUND: Despite evidence supporting the safety of breast implants, some women associate their implants with adverse health effects and have called this syndrome "breast implant illness." We sought to characterize breast implant illness symptoms and to report how implant removal affects their symptoms. METHODS: An anonymous 20 question survey was administered to the Facebook group: "UTAH Breast Implant Illness" to characterize the symptoms these women attributed to their breast implants. Several questions allowed us to evaluate how implant removal affected women's symptoms. RESULTS: Of the 182 respondents, 97% report that implants negatively affect their health and 95% identify these symptoms with breast implant illness. Ninety-six percent of respondents had implants placed for cosmetic reasons and 51% had silicone implants. The most common symptoms associated with breast implant illness are brain fog (95%), fatigue (92%), joint pain (80%), and hair loss (74%). Sixty percent of respondents learned about breast implant illness from family/friends and/or social media platforms (56%), 40% of respondents had their implants removed, and 97% report relief of their symptoms post-removal (23% complete, 74% partial). Following explantation, there was a significant improvement in all but one reported symptom. An association was found between the number of symptoms reported prior to explantation and the number of symptoms resolving following explantation. CONCLUSIONS: Breast implant illness is a syndrome characterized by fatigue, decreased focus, hair loss, and joint pain after the placement of breast implants. Nearly all patients report improvement of symptoms after implant removal. Significant efforts should be made to better understand breast implant illness and its etiology.

The 5-Factor Modified Frailty Index as a Predictor of 30-day Complications in Pressure Ulcer Repair.

BACKGROUND: The 5-item modified frailty index (mFI-5) is a validated tool to assess postoperative risks in older surgical candidates. We sought to compare the predictive ability of mFI-5 to its individual components and other established risk factors for complications in flap reconstruction of late-stage pressure ulcer repair. METHODS: The 2012 to 2018 American College of Surgeons National Surgical Quality Improvement Project (ACS-NSQIP) database was queried for pressure ulcer diagnosis and reconstructive flap repair procedures. Univariate and multivariate regression analysis models were used to assess how mFI-5, the components of the mFI-5 (functional status before surgery, diabetes, history of chronic obstructive pulmonary disease, history of congestive heart failure, and history of hypertension requiring medicine), and other factors commonly used to risk-stratify (age, obesity, ASA classification, and history of smoking) were associated with complications. RESULTS: 35.1% of the total 1254 flap reconstructive procedures for pressure ulcer repair experienced complications. Most cases had at least one of the five mFI-5 factors in both the complication (42.7%) and no complication (45.7%) cohorts. Compared with the factors making up the mFI-5 score and other common variables used to risk-stratify, mFI-5 was significantly associated with complications in the univariate (OR 1.17, CI 1.03 - 1.33; P = 0.02) and multivariate analysis (OR 1.16, CI 1.02 - 1.34; P = 0.043). CONCLUSIONS: The mFI-5 is a useful predictor of postoperative outcomes in patients undergoing reconstructive flap surgery for pressure ulcer injuries compared to other historically considered risk factors for surgical complications.

A population-based study of breast implant illness

Background@#Despite evidence supporting the safety of breast implants, some women associate their implants with adverse health effects and have called this syndrome “breast implant illness.” We sought to characterize breast implant illness symptoms and to report how implant removal affects their symptoms. @*Methods@#An anonymous 20 question survey was administered to the Facebook group: “UTAH Breast Implant Illness” to characterize the symptoms these women attributed to their breast implants. Several questions allowed us to evaluate how implant removal affected women’s symptoms. @*Results@#Of the 182 respondents, 97% report that implants negatively affect their health and 95% identify these symptoms with breast implant illness. Ninety-six percent of respondents had implants placed for cosmetic reasons and 51% had silicone implants. The most common symptoms associated with breast implant illness are brain fog (95%), fatigue (92%), joint pain (80%), and hair loss (74%). Sixty percent of respondents learned about breast implant illness from family/friends and/or social media platforms (56%), 40% of respondents had their implants removed, and 97% report relief of their symptoms post-removal (23% complete, 74% partial). Following explantation, there was a significant improvement in all but one reported symptom. An association was found between the number of symptoms reported prior to explantation and the number of symptoms resolving following explantation. @*Conclusions@#Breast implant illness is a syndrome characterized by fatigue, decreased focus, hair loss, and joint pain after the placement of breast implants. Nearly all patients report improvement of symptoms after implant removal. Significant efforts should be made to better understand breast implant illness and its etiology.

A population-based study of breast implant illness

Background@#Despite evidence supporting the safety of breast implants, some women associate their implants with adverse health effects and have called this syndrome “breast implant illness.” We sought to characterize breast implant illness symptoms and to report how implant removal affects their symptoms. @*Methods@#An anonymous 20 question survey was administered to the Facebook group: “UTAH Breast Implant Illness” to characterize the symptoms these women attributed to their breast implants. Several questions allowed us to evaluate how implant removal affected women’s symptoms. @*Results@#Of the 182 respondents, 97% report that implants negatively affect their health and 95% identify these symptoms with breast implant illness. Ninety-six percent of respondents had implants placed for cosmetic reasons and 51% had silicone implants. The most common symptoms associated with breast implant illness are brain fog (95%), fatigue (92%), joint pain (80%), and hair loss (74%). Sixty percent of respondents learned about breast implant illness from family/friends and/or social media platforms (56%), 40% of respondents had their implants removed, and 97% report relief of their symptoms post-removal (23% complete, 74% partial). Following explantation, there was a significant improvement in all but one reported symptom. An association was found between the number of symptoms reported prior to explantation and the number of symptoms resolving following explantation. @*Conclusions@#Breast implant illness is a syndrome characterized by fatigue, decreased focus, hair loss, and joint pain after the placement of breast implants. Nearly all patients report improvement of symptoms after implant removal. Significant efforts should be made to better understand breast implant illness and its etiology.

Fidaxomicin versus oral vancomycin for severe Clostridium difficile infection: a retrospective cohort study.

OBJECTIVES: This study was conducted to compare clinical outcomes of fidaxomicin versus oral vancomycin in the management of severe Clostridium difficile infection (CDI). METHODS: The investigation was a retrospective, multicentre, propensity score-matched analysis using a national clinical administrative database. Veterans treated for severe CDI from any Veterans Affairs Medical Center between 1 June 2011 and 30 June 2017 were included if they received fidaxomicin or an oral vancomycin regimen for treatment. The two groups were matched by the nearest-neighbour method from a propensity score derived from independent variables associated with the selection of a fidaxomicin course. RESULTS: Propensity score matching resulted in two well-matched cohorts consisting of 213 fidaxomicin and 639 oral vancomycin courses. No statistically-significant difference was found for the primary outcome of combined clinical failure or recurrence (68/213 (31.9%) versus 163/639 (25.5%), respectively, p 0.071). Additionally, no statistically significant differences were found for the secondary outcomes of 30-day (23/213 (10.8%) versus 75/639 (11.7%), respectively, p 0.71), 90-day (48/213 (22.5%) versus 140/639 (21.9%), respectively, p 0.85), and 180-day mortality (62/213 (29.1%) versus 186/639 (29.1%), respectively, p 1.0) between the two treatment groups. CONCLUSIONS: Courses of fidaxomicin or oral vancomycin for severe CDI resulted in similar treatment outcomes. Study findings are consistent with current treatment guideline recommendations for the use of either agent in the management of severe CDI.

Evaluation of fidaxomicin usage patterns and outcomes for Clostridium difficile infection across the United States Veterans Health Administration.

WHAT IS KNOWN AND OBJECTIVE: Fidaxomicin was recently approved for the treatment of Clostridium difficile infection (CDI). Limited data on its use exist outside of the phase 3 trials. The purposes of this study were to assess the compliance with the Veterans Health Administration (VHA) fidaxomicin criteria for use and describe patient characteristics and outcomes following fidaxomicin treatment for CDI using real-world data within the VHA system. METHODS: This was a multicentre, retrospective, observational study including all adult patients who received at least 1 dose of fidaxomicin at any Veterans Affairs Medical Center. RESULTS AND DISCUSSION: A total of 880 unique patients received 1098 courses of fidaxomicin, resulting in an overall usage rate per C. difficile-positive laboratory test of 1.98%. The rate of fidaxomicin courses per 1000 C. difficile-positive diagnostic tests increased steadily from 2011 through 2015 and plateaued from 2015 to 2016. Compliance with the VHA criteria for use was low (9.1%). The majority of courses were given for a first recurrence (25.0%), followed by an initial episode (23.9%) of CDI. The failure and recurrence rates were 6.8% and 24.4%, respectively. WHAT IS NEW AND CONCLUSION: Although overall use of fidaxomicin was low, compliance with the VHA criteria for use was also low, suggesting that the criteria may need to be revised. Further studies are warranted to clarify the role of fidaxomicin in clinical practice.

Prevalence of the Clostridium difficile BI/NAP1/027 strain across the United States Veterans Health Administration.

OBJECTIVES: The increased incidence and severity of Clostridium difficile infection (CDI) are thought to result partly from the emergence of the hypervirulent BI/NAP1/027 strain. Limited recent data are available on the prevalence of BI/NAP1/027 in the United States (US). The objective of this study was to assess the recent prevalence of BI/NAP1/027 within the US Veterans Health Administration (VHA). METHODS: Patients with CDI at any Veterans Affairs Medical Center found to routinely test for the presence of BI/NAP1/027 during the study period were included between 1 June 2011 and 30 June 2016 in this retrospective, observational, nationwide study. RESULTS: In total, 7571 patients had 8224 positive C. difficile tests that had a corresponding BI/NAP1/027 test. Of those, there were 1810 (22.0%) presumptive positive for BI/NAP1/027. The overall prevalence of BI/NAP1/027 decreased from a high of 26.2% in 2013 to 16.9% in 2016. Statistically significant reductions in rates from 2012 to 2016 occurred in seven of nine US Census Bureau regions. CONCLUSIONS: The prevalence of C. difficile with the BI/NAP1/027 strain was 22.0% across the VHA between 2012 and 2016. Further studies are needed to confirm these results and for continued monitoring of the trends in BI/NAP1/027 prevalence.

4α-phorbol 12,13-didecanoate activates cultured mouse dorsal root ganglia neurons independently of TRPV4.

BACKGROUND AND PURPOSE: The Ca(2+) -permeable cation channel TRPV4 is activated by mechanical disturbance of the cell membrane and is implicated in mechanical hyperalgesia. Nerve growth factor (NGF) is increased during inflammation and causes mechanical hyperalgesia. 4α-phorbol 12,13-didecanoate (4αPDD) has been described as a selective TRPV4 agonist. We investigated NGF-induced hyperalgesia in TRPV4 wild-type (+/+) and knockout (-/-) mice, and the increases in [Ca(2+) ](i) produced by 4αPDD in cultured mouse dorsal root ganglia neurons following exposure to NGF. EXPERIMENTAL APPROACH: Withdrawal thresholds to heat, von Frey hairs and pressure were measured in mice before and after systemic administration of NGF. Changes in intracellular Ca(2+) concentration were measured by ratiometric imaging with Fura-2 in cultured DRG and trigeminal ganglia (TG) neurons during perfusion of TRPV4 agonists. KEY RESULTS: Administration of NGF caused a significant sensitization to heat and von Frey stimuli in TRPV4 +/+ and -/- mice, but only TRPV4 +/+ mice showed sensitization to noxious pressure. 4αPDD stimulated a dose-dependent increase in [Ca(2+) ](i) in neurons from +/+ and -/- mice, with the proportion of responding neurons and magnitude of increase unaffected by the genotype. In contrast, the selective TRPV4 agonist GSK1016790A failed to stimulate an increase in intracellular Ca(2+) in cultured neurons. Responses to 4αPDD were unaffected by pretreatment with NGF. CONCLUSIONS AND IMPLICATIONS: TRPV4 contributes to mechanosensation in vivo, but there is little evidence for functional TRPV4 in cultured DRG and TG neurons. We conclude that 4αPDD activates these neurons independently of TRPV4, so it is not appropriate to refer to 4αPDD as a selective TRPV4 agonist.

Pain-like behaviour and spinal changes in the monosodium iodoacetate model of osteoarthritis in C57Bl/6 mice.

BACKGROUND: Osteoarthritis (OA) is a highly prevalent, age-related pain condition that poses a significant clinical problem. Here, in the monosodium iodoacetate (MIA) model of OA, we have characterized pain behaviours and associated changes at the first pain synapse in the dorsal horn of the spinal cord. METHODS: Mice received intra-articular injections of 0.5, 0.75 and 1 mg MIA and mechanical paw withdrawal threshold was monitored for up to 4 weeks. An intrathecal injection of peptide antagonist calcitonin gene-related peptide (CGRP8-37 ) was given 3 weeks post MIA and paw withdrawal thresholds were measured after 1 and 3 h. Immunohistochemical analysis of the lumbar dorsal horn was carried out and activity-evoked CGRP release was measured from isolated lumbar dorsal horn slices - with dorsal roots attached. RESULTS: By 2 weeks after intra-articular MIA injection, mechanical hypersensitivity was established in the ipsilateral hindpaw. There was no evidence of sensory neuron damage in lumbar dorsal root ganglia 7 days after 1 mg MIA. However, both dorsal horn neuron activation and microglial response (Fos and Iba-1 immunostaining) but not reactive astrocytes (glial fibrillary acidic protein) were observed. Evoked CGRP release was greater from dorsal horn slices of MIA-treated mice compared with control. Furthermore, intrathecal administration of peptide antagonist CGRP8-37 acutely attenuated established MIA-induced mechanical hypersensitivity. CONCLUSIONS: Intra-articular MIA is associated with referred mechanical hypersensitivity and increased release of CGRP from primary afferent fibres in the dorsal horn where second-order neuron activation is associated with a microglial response. Antagonism of CGRP receptor activation provides a therapeutic avenue for the treatment of pain in OA.

Familial prevalence of uterine fibroids is associated with distinct clinical and molecular features.

BACKGROUND: Although uterine fibroids are very common, their pathogenesis and clinical behaviour are poorly understood. Since they may be prevalent in some families, we investigated whether such a prevalence was associated with distinctive clinical and molecular features. METHODS: A case-control questionnaire study of 300 multi-ethnic women with uterine fibroids at a London university hospital was undertaken, with review of case notes and immunohistochemical determination of vascular endothelial growth factor (VEGF-A) in fibroids. RESULTS: When compared with families with sporadic fibroids, familial prevalence of fibroids was associated with a higher incidence of abdominal swelling (59.1% versus 41.6%; P=0.037), menorrhagia (84.4% versus 51.9%; P=0.042), dysmenorrhoea (64.4% versus 46.3%; P=0.004), dyspareunia (43.2% versus 27.9%; P=0.012) and family history of cancers (52.3% versus 32.4%; P<0.01). The fibroids were also more multiple (mean +/- SEM: 7 +/- 0.86 versus 3 +/- 0.42; P<0.011) and strong VEGF-A expression in fibroids was more common in the familial group (64% versus 28%). Racial distribution was the same in both groups (blacks 49%, whites 33.4%, others 18.6%). CONCLUSIONS: Familial prevalence of uterine fibroids is associated with distinct clinical and molecular features that differ from those found when fibroids occur sporadically in families.

Regulation and function of spinal and peripheral neuronal B1 bradykinin receptors in inflammatory mechanical hyperalgesia.

Activation of either B1 or B2 bradykinin receptors by kinins released from damaged tissues contributes to the development and maintenance of inflammatory hyperalgesia. Whereas B2 agonists activate sensory neurones directly, B1 agonists were thought only to have indirect actions on sensory neurones. The recent discovery of constitutive B1 receptor expression in the rat nervous system lead us to re-investigate the role of neuronal B1 receptors in inflammatory hyperalgesia. Therefore we have examined B1 bradykinin receptor regulation in rat dorsal root ganglia in a model of inflammatory hyperalgesia, and correlated it with hyperalgesic behaviour. Twenty-four hours after injection of Freund's complete adjuvant into one hindpaw, there was a significant increase in B1 protein expression (measured by immunohistochemistry) in both ipsilateral and contralateral dorsal root ganglion neurones, whereas axotomy resulted in reduction of B1 protein in ipsilateral dorsal root ganglia. In behavioural experiments, the B1 antagonist desArg10HOE140, administered by either intrathecal or systemic routes, attenuated Freund's complete adjuvant-induced mechanical hyperalgesia in the inflamed paw, but did not affect mechanical allodynia. The B1 agonist, desArg9BK, did not affect paw withdrawal thresholds in nai;ve rats following intraplantar administration into the paw, whilst intrathecal administration elicited mechanical hyperalgesia. However, after Freund's complete adjuvant-induced inflammation, desArg9BK caused a marked mechanical hyperalgesia, by either route, of the contralateral, uninflamed hindpaw, correlating with the observed contralateral and ipsilateral increases in receptor levels. Our results suggest a functional role for B1 receptors expressed both in the periphery and in the spinal cord, in mechanical hyperalgesia during inflammation.

La función de los receptores cannabinoides1 centrales y periféricos en la actividad antihiperalgésica de los cannabinoides en un modelo de dolor neuropático / The role of central and peripheral cannabinoid1 receptors in the antihyperalgesic activity of cannabinoids in a model of neuropathic pain

Se examinaron los efectos de los agonistas cannabinoides en la hiperalgesia en un modelo de dolor neuro p á t i c o en la rata y se investigaron los posibles sitios de acción. Se comparó la actividad antihiperalgésica de los cannabinoides con su capacidad de provocar efectos en la conducta característicos de la actividad cannabinoide central.WIN55,212-2 (0,3-10 mg.kg- 1), CP-55,940 (0,03-1 mg.kg-1) y HU-210 (0,001-0,03 mg.kg- 1) fueron todos ellos activos en una "tétrada" de pruebas consistentes en movimiento de la cola, catalepsia, rodillo giratorio e hipotermia después de su administración subcutánea, con una jerarquía de potencias en todas ellas de HU-210 > CP-55,940 > WIN55,212-2. Los efectos de WIN55,212-2 en sendas pruebas fueron bloqueados por el antagonista cannabinoid e1 ( C B1) SR141716A. En el modelo de dolor neuro pático por ligadura parcial del nervio ciático, WIN55,212-2, CP55,940 y HU-210 produjeron una reversión completa de la hiperalgesia mecánica en las 3 horas siguientes a su administración subcutánea, con valores D5 0 de 0,52, 0,08 y 0,005 mg.kg- 1, respectivamente. En este modelo, WIN55,212-2 fue también eficaz frente a la hiperalgesia térmica y la alodinia mecánica. WIN55,212-2 produjo una marcada reversión de la hiperalgesia mecánica después de su administración intratecal, un efecto bloqueado por el antagonista CB1 SR141716A. Tras su administración intraplantar en la pata trasera ipsilateral, WIN55,212-2 revirtió hasta en un 70 por ciento la hipealgesia mecánica, aunque también se observó actividad con dosis altas tras su inyección en la pata contralateral. El efecto antihiperalgésico de WIN55,212-2 inyectado en la pata ipsilateral se bloqueó con la administración subcutánea de SR141716A, pero no se vio afectado por la administración intratecal de ese compuesto. Estos datos indican que los cannabinoides son unos agentes antihiperalgésicos muy potentes y eficaces en un modelo de dolor neuropático, una actividad que probablemente éste mediada por su acción tanto en el SNC como en la periferia (AU)

Regulation of nicotinic acetylcholine receptor numbers and function by chronic nicotine exposure.

Recent advances concerning effects of chronic nicotine exposure on nicotinic acetylcholine receptor (nAChR) expression are reviewed. Implications are assessed of these findings for roles of nAChR in health and disease and for design of drugs for treatment of neurological and psychiatric disorders. Most studies continue to show that chronic nicotine exposure induces increases in numbers of nAChR-like binding or antigenic sites ("upregulation") across all nAChR subtypes investigated, but with time- and dose-dependencies and magnitudes for these effects that are unique to subsets of nAChR subtypes. These effects appear to be post-transcriptionally based, but mechanisms involved remain obscure. With notable exceptions, most studies also show that chronic nicotine exposure induces several phases of nAChR functional loss ("desensitization" and longer-lasting "persistent inactivation") assessed in response to acute nicotinic agonist challenges. Times for onset and recovery and dose-dependencies for nicotine-induced functional loss also are nAChR subtype-specific. Some findings suggest that upregulation and functional loss are not causally- or mechanistically-related. It is suggested that upregulation is not as physiologically significant in vivo as functional effects of chronic nicotine exposure. By contrast, brain levels of nicotine in tobacco users, and perhaps levels of acetylcholine in the extracellular space, clearly are in the range that would alter the balance between nAChR in functionally ready or inactivated states. Further work is warranted to illuminate how effects of chronic nicotinic ligand exposure are integrated across nAChR subtypes and the neuronal circuits and chemical signaling pathways that they service to produce nicotine dependence and/or therapeutic benefit.

Local anesthetics noncompetitively inhibit function of four distinct nicotinic acetylcholine receptor subtypes.

Local anesthetics (LAs) are considered to act primarily by inhibiting voltage-gated Na(+) channels. However, LAs also are pharmacologically active at other ion channels including nicotinic acetylcholine receptors (nAChR). nAChR exist as a family of diverse subtypes, each of which has a unique pharmacological profile. The current studies established effects of LAs on function of four human nAChR subtypes: naturally expressed muscle-type (alpha1*-nAChR) or autonomic (alpha3beta4*-nAChR) nAChR, or heterologously expressed nAChR containing alpha4 with either beta2- or beta4-subunits (alpha4beta2- or alpha4beta4-nAChR). Of the LAs tested, those with structures containing two separated aromatic rings (e.g., proadifen and adiphenine) had the greatest inhibition potency (IC(50) values between 0.34 and 6.3 microM) but lowest selectivity (approximately 4-fold) across the four nAChR subtypes examined. From the fused, two-ring (isoquinoline backbone) class of LAs, dimethisoquin had comparatively moderate inhibition potency (IC(50) values between 2.4 and 61 microM) and approximately 30-fold selectivity across nAChR subtypes. Lidocaine, a commonly used LA from the single ring category of LAs, blocked nAChR function with IC(50) values of between 52 and 250 microM and had only approximately 5-fold selectivity across nAChR subtypes. Its quaternary triethyl ammonium analog, QX-314, had greater inhibition potency, but the trimethyl ammonium derivative, QX-222, was the least potent LA at all but the alpha4beta2-nAChR subtype. With only a few exceptions, LA effects were consistent with noncompetitive inhibition of nAChR function and occurred at therapeutic doses. These studies suggest structural determinants for LA action at diverse nAChR subtypes and that nAChR likely are clinically relevant targets of LAs.