Fostering eating after stroke (FEASt) trial for improving post-stroke dysphagia with non-invasive brain stimulation.

Dysphagia is a serious stroke complication but lacks effective therapy. We investigated safety and preliminary efficacy of anodal transcranial direct current stimulation (atDCS) paired with swallowing exercises in improving post-stroke dysphagia from an acute unilateral hemispheric infarction (UHI). We conducted a double-blind, early phase-2 randomized controlled trial, in subjects (n = 42) with moderate-severe dysphagia [Penetration and Aspiration Scale (PAS) score ≥ 4], from an acute-subacute UHI. Subjects were randomized to Low-Dose, High-Dose atDCS or Sham stimulation for 5 consecutive days. Primary safety outcomes were incidence of seizures, neurological, motor, or swallowing function deterioration. Primary efficacy outcome was a change in PAS scores at day-5 of intervention. Main secondary outcome was dietary improvement at 1-month, assessed by Functional Oral Intake (FOIS) score. No differences in pre-defined safety outcomes or adjusted mean changes in PAS, FOIS scores, between groups, were observed. Post-hoc analysis demonstrated that 22 /24 subjects in the combined atDCS group had a clinically meaningful dietary improvement (FOIS score ≥ 5) compared to 8 /14 in Sham (p = 0.037, Fisher-exact). atDCS application in the acute-subacute stroke phase is safe but did not decrease risk of aspiration in this early phase trial. The observed dietary improvement is promising and merits further investigation.

In situ probe and inhibitory RNA synthesis using streamlined gene cloning with Gibson assembly.

The synthesis of single-stranded riboprobes or double-stranded RNAs for in situ hybridization and gene knockdowns often use vectors that require time-consuming plasmid restriction digests and inefficient gel purifications. Here, we present a faster protocol for the simultaneous plasmid restriction digestion and Gibson assembly of vectors for the synthesis of both riboprobes and double-stranded RNAs for in situ and RNA interference experiments, respectively. We illustrate the protocol with planaria in situ and RNAi assays, but it is applicable to any organism.

The impact of time after radiation treatment on dysphagia in patients with head and neck cancer enrolled in a swallowing therapy program.

BACKGROUND: Swallowing dysfunction after radiotherapy (RT) for head and neck cancer can be devastating. A randomized control trial compared swallow exercises versus exercise plus neuromuscular electrical stimulation therapy and found no overall difference in outcomes. METHODS: Quality of life (QOL), diet, and swallowing variables collected at discrete intervals on 117 patients were reanalyzed to test the hypothesis that shorter time between the completion of radiotherapy and beginning of the swallowing therapy program yielded improved outcomes. RESULTS: At baseline, subjects < 1 year post radiation had significantly better function than subjects >2 years post RT in several measures. Over the therapy program, the early group showed significant improvement in diet and QOL. Swallowing physiologic variables showed no difference between groups. CONCLUSION: Beginning a swallowing therapy program within 1 year of completion of radiotherapy demonstrates more consistent improvement in QOL and diet performance compared to later periods.

Donation After Circulatory Death Lungs Transplantable Up to Six Hours After Ex Vivo Lung Perfusion.

BACKGROUND: Despite the critical need for donor lungs, logistic and geographic barriers hinder lung utilization. We hypothesized that lungs donated after circulatory death subjected to 6 hours of cold preservation after ex vivo lung perfusion (EVLP) would have similar outcomes after transplantation as lungs transplanted immediately after EVLP, and that both would perform superiorly compared with lungs transplanted immediately after procurement. METHODS: Donor porcine lungs were procured after circulatory death and 15 minutes of warm ischemia. Three groups (n = 5 per group) were randomized: immediate left lung transplantation (Immediate group), EVLP for 4 hours followed by transplantation (EVLP group), or EVLP for 4 hours followed by 6 hours of cold preservation followed by transplantation (EVLP+Cold group). Lungs were reperfused for 2 hours before obtaining pulmonary vein samples for partial pressure of oxygen/fraction of inspired oxygen ratio calculations, airway pressures for compliance measurements, and wet/dry weight ratios. RESULTS: The partial pressure of oxygen/fraction of inspired oxygen ratios in the EVLP and EVLP+Cold groups were significantly improved compared with those in the Immediate group (429.7 ± 51.8 and 436.7 ± 48.2 versus 117.4 ± 22.9 mm Hg, respectively). In addition, dynamic compliance was significantly improved in the EVLP and EVLP+Cold groups compared with immediate group (26.2 ± 4.2 and 27.9 ± 3.5 versus 11.1 ± 2.4 mL/cmH2O, respectively). There were no differences in oxygenation capacity or dynamic compliance between the EVLP and EVLP+Cold groups. Inflammatory cytokine levels were significantly lower in the EVLP and EVLP+Cold groups. CONCLUSIONS: Lungs donated after circulatory death can be successfully transplanted as much as 6 hours after EVLP. Cold preservation of lungs after ex vivo assessment and rehabilitation may improve organ allocation, even to distant recipients, without compromising allograft function.

Technique for venipuncture of the transverse facial vein in the black rhinoceros (Diceros bicornis).

Through the use of operant conditioning, the authors developed a technique to facilitate obtaining blood samples from a black rhinoceros diagnosed with idiopathic epilepsy. The technique involved operant conditioning to facilitate venipuncture of the transverse facial vein, at an anatomic landmark on the lateral side of the face ventral to the medial canthus of the eye, and dorsal to the lateral commissure of the mouth. The investigators used standard operant conditioning protocols to train the animal for desensitization to a needle puncture in the facial vein. Blood samples obtained from the facial location were free of excessive hemolysis and allowed for large volumes to be collected. The procedure was well-tolerated by the rhinoceros and could be performed regularly without complication. Zoo Biol. 35:570-573, 2016. © 2016 Wiley Periodicals, Inc.

Risk of Stroke-Associated Pneumonia and Oral Hygiene.

BACKGROUND: Pneumonia is a major complication of stroke, but effective prevention strategies are lacking. Since aspiration of oropharyngeal secretions is the primary mechanism for development of stroke-associated pneumonia, strategies that decrease oral colonization with pathogenic bacteria may help curtail pneumonia risk. We therefore hypothesized that systematic oral care protocols can help decrease pneumonia risk in hospitalized stroke patients. In this study, we investigated the impact of a systematic oral hygiene care (OHC) program in reducing hospital-acquired pneumonia in patients with acute-subacute stroke. METHODS: This study compared the proportion of pneumonia cases in hospitalized stroke patients before and after implementation of a systematic OHC intervention. All patients hospitalized with acute ischemic stroke or intracerebral hemorrhage admitted to a large, urban academic medical center in Boston, Mass., USA from May 31, 2008, to June 1, 2010 (epoch prior to implementation of OHC), and from January 1, 2012, to December 31, 2013 (epoch after full implementation of OHC), who were 18 years of age and hospitalized for ≥ 2 days were eligible for inclusion. The cohort in the first epoch constituted the control group whereas the cohort in the second epoch formed the intervention group. Multivariate logistic regression was used to control for confounders. The main outcome measure was hospital-acquired pneumonia, defined via International Classification of Diseases, Ninth Revision, Clinical Modification codes. RESULTS: The cohort comprised 1,656 admissions (707 formed historical controls; 949 were in the intervention group). The unadjusted incidence of hospital-acquired pneumonia was lower in the group assigned to OHC compared to controls (14 vs. 10.33%; p = 0.022) with an unadjusted OR of 0.68 (95% CI 0.48-0.95; p = 0.022). After adjustment for influential confounders, the OR of hospital-acquired pneumonia in the intervention group remained significantly lower at 0.71 (95% CI 0.51-0.98; p = 0.041). CONCLUSION: In this large hospital-based cohort of patients admitted with acute stroke, systematic OHC use was associated with decreased odds of hospital-acquired pneumonia.

Ex vivo lung perfusion with adenosine A2A receptor agonist allows prolonged cold preservation of lungs donated after cardiac death.

OBJECTIVE: Ex vivo lung perfusion has been successful in the assessment of marginal donor lungs, including donation after cardiac death (DCD) donor lungs. Ex vivo lung perfusion also represents a unique platform for targeted drug delivery. We sought to determine whether ischemia-reperfusion injury would be decreased after transplantation of DCD donor lungs subjected to prolonged cold preservation and treated with an adenosine A2A receptor agonist during ex vivo lung perfusion. METHODS: Porcine DCD donor lungs were preserved at 4°C for 12 hours and underwent ex vivo lung perfusion for 4 hours. Left lungs were then transplanted and reperfused for 4 hours. Three groups (n = 4/group) were randomized according to treatment with the adenosine A2A receptor agonist ATL-1223 or the dimethyl sulfoxide vehicle: Infusion of dimethyl sulfoxide during ex vivo lung perfusion and reperfusion (DMSO), infusion of ATL-1223 during ex vivo lung perfusion and dimethyl sulfoxide during reperfusion (ATL-E), and infusion of ATL-1223 during ex vivo lung perfusion and reperfusion (ATL-E/R). Final Pao2/Fio2 ratios (arterial oxygen partial pressure/fraction of inspired oxygen) were determined from samples obtained from the left superior and inferior pulmonary veins. RESULTS: Final Pao2/Fio2 ratios in the ATL-E/R group (430.1 ± 26.4 mm Hg) were similar to final Pao2/Fio2 ratios in the ATL-E group (413.6 ± 18.8 mm Hg), but both treated groups had significantly higher final Pao2/Fio2 ratios compared with the dimethyl sulfoxide group (84.8 ± 17.7 mm Hg). Low oxygenation gradients during ex vivo lung perfusion did not preclude superior oxygenation capacity during reperfusion. CONCLUSIONS: After prolonged cold preservation, treatment of DCD donor lungs with an adenosine A2A receptor agonist during ex vivo lung perfusion enabled Pao2/Fio2 ratios greater than 400 mm Hg after transplantation in a preclinical porcine model. Pulmonary function during ex vivo lung perfusion was not predictive of outcomes after transplantation.

Subvalvular techniques to optimize surgical repair of ischemic mitral regurgitation.

PURPOSE OF REVIEW: Surgical treatment of ischemic mitral regurgitation with reduction annuloplasty is the current standard of practice, yet recurrence rates approaching 30% limit the benefits of repair in this subset of patients. In an effort to improve outcomes, attention has turned to understanding the contribution of leaflet tethering in this disease process. Subvalvular techniques to alleviate leaflet restriction have recently been incorporated into methods of repair. RECENT FINDINGS: Parameters of left ventricular remodeling have been quantified as risk factors for recurrence of mitral regurgitation following reduction annuloplasty. Papillary muscle relocation restores the physiologic configuration of the subvalvular apparatus, and results in significantly reduced rates of recurrent mitral regurgitation and adverse cardiac events over time. Secondary chordal cutting or reimplantation results in significantly increased leaflet mobility, decreased severity of recurrent mitral regurgitation, and improved reverse remodeling without adverse effect on left ventricular function. SUMMARY: A superior repair with decreased recurrence of mitral regurgitation and enhanced reversal of left ventricular remodeling is possible when subvalvular techniques are combined with traditional ring annuloplasty. Further understanding of preoperative parameters that predict disease recurrence and inclusion of concomitant subvalvular techniques in this subset of patients will be the next major advance in this field.

Protective value of TIPS against the development of hydrothorax/ascites and upper gastrointestinal bleeding after balloon-occluded retrograde transvenous obliteration (BRTO).

OBJECTIVES: The objective of this study was to evaluate the incidence of post-balloon-occluded retrograde transvenous obliteration (BRTO) ascites/hepatic hydrothorax and rebleeding rate (variceal and non-variceal) in the presence and absence of a transjugular intrahepatic portosystemic shunt (TIPS). METHODS: A retrospective audit of consecutive patients undergoing BRTO was performed (August 2007-October 2010). The population was divided into two groups: patients who underwent BRTO only (BRTO-only group) and those who underwent BRTO in the presence of TIPS (BRTO+TIPS group). Post-BRTO rebleeding was categorized for the source of bleeding. Ascites and/or hepatic hydrothorax were categorized according to clinical severity. Comparisons, utilizing the Kaplan-Meier method, between both groups were made for patient survival, incidence of ascites/hydrothorax, and rebleeding. RESULTS: Thirty-nine patients underwent BRTO (three technical failures of BRTO-only group). Of the 36 technically successful BRTO procedures, 27 patients (75%) underwent BRTO-only and 9 patients (25%) underwent BRTO in the presence of a TIPS. Pre-BRTO ascites/hydrothorax resolved in BRTO-only vs. BRTO+TIPS in 7% (N=2/27) and 56% (N=5/9), respectively (P=0.006). The ascites/hydrothorax free rate at 6, 12, and 24 months after BRTO for BRTO-only vs. BRTO+TIPS was 58%, 43%, 29%, and 100%, 100%, 100%, respectively (P=0.01). Recurrent hemorrhage for BRTO-only vs. BRTO+TIPS groups, and for the same time periods was 9%, 9%, 21% vs. 0%, 0%, 0%, respectively (P=0.03). The 1-year patient survival of both groups (80-88%) was similar (P>0.05). CONCLUSIONS: This study concludes that the presence of TIPS has a protective value against the development of post-BRTO ascites/hydrothorax as well as recurrent hemorrhage but this does not translate to improved patient survival.

The effect of balloon-occluded transvenous obliteration of gastric varices and gastrorenal shunts on the hepatic synthetic function: a comparison between Child-Pugh and model for end-stage liver disease scores.

PURPOSE: To evaluate the effect of balloon-occluded transvenous obliteration (BRTO) on the model for end-stage liver disease (MELD) and the Child-Pugh (C-P) score and their individual components. METHODS: A retrospective review of patients undergoing only BRTO without transjugular intrahepatic portosystemic shunt was performed (08, 2007 to 06, 2010). Pre- and post-BRTO MELD and C-P scores were calculated. The post-BRTO MELD and C-P score samplings were categorized as (1) immediate (within 14 days), (2) early (14-90 days), and (3) delayed (90-180 days) post-BRTO. The C-P and MELD scores and their individual components before and after (various sample intervals) were compared. RESULTS: A total of 29 consecutive successful BRTO procedures were found and assessed. In all, 26 had immediate post-BRTO sampling (average 1.8 days after BRTO), 13 (57%) had an early post-BRTO sampling (average 47 days from BRTO), and 10 (38%) had a delayed post-BRTO sampling (average 121 days from BRTO). The bilirubin rises significantly (P = .007) within days after BRTO, but synthetic function improves significantly between 1.5 and 4.0 months post-BRTO (international normalized ration: P = .02, bilirubin: P = .027, and albumin: P = .012). However, 31% (N = 8/ 26) of the patients had worsening ascites with or without hydrothorax. The MELD score significantly improved circa 4 months post-BRTO (from 14.1 to 10.7, P = .0008). However, the C-P score did not change significantly (from 7.6 to 6.7, P = .063). CONCLUSION: The BRTO has a positive effect on the hepatic synthetic function. However, there is a high incidence of post-BRTO ascites (31% of the patients). As a result, the MELD score appears to be a more sensitive gauge for hepatic synthetic function compared to the C-P score for patients undergoing BRTO.

Balloon-occlusion catheter rupture during balloon-occluded retrograde transvenous obliteration of gastric varices utilizing sodium tetradecyl sulfate: incidence and consequences.

Balloon-occluded retrograde transvenous obliteration (BRTO) is an established procedure for the management of bleeding gastric varices in Asia. Invariably, the sclerosant utilized in Asia is ethanolamine oleate and the inventory used (vascular sheaths, balloon-occlusion catheters, and microcatheters) is not available outside Asia. A total of 41 BRTO procedures were performed with a technical and obliterative (gastric varix obliteration) success rate of 95% (n = 39 of 41) and 85% (n = 35 of 41), respectively. Complications were 4.9% (n = 2/41). A total of 6 balloon ruptures occurred (14.6%, n = 6 of 41). One rupture (16.7%, n = 1 of 6 of ruptures) lead to a technical failure and 2 ruptures (33.3%, n = 2 of 6 of ruptures) lead to an obliterative failure. Balloon rupture contributed to 50% of technical failures (n = 1/2, P = .274) and 33% of obliteration failures (n = 2/6, P = .148). In conclusion, the incidence of balloon-occlusion catheter rupture utilizing 3% sodium tetradecyl sulfate (STS) and inventory unique to the United States is significantly higher than in Asia (<8% rupture rate). However, these ruptures have no significant technical or clinical consequences.

Preoperative care management of patients with hip fractures during the wait time between emergency department discharge and operating room admission for surgical repair.

BACKGROUND: Recognizing a patient's needs during the emergency department to operating room interval is crucial to identify areas for improvement. A review of the literature provided no pertinent research regarding this phase of the preoperative experience. PURPOSE: This descriptive study examined the preoperative care management of patients with hip fractures during the wait time between emergency department discharge and operating room admission. METHOD: Data were collected through a systematic retrospective chart review. Demographic variables included gender, age, and comorbidities. Preoperative patient variables included type of analgesia, level of pain, antiembolism interventions, fluid intake, sensory perception/cognition, mobility, and nutritional intake. Subjects were patients cared for at 3 sites in a large multihospital system. A total of 137 charts were reviewed. FINDINGS: Although findings were not statistically significant, opportunities to improve care were identified. More attention is needed to evaluate patients effectively for pain, particularly where there are cognitive deficits. Designing and implementing a program for increased bed mobility and protocols that closely monitor and manage fluid intake may offset postoperative complications.

Endovascular management of vascular complications in pancreatic transplants.

Vascular complications after pancreatic transplantation carry a high rate of graft loss. Endovascular management of these complications is confined to stent placement for iliac artery inflow disease and embolization for arteriovenous fistulae (AVFs), pseudoaneurysms, or active bleeding. The current study describes the endovascular management of pancreatic transplant venous thrombosis (N = 1), arterial stenosis (N = 5), thrombosis (N = 3), pseudoaneurysms (N = 1), and AVF (N = 2). In addition, embolization of nonfunctioning grafts is described as an endovascular alternative to pancreatectomy.

Predictors of percutaneous endoscopic gastrostomy tube placement in patients with severe dysphagia from an acute-subacute hemispheric infarction.

This study investigated the influence of age, National Institutes of Health Stroke Scale (NIHSS) score, time from stroke onset, infarct location and volume in predicting placement of a percutaneous endoscopic gastrostomy (PEG) tube in patients with severe dysphagia from an acute-subacute hemispheric infarction. We performed a retrospective analysis of a hospital-based patient cohort to analyze the effect of the aforementioned variables on the decision of whether or not to place a PEG tube. Consecutive patients were identified using International Classification of Diseases, Ninth Revision (ICD-9) codes for acute ischemic stroke, Current Procedural Terminology (CPT)-4 codes for a formal swallowing evaluation by a speech pathologist, and procedure codes for PEG placement over a 5-year period from existing medical records at our institution. Only patients with severe dysphagia were enrolled. A total of 77 patients met inclusion criteria; 20 of them underwent PEG placement. The relationship between age (dichotomized; < and ≥75 years), time from stroke onset (days), NIHSS score, acute infarct lesion volume (dichotomized; < and ≥100 cc), and infarct location (ie, insula, anterior insula, periventricular white matter, inferior frontal gyrus, motor cortex, or bilateral hemispheres) with PEG tube placement were analyzed using logistic regression analysis. In univariate analysis, NIHSS score (P = .005), lesion volume (P = .022), and presence of bihemispheric infarction (P = .005) were found to be the main predictors of interest. After multivariate adjustment, only NIHSS score (odds ratio [OR], 1.15; 90% confidence interval [CI], 1.02-1.29; P = .04) and presence of bihemispheric infarcts (OR, 4.67; 90% CI, 1.58-13.75; P = .018) remained significant. Our data indicates that baseline NIHSS score and the presence of bihemispheric infarcts predict PEG placement during hospitalization from an acute-subacute hemispheric infarction in patients with severe dysphagia. These results require further validation in future studies.

An extracellular matrix protein prevents cytokinesis failure and aneuploidy in the C. elegans germline.

Interactions between extracellular matrix (ECM) proteins and their transmembrane receptors mediate cytoskeletal reorganization and corresponding changes in cell shape during cell migration, adhesion, differentiation and polarization. Cytokinesis is the final step in cell division as cells employ a contractile ring composed of actin and myosin to partition one cell into two. Cells undergo dramatic changes in cell shape during the division process, creating new membrane and forming an extracellular invagination called the cleavage furrow. However, existing models of cytokinesis include no role for the ECM. In a recent paper, we demonstrate that depletion of a large secreted protein, hemicentin, results in membrane destabilization, cleavage furrow retraction and cytokinesis failure in C. elegans germ cells and in pre-implantation mouse embryos. Here, we demonstrate that cytokinesis failure produces tetraploid intermediate cells with multipolar spindles, providing a potential explanation for the large number of aneuploid progeny observed among C. elegans hemicentin mutant hermaphrodites.

Noninvasive brain stimulation may improve stroke-related dysphagia: a pilot study.

BACKGROUND AND PURPOSE: Treatment options for stroke-related dysphagia are currently limited. In this study, we investigated whether noninvasive brain stimulation in combination with swallowing maneuvers facilitates swallowing recovery in dysphagic stroke patients during early stroke convalescence. METHODS: Fourteen patients with subacute unilateral hemispheric infarction were randomized to anodal transcranial direct current stimulation (tDCS) versus sham stimulation to the sensorimotor cortical representation of swallowing in the unaffected hemisphere over the course of 5 consecutive days with concurrent standardized swallowing maneuvers. Severity of dysphagia was measured using a validated swallowing scale, Dysphagia Outcome and Severity scale, before the first and after the last session of tDCS or sham. The effect of tDCS was analyzed in a multivariate linear regression model using changes in Dysphagia Outcome and Severity Scale as the outcome variable after adjusting for the effects of other potential confounding variables such as the National Institutes of Health Stroke Scale and Dysphagia Outcome and Severity scale scores at baseline, acute ischemic lesion volumes, patient age, and time from stroke onset to stimulation. RESULTS: Patients who received anodal tDCS gained 2.60 points of improvement in Dysphagia Outcome and Severity scale scores compared to patients in the sham stimulation group who showed an improvement of 1.25 points (P=0.019) after controlling for the effects of other aforementioned variables. Six out 7 (86%) patients in tDCS stimulation group gained at least 2 points of improvement compared with 3 out 7 (43%) patients in the sham group (P=0.107). CONCLUSIONS: Because brain stem swallowing centers have bilateral cortical innervations, measures that enhance cortical input and sensorimotor control of brain stem swallowing may be beneficial for dysphagia recovery.

Effectiveness of dust control methods for crystalline silica and respirable suspended particulate matter exposure during manual concrete surface grinding.

Concrete grinding exposes workers to unacceptable levels of crystalline silica dust, known to cause diseases such as silicosis and possibly lung cancer. This study examined the influence of major factors of exposure and effectiveness of existing dust control methods by simulating field concrete grinding in an enclosed workplace laboratory. Air was monitored during 201 concrete grinding sessions while using a variety of grinders, accessories, and existing dust control methods, including general ventilation (GV), local exhaust ventilation (LEV), and wet grinding. Task-specific geometric mean (GM) of respirable crystalline silica dust concentrations (mg/m³ for LEV:HEPA-, LEV:Shop-vac-, wet-, and uncontrolled-grinding, while GV was off/on, were 0.17/0.09, 0.57/0.13, 1.11/0.44, and 23.1/6.80, respectively. Silica dust concentrations (mg/m³ using 100-125 mm (4-5 inch) and 180 mm (7 inch) grinding cups were 0.53/0.22 and 2.43/0.56, respectively. GM concentrations of silica dust were significantly lower for (1) GV on (66.0%) vs. off, and (2) LEV:HEPA- (99.0%), LEV:Shop-vac- (98.1%) or wet- (94.4%) vs. uncontrolled-grinding. Task-specific GM of respirable suspended particulate matter (RSP) concentrations (mg/m³ for LEV:HEPA-, LEV:Shop-vac-, wet-, and uncontrolled grinding, while GV was off/on, were 1.58/0.63, 7.20/1.15, 9.52/4.13, and 152/47.8, respectively. GM concentrations of RSP using 100-125 mm and 180 mm grinding cups were 4.78/1.62 and 22.2/5.06, respectively. GM concentrations of RSP were significantly lower for (1) GV on (70.2%) vs. off, and (2) LEV:HEPA- (98.9%), LEV:Shop-vac- (96.9%) or wet- (92.6%) vs. uncontrolled grinding. Silica dust and RSP were not significantly affected by (1) orientation of grinding surfaces (vertical vs. inclined); (2) water flow rates for wet grinding; (3) length of task-specific sampling time; or, (4) among cup sizes of 100, 115 or 125 mm. No combination of factors or control methods reduced an 8-hr exposure level to below the recommended criterion of 0.025 mg/m³ for crystalline silica, requiring further refinement in engineering controls, administrative controls, or the use of respirators.

xnd-1 regulates the global recombination landscape in Caenorhabditis elegans.

Meiotic crossover (CO) recombination establishes physical linkages between homologous chromosomes that are required for their proper segregation into developing gametes, and promotes genetic diversity by shuffling genetic material between parental chromosomes. COs require the formation of double strand breaks (DSBs) to create the substrate for strand exchange. DSBs occur in small intervals called hotspots and significant variation in hotspot usage exists between and among individuals. This variation is thought to reflect differences in sequence identity and chromatin structure, DNA topology and/ or chromosome domain organization. Chromosomes show different frequencies of nondisjunction (NDJ), reflecting inherent differences in meiotic crossover control, yet the underlying basis of these differences remains elusive. Here we show that a novel chromatin factor, X non-disjunction factor 1 (xnd-1), is responsible for the global distribution of COs in C. elegans. xnd-1 is also required for formation of double-strand breaks (DSBs) on the X, but surprisingly XND-1 protein is autosomally enriched. We show that xnd-1 functions independently of genes required for X chromosome-specific gene silencing, revealing a novel pathway that distinguishes the X from autosomes in the germ line, and further show that xnd-1 exerts its effects on COs, at least in part, by modulating levels of H2A lysine 5 acetylation.

Synthetic Peptide dendrimers block the development and expression of experimental allergic encephalomyelitis.

Multiple Ag peptides (MAPs) containing eight proteolipid protein (PLP)(139-151) peptides arranged around a dendrimeric branched lysine core were used to influence the expression and development of relapsing experimental allergic encephalomyelitis (EAE) in SJL mice. The PLP(139-151) MAPs were very efficient agents in preventing the development of clinical disease when administered after immunization with the PLP(139-151) monomeric encephalitogenic peptide in CFA. The treatment effect with these MAPs was peptide specific; irrelevant multimeric peptides such as guinea pig myelin basic protein GPBP(72-84) MAP (a dendrimeric octamer composed of the 72-84 peptide) and PLP(178-191) MAP (a dendrimeric octamer composed of the PLP(178-191) peptide) had no treatment effect on PLP(139-151)-induced EAE. PLP(139-151) MAP treatment initiated after clinical signs of paralysis also altered the subsequent course of EAE; it limited developing signs of paralysis and effectively limited the severity and number of disease relapses in MAP-treated mice over a 60-day observation period. PLP(139-151) MAP therapy initiated before disease onset acts to limit the numbers of Th17 and IFN-gamma-producing cells that enter into the CNS. However, Foxp3(+) cells entered the CNS in numbers equivalent for nontreated and PLP(139-151) MAP-treated animals. The net effect of PLP(139-151) MAP treatment dramatically increases the ratio of Foxp3(+) cells to Th17 and IFN-gamma-producing cells in the CNS of PLP(139-151) MAP-treated animals.

Inner-city asthma: the role of the community.

Asthma morbidity and mortality are disproportionately high in low-income minority populations. Variations in environmental exposures, stress, and access to appropriate health care all contribute to these disparities. The complex nature of asthma with strong contributions from environmental, psychosocial, and biological factors suggest that community-based approaches focused on the unique needs of high-risk populations may be effective. The few previous randomized trials suggest that case management with professionals and/or community health educators may reduce asthma morbidity. Health-educator programs should be lodged in stable infrastructures with training and funding for community health workers to obtain long-term sustainability. Factors not amenable to individual intervention, however, such as poor condition of homes, outdoor pollution, and lack of access to appropriate care, will require collaborative efforts of community groups, academic professionals, public agencies, and health-care providers.