Verticillium dahliae Vta3 promotes ELV1 virulence factor gene expression in xylem sap, but tames Mtf1-mediated late stages of fungus-plant interactions and microsclerotia formation.

Verticillium transcription activator of adhesion 3 (Vta3) is required for plant root colonization and pathogenicity of the soil-borne vascular fungus Verticillium dahliae. RNA sequencing identified Vta3-dependent genetic networks required for growth in tomato xylem sap. Vta3 affects the expression of more than 1,000 transcripts, including candidates with predicted functions in virulence and morphogenesis such as Egh16-like virulence factor 1 (Elv1) and Master transcription factor 1 (Mtf1). The genes encoding Elv1 and Mtf1 were deleted and their functions in V. dahliae growth and virulence on tomato (Solanum lycopersicum) plants were investigated using genetics, plant infection experiments, gene expression studies and phytohormone analyses. Vta3 contributes to virulence by promoting ELV1 expression, which is dispensable for vegetative growth and conidiation. Vta3 decreases disease symptoms mediated by Mtf1 in advanced stages of tomato plant colonization, while Mtf1 induces the expression of fungal effector genes and tomato pathogenesis-related protein genes. The levels of pipecolic and salicylic acids functioning in tomato defense signaling against (hemi-) biotrophic pathogens depend on the presence of MTF1, which promotes the formation of resting structures at the end of the infection cycle. In summary, the presence of VTA3 alters gene expression of virulence factors and tames the Mtf1 genetic subnetwork for late stages of plant disease progression and subsequent survival of the fungus in the soil.

Relative contributions of the novel diarylquinoline TBAJ-876 and its active metabolite to the bactericidal activity in a murine model of tuberculosis.

BACKGROUND: TBAJ-876 is a next-generation diarylquinoline. In vivo, diarylquinoline metabolites are formed with activity against Mycobacterium tuberculosis. Species-specific differences in parent drug-to-metabolite ratios might impact the translational value of animal model-based predictions. This study investigates the contribution of TBAJ-876 and its major active metabolite, TBAJ-876-M3 (M3), to the total bactericidal activity in a mouse tuberculosis model. METHODS: In vitro activity of TBAJ-876 and M3 was investigated and compared to bedaquiline. Subsequently, a dose-response study was conducted in M. tuberculosis-infected BALB/c mice treated with TBAJ-876 (1.6/6.3/25 mg/kg) or M3 (3.1/12.5/50 mg/kg). Colony-forming units in the lungs and TBAJ-876 and M3 plasma concentrations were determined. M3's contribution to TBAJ-876's bactericidal activity was estimated based on M3-exposure following TBAJ-876 treatment and corresponding M3-activity observed in M3-treated animals. RESULTS: TBAJ-876 and M3 demonstrated profound bactericidal activity. Lungs of mice treated for 4 weeks with 50 mg/kg M3 were culture-negative. Following TBAJ-876 treatment, M3-exposures were 2.2-3.6x higher than for TBAJ-876. TBAJ-876 activity was substantially attributable to M3, given its high exposure and potent activity. CONCLUSION: These findings emphasize the need to consider metabolites and their potentially distinct exposure and activity profiles compared to parent drugs to enhance the translational value of mouse model-driven predictions.

Long-Term Consumption of Nuts (Including Peanuts, Peanut Butter, Walnuts, and Other Nuts) in Relation to Risk of Frailty in Older Women: Evidence from a Cohort Study.

BACKGROUND: Adherence to a healthy diet is inversely associated with frailty. However, the relationship between nuts, a key food group of Mediterranean diet, and frailty is unclear. OBJECTIVES: This study aimed to evaluate the association between nut consumption and frailty in an aging female population. METHODS: This population-based observational study included nonfrail women (≥60 y old) in the NHS from 11 states of the United States. Outcome was incident frailty, defined as having ≥3 of the FRAIL components (fatigue, lower strength, reduced aerobic capacity, multiple chronic conditions, and significant weight loss) and assessed every 4 y from 1992 to 2016. From 1990 to 2014, FFQs were used to assess the intakes of peanuts, peanut butter, walnuts (added in 1998), and other nuts at 4-y intervals. Exposure was total nut consumption, calculated as the sum of intakes of peanuts, peanut butter, walnuts, and other nuts and categorized into <1 serving/mo, 1-3 servings/mo, 1 serving/wk, 2-4 servings/wk, and ≥5 servings/wk. The relations of intakes of peanuts, peanut butter, and walnuts with frailty were also investigated separately. Cox proportional hazards models were used to assess the associations between nut consumption and frailty after adjusting for age, smoking, BMI, EI, diet quality, and medication use. RESULTS: Among 71,704 participants, 14,195 incident frailty cases occurred over 1,165,290 person-years. The adjusted HR (95% CI) for consuming ≥5 servings/wk of nuts was 0.80 (0.73, 0.87), as compared with <1 serving/mo. Higher intakes of peanuts and walnuts, but not peanut butter, were also inversely associated with frailty. CONCLUSIONS: This large prospective cohort study showed a strong and consistent inverse association between regular nut consumption and incident frailty. This suggests that nut consumption should be further tested as a convenient public health intervention for the preservation of health and well-being in older adults.

Long-term recurrence after endoscopic versus surgical ampullectomy of sporadic ampullary adenomas: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Ampullary adenomas are treated both surgically and endoscopically, however, data comparing both techniques are lacking. We aimed to compare long-term recurrence of benign sporadic adenomas after endoscopic (EA) and surgical ampullectomy (SA). METHODS: A comprehensive literature search of multiple databases (until December 29, 2020) was performed to identify studies reporting outcomes of EA or SA of benign sporadic ampullary adenomas. The outcome was recurrence rate at 1 year, 2-year, 3 year and 5 years after EA and SA. RESULTS: A total of 39 studies with 1753 patients (1468 EA [age 61.1 ± 4.0 years, size 16.1 ± 4.0 mm], 285 SA [mean age 61.6 ± 4.48 years, size 22.7 ± 5.4 mm]) were included in the analysis. At year 1, pooled recurrence rate of EA was 13.0% (95% confidence interval [CI] 10.5-15.9], I2 = 31%) as compared to SA 14.1% (95% CI 9.5-20.3 I2 = 15.8%) (p = 0.82). Two (12.5%, [95% CI, 8.9-17.2] vs. 14.3 [95% CI, 9.1-21.6], p = 0.63), three (13.3%, [95% CI, 7.3-21.6] vs. 12.9 [95% CI, 7.3-21.6], p = 0.94) and 5 years (15.7%, [95% CI, 7.8-29.1] vs. 17.6% [95% CI, 6.2-40.8], p = 0.85) recurrence rate were comparable after EA and SA. On meta-regression, age, size of lesion or enbloc and complete resection were not significant predictors of recurrence. CONCLUSION: EA and SA of sporadic adenomas have similar recurrence rates at 1, 2, 3 and 5 years of follow up.

Higher abdominal adiposity is associated with higher lean muscle mass but lower muscle quality in middle-aged and older men and women: the Framingham Heart Study.

BACKGROUND: The objective was to determine if abdominal fat is related to poor muscle health. METHODS: This cross-sectional study included 428 males and 534 females with appendicular lean mass (ALM, kg) from dual-energy X-ray absorptiometry (DXA), grip strength (kg), and upper extremity muscle "quality" (grip strength/arm lean mass) measured (1996-2001) in the Framingham Offspring Study. Sex-specific linear regressions associated adiposity measures [waist circumference (WC, cm) and visceral adipose tissue (VAT, cm3), and subcutaneous adipose tissue (SAT, cm3)] as Z-scores with each measure of muscle, adjusting for covariates. Models were further stratified by body mass index (BMI, < 30, ≥ 30 kg/m2). RESULTS: Mean (± SD) age was 60 ± 9 years and BMI was 28.9 ± 4.6 kg/m2 (men) and 27.7 ± 5.8 kg/m2, (women). In men, the BMI-stratified analyses showed higher WC was associated with higher ALM (P < 0.0001 each) but with lower muscle quality (P < 0.02) in both BMI groups. Higher SAT was also associated with higher ALM (P = 0.0002) and lower muscle quality (P = 0.0002) in men with BMI < 30, but not in obese men. In women, higher WC, SAT, and VAT were each associated with higher ALM but lower muscle quality, particularly in obese women. Higher SAT (P = 0.05) and VAT (P = 0.04) were associated with higher quadriceps strength in women with BMI < 30 kg/m2 but not in obese women. CONCLUSIONS: Higher abdominal fat may be associated with greater lean mass but poorer muscle quality, particularly in obese women. This suggests that adipose tissue may have endocrine influences on muscle, which should be confirmed in longitudinal studies.

Dairy food intake is not associated with spinal trabecular bone score in men and women: the Framingham Osteoporosis Study.

BACKGROUND: Previous studies reported that dairy foods are associated with higher areal bone mineral density (BMD) in older adults. However, data on bone texture are lacking. We determined the association of dairy food intake (milk, yogurt, cheese, milk + yogurt and milk + yogurt + cheese) with spinal trabecular bone score (TBS). METHODS: In this cross-sectional study, a validated semi-quantitative food frequency questionnaire was used to assess dairy food intake (servings/wk). TBS, an analysis of bone texture, was calculated from dual energy X-ray absorptiometry (DXA) scans. Sex-specific multivariable linear regression was used to estimate the association of dairy food intake (energy adjusted via residual methods) with each bone measure adjusting for covariates. RESULTS: Mean age of 4,740 participants was 49 (SD: 13) years and mean milk + yogurt + cheese intake was 10.1 (SD: 8.4) servings/week in men and 10.9 (SD: 8.0) servings/week in women. There were no associations between dairy food intake and spinal TBS in adjusted models. CONCLUSIONS: In this cohort of primarily healthy adults, dairy intake was not associated with bone texture.

Surgical management outcomes of intracranial arteriovenous malformations after preoperative embolization: a systematic review and meta-analysis.

OBJECTIVE: Preoperative embolization for brain arteriovenous malformations (AVMs) has been shown to mitigate morbidity for high-risk AVMs, chiefly by reducing lesional blood flow before resection. However, associated risks include postembolization AVM rupture, and the effect of preoperative embolization on outcome remains uncertain. We performed a meta-analysis of the literature on preoperative embolization for microsurgically treated AVMs. METHODS: A systematic review and meta-analysis were conducted of all English-language publications reporting clinical outcomes after combined embolization and surgical resection for AVMs. Single- and 2-arm analyses were performed using random-effects modeling. RESULTS: Thirty-six studies with 2108 patients were included in this analysis. Most patients (90.6%) who underwent embolization had at least a 50% obliteration of AVMs on posttreatment preoperative angiography, with a mean rate of obliteration of approximately 80% (range 28.8-100%). Among patients who had combined treatment, 3.4% (95% confidence interval [CI] 2.1-4.6%) experienced embolization-related hemorrhagic complications before surgery. Both treatment groups achieved excellent postsurgical complete resection rates (odds ratio [OR] 1.05; 95% CI 0.60-1.85). Neither the clinical outcome (OR 1.42; 95% CI 0.84-2.40) nor the total number of hemorrhagic complications (OR 1.84; 95% CI 0.88-3.85) was significantly different between the treatment groups. CONCLUSIONS: In this meta-analysis, preoperative embolization appears to have substantially reduced the lesional volume with active AV shunting before AVM resection. Anecdotally, preoperative embolization facilitates safe and efficient resection; however, differences in outcomes were not significant. The decision to pursue preoperative embolization remains a nuanced decision based on individual lesion anatomy and treatment team experience.

Management of injuries on the 16th-century battlefield: Ambroise Paré's contributions to neurosurgery and functional recovery.

During the 1536 siege of Turin in northern Italy, a young French barber-surgeon abandoned the conventional treatment of battle-inflicted wounds, launching a revolution in military medicine and surgical techniques. Ambroise Paré (1510-1590) was born into a working-class Huguenot family in Laval, France, during an era when surgery was not considered a respectable profession. He rose from humble origins as a barber-surgeon, a low-ranked occupation in the French medical hierarchy, to become a royal surgeon (chirurgien ordinaire du Roi) serving 4 consecutive French monarchs. His innovative ideas and surgical practice were a response to the environment created by new military technology on 16th-century European battlefields. Gunpowder weapons caused unfamiliar, complicated injuries that challenged Paré to develop new techniques and surgical instruments. Although Paré's contributions to the treatment of wounds and functional prosthetics are documented, a deeper appreciation of his role in military neurosurgery is needed. This paper examines archives, primary texts, and written accounts by Paré that reveal specific patient cases highlighting his innovative contributions to neurotrauma and neurosurgery during demanding and harrowing circumstances, on and off the battlefield, in 16th-century France. Notably, trepanation indications increased because of battlefield head injuries, and Paré frequently described this technique and improved the design of the trepan tool. His contribution to neurologically related topics is extensive; there are more chapters devoted to the nervous system than to any other organ system in his compendium, Oeuvres. Regarding anatomical knowledge as fundamentally important and admiring the contemporary contributions of Andreas Vesalius, Paré reproduced many images from Vesalius' works at his own great expense. The manner in which Paré's participation in military expeditions enabled collaboration with multidisciplinary artisans on devices, including surgical tools and prosthetics, to restore neurologically associated functionality is also discussed. Deeply religious, in a life filled with adventure, and serving in often horrendous conditions during a time when Galenic dogma still dominated medical practice, Paré developed a reputation for logic, empiricism, technology, and careful treatment. "I have [had] the opportunity to praise God, for what he called me to do in medical operation, which is commonly called surgery, which could not be bought with gold or silver, but by only virtue and great experimentation."

Real-time intraoperative surgical telepathology using confocal laser endomicroscopy.

OBJECTIVE: Communication between neurosurgeons and pathologists is mandatory for intraoperative decision-making and optimization of resection, especially for invasive masses. Handheld confocal laser endomicroscopy (CLE) technology provides in vivo intraoperative visualization of tissue histoarchitecture at cellular resolution. The authors evaluated the feasibility of using an innovative surgical telepathology software platform (TSP) to establish real-time, on-the-fly remote communication between the neurosurgeon using CLE and the pathologist. METHODS: CLE and a TSP were integrated into the surgical workflow for 11 patients with brain masses (6 patients with gliomas, 3 with other primary tumors, 1 with metastasis, and 1 with reactive brain tissue). Neurosurgeons used CLE to generate video-flow images of the operative field that were displayed on monitors in the operating room. The pathologist simultaneously viewed video-flow CLE imaging using a digital tablet and communicated with the surgeon while physically located outside the operating room (1 pathologist was in another state, 4 were at home, and 6 were elsewhere in the hospital). Interpretations of the still CLE images and video-flow CLE imaging were compared with the findings on the corresponding frozen and permanent H&E histology sections. RESULTS: Overall, 24 optical biopsies were acquired with mean ± SD 2 ± 1 optical biopsies per case. The mean duration of CLE system use was 1 ± 0.3 minutes/case and 0.25 ± 0.23 seconds/optical biopsy. The first image with identifiable histopathological features was acquired within 6 ± 0.1 seconds. Frozen sections were processed within 23 ± 2.8 minutes, which was significantly longer than CLE usage (p < 0.001). Video-flow CLE was used to correctly interpret tissue histoarchitecture in 96% of optical biopsies, which was substantially higher than the accuracy of using still CLE images (63%) (p = 0.005). CONCLUSIONS: When CLE is employed in tandem with a TSP, neurosurgeons and pathologists can view and interpret CLE images remotely and in real time without the need to biopsy tissue. A TSP allowed neurosurgeons to receive real-time feedback on the optically interrogated tissue microstructure, thereby improving cross-functional communication and intraoperative decision-making and resulting in significant workflow advantages over the use of frozen section analysis.

Hydrogen peroxide assisted endoscopic necrosectomy for walled-off pancreatic necrosis: A systematic review and meta-analysis.

BACKGROUND AND AIMS: Endoscopic necrosectomy (EN) is the preferred approach for management of symptomatic or infected walled-off pancreatic necrosis (WOPN). Hydrogen peroxide (H2O2) has been reported to be a good adjunctive therapy for EN. We performed a systematic review and meta-analysis to evaluate effectiveness and safety of H2O2 assisted EN for WOPN. METHODS: A comprehensive search of multiple databases (through December 2020) was performed to identify studies that reported outcomes of H2O2 assisted EN for WOPN. Outcomes assessed included clinical success, technical success, and adverse events. RESULTS: A total of 454 patients with mean age (47.3 ± 7.9 years) and WOPN size (12.4 ± 3.1 cm) were included from 15 studies. The median H2O2 concentration was 3% (range 0.1-3%), with dilution and volume ranging from 1:1 to 10:1 and 20 ml to 1 L, respectively. The rates of technical success, clinical success and adverse events was 97.3% (95% confidence interval [CI]: 94.8-98.6, I2 = 0), 89.8% (95% CI: 86.3-92.5, I2 = 0) and 17.9% (95% CI: 12.6-24.7, I2 = 38), respectively. The most common adverse event was bleeding (7.1%) followed by stent migration (5.3%). On meta-regression, WOPN size, patient age, use of metal stent, number of necrosectomies and transgastric access were not significant predictor for technical success, clinical success or adverse events. CONCLUSION: H2O2 assisted EN is effective and safe for management of WOPN. Its use may be encouraged, and future randomized controlled studies are needed to study the optimal technique, concentration and best predictors of success.

Therapeutic Efficacy of Novel Antimicrobial Peptide AA139-Nanomedicines in a Multidrug-Resistant Klebsiella pneumoniae Pneumonia-Septicemia Model in Rats.

Antimicrobial peptides (AMPs) have seen limited clinical use as antimicrobial agents, largely due to issues relating to toxicity, short biological half-life, and lack of efficacy against Gram-negative bacteria. However, the development of novel AMP-nanomedicines, i.e., AMPs entrapped in nanoparticles, has the potential to ameliorate these clinical problems. The authors investigated two novel nanomedicines based on AA139, an AMP currently in development for the treatment of multidrug-resistant Gram-negative infections. AA139 was entrapped in polymeric nanoparticles (PNPs) or lipid-core micelles (MCLs). The antimicrobial activity of AA139-PNP and AA139-MCL was determined in vitro The biodistribution and limiting doses of AA139-nanomedicines were determined in uninfected rats via endotracheal aerosolization. The early bacterial killing activity of the AA139-nanomedicines in infected lungs was assessed in a rat model of pneumonia-septicemia caused by extended-spectrum ß-lactamase-producing Klebsiella pneumoniae In this model, the therapeutic efficacy was determined by once-daily (q24h) administration over 10 days. Both AA139-nanomedicines showed equivalent in vitro antimicrobial activities (similar to free AA139). In uninfected rats, they exhibited longer residence times in the lungs than free AA139 (∼20% longer for AA139-PNP and ∼80% longer for AA139-MCL), as well as reduced toxicity, enabling a higher limiting dose. In rats with pneumonia-septicemia, both AA139-nanomedicines showed significantly improved therapeutic efficacy in terms of an extended rat survival time, although survival of all rats was not achieved. These results demonstrate potential advantages that can be achieved using AMP-nanomedicines. AA139-PNP and AA139-MCL may be promising novel therapeutic agents for the treatment of patients suffering from multidrug-resistant Gram-negative pneumonia-septicemia.

Learning-induced intrinsic and synaptic plasticity in the rodent medial prefrontal cortex.

In rodents, the anterior cingulate (ACC), prelimbic (PL), and infralimbic cortex (IL) comprise the medial prefrontal cortex (mPFC). Through extensive connections with cortical and subcortical structures, the mPFC plays a key modulatory role in the neuronal circuits underlying associative fear and reward learning. In this article, we have compiled the evidence that associative learning induces plasticity in both the intrinsic and synaptic excitability of mPFC neurons to modulate conditioned fear and cocaine seeking behavior. The literature highlights the accumulating evidence that plasticity in the intrinsic excitability of mPFC neurons represents a major cellular mechanism that interacts with synaptic changes to alter the impact of the mPFC on fear and reward circuits.

Joint hypermobility is not positively associated with prevalent multiple joint osteoarthritis: a cross-sectional study of older adults.

BACKGROUND: This cross-sectional study evaluated associations of joint hypermobility and multiple joint osteoarthritis (MJOA) in a community-based cohort of adults 45+ years of age. METHODS: MJOA and joint hypermobility data were from 1677 participants (mean age 69 years, 68% women) who completed research clinic visits during 2003-2010. Prevalent MJOA was defined in four ways. Radiographic OA (rOA) was defined as Kellgren-Lawrence (KL) > 2 at any included study joint; symptomatic OA (sxOA) required both symptoms and rOA in a joint. Joint hypermobility was defined as a Beighton score of > 4. Separate logistic regression models were used to estimate odds ratios (OR) between joint hypermobility and each MJOA definition, adjusting for age, sex, race, body mass index, and baseline visit. RESULTS: In this cohort, 4% had Beighton score > 4 and 63% met any definition of MJOA. Joint hypermobility was associated with significantly lower odds of radiographic and symptomatic MJOA-1 (multiple joint OA-definition 1: involvement of > 1 IP (interphalangeal) nodes and > 2 sites of hip, knee, and spine; 74 and 58% lower, respectively). However, for the other MJOA definitions (i.e., MJOA-2:involvement of > 2 IP joints, > 1 carpometacarpal [CMC] joints, and knee or hip sites; MJOA-3: involvement of > 5 joint sites from among distal interphalangeal, proximal interphalangeal, CMC, hip, knee, or spine sites; and MJOA-4:involvement of > 2 lower body sites (hip, knee, or spine), there were no statistically significant associations. For associations between site-specific hypermobility and any MJOA definition, most adjusted ORs were less than one, but few were statistically significant. CONCLUSIONS: Overall, joint hypermobility was not positively associated with any definition of prevalent MJOA in this cohort, and an inverse association existed with one definition of MJOA. Longitudinal studies are needed to determine the contribution of hypermobility to the incidence and progression of MJOA outcomes.

Relationship of joint hypermobility with low Back pain and lumbar spine osteoarthritis.

BACKGROUND: Chronic low back pain (cLBP) affects millions of Americans and costs billions. Studies suggest a link between cLBP and joint hypermobility. METHODS: We conducted cross-sectional primary analyses of joint hypermobility and cLBP, lumbar spine osteoarthritis (OA), and lumbar facet joint OA (FOA) in 3 large studies-the Generalized Osteoarthritis Study, Genetics of Generalized Osteoarthritis Study, and Johnston County Osteoarthritis Project (total n = 5072). Associations of joint hypermobility and Beighton trunk flexion with cLBP and lumbar OA were estimated using separate adjusted logistic regression models. Adjusted pooled odds ratios (pORs) and 95% confidence intervals (CIs) were then summarized-using random effect univariate, multivariate crude, and adjusted models-and heterogeneity was determined (I2 statistic). RESULTS: In univariate models, hypermobility was associated with symptomatic FOA (pOR = 0.64 [95% CI 0.44, 0.93]) but this result was not found in the multivariate models. In multivariate adjusted models, hypermobility was not significantly associated with cLBP and lumbar OA, but trunk flexion was inversely associated with cLBP (pOR = 0.40 [95% 0.26, 0.62]), spine OA (pOR = 0.66 [95% CI 0.50, 0.87]), symptomatic spine OA (pOR = 0.39 [95% CI 0.28, 0.53]), and symptomatic FOA (pOR = 0.53 [95% CI 0.37, 0.77]). Generally, between-study heterogeneity was moderate-high. CONCLUSIONS: Hypermobility was not associated with cLBP or lumbar OA. The inverse association of trunk flexion with cLBP and lumbar OA may indicate a role for a flexible spine in avoiding or managing these conditions.

Contrasting the Role of xCT and GLT-1 Upregulation in the Ability of Ceftriaxone to Attenuate the Cue-Induced Reinstatement of Cocaine Seeking and Normalize AMPA Receptor Subunit Expression.

Long-term treatment with ceftriaxone attenuates the reinstatement of cocaine seeking while increasing the function of the glutamate transporter 1 (GLT-1) and system xC- (Sxc) in the nucleus accumbens core (NAc). Sxc contributes the majority of nonsynaptic extracellular glutamate in the NAc, while GLT-1 is responsible for the majority of glutamate uptake. Here we used antisense to decrease the expression of GLT-1 and xCT (a catalytic subunit of Sxc) to determine the relative importance of both proteins in mediating the ability of ceftriaxone to prevent cue-induced reinstatement of cocaine seeking and normalize glutamatergic proteins in the NAc of rats. Intra-NAc xCT knockdown prevented ceftriaxone from attenuating reinstatement and from upregulating GLT-1 and resulted in increased surface expression of AMPA receptor subunits GluA1 and GluA2. Intra-NAc GLT-1 knockdown also prevented ceftriaxone from attenuating reinstatement and from upregulating xCT expression, without affecting GluA1 and GluA2 expression. In the absence of cocaine or ceftriaxone treatment, xCT knockdown in the NAc increased the expression of both GluA1 and GluA2 without affecting GLT-1 expression while GLT-1 knockdown had no effect. PCR and immunoprecipitation of GLT-1 revealed that ceftriaxone does not upregulate GLT-1 and xCT through a transcriptional mechanism, and their coregulation by ceftriaxone is not mediated by physical interaction. These data support important and distinct roles for xCT and GLT-1 in the actions of ceftriaxone and add to a body of literature finding evidence for coregulation of these transporters. Our results also point to xCT expression and subsequent basal glutamate levels as being a key mediator of AMPA receptor expression in the NAc.SIGNIFICANCE STATEMENT Ceftriaxone attenuates the reinstatement of cocaine, alcohol, and heroin seeking. The mechanism of action of this behavioral effect has been attributed to glutamate transporter 1 (GLT-1) and xCT (a catalytic subunit of Sxc)/Sxc upregulation in the nucleus accumbens core. Here we used an antisense strategy to knock down GLT-1 or xCT in the nucleus accumbens core and examined the behavioral and molecular consequences. While upregulation of both xCT and GLT-1 are essential to the ability of ceftriaxone to attenuate cue-induced reinstatement of cocaine seeking, each protein uniquely affects the expression of other glutamate receptor and transporter proteins. We also report that reducing basal glutamate levels through the manipulation of xCT expression increases the surface expression of AMPA receptor subunits, providing insight to the mechanism by which cocaine alters AMPA surface expression.

Chitinase Induction Prior to Caspofungin Treatment of Experimental Invasive Aspergillosis in Neutropenic Rats Does Not Enhance Survival.

Host chitinases, chitotriosidase and acidic mammalian chitinase (AMCase), improved the antifungal activity of caspofungin (CAS) against Aspergillus fumigatus in vitro These chitinases are not constitutively expressed in the lung. Here, we investigated whether chitosan derivatives were able to induce chitinase activity in the lungs of neutropenic rats and, if so, whether these chitinases were able to prolong survival of rats with invasive pulmonary aspergillosis (IPA) or of rats with IPA and treated with CAS. An oligosaccharide-lactate chitosan (OLC) derivative was instilled in the left lung of neutropenic rats to induce chitotriosidase and AMCase activities. Rats instilled with OLC or with phosphate-buffered saline (PBS) were subsequently infected with A. fumigatus and then treated with suboptimal doses of CAS. Survival, histopathology, and galactomannan indexes were determined. Instillation of OLC resulted in chitotriosidase and AMCase activities. However, instillation of OLC did not prolong rat survival when rats were subsequently challenged with A. fumigatus In 5 of 7 rats instilled with OLC, the fungal foci in the lungs were smaller than those in rats instilled with PBS. Instillation of OLC did not significantly enhance the survival of neutropenic rats challenged with A. fumigatus and treated with a suboptimal dosage of CAS. Chitotriosidase and AMCase activities can be induced with OLC, but the presence of active chitinases in the lung did not prevent the development of IPA or significantly enhance the therapeutic outcome of CAS treatment.

Design of Aminobenzothiazole Inhibitors of Rho Kinases 1 and 2 by Using Protein Kinase†A as a Structure Surrogate.

We describe the design, synthesis, and structure-activity relationships (SARs) of a series of 2-aminobenzothiazole inhibitors of Rho kinases (ROCKs) 1 and 2, which were optimized to low nanomolar potencies by use of protein kinase A (PKA) as a structure surrogate to guide compound design. A subset of these molecules also showed robust activity in a cell-based myosin phosphatase assay and in a mechanical hyperalgesia in vivo pain model.

Interaction between caffeine and polymorphisms of glutamate ionotropic receptor NMDA type subunit 2A (GRIN2A) and cytochrome P450 1A2 (CYP1A2) on Parkinson's disease risk.

BACKGROUND: Caffeine intake has been inversely associated with Parkinson's disease (PD) risk. This relationship may be modified by polymorphisms of glutamate ionotropic receptor NMDA type subunit 2A (GRIN2A) and cytochrome P450 1A2 (CYP1A2), but the results of previous studies have been inconsistent. METHOD: We examined the interaction of caffeine intake with GRIN2A-rs4998386 and CYP1A2-rs762551 polymorphisms in influencing PD risk among 829 incident cases of PD and 2,754 matched controls selected among participants in the following 3 large prospective ongoing cohorts: the Nurses' Health Study, the Health Professionals' Follow-up Study, and the Cancer Prevention Study II Nutrition Cohort. Matching factors included cohort, birth year, source of DNA, date of DNA collection, and race. Relative risks and 95% confidence intervals were estimated using conditional logistic models. Interactions were tested both on the multiplicative scale and on the additive scale. RESULTS: Overall, caffeine intake was associated with a lower PD risk (adjusted relative risk for highest versus lowest tertile = 0.70; 95% confidence interval, 0.57-0.86; p < .001). In analyses stratified by the GRIN2A-rs4998386 genotype, the multivariable-adjusted relative risk of PD comparing the highest to the lowest tertile of caffeine was 0.69 (95% confidence interval, 0.55-0.88; p < .01) among individuals homozygous for the C allele, and 0.85 (95% confidence interval, 0.55-1.32; p = .47; pRERI = .43) among carriers for the T allele. Interactions between caffeine and GRIN2A were not significant in either the multiplicative or additive scales. We also did not observe significant interactions for CYP1A2-rs762551 and incident PD risk. CONCLUSION: Our findings do not support the hypothesis of an interaction between the GRIN2A-rs4998386 or CYP1A2-rs762551 polymorphism and caffeine intake in determining PD risk. © 2018 International Parkinson and Movement Disorder Society.

Lower Lean Mass Measured by Dual-Energy X-ray Absorptiometry (DXA) is Not Associated with Increased Risk of Hip Fracture in Women: The Framingham Osteoporosis Study.

Although muscle mass influences strength in older adults, it is unclear whether low lean mass measured by dual-energy X-ray absorptiometry (DXA) is an independent risk factor for hip fracture. Our objective was to determine the association between DXA lean mass and incident hip fracture risk among 1978 women aged 50 years and older participating in the Framingham Study Original and Offspring cohorts. Leg and total body lean mass (kg) were assessed from whole-body DXA scans collected in 1992-2001. Hip fracture follow-up extended from DXA assessment to the occurrence of fracture, death, drop-out, or end of follow-up in 2007. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) estimating the relative risk of hip fracture associated with a 1-kg increase in baseline lean mass. Mean age was 66 years (range 50-93). Over a median of 8 years of follow-up, 99 hip fractures occurred. In models adjusted for age, height, study cohort, and percent total body fat, neither leg (HR 1.11; 95% CI 0.94, 1.31) nor total body (HR 1.06; 95% CI 0.99, 1.13) lean mass were associated with hip fracture. After further adjustment for femoral neck bone mineral density, leg lean mass results were similar (HR 1.10; 95% CI 0.93, 1.30). In contrast, 1 kg greater total body lean mass was associated with 9% higher hip fracture risk (HR 1.09; 95% CI 1.02, 1.18). Our findings suggest that in women, lower lean mass measured by DXA is not associated with increased risk of hip fracture.