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Purpose: Comparison of two different methods for management of second stage of labor: immediate pushing at complete cervical dilation of 10 cm and delayed pushing 90 minutes after complete cervical dilation. Study Design and Methods: This study was a randomized clinical trial in a labor and delivery unit of a not-for-profit community hospital. A sample of 44 nulliparous mothers with continuous epidural anesthesia were studied after random assignment to treatment groups. Subjects were managed with either immediate or delayed pushing during the second stage of labor at the time cervical dilation was complete. The primary outcome measure was the length of pushing during second stage of labor. Secondary outcomes included length of second stage of labor, maternal fatigue and perineal injuries, and fetal heart rate decelerations. Two-tailed, unpaired Student's t-tests and Chi-square analysis were used for data analysis. Level of significance was set at p < .01 following a Bonferroni correction for multiple t-tests. Results: A total of 44 subjects received the study intervention (N = 28 immediate pushing; N = 16 delayed pushing). The delayed pushing group had significantly shorter amount of time spent in pushing compared with the immediate pushing group (38.9 ± 6.9 vs. 78.7 ± 7.9 minutes, respectively, p = .002). Maternal fatigue scores, perineal injuries, and fetal heart rate decelerations were similar for both groups. Clinical Implications: Delaying pushing for up to 90 minutes after complete cervical dilation resulted in a significant decrease in the time mothers spent pushing without a significant increase in total time in second stage of labor.In clinical practice, healthcare providers sometimes resist delaying the onset of pushing after second stage of labor has begun because of a belief it will increase labor time. This study's finding of a 51% reduction in pushing time when mothers delay pushing for up to 90 minutes, with no significant increase in overall time for second stage of labor, disputes that concern. [ABSTRACT FROM AUTHOR]

The aim of this study was to assess any differences between the inclusion or omission of medical bowel confinement relative to postoperative morbidity and patient tolerance after anorectal reconstructive surgery.Between January 1995 and February 1997 a prospective randomized trial was conducted for patients without stomas who underwent anorectal reconstructive surgery. All patients were randomly assigned either to medical bowel confinement (a clear liquid diet with loperamide 4 mg by mouth three times per day and codeine phosphate 30 mg by mouth four times per day until the third postoperative day) or to a regular diet, beginning the day of surgery. All patients in both groups underwent the identical preoperative oral mechanical preparation, preoperative oral and parenteral antibiotics, and postoperative antibiotics. Wound closure and wound care were identical in both groups.Fifty-four patients (46 females) were prospectively, randomly assigned to medical bowel confinement (n=27; 50 percent) or a regular diet (n=27; 50 percent); the mean ages were 51.0 (range, 28-80) and 47.2 (range, 23-87) years, respectively. Indications for surgery were fecal incontinence in 32 patients, complicated fistulas in 17 patients, anal stenosis in 4 patients, a Whitehead deformity in 1 patient, and a chronic unhealed fissure in 1 patient. Fifty-four patients underwent 55 procedures: 32 patients underwent sphincteroplasty, 18 patients underwent transanal advancement flaps, and 5 patients underwent anoplasties. There were no differences between the two groups in the incidence of either septic or urologic complications. Nausea and vomiting were recorded in seven (26 percent) medical bowel confinement and three (11 percent) regular-diet patients. The first postoperative bowel movement occurred at a mean of 3.9 days in the medical bowel confinement group and 2.8 days in the regular diet group (P <0.05). Fecal impaction occurred in seven (26 percent) of the patients in the medical bowel confinement group and two (7 percent) of the patients in the regular diet group. Hospital charges analysis showed a mean cost of hospitalization of $12,586.00 (range, $3,436.00-$20,375.00) for the medical bowel confinement group and $10,685.00 (range, $3,954.00-$18,574.00) in the regular diet group, representing a mean difference of $1,901.00 (P =0.06). Mean follow-up was 13 months for both groups (range, 1-24 months in the regular diet group and 2-25 months in the medical bowel confinement group). No statistical difference was shown in the functional outcome of sphincteroplasties between the medical bowel confinement group and the regular diet group.The outcome of reconstructive anorectal surgery was not adversely affected by the omission of medical bowel confinement. Moreover, cost savings can be achieved by the omission of routine bowel confinement. [ABSTRACT FROM AUTHOR]

The stimulated gracilis neosphincter is accepted as a viable option in select patients with fecal incontinence. The aim of this study was to review the initial problems and complications.A prospective analysis of all patients who underwent this procedure was undertaken. Stage I consisted of the distal vascular delay of the muscle and creation of a temporary stoma. Stage II was the transposition of the muscle and implantation of the stimulator and electrodes. Low frequency electrical stimulation was applied to the muscle for 12 weeks, after which Stage III (stoma closure) was undertaken.From March 1993 to December 1995, 17 patients (9 females and 8 males) with a mean age of 42.2 (range, 19-72) years underwent the procedure. One patient died from pancreatitis and another from small-bowel adenocarcinoma, three and six months after the procedure, respectively. Two patients (one with Crohn's disease) required permanent stomas. One additional patient required a permanent stoma because of lead fibrosis. Other complications noted during ascent of the learning curve included seroma of the thigh incision, excoriation of the skin above the stimulator, fecal impaction, anal fissure, parastomal hernia, rotation of the stimulator, premature battery discharge, fracture of the lead, perineal skin irritation, perineal sepsis, rupture of the tendon, tendon erosion, muscle fatigue during programming sessions, and electrode displacement from the nerve or fibrosis around the nerve. However, ultimately after rectification of these problems, 13 of the 15 eligible patients had stoma reversal. Manometric results showed an average basal pressure of 43 mmHg and an average maximum squeeze pressure that increased from 36 mmHg before surgery to 145 mmHg by stimulation (P <0.01). Based on objective functional questionnaires, 9 of 15 (60 percent) evaluable patients reported improvement in continence, social interactions, and quality of life. Three of these nine patients require daily use of enemas.Although the stimulated gracilis operation is a feasible procedure for selected patients with severe incontinence, the learning curve is steep. Although the ultimate outcome in a selected group of patients can be very gratifying, major technical modifications are required before use beyond a research protocol setting. Furthermore, patients must have the psychological strength, emotional commitment, and financial resources that may be necessary for multiple revisional surgeries or ultimate device failure. [ABSTRACT FROM AUTHOR]

Maxillary osteotomies as a component of orthognathic surgery disrupt the normal anatomy and function of the sinus. The osteotomy with advancement of the inferior component of the sinus leaves a bony and mucosal opening in the sinus. Immediately after surgery, nasal drainage is impeded because of intranasal swelling. Acute and chronic maxillary sinusitis would be expected; however, its incidence as an expected complication is not well documented. A systematic review and meta-analysis was completed using PubMed to determine the incidence of sinusitis after maxillary orthognathic surgery. Studies were reviewed by two authors, and incidence data were extracted. Two hundred six articles were identified with 24 meeting the criteria for analysis. The incidence of sinusitis was based on 4213 participants who had undergone orthognathic surgery. Twenty-three studies reported a total number of sinusitis cases, and the results demonstrated a pooled incidence of 3.3% (95% confidence interval: 1.77, 6.06). One study did not report a total number of cases but reported chronic sinusitis survey-duration-based and Lund-Mackay scores. These scores, respectively, worsened from 7.6 to 14.8 and from 1.58 to 2.90 postoperatively. Despite the variability of maxillary surgery, the surgical technique, and the postoperative management, the incidence is low but sinusitis does occur. Prospective studies with validated questionnaires within the context of a specific protocol may further elucidate the causality of sinusitis. Further, patients with sinonasal symptoms postsurgery should be encouraged to consult with an otolaryngologist to ensure prompt treatment., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by Mutaz B. Habal, MD.)

Background: Compared with patients with hypertension only, those with hypertension and diabetes (HTN/DM) have worse prognosis. We aimed to characterize morphological differences between hypertension and HTN/DM using cardiovascular magnetic resonance; and compare differentially expressed proteins associated with myocardial fibrosis using high throughput multiplex assays., Methods: Asymptomatic patients underwent cardiovascular magnetic resonance: 438 patients with hypertension (60±8 years; 59% males) and 167 age- and sex-matched patients with HTN/DM (60±10 years; 64% males). Replacement myocardial fibrosis was defined as nonischemic late gadolinium enhancement on cardiovascular magnetic resonance. Extracellular volume fraction was used as a marker of diffuse myocardial fibrosis. A total of 184 serum proteins (Olink Target Cardiovascular Disease II and III panels) were measured to identify unique signatures associated with myocardial fibrosis in all patients., Results: Despite similar left ventricular mass ( P =0.344) and systolic blood pressure ( P =0.086), patients with HTN/DM had increased concentricity and worse multidirectional strain ( P <0.001 for comparison of all strain measures) compared to hypertension only. Replacement myocardial fibrosis was present in 28% of patients with HTN/DM compared to 16% of those with hypertension ( P <0.001). NT-proBNP (N-terminal pro-B-type natriuretic peptide) was the only protein differentially upregulated in hypertension patients with replacement myocardial fibrosis and independently associated with extracellular volume. In patients with HTN/DM, GDF-15 (growth differentiation factor 15) was independently associated with replacement myocardial fibrosis and extracellular volume. Ingenuity Pathway Analysis demonstrated a strong association between increased inflammatory response/immune cell trafficking and myocardial fibrosis in patients with HTN/DM., Conclusions: Adverse cardiac remodeling was observed in patients with HTN/DM. The novel proteomic signatures and associated biological activities of increased immune and inflammatory response may partly explain these observations., Competing Interests: Disclosures None.

Background: Ventricular tachycardia (VT) storm is associated with significantly increased morbidity, mortality, and exponential healthcare utilization. Although catheter ablation (CA) may be curative, there are limited data directly comparing outcomes of early CA with initial medical therapy., Methods: We compared outcomes of patients presenting with VT storm treated with initial CA versus those treated with initial medical therapy during their first storm presentation in an observational study. Retrospective data from the host institution from January 2014 to April 2020 of 129 patients with their first VT storm presentation were analyzed (58 underwent initial CA, 71 underwent treatment with initial medical therapy). Outcomes were compared in follow-up., Results: Median time to initial CA was 6 days. Over a median follow-up of 702 days, patients who underwent initial CA compared with those treated with initial medical therapy had significantly less: (i) VA recurrence (43% versus 92%; P =0.002); (ii) VT storm recurrence (28% versus 73%; P <0.001); (iii) composite end point of death, heart transplant, VT storm recurrence, and VT-related hospitalization (47% versus 89%; P =0.002); (iv) iatrogenic complications (at 12 months: 17% versus 45%; P <0.001); (v) cardiovascular-related hospitalizations (50% versus 89%; P =0.01); (vi) total number of hospitalizations (median 1 versus 4; P <0.001); and (vi) cumulative days in hospital (median 0.5 versus 18; P <0.001). There were no intraprocedural deaths in patients treated with early CA., Conclusion: In an observational setting in which patients presenting with storm, early CA appears superior to initial medical therapy in terms of VT recurrence, storm recurrence, iatrogenic complications, cardiovascular hospitalizations, and cumulative days in hospital in follow-up.

Competing Interests: The authors declare no conflict of interest.

Background: Optic neuropathy in the context of leukemia and lymphoma raises concern for central nervous system involvement or relapse and warrants prompt evaluation and treatment. To date, a gold standard for the diagnosis and management of leukemic optic neuropathy has yet to be established., Methods: Case series and review of the literature. Two illustrative cases were selected to discuss their treatment course and outcome., Results: We report 7 cases of patients with leukemia or lymphoma presenting with optic nerve infiltration. All patients received steroid therapy for presumed infiltrative optic neuropathy, and 4 patients underwent radiation therapy. Along with systemic chemotherapy, all patients received intrathecal chemotherapy except one. Three patients received chimeric antigen receptor T-cell therapy., Conclusions: Leukemic and lymphomatous optic neuropathy is difficult to diagnose and treat, and there is no gold standard for diagnosis or treatment in the current literature. We help clarify how this disease should be approached in a multidisciplinary fashion and on an individual basis to correctly diagnose and treat the vision loss, while considering the patient's long-term prognosis based on their systemic disease., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by North American Neuro-Ophthalmology Society.)

Meningiomas are highly vascularized tumors originating from arachnoid cap cells of the leptomeninges. The majority of meningiomas are classified as World Health Organization (WHO) grade I and display a benign clinical course with a low risk of recurrence. In contrast, WHO grade III meningiomas carry a high risk of recurrence and poor prognosis. However, it is commonly recognized that histopathologic grading does not always reliably predict recurrence or progression of meningiomas. Fatty acid-binding protein 4 (FABP4) is a small molecular weight lipid chaperone that plays a proangiogenic role in vascular endothelial cells. FABP4 is not expressed in normal brain vasculature but is detected in some glioblastoma and arteriovenous malformations. The expression pattern of FABP4 in meningiomas have not been reported to date. We analyzed FABP4 expression in a cohort of paraffin-embedded meningioma specimens by immunohistochemistry and double immunofluorescence analyses. FABP4 expression was detected in a subset of endothelial cells in 47 of 48 meningioma samples analyzed. Interestingly, tumor cell-FABP4 expression was also detected in only 1 of 22 grade I, none of grade II, but 10 of 12 grade III meningiomas (P<0.0001). These results demonstrate that FABP4 is commonly expressed in meningioma vascular endothelial cells while tumor cell expression of FABP4 is primarily observed in anaplastic meningiomas. A combination of FABP4 immunostaining with histopathologic grading might provide a more accurate prediction of the biological behavior of meningiomas than histopathologic grading alone., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Pathologic fractures from bone metastases can significantly affect quality-of-life, although it is unclear which patients may be at high risk of this outcome. We aim to determine risk factors for pathologic fracture among patients admitted with bone metastases and to evaluate the association of pathologic fracture with clinical and economic outcomes., Methods: The Healthcare Cost and Utilization Project National Inpatient Sample was queried for all patients hospitalized with bone metastases in 2016. Baseline differences between patients with and without pathologic fractures were assessed by χ and analysis of variance testing. Multivariable logistic regression was used to identify factors associated with fractures., Results: In 2016, 272,275 hospital admissions were associated with a diagnosis of bone metastases, of which 11,960 (4.4%) had a primary diagnosis of pathologic fracture. Patients with pathologic fractures had a longer length-of-hospital-stay (mean 7.5 vs. 6.4 d; P<0.001) and higher cost-of-hospital-stay (mean $23,611 vs. $15,942; P<0.001) compared to patients without pathologic fractures. Primary cancers associated with increased likelihood of pathologic fracture included liver and intrahepatic bile duct (odds ratio [OR] 2.34; 95% confidence interval [CI], 1.65-3.32), multiple myeloma (OR 1.94; 95% CI, 1.31-2.86), and kidney and renal pelvis cancer (OR 1.89; 95% CI, 1.50-2.37)., Conclusions: Nearly 5% of hospitalizations with bone metastases presented with a concomitant pathologic fracture, which was associated with longer inpatient stay and higher cost. Patients with hepatobiliary, renal cell carcinoma, or multiple myeloma, had a higher likelihood of pathologic fracture. These groups may benefit from increased outpatient monitoring, prophylactic stabilization, or early irradiation.

Prior studies have documented an association of obesity with chronic pain, but the mechanism explaining the association remains unknown. This study evaluated the degree to which dietary intake of foods with anti-inflammatory effects mediates the relationship of body fat to body pain. Ninety-eight community-residing healthy adults (60% women; mean age = 43.2 ± 15.3 years; range: 20-78 years) participated in a home-based study of home environment, food-related behaviors, health, and adiposity. During a 3-hour home visit evaluation, 3 measures of body fat were collected, including height and weight for calculation of body mass index (BMI). Participants also completed a 24-hour food recall interview and self-report measures of bodily pain (BP; BP subscale from the Medical Outcomes Study Short Form-36) and psychological distress (Hospital Anxiety and Depression Scale). Quality of dietary intake was rated using the Healthy Eating Index-2010. Mediation models were conducted with the PROCESS macro in SAS 9.3. Mean BMI was consistent with obesity (30.4 ± 7.8; range: 18.2-53.3), and BP values (73.2 ± 22.1; range: 0-100) and dietary intake quality (59.4 ± 15.5; range: 26.8-88.1) were consistent with population norms. Modeling in PROCESS revealed that Healthy Eating Index-2010 scores mediated the relationship between BMI and BP (bindirect = -0.34, 95% confidence interval = -0.68 to -0.13). The mediation model remained significant when controlling for biomechanical factors (arthritis/joint pain), medication use, psychological distress, age, and education, and models remained significant using the other 2 body fat measures. Thus, the data indicate that dietary intake of foods with anti-inflammatory effects mediates the relationship of body fat to body pain in healthy men and women.

Background: Little is known about the influence of cancer on the adolescent's developing self-identity and social relationships as he/she transitions back to school following cancer treatment., Objective: The purpose of this study was to explore the meaning of returning to school for adolescents who have completed cancer treatment., Methods: In this qualitative study, in-depth interviews using an interpretive descriptive approach were conducted with 11 adolescents (aged 13-17 years) who had completed treatment for cancer. The transcripts of the audiotaped interviews were analyzed thematically and reviewed by the study team., Results: Three main themes suggested that the return to school hallmarked the end of an illness episode and a welcome return to a sense of well-being: (a) being on the right track, (b) bridging two worlds, and (c) establishing a new life at school. Nearly all adolescents described being negatively impacted by the cancer experience. However, the ability to maintain friendships during the transition emerged as particularly salient to allow the adolescents to rise above the challenges and residual effects of cancer treatment., Conclusions: Returning to school following cancer treatment affects adolescents' beliefs about themselves, their self-identity, and their social relationships. Understanding the meaning that adolescents ascribed to returning to school facilitated the development of practice recommendations to improve adjustment to school., Implications for Practice: Our study findings illuminate an important gap in the existing resources for adolescents in the posttreatment phase of cancer. Recommendations to promote healthy psychosocial development are proposed to better support adolescents during the reintegration to school.

Stereotactic radiosurgery (SRS) is an increasingly used treatment modality in adults, but its use and effectiveness in pediatric brain tumors is still uncertain. We describe 3 patients with metastatic relapse of medulloblastoma, who were treated with SRS, and achieved prolonged, progression-free survival. Tolerability of the treatment was excellent with no adverse effects reported. This work adds to the growing evidence that SRS may have an important role to play in the treatment of pediatric brain tumors.

Biliary stent implantation is an established treatment of biliary strictures. Stent migration has been previously reported to cause bronchopleuralbiliary fistula. We report a case of pericardialbiliary fistula causing cardiac tamponade as a result of biliary stent migration which has been successfully treated with pericardiocentesis and biliary stent retrieval via endoscopic retrograde cholangiopancreatography (ERCP).

Objective: To assess the off-target effects of the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA) in human primary CD4 T cells., Design: A pharmacologically relevant concentration (340 nmol/l) of SAHA was shown to significantly increase histone hyperacetylation by 24 h and this length of treatment was selected to determine its impact on gene expression in primary CD4 T cells., Methods: Illumina Beadchips for microarray gene expression analysis were used to analyze differential gene expression between cells treated or not with SAHA with a paired analysis using multivariate permutation tests. Gene ontology, biological pathway and protein interaction network analyses were used to identify the higher order biological processes affected by SAHA treatment., Results: Modest modulation by SAHA was observed for 1847 genes with 80% confidence level of no more than 10% false positives. A thousand genes were upregulated by SAHA and 847 downregulated. Pathways and gene ontologies overrepresented in the list of differentially expressed genes included Glycolysis/Gluconeogenesis, tRNA Modification, and the Histone Acetyltransferase Complex. Protein interaction network analysis revealed that transcription factor c-Myc, which was downregulated by SAHA treatment at the mRNA level, interacts with a number of SAHA-responsive genes., Conclusions: The effects on transcription by SAHA were sufficiently modest to support trials to activate HIV replication as part of an eradication strategy. SAHA did not appear to modulate proliferative or apoptotic processes to a great extent, which might impact the ability of patients to eradicate the virus reservoir following activation by HDACi treatment.

We described a patient of refractory cytomegalovirus (CMV) limbic encephalitis who received matched unrelated bone marrow transplantation. Pyrosequencing study on serial cerebrospinal fluid samples revealed the emergence of resistant strains associated with exposure of antiviral agents. Combinations of antiviral agents had a role in partial suppression of CMV viral load but the clearance of virus mainly relied on the recovery of host's immunity and resulted in intact survival of host. Donor's CMV-seronegative status may contribute to the delay in controlling this serious infection. Prompt identification of drug-resistant mutant helps in selection of antiviral agents.

Elevated intraocular pressure-induced interlamellar stromal keratitis (PISK) is an entity of interface haze usually occurring weeks to months after laser in situ keratomileusis (LASIK) that is associated with elevated intraocular pressures and worsening with steroid treatment. There is evidence that this interface haze is the result of abnormal fluid dynamics that occur in the cornea after LASIK. We present a case of pressure-induced interlamellar stromal keratitis occurring 9 years after LASIK in the setting of anterior uveitis. This case emphasizes the importance of considering such diagnoses as pressure-induced interlamellar stromal keratitis in the differential diagnosis when presented with a patient with corneal haze and a history of LASIK.

Objective: To identify antemortem CSF diagnostic biomarkers that can potentially distinguish between the 2 main causes of frontotemporal lobar degeneration (FTLD), i.e., FTLD with TDP-43 pathology (FTLD-TDP) and FTLD with tau pathology (FTLD-tau)., Methods: CSF samples were collected antemortem from 23 patients with FTLD with known pathology to form a autopsy cohort as part of a comparative biomarker study that additionally included 33 living cognitively normal subjects and 66 patients with autopsy-confirmed Alzheimer disease (AD). CSF samples were also collected from 80 living patients clinically diagnosed with frontotemporal dementia (FTD). Levels of 151 novel analytes were measured via a targeted multiplex panel enriched in neuropeptides, cytokines, and growth factors, along with levels of CSF biomarkers for AD., Results: CSF levels of multiple analytes differed between FTLD-TDP and FTLD-tau, including Fas, neuropeptides (agouti-related peptide and adrenocorticotropic hormone), and chemokines (IL-23, IL-17). Classification by random forest analysis achieved high sensitivity for FTLD-TDP (86%) with modest specificity (78%) in the autopsy cohort. When the classification algorithm was applied to a living FTD cohort, semantic dementia was the phenotype with the highest predicted proportion of FTLD-TDP. When living patients with behavioral variant FTD were examined in detail, those predicted to have FTLD-TDP demonstrated neuropsychological differences vs those predicted to have FTLD-tau in a pattern consistent with previously reported trends in autopsy-confirmed cases., Conclusions: Clinical cases with FTLD-TDP and FTLD-tau pathology can be potentially identified antemortem by assaying levels of specific analytes that are well-known and readily measurable in CSF.

We present a direct cell printing technique to pattern neural cells in a three-dimensional (3D) multilayered collagen gel. A layer of collagen precursor was printed to provide a scaffold for the cells, and the rat embryonic neurons and astrocytes were subsequently printed on the layer. A solution of sodium bicarbonate was applied to the cell containing collagen layer as nebulized aerosols, which allowed the gelation of the collagen. This process was repeated layer-by-layer to construct the 3D cell-hydrogel composites. Upon characterizing the relationship between printing resolutions and the growth of printed neural cells, single/multiple layers of neural cell-hydrogel composites were constructed and cultured. The on-demand capability to print neural cells in a multilayered hydrogel scaffold offers flexibility in generating artificial 3D neural tissue composites.

Hemorrhage and resuscitation (H/R) leads to phosphorylation of mitogen-activated stress kinases, an event that is associated with organ damage. Recently, a specific, cell-penetrating, protease-resistant inhibitory peptide of the mitogen-activated protein kinase c-JUN N-terminal kinase (JNK) was developed (D-JNKI-1). Here, using this peptide, we tested if inhibition of JNK protects against organ damage after H/R. Male Sprague-Dawley rats were treated with D-JNKI-1 (11 mg/kg, i.p.) or vehicle. Thirty minutes later, rats were hemorrhaged for 1 h to a MAP of 30 to 35 mmHg and then resuscitated with 60% of the shed blood and twice the shed blood volume as Ringer lactate. Tissues were harvested 2 h later. ANOVA with Tukey post hoc analysis or Kruskal-Wallis ANOVA on ranks, P < 0.05, was considered significant. c-JUN N-terminal kinase inhibition decreased serum alanine aminotransferase activity as a marker of liver injury by 70%, serum creatine kinase activity by 67%, and serum lactate dehydrogenase activity by 60% as compared with vehicle treatment. The histological tissue damage observed was blunted after D-JNKI-1 pretreatment both for necrotic and apoptotic cell death. Hepatic leukocyte infiltration and serum IL-6 levels were largely diminished after D-JNKI-1 pretreatment. The extent of oxidative stress as evaluated by immunohistochemical detection of 4-hydroxynonenal was largely abrogated after JNK inhibition. After JNK inhibition, activation of cJUN after H/R was also reduced. Hemorrhage and resuscitation induces a systemic inflammatory response and leads to end-organ damage. These changes are mediated, at least in part, by JNK. Therefore, JNK inhibition deserves further evaluation as a potential treatment option in patients after resuscitated blood loss.

Background: The natural history of patients with pathologically proven frontotemporal lobar degeneration (FTLD) is important from clinical and biologic perspectives, but is not well documented quantitatively., Methods: We examine longitudinal decline in cognitive functioning in an autopsy-proven cohort of patients with the clinical diagnosis of a FTLD spectrum disorder or FTLD pathology using a panel of neuropsychological measures. Patients are categorized according to findings at autopsy into tau-positive FTLD, tau-negative FTLD, and frontal variant-Alzheimer disease (fvAD) subgroups., Results: Patients decline significantly over time on all neuropsychological measures. Moreover, several measures differentiate between histopathologically distinct subgroups throughout the course of the disease process. This includes a significant double dissociation involving relative difficulty on a visual constructional measure in tau-positive patients compared to relatively impaired visual confrontation naming in tau-negative patients. Longitudinal measures of FAS naming fluency and animal naming fluency also distinguish tau-positive patients and tau-negative patients with FTLD from patients with fvAD. Other measures show significant decline but do not distinguish between histopathologic groups longitudinally., Conclusion: Our findings suggest different longitudinal patterns of cognitive decline in pathologically defined subgroups of patients. Measures consistently distinguishing between patient subgroups can be used to bolster diagnostic accuracy throughout the course of these diseases, while measures demonstrating undifferentiated longitudinal decline may serve as useful endpoints in treatment trials.

Objective: To evaluate the diagnostic value of CSF biomarkers in patients with known pathology due to frontotemporal lobar degeneration (FTLD)., Background: It is important to distinguish FTLD from other neurodegenerative diseases like Alzheimer disease (AD), but this may be difficult clinically because of atypical presentations., Methods: Patients with FTLD (n = 30) and AD (n = 19) were identified at autopsy or on the basis of genetic testing at University of Pennsylvania and Erasmus University Medical Center. CSF was obtained during a diagnostic lumbar puncture and was analyzed using assays for total tau and amyloid-beta 1-42 (A beta(42)). Patients also were assessed with a brief neuropsychological battery., Results: CSF total tau level and the ratio of CSF total tau to A beta(42) (tau/A beta(42)) were significantly lower in FTLD than in AD. Receiver operating characteristic curve analyses confirmed that the CSF tau/A beta(42) ratio is sensitive and specific at discriminating between FTLD and AD, and is more successful at this than CSF total tau alone. Although some neuropsychological measures are significantly different in autopsy-proven FTLD and AD, combining these neuropsychological measures with CSF biomarkers did not improve the ability to distinguish FTLD from AD., Conclusions: The ratio of CSF tau/A beta(42) is a sensitive and specific biomarker at discriminating frontotemporal lobar degeneration from Alzheimer disease in patients with known pathology.

Background: Mutations in the LRRK2 gene are an important cause of familial and nonfamilial parkinsonism. Despite pleomorphic pathology, LRRK2 mutations are believed to manifest clinically as typical Parkinson disease (PD). However, most genetic screens have been limited to PD clinic populations., Objective: To clinically characterize LRRK2 mutations in cases recruited from a spectrum of neurodegenerative diseases., Methods: We screened for the common G2019S mutation and several additional previously reported LRRK2 mutations in 434 individuals. A total of 254 patients recruited from neurodegenerative disease clinics and 180 neurodegenerative disease autopsy cases from the University of Pennsylvania brain bank were evaluated., Results: Eight cases were found to harbor a LRRK2 mutation. Among patients with a mutation, two presented with cognitive deficits leading to clinical diagnoses of corticobasal syndrome and primary progressive aphasia., Conclusion: The clinical presentation of LRRK2-associated neurodegenerative disease may be more heterogeneous than previously assumed.

Our earlier study indicated that functional magnetic resonance imaging (fMRI)-based detection and feedback of regional cortical activity from the auditory area enabled a group of individuals to increase the level of activation mediated by auditory attention during sound stimulation. The long-term ability to maintain an increased level of cortical activation, extending to a time period of a few weeks, however, has not been investigated. We used real-time fMRI to confirm the utility of fMRI in forming a basis for the regulation of brain function to increase the activation in the auditory areas, and demonstrated that the learned ability could be retained after a 2-week period, with additional involvement of an attention-related neural network.

Background and Purpose: Recent studies suggest that normobaric oxygen therapy (NBO) is neuroprotective in acute ischemic stroke., Methods: We performed multivoxel magnetic resonance spectroscopic imaging and diffusion/perfusion MRI in patients with stroke treated with NBO or room air. Imaging was performed before, during, and after therapy., Results: Voxel-based analysis showed excellent correlation between apparent diffusion coefficient values, lactate, and N-acetyl-aspartate levels at all time points. Lactate decreased during NBO and increased post-NBO. N-acetyl-aspartate decreased in patients receiving room air but not in NBO-treated patients., Conclusions: These data suggest that NBO improves aerobic metabolism and preserves neuronal integrity in the ischemic brain.