Total Intravenous Anesthesia with Propofol Reduces Discharge Times Compared with Inhaled General Anesthesia in Shoulder Arthroscopy: A Randomized Controlled Trial.

BACKGROUND: Shoulder arthroscopy is commonly performed at ambulatory surgical centers (ASCs) with use of an interscalene block and inhaled general anesthesia (IGA). However, an alternative option known as total intravenous anesthesia with propofol (TIVA-P) has shown promising results in reducing recovery time for other surgeries. The objective of this study was to assess whether there is a clinically meaningful difference in post-anesthesia care unit phase-I (PACU-I) time following shoulder arthroscopy between patients receiving an interscalene block with IGA and those receiving an interscalene block with TIVA-P. METHODS: Patients who underwent shoulder arthroscopy performed by a single surgeon at the ASC of our institution between 2020 and 2023 were enrolled. Enrollment was conducted in blocks, with up to 3 planned interim analyses. After 2 blocks, enrollment was halted because the study arms demonstrated a significant difference in the primary outcome measure, PACU-I time. A total of 96 patients were randomized into the TIVA-P and IGA groups; after patient withdrawals, the groups comprised 42 and 40 patients, respectively. Patients underwent shoulder arthroscopy with use of the anesthesia method corresponding to their assigned group. Pain, satisfaction, antiemetic use, perioperative interventions, surgical time, PACU-II time, postoperative care time, and total time until discharge were recorded and were analyzed with use of chi-square and Mann-Whitney U tests with a significance cutoff of 0.0167 to account for the interim analyses. RESULTS: Across groups, 81.7% of patients were non-Hispanic White and 58.5% were male. Significant differences were observed between the TIVA-P and IGA groups with respect to median PACU-I time (0.0 minutes [interquartile range (IQR), 0.0 to 6.0 minutes] versus 25.5 minutes [IQR, 20.5 to 32.5 minutes]; p < 0.001) and median total time until discharge (135.5 minutes [IQR, 118.5 to 156.8 minutes] versus 148.5 minutes [IQR, 133.8 to 168.8 minutes]; p = 0.0104). The TIVA-P group had a 9.1% quicker discharge time, primarily as a result of bypassing PACU-I (66.7% of patients) and spending 25.5 fewer minutes there overall. The TIVA-P group also had a lower rate of antiemetic use than the IGA group (59.5% versus 92.5% of patients; p = 0.0013). No significant differences were detected between the TIVA-P and IGA groups in terms of median pain improvement (1.0 [IQR, 0.0 to 2.0] versus 1.0 [IQR, 0.0 to 2.0]; p = 0.6734), perioperative interventions (78.6% versus 77.5% of patients, p = 1.0000), or median patient satisfaction (4.0 [IQR, 4.0 to 4.0] versus 4.0 [IQR, 3.8 to 4.0]; p = 0.4148). CONCLUSIONS: TIVA-P showed potential to improve both PACU-I time and the total time until discharge while reducing antiemetic use without impacting pain or satisfaction. TIVA-P thus warrants consideration by orthopaedic surgeons for use in shoulder arthroscopy performed at ASCs. LEVEL OF EVIDENCE: Therapeutic Level I . See Instructions for Authors for a complete description of levels of evidence.

The effect of operative time on surgical-site infection following total shoulder arthroplasty.

BACKGROUND: Many factors contribute to the risk of surgical-site infection (SSI) following total shoulder arthroplasty (TSA). Operative time is a modifiable factor that may contribute to SSI occurrence after TSA. This study aimed to determine the correlation between operative time and SSI following TSA. MATERIALS AND METHODS: By use of the American College of Surgeons National Surgical Quality Improvement Program database, a total of 33,987 patient records were queried from 2006 to 2020 and sorted by operative time and the development of an SSI in the 30-day postoperative period. Odds ratios for the development of an SSI were calculated based on operative time. RESULTS: An SSI developed in the 30-day postoperative period in 169 of the 33,470 patients in this study, resulting in an overall SSI rate of 0.50%. A positive correlation was identified between operative time and the SSI rate. An inflection point was identified at an operative time of 180 minutes, with a significant increase in the rate of SSI occurrence for operative times >180 minutes. DISCUSSION AND CONCLUSION: Increased operative time was shown to be strongly correlated with an increased risk of SSI within 30 days following surgery, with a significant inflection point at 180 minutes. The target operative time for TSA should be <180 minutes to reduce the risk of SSI.

Patients Who Undergo Rotator Cuff Repair Can Safely Return to Driving at 2 Weeks Postoperatively.

BACKGROUND: Evidence-based guidelines are lacking for return to driving following rotator cuff repair (RCR). As a result, surgeons are often overly conservative in their recommendations, placing potential undue burden on patients and their families. Therefore, the primary objective of this study was to formulate evidence-based return-to-driving guidelines. METHODS: Thirty-two subjects planning to undergo primary RCR were enrolled. Driving fitness was assessed in a naturalistic setting with an instrumented vehicle on public streets with a safety monitor onboard. Driving kinematic measures and behavioral data were obtained from vehicle data and camera capture. Several driving tasks and maneuvers were evaluated, including parking, left and right turns, straightaways, yielding, highway merges, and U-turns. The total course length was 15 miles (24 km) and the course took 45 to 55 minutes to complete. The subjects' baseline drive was performed prior to RCR and postoperative drives occurred at 2, 4, 6, and 12 weeks after RCR. All drives consisted of identical routes, tasks, and maneuvers. Driving metrics were analyzed for differences between baseline and postoperative drives, including differences in gravitational force equivalents (g). RESULTS: Twenty-seven subjects (mean age, 58.6 years [range, 43 to 68 years]) completed all 5 drives. Of the 13 analyzed kinematic metrics measured from 14 of 17 driving events, all exhibited noninferiority across all postoperative drives (2 to 12 weeks) after RCR compared with baseline. Beginning at postoperative week 2, subjects generally braked less aggressively, steered more smoothly, and drove more stably. Kinematic metrics during the performance of specific maneuver types also showed noninferiority when compared with baseline. Of note, subjects drove more smoothly on highway merges starting at postoperative week 2 (minimum longitudinal acceleration, -0.35 g [95% confidence interval (CI), -0.050 to -0.019 g]; standard deviation of longitudinal acceleration, 0.008 g [95% CI, 0.003 to 0.013 g]), but exhibited more aggressive driving and acceleration on highway merges at postoperative week 12 (maximum absolute yaw, -0.8°/sec [95% CI, -1.2°/sec to -0.4°/sec]). CONCLUSIONS: Patients showed no clinically important negative impact on driving fitness as early as 2 weeks after RCR. Adaptive behaviors were present both preoperatively and postoperatively. LEVEL OF EVIDENCE: Prognostic Level II . See Instructions for Authors for a complete description of levels of evidence.

The relationship of shoulder elevation strength to patient-reported outcome after anatomic total shoulder arthroplasty.

BACKGROUND: Most patient-reported outcome measures (PROMs) used to assess outcomes after anatomic total shoulder arthroplasty (aTSA) focus on pain and function. Although strength is considered an important component of function, only the Constant-Murley score (CMS) includes an objective measurement of shoulder strength. The purpose of this study was to evaluate the relationship between shoulder elevation strength (SES) and PROMs after aTSA for the treatment of primary glenohumeral osteoarthritis (GHOA). METHODS: This was a retrospective analysis of 605 patients enrolled in a multicenter clinical database who underwent aTSA to treat primary GHOA. Patients were evaluated preoperatively and at 24 months after surgery. Outcome was assessed with the CMS, American Shoulder and Elbow Surgeons score, Western Ontario Osteoarthritis of the Shoulder score, Single Assessment Numeric Evaluation score, and patient satisfaction. Relationships between SES and outcomes were investigated. RESULTS: The correlations between SES and the PROMs before and after treatment were very weak and weak, respectively (r ≤ 0.262 for all). The strength of the correlations between the absolute and adjusted CMS and the other PROMs varied from weak to moderate (r = 0.180 to r = 0.455), and the strength of the correlations was greater postoperatively. With the strength component removed from the CMS, the correlations between the CMS and other PROMs were stronger (r = 0.194 to r = 0.495). CONCLUSIONS: Although measurement of SES provides objective information about shoulder function and outcome related to the treatment of primary GHOA with aTSA, the actual relevance to patients is unclear as the correlations between SES and PROMs were weak. Furthermore, the variable correlations between the CMS and PROMs call into question the exclusive use of the CMS and support the use of other PROMs that may more accurately reflect patient perception of outcome.

Assessment of Flexion Strength Following Single- Versus Double-Hamstring Tendon Harvest for Anterior Cruciate Ligament Reconstruction.

PURPOSE: To compare isometric hamstring strength deficits, knee laxity, functional outcomes, and patient-reported outcomes between patients who underwent anterior cruciate ligament (ACL) reconstruction with doubled semitendinosus and gracilis tendon autograft (ST/G) versus quadrupled semitendinosus autograft (ST), at a minimum follow-up of 1-year postoperatively. METHODS: Patients who underwent ACL reconstruction with ST/G or ST hamstring autografts were retrospectively identified. Isometric hamstring strength was tested with a hand-held dynamometer at 30, 60, and 90° of knee flexion. Anterior knee laxity was assessed using a KT-1000 arthrometer. Functional outcomes were collected using the single-leg hop test and single-leg squat test. Side-to-side differences were determined and compared between the ST/G and ST groups. Patient-reported outcomes were collected on all patients. RESULTS: Eighty-four patients who underwent ST/G (n = 34) or ST (n = 50) autograft ACL reconstruction were recruited to participate in this study. There was no difference in knee laxity between the groups. Side-to-side hamstring strength deficits increased with increased flexion angles. At 90° of flexion, the ST/G group had a significantly greater flexion strength deficit compared with the ST group (37.8 ± 15.1% vs 24.7 ± 12.5%, P < .001). Aside from a significant difference in the KOOS pain Score (P .045), no other significant differences in functional or patient reported outcomes between the groups were identified. CONCLUSIONS: Patients who underwent ACL reconstruction with ST/G compared with ST autograft have a significantly greater isometric flexion strength deficit at 90° of flexion. Future investigations are required to determine the clinical relevance of this difference and whether specialized therapy protocols can mitigate this deficit. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Hemophilic Arthropathy.

The musculoskeletal manifestations of hemophilia A and B are some of the most common presenting symptoms and continue to be challenging to practitioners. Hemophilic arthropathy, if not initially adequately treated and managed, may lead to debilitating disease and eventually require the consideration of major surgery, including total joint arthroplasty. Thorough comprehension of the pathophysiology, diagnosis, and both medical and surgical interventions is critical in establishing an appropriate treatment regimen for these patients. Furthermore, a true multidisciplinary approach involving hematology, orthopedics, and physical therapy is essential for a patient with hemophilic arthropathy. The authors present a comprehensive review of hemophilic arthropathy from an orthopedist's perspective. [Orthopedics. 2017; 40(6):e940-e946.].

Modifications to a LATE MERISTEM IDENTITY1 gene are responsible for the major leaf shapes of Upland cotton (Gossypium hirsutum L.).

Leaf shape varies spectacularly among plants. Leaves are the primary source of photoassimilate in crop plants, and understanding the genetic basis of variation in leaf morphology is critical to improving agricultural productivity. Leaf shape played a unique role in cotton improvement, as breeders have selected for entire and lobed leaf morphs resulting from a single locus, okra (l-D1), which is responsible for the major leaf shapes in cotton. The l-D1 locus is not only of agricultural importance in cotton, but through pioneering chimeric and morphometric studies, it has contributed to fundamental knowledge about leaf development. Here we show that an HD-Zip transcription factor homologous to the LATE MERISTEM IDENTITY1 (LMI1) gene of Arabidopsis is the causal gene underlying the l-D1 locus. The classical okra leaf shape allele has a 133-bp tandem duplication in the promoter, correlated with elevated expression, whereas an 8-bp deletion in the third exon of the presumed wild-type normal allele causes a frame-shifted and truncated coding sequence. Our results indicate that subokra is the ancestral leaf shape of tetraploid cotton that gave rise to the okra allele and that normal is a derived mutant allele that came to predominate and define the leaf shape of cultivated cotton. Virus-induced gene silencing (VIGS) of the LMI1-like gene in an okra variety was sufficient to induce normal leaf formation. The developmental changes in leaves conferred by this gene are associated with a photosynthetic transcriptomic signature, substantiating its use by breeders to produce a superior cotton ideotype.

Effects of Tranexamic Acid Cytotoxicity on In Vitro Chondrocytes.

Use of topical tranexamic acid (TXA) in orthopedic surgery has been expanding over the past decade, with increasing evidence confirming reductions in perioperative blood loss and transfusion requirements, but there is minimal evidence regarding effects of TXA on native cartilage. We conducted a study to understand the in vitro effects of TXA on bovine cartilage and murine chondrocytes and ultimately to expand the clinical application of topical TXA to include scenarios with retained native cartilage, such as hemiarthroplasty. Bovine cartilage explants were exposed to TXA at a concentration of 100 mg/mL, and glycosaminoglycan (GAG) release and cell viability were measured at 8, 24, and 48 hours. Monolayer murine chondrocytes were exposed to TXA 25, 50, and 100 mg/mL, and viability was measured at 8, 24, and 48 hours. GAG released from bovine explants was significantly higher in the samples exposed to TXA 100 mg/mL at all time points. Cell viability was significantly decreased in the explants exposed to TXA 24 and 48 hours after initial incubation. Bovine chondrocyte viability was not affected by TXA 25 mg/mL. Murine chondrocyte viability was similar between the TXA 25 mg/mL and control samples at all time points. The TXA 50 mg/mL sample dropped from 66.51% viability at 8 hours to 6.81% viability at 24 hours and complete cell death by 48 hours. The TXA 100 mg/mL samples had no observable viable cells at 8, 24, and 48 hours. Our data indicated that TXA 100 mg/mL damaged and was cytotoxic to bovine explanted cartilage and was cytotoxic to murine chondrocytes. Murine and bovine chondrocyte viability were not affected by TXA 25 mg/mL.

Metabolomic and transcriptomic insights into how cotton fiber transitions to secondary wall synthesis, represses lignification, and prolongs elongation.

BACKGROUND: The morphogenesis of single-celled cotton fiber includes extreme elongation and staged cell wall differentiation. Designing strategies for improving cotton fiber for textiles and other uses relies on uncovering the related regulatory mechanisms. In this research we compared the transcriptomes and metabolomes of two Gossypium genotypes, Gossypium barbadense cv Phytogen 800 and G. hirsutum cv Deltapine 90. When grown in parallel, the two types of fiber developed similarly except for prolonged fiber elongation in the G. barbadense cultivar. The data were collected from isolated fibers between 10 to 28 days post anthesis (DPA) representing: primary wall synthesis to support elongation; transitional cell wall remodeling; and secondary wall cellulose synthesis, which was accompanied by continuing elongation only in G. barbadense fiber. RESULTS: Of 206 identified fiber metabolites, 205 were held in common between the two genotypes. Approximately 38,000 transcripts were expressed in the fiber of each genotype, and these were mapped to the reference set and interpreted by homology to known genes. The developmental changes in the transcriptomes and the metabolomes were compared within and across genotypes with several novel implications. Transitional cell wall remodeling is a distinct stable developmental stage lasting at least four days (18 to 21 DPA). Expression of selected cell wall related transcripts was similar between genotypes, but cellulose synthase gene expression patterns were more complex than expected. Lignification was transcriptionally repressed in both genotypes. Oxidative stress was lower in the fiber of G. barbadense cv Phytogen 800 as compared to G. hirsutum cv Deltapine 90. Correspondingly, the G. barbadense cultivar had enhanced capacity for management of reactive oxygen species during its prolonged elongation period, as indicated by a 138-fold increase in ascorbate concentration at 28 DPA. CONCLUSIONS: The parallel data on deep-sequencing transcriptomics and non-targeted metabolomics for two genotypes of single-celled cotton fiber showed that a discrete developmental stage of transitional cell wall remodeling occurs before secondary wall cellulose synthesis begins. The data showed how lignification can be transcriptionally repressed during secondary cell wall synthesis, and they implicated enhanced capacity to manage reactive oxygen species through the ascorbate-glutathione cycle as a positive contributor to fiber length.

Virus-induced gene silencing of fiber-related genes in cotton.

Virus-Induced Gene Silencing (VIGS) is a useful method for transient downregulation of gene expression in crop plants. The geminivirus Cotton leaf crumple virus (CLCrV) has been modified to serve as a VIGS vector for persistent gene silencing in cotton. Here the use of Green Fluorescent Protein (GFP) is described as a marker for identifying silenced tissues in reproductive tissues, a procedure that requires the use of transgenic plants. Suggestions are given for isolating and cloning combinations of target and marker sequences so that the total length of inserted foreign DNA is between 500 and 750 bp. Using this strategy, extensive silencing is achieved with only 200-400 bp of sequence homologous to an endogenous gene, reducing the possibility of off-target silencing. Cotyledons can be inoculated using either the gene gun or Agrobacterium and will continue to show silencing throughout fruit and fiber development. CLCrV is not transmitted through seed, and VIGS is limited to genes expressed in the maternally derived seed coat and fiber in the developing seed. This complicates the use of GFP as a marker for VIGS because cotton fibers must be separated from unsilenced tissue in the seed to determine if they are silenced. Nevertheless, fibers from a large number of seeds can be rapidly screened following placement into 96-well plates. Methods for quantifying the extent of silencing using semiquantitative RT-PCR are given.

Cost benefit analysis of topical tranexamic acid in primary total hip and knee arthroplasty.

The purpose of this study was to provide a cost-benefit analysis of topical tranexamic acid (TXA) in primary total hip and knee arthroplasty patients. A retrospective cohort of 591 consecutive patients, 311 experimental and 280 control, revealed a transfusion rate reduction from 17.5% to 5.5%, increased postoperative hemoglobin, and decreased delta hemoglobin without an increase in adverse events (all P < 0.001). This led to saving $83.73 per patient based on transfusion costs alone after accounting for the cost of TXA. Hospital disposition to home compared to subacute nursing facility was also significantly increased by 9.3% (P < 0.02). We conclude that topical TXA reduces transfusion rate, increases home disposition, and reduces cost in primary hip and knee arthroplasty.

Dual-camera technique for arthroscopic rotator cuff repair.

An all-arthroscopic rotator cuff repair demands a high level of technical skill and is associated with a steep learning curve. It is well accepted that small rotator cuff tears or partial tears can be more difficult than large or even massive tears to repair. Part of the reason is the difficulty in visualizing the tear, as well as important surrounding structures, during repair. To improve visibility during the repair process, we have introduced a second arthroscopic camera. Two cameras allow the surgeon to observe the rotator cuff from both the articular and bursal sides. We find this technique has merit in small or partial-thickness rotator cuff tears; however, there may be other applications.

Method: low-cost delivery of the cotton leaf crumple virus-induced gene silencing system.

BACKGROUND: We previously developed a virus-induced gene silencing (VIGS) vector for cotton from the bipartite geminivirusCotton leaf crumple virus (CLCrV). The original CLCrV VIGS vector was designed for biolistic delivery by a gene gun. This prerequisite limited the use of the system to labs with access to biolistic equipment. Here we describe the adaptation of this system for delivery by Agrobacterium (Agrobacterium tumefaciens). We also describe the construction of two low-cost particle inflow guns. RESULTS: The biolistic CLCrV vector was transferred into two Agrobacterium binary plasmids. Agroinoculation of the binary plasmids into cotton resulted in silencing and GFP expression comparable to the biolistic vector. Two homemade low-cost gene guns were used to successfully inoculate cotton (G. hirsutum) and N. benthamiana with either the CLCrV VIGS vector or the Tomato golden mosaic virus (TGMV) VIGS vector respectively. CONCLUSIONS: These innovations extend the versatility of CLCrV-based VIGS for analyzing gene function in cotton. The two low-cost gene guns make VIGS experiments affordable for both research and teaching labs by providing a working alternative to expensive commercial gene guns.

Cotton fiber: a powerful single-cell model for cell wall and cellulose research.

Cotton fibers are single-celled extensions of the seed epidermis. They can be isolated in pure form as they undergo staged differentiation including primary cell wall synthesis during elongation and nearly pure cellulose synthesis during secondary wall thickening. This combination of features supports clear interpretation of data about cell walls and cellulose synthesis in the context of high throughput modern experimental technologies. Prior contributions of cotton fiber to building fundamental knowledge about cell walls will be summarized and the dynamic changes in cell wall polymers throughout cotton fiber differentiation will be described. Recent successes in using stable cotton transformation to alter cotton fiber cell wall properties as well as cotton fiber quality will be discussed. Futurec prospects to perform experiments more rapidly through altering cotton fiberwall properties via virus-induced gene silencing will be evaluated.

Investigation of antigen specific lymphocyte responses in healthy horses vaccinated with an inactivated West Nile virus vaccine.

West Nile virus (WNV) is a single-stranded, enveloped RNA virus capable of causing encephalitic disease in horses. Unvaccinated horses are at risk for developing WNV disease in endemic geographic regions. Effective vaccination reduces disease frequency and diminishes disease severity in vaccinated individuals that become infected with WNV. Recent data indicate CD4+ lymphocytes are required for effective protection against disease; in particular, cross talk between CD4+ and CD8+ lymphocytes must be functional. The objective of this project was to investigate immune responses in horses throughout a series of three vaccinations using a commercial inactivated vaccine under natural conditions. Immune responses to vaccination were determined by neutralizing antibody titers with plaque reduction neutralization test (PRNT), IgM titer (capture ELISA), WNV specific antibody Ig subclass responses, WNV lymphocyte proliferative responses and intracellular cytokine expression. Horses were vaccinated with a series of three vaccines at 3-week intervals using an inactivated product. An initial measure of immune activation following vaccination was determined by evaluating changes in lymphocyte cytokine expression. Interferon (IFN) gamma and interleukin (IL)-4 expressing CD4+ lymphocytes significantly increased 14 days following initial vaccination compared to unvaccinated horses (P<0.05). IFN-gamma expressing CD8+ lymphocytes also increased and remained elevated for 110 days. Antigen specific lymphocyte proliferative responses were significantly increased up to 90 days following the third vaccination (P<0.05). As expected, vaccinated horses produced increased neutralizing antibody based on PRNT data and WNV antigen-specific Ig subclass responses compared with unvaccinated horses (P<0.05). Our data indicate that WNV vaccination with an inactivated product effectively induced an antigen-specific antibody responses, as well as CD4+ and CD8+ lymphocyte activation.

Geminivirus-mediated gene silencing from Cotton leaf crumple virus is enhanced by low temperature in cotton.

A silencing vector for cotton (Gossypium hirsutum) was developed from the geminivirus Cotton leaf crumple virus (CLCrV). The CLCrV coat protein gene was replaced by up to 500 bp of DNA homologous to one of two endogenous genes, the magnesium chelatase subunit I gene (ChlI) or the phytoene desaturase gene (PDS). Cotyledons of cotton cultivar 'Deltapine 5415' bombarded with the modified viral vectors manifested chlorosis due to silencing of either ChlI or PDS in approximately 70% of inoculated plants after 2 to 3 weeks. Use of the green fluorescence protein gene showed that replication of viral DNA was restricted to vascular tissue and that the viral vector could transmit to leaves, roots, and the ovule integument from which fibers originate. Temperature had profound effects on vector DNA accumulation and the spread of endogenous gene silencing. Consistent with reports that silencing against viruses increases at higher temperatures, plants grown at a 30 degrees C/26 degrees C day/night cycle had a greater than 10-fold reduction in viral DNA accumulation compared to plants grown at 22 degrees C/18 degrees C. However, endogenous gene silencing decreased at 30 degrees C/26 degrees C. There was an approximately 7 d delay in the onset of gene silencing at 22 degrees C/18 degrees C, but silencing was extensive and persisted throughout the life of the plant. The extent of silencing in new growth could be increased or decreased by changing temperature regimes at various times following the onset of silencing. Our experiments establish the use of the CLCrV silencing vector to study gene function in cotton and show that temperature can have a major impact on the extent of geminivirus-induced gene silencing.

Efficacy and tolerability of darifenacin, a muscarinic M3 selective receptor antagonist (M3 SRA), compared with oxybutynin in the treatment of patients with overactive bladder.

A randomized, double-blind, placebo-controlled, four-way crossover, safety study of darifenacin versus oxybutynin was carried out on 76 patients with overactive bladder (OAB). Adults with OAB received 2 weeks each of darifenacin 15 and 30 mg once daily (q.d.), oxybutynin 5 mg three times daily (t.i.d.) and placebo, in random sequence at 10-day intervals. Darifenacin and oxybutynin significantly reduced incontinence episodes, and the number/severity of urgency episodes (all P<0.05 versus placebo). Improvements in OAB symptoms with darifenacin were dose-dependent. Dry mouth was less common with darifenacin 15 mg than oxybutynin (13% and 36%; P<0.05), while constipation was comparable (10% and 8%, respectively). Corresponding rates for darifenacin 30 mg were 34% and 21%, respectively. Patients only reported blurred vision or dizziness with oxybutynin (3% and 2%, respectively). Darifenacin (15 mg q.d.) provides comparable efficacy with improved tolerability versus oxybutynin (5 mg t.i.d.) in the treatment of patients with OAB.

Cloning and characterization of mouse E2F8, a novel mammalian E2F family member capable of blocking cellular proliferation.

The E2F transcription factor family plays a crucial and well established role in cell cycle progression. Deregulation of E2F activities in vivo leads to developmental defects and cancer. Based on current evidence in the field, mammalian E2Fs can be functionally categorized into either transcriptional activators (E2F1, E2F2, and E2F3a) or repressors (E2F3b, E2F4, E2F5, E2F6, and E2F7). We have identified a novel E2F family member, E2F8, which is conserved in mice and humans and has its counterpart in Arabidopsis thaliana (E2Ls). Interestingly, E2F7 and E2F8 share unique structural features that distinguish them from other mammalian E2F repressor members, including the presence of two distinct DNA-binding domains and the absence of DP-dimerization, retinoblastoma-binding, and transcriptional activation domains. Similar to E2F7, overexpression of E2F8 significantly slows down the proliferation of primary mouse embryonic fibroblasts. These observations, together with the fact that E2F7 and E2F8 can homodimerize and are expressed in the same adult tissues, suggest that they may have overlapping and perhaps synergistic roles in the control of cellular proliferation.

Genetic suppression of intronic +1G mutations by compensatory U1 snRNA changes in Caenorhabditis elegans.

Mutations to the canonical +1G of introns, which are commonly found in many human inherited disease alleles, invariably result in aberrant splicing. Here we report genetic findings in C. elegans that aberrant splicing due to +1G mutations can be suppressed by U1 snRNA mutations. An intronic +1G-to-U mutation, e936, in the C. elegans unc-73 gene causes aberrant splicing and loss of gene function. We previously showed that mutation of the sup-39 gene promotes splicing at the mutant splice donor in e936 mutants. We demonstrate here that sup-39 is a U1 snRNA gene; suppressor mutations in sup-39 are compensatory substitutions in the 5' end, which enhance recognition of the mutant splice donor. sup-6(st19) is an allele-specific suppressor of unc-13(e309), which contains an intronic +1G-to-A transition. The e309 mutation activates a cryptic splice site, and sup-6(st19) restores splicing to the mutant splice donor. sup-6 also encodes a U1 snRNA and the mutant contains a compensatory substitution at its 5' end. This is the first demonstration that U1 snRNAs can act to suppress the effects of mutations to the invariant +1G of introns. These findings are suggestive of a potential treatment of certain alleles of inherited human genetic diseases.