Defining and quantifying frustration in the energy landscape: Applications to atomic and molecular clusters, biomolecules, jammed and glassy systems.

The emergence of observable properties from the organisation of the underlying potential energy landscape is analysed, spanning a full range of complexity from self-organising to glassy and jammed systems. The examples include atomic and molecular clusters, a ß-barrel protein, the GNNQQNY peptide dimer, and models of condensed matter that exhibit structural glass formation and jamming. We have considered measures based on several different properties, namely, the Shannon entropy, an equilibrium thermodynamic measure that uses a sample of local minima, and indices that require additional information about the connections between local minima in the form of transition states. A frustration index is defined that correlates directly with key properties that distinguish relaxation behaviour within this diverse set. The index uses the ratio of the energy barrier to the energy difference with reference to the global minimum. The contributions for each local minimum are weighted by the equilibrium occupation probabilities. Hence we obtain fundamental insight into the connections and distinctions between systems that cover the continuum from efficient structure-seekers to landscapes that exhibit broken ergodicity and rare event dynamics.

Building Bridges for Innovation in Ageing: Synergies between Action Groups of the EIP on AHA.

The Strategic Implementation Plan of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) proposed six Action Groups. After almost three years of activity, many achievements have been obtained through commitments or collaborative work of the Action Groups. However, they have often worked in silos and, consequently, synergies between Action Groups have been proposed to strengthen the triple win of the EIP on AHA. The paper presents the methodology and current status of the Task Force on EIP on AHA synergies. Synergies are in line with the Action Groups' new Renovated Action Plan (2016-2018) to ensure that their future objectives are coherent and fully connected. The outcomes and impact of synergies are using the Monitoring and Assessment Framework for the EIP on AHA (MAFEIP). Eight proposals for synergies have been approved by the Task Force: Five cross-cutting synergies which can be used for all current and future synergies as they consider overarching domains (appropriate polypharmacy, citizen empowerment, teaching and coaching on AHA, deployment of synergies to EU regions, Responsible Research and Innovation), and three cross-cutting synergies focussing on current Action Group activities (falls, frailty, integrated care and chronic respiratory diseases).

Developing research priorities for palliative care of people with intellectual disabilities in Europe: a consultation process using nominal group technique.

BACKGROUND: Empirical knowledge around palliative care provision and needs of people with intellectual disabilities is extremely limited, as is the availability of research resources, including expertise and funding. This paper describes a consultation process that sought to develop an agenda for research priorities for palliative care of people with intellectual disabilities in Europe. METHODS: A two-day workshop was convened, attended by 16 academics and clinicians in the field of palliative care and intellectual disability from six European countries. The first day consisted of round-table presentations and discussions about the current state of the art, research challenges and knowledge gaps. The second day was focused on developing consensus research priorities with 12 of the workshop participants using nominal group technique, a structured method which involved generating a list of research priorities and ranking them in order of importance. RESULTS: A total of 40 research priorities were proposed and collapsed into eleven research themes. The four most important research themes were: investigating issues around end of life decision making; mapping the scale and scope of the issue; investigating the quality of palliative care for people with intellectual disabilities, including the challenges in achieving best practice; and developing outcome measures and instruments for palliative care of people with intellectual disabilities. CONCLUSIONS: The proposal of four major priority areas and a range of minor themes for future research in intellectual disability, death, dying and palliative care will help researchers to focus limited resources and research expertise on areas where it is most needed and support the building of collaborations. The next steps are to cross-validate these research priorities with people with intellectual disabilities, carers, clinicians, researchers and other stakeholders across Europe; to validate them with local and national policy makers to determine how they could best be incorporated in policy and programmes; and to translate them into actual research studies by setting up European collaborations for specific studies that require such collaboration, develop research proposals and attract research funding.

Laparoscopy shows superiority over endoscopy for early detection of malignant atrophic papulosis gastrointestinal complications: a case report and review of literature.

BACKGROUND: The malignant form of atrophic papulosis (Köhlmeier-Degos disease) is a rare thrombo-occlusive vasculopathy that can affect multiple organ systems. Patients typically present with distinctive skin lesions reflective of vascular drop out. The small bowel is the most common internal organ involved, resulting in considerable morbidity and mortality attributable to ischemic microperforations. Determination of the presence of gastrointestinal lesions is critical in distinguishing systemic from the benign, cutaneous only disease and in identifying candidates for treatment. CASE PRESENTATION: We describe an 18 year old male who first presented with cutaneous atrophic papulosis but became critically ill from small bowel microperforations. He had an almost immediate and dramatic response to treatment. Prior to his presentation with acute abdomen he had upper and lower endoscopy showing areas of nonspecific patchy erythema. At laparotomy, innumerable characteristic lesions with central pearly hue and erythematous border were seen. PubMed was used for a literature search using the keywords malignant atrophic papulosis, Degos disease, endoscopy, laparoscopy and laparotomy. This search yielded 200 articles which were further analyzed for diagnostic procedures and findings. Among the 200 articles we identified only 11 cases in which endoscopy was performed. Results of endoscopy and laparotomy in our patient with malignant atrophic papulosis were compared to those in the literature. Endoscopy of the gastrointestinal tract has shown gastritis and non-specific inflammation whereas laparoscopy shows white plaques with red borders on the serosal surface of the small bowel and the peritoneum. From personal communications with other physicians worldwide, we identified three additional unpublished cases in which endoscopy revealed only minimal changes while laparoscopy showed dramatic lesions. From our experience the endoscopic findings are often subtle and nonspecific, whereas laparascopy or laparotomy will reveal pathognomic lesions on the serosal surface of the intestine. CONCLUSION: Our report contrasts the endoscopic and laparoscopic findings in malignant atrophic papulosis which suggest laparoscopy is the more powerful means of detecting gastrointestinal involvement. Imaging studies may serve as a key indicator of systemic progression. Based on our experience, laparoscopy should be performed when there is a high index of suspicion for gastrointestinal malignant atrophic papulosis, even if endoscopic examination is non-diagnostic or normal.

Favorable outcomes in high-risk congenital pulmonary airway malformations treated with multiple courses of maternal betamethasone.

BACKGROUND/PURPOSE: Congenital pulmonary airway malformations (CPAMs) are rare congenital lung lesions often diagnosed by prenatal ultrasound. High-risk cases can result in hydrops and prenatal or postnatal demise. Antenatal betamethasone has resulted in improved survival but it is unclear how to manage patients who do not respond to a single course. METHODS: We present a bi-institutional retrospective review of patients treated with multiple courses of prenatal steroids for high-risk CPAMs between 2007 and 2013. RESULTS: Nine patients met inclusion criteria. All but one either had an increased CPAM volume ratio (CVR) or number of fluid-containing compartments involved after a single course of antenatal betamethasone, prompting additional courses. Four patients stabilized, three improved and two progressed after the second course. The two cases with disease progression underwent an in utero resection. There were one in utero fetal demise and two deaths within the delivery room. Both fetuses that underwent a fetal resection died. All but one mother who delivered a viable fetus had complications of pregnancy. CONCLUSIONS: Multiple courses of antenatal betamethasone for high-risk fetal CPAMs often result in favorable short-term outcomes without the need for open fetal resection. Pregnancy complications are common and women within this cohort should be monitored closely.

Osteoarthritis in temporomandibular joint of Col2a1 mutant mice.

OBJECTIVE: Col2a1 gene mutations cause premature degeneration of knee articular cartilage in disproportionate micromelia (Dmm) and spondyloepiphesial dysplasia congenita (sedc) mice. The present study analyses the temporomandibular joint (TMJ) in Col2a1 mutant mice in order to provide an animal model of TMJ osteoarthritis (OA) that may offer better understanding of the progression of this disease in humans. DESIGN: Dmm/+ mice and controls were compared at two, six, nine and 12 months. Craniums were fixed, processed to paraffin sections, stained with Safranin-O/Fast Green, and analysed with light microscopy. OA was quantified using a Mankin scoring procedure. Unfolded protein response (UPR) assay was performed and immunohistochemistry (IHC) was used to assay for known OA biomarkers. RESULTS: Dmm/+ TMJs showed fissuring of condylar cartilage as early as 6 months of age. Chondrocytes were clustered, leaving acellular regions in the matrix. Significant staining of HtrA1, Ddr2 and Mmp-13 was observed in Dmm/+ mice (p<0.01). We detected upregulation of the UPR in knee but not TMJ. CONCLUSIONS: Dmm/+ mice are subject to early-onset OA in the TMJ. We observed upregulation of biomarkers and condylar cartilage degradation concomitant with OA. An upregulated UPR may exacerbate the onset of OA. The Dmm/+ mouse TMJ is a viable model for the study of the progression of OA in humans.

Osteoarthritis-like changes in the heterozygous sedc mouse associated with the HtrA1-Ddr2-Mmp-13 degradative pathway: a new model of osteoarthritis.

OBJECTIVE: To test the hypothesis that the spondyloepiphyseal dysplasia congenita (sedc) heterozygous (sedc/+) mouse, a COL2A1 mutant, is a model for the study of osteoarthritis (OA) in the absence of dwarfism and to investigate the presence of HtrA1, Ddr2, and Mmp-13 and their possible involvement in a universal mechanism leading to OA. DESIGN: Whole mount skeletons of adult animals were analyzed to determine whether sedc/+ mice exhibit dwarfism. To characterize progression of osteoarthritic degeneration over time, knee and temporomandibular joints from sedc/+ and wild-type mice were analyzed histologically, and severity of articular cartilage degradation was graded using the Osteoarthritis Research Society International (OARSI) scoring system. Immunohistochemistry was used to detect changes in expression of HtrA1, Ddr2, and Mmp-13 in articular cartilage of knees. RESULTS: As previously reported, the sedc/+ skeleton morphology was indistinguishable from wild type, and skeletal measurements revealed no significant differences. The sedc/+ mouse did, however, show significantly higher OARSI scores in knee (9, 12 and 18 months) and temporomandibular joints at all ages examined. Histological staining showed regions of proteoglycan degradation as early as 2 months in both temporomandibular and knee joints of the mutant. Cartilage fissuring and erosion were observed to begin between 2 and 6 months in temporomandibular joints and 9 months in knee joints from sedc/+ mice. Immunohistochemistry of mutant knee articular cartilage showed increased expression of HtrA1, Ddr2, and Mmp-13 compared to wild type, which upregulation preceded fibrillation and fissuring of the articular surfaces. CONCLUSIONS: With regard to skeletal morphology, the sedc/+ mouse appears phenotypically normal but develops premature OA as hypothesized. We conclude that the sedc/+ mouse is a useful model for the study of OA in individuals with overtly normal skeletal structure and a predisposition for articular cartilage degeneration.

Cytidine deaminase single-nucleotide polymorphism is predictive of toxicity from gemcitabine in patients with pancreatic cancer: RTOG 9704.

The aim of this study is to validate the prognostic and predictive value of the non-synonymous cytidine deaminase (CDA) Lys²7Gln polymorphism for hematological toxicity and survival using a randomized phase III adjuvant trial (Radiation Therapy Oncology Group (RTOG) 9704) in pancreatic cancer in which one treatment arm received gemcitabine. CDA is involved in gemcitabine inactivation, and there is conflicting data on the role of the non-synonymous CDA Lys²7Gln polymorphism in predicting toxicity and survival in cancer patients treated with gemcitabine. RTOG 9704 randomized 538 patients after pancreatic resection to receive radiotherapy with either 5-fluorouracil (5-FU) or gemcitabine. CDA Lys²7Gln polymorphism genotype was analyzed. We tested an association between CDA single-nucleotide polymorphism genotype and the survival outcome by the Cox proportional hazard model adjusting for other covariates, as well as toxicity by the logistic regression model. There is statistically significant more severe hematological toxicity in patients treated with gemcitabine with either the homozygote wild-type genotype (Lys/Lys) alone (odds ratio (OR)=0.06, P=0.01), or in combination with the heterozygote (Lys/Gln; OR=0.14, P=0.03) when compared with homozygote variant genotype (Gln/Gln) when adjusted for other covariates. This was not seen in the non-gemcitabine treated arm. There are no genotype differences with respect to survival outcome. In conclusion, in this prospective randomized adjuvant study of patients with pancreatic cancer, the CDA Lys²7Gln polymorphism is validated as a predictive marker of gemcitabine hematological toxicity, but not with treatment response or survival.

Risk of malignancy in resected cystic tumors of the pancreas < or =3 cm in size: is it safe to observe asymptomatic patients? A multi-institutional report.

Recent international consensus guidelines propose that cystic pancreatic tumors less than 3 cm in size in asymptomatic patients with no radiographic features concerning for malignancy are safe to observe; however, there is little published data to support this recommendation. The purpose of this study was to determine the prevalence of malignancy in this group of patients using pancreatic resection databases from five high-volume pancreatic centers to assess the appropriateness of these guidelines. All pancreatic resections performed for cystic neoplasms < or =3 cm in size were evaluated over the time period of 1998-2006. One hundred sixty-six cases were identified, and the clinical, radiographic, and pathological data were reviewed. The correlation with age, gender, and symptoms (abdominal pain, nausea and vomiting, jaundice, presence of pancreatitis, unexplained weight loss, and anorexia), radiographic features suggestive of malignancy by either computed tomography, magnetic resonance imaging, or endoscopic ultrasound (presence of solid component, lymphadenopathy, or dilated main pancreatic duct or common bile duct), and the presence of malignancy was assessed using univariate and multivariate analysis. Among the 166 pancreatic resections for cystic pancreatic tumors < or =3 cm, 135 cases were benign [38 serous cystadenomas, 35 mucinous cystic neoplasms, 60 intraductal papillary mucinous neoplasms (IPMN), 1 cystic papillary tumor, and 1 cystic islet cell tumor], whereas 31 cases were malignant (14 mucinous cystic adenocarcinomas and 13 invasive carcinomas and 4 in situ carcinomas arising in the setting of IPMN). A greater incidence of cystic neoplasms was seen in female patients (99/166, 60%). Gender was a predictor of malignant pathology, with male patients having a higher incidence of malignancy (19/67, 28%) compared to female patients (12/99, 12%; p < 0.02). Older age was associated with malignancy (mean age 67 years in patients with malignant disease vs 62 years in patients with benign lesions (p < 0.05). A majority of the patients with malignancy were symptomatic (28/31, 90%). Symptoms that correlated with malignancy included jaundice (p < 0.001), weight loss (p < 0.003), and anorexia (p < 0.05). Radiographic features that correlated with malignancy were presence of a solid component (p < 0.0001), main pancreatic duct dilation (p = 0.002), common bile duct dilation (p < 0.001), and lymphadenopathy (p < 0.002). Twenty-seven of 31(87%) patients with malignant lesions had at least one radiographic feature concerning for malignancy. Forty-five patients (27%) were identified as having asymptomatic cystic neoplasms. All but three (6.6%) of the patients in this group had benign disease. Of the patients that had no symptoms and no radiographic features, 1 out of 30 (3.3%) had malignancy (carcinoma in situ arising in a side branch IPMN). Malignancy in cystic neoplasms < or =3 cm in size was associated with older age, male gender, presence of symptoms (jaundice, weight loss, and anorexia), and presence of concerning radiographic features (solid component, main pancreatic duct dilation, common bile duct dilation, and lymphadenopathy). Among asymptomatic patients that displayed no discernable radiographic features suggestive of malignancy who underwent resection, the incidence of occult malignancy was 3.3%. This study suggests that a group of patients with small cystic pancreatic neoplasms who have low risk of malignancy can be identified, and selective resection of these lesions may be appropriate.

Human papillomavirus genotypes associated with cervical cytologic abnormalities and HIV infection in Ugandan women.

Human papillomavirus (HPV) infection is associated with almost all cases of cervical cancer, and cervical cancer is a common malignancy in women living in developing countries. A cross-sectional study was conducted to determine the prevalence of HPV infection, human immunodeficiency virus (HIV) infection, and cervical cytologic abnormalities in women presenting to a sexually transmitted infections clinic in Kampala, Uganda. In June and July, 2002, 135 women underwent complete physical exams including Papanicolaou (Pap) smears. HIV status was evaluated by serology. Cervical and vaginal swabs were obtained by clinicians and tested for HPV genotypes by PCR/reverse blot strip assay. Of the 106 women with cervical swabs adequate for HPV testing, the HPV prevalence was 46.2% (49/106). HIV prevalence was 34.9% (37/106). High risk genotypes 52, 58, and 16 were the genotypes detected most commonly. Eighteen percent (9/49) of women infected with HPV were found to have genotypes 16 and/or 18. Seventy-three percent (27/37) of HIV-positive women versus 16% (10/63) of HIV-negative women had abnormal Pap smears (P < 0.0001). Among HIV-positive women, abnormal Pap smears were associated with the presence of high risk HPV genotypes (P < 0.001). The majority of women infected with HPV attending this sexually transmitted infections clinic in Uganda were infected with high risk HPV genotypes other than 16 and 18. Future studies should focus on whether current HPV vaccine formulations, that are limited to high risk genotypes 16 and 18, would be effective at decreasing the burden of cervical cancer in this population.

Fetal hemoglobin in sickle cell anemia: genetic determinants of response to hydroxyurea.

The increase in fetal hemoglobin (HbF) in response to hydroxyurea (HU) varies among patients with sickle cell anemia. Twenty-nine candidate genes within loci previously reported to be linked to HbF level (6q22.3-q23.2, 8q11-q12 and Xp22.2-p22.3), involved in metabolism of HU and related to erythroid progenitor proliferation were studied in 137 sickle cell anemia patients treated with HU. Three-hundred and twenty tagging single nucleotide polymorphisms (SNPs) for genotyping were selected based on HapMap data. Multiple linear regression and the nonlinear regression Random Forest method were used to investigate the association between SNPs and the change in HbF level after 2 years of treatment with HU. Both methods revealed that SNPs in genes within the 6q22.3-23.2 and 8q11-q12 linkage peaks, and also the ARG2, FLT1, HAO2 and NOS1 genes were associated with the HbF response to HU. Polymorphisms in genes regulating HbF expression, HU metabolism and erythroid progenitor proliferation might modulate the patient response to HU.

Endoscopic retrograde cholangiopancreatography after pancreaticoduodenectomy for benign and malignant disease: indications and technical outcomes.

BACKGROUND AND STUDY AIMS: Patients undergoing pancreaticoduodenectomy develop postoperative complications related to surgery and their disease. Very little data are available on the role or success of endoscopic retrograde cholangiopancreatography (ERCP) in such patients. The aim of this study was to evaluate the indications and role of diagnostic and therapeutic ERCP after pancreaticoduodenectomy for both benign and malignant disease. PATIENTS AND METHODS: This study was a 10-year (1990 - 2000) single institution retrospective review of all ERCPs performed on patients who had undergone pancreaticoduodenectomy surgery. Indications for the ERCP and technical procedural success were studied. RESULTS: 29 patients with a pancreaticoduodenectomy underwent 56 ERCPs. Reasons for surgery were neoplasia and chronic pancreatitis. Indications for ERCP included evaluation of jaundice and pain. Technical success related to the clinical indication (jaundice 69 %, pain 54 %). CONCLUSION: ERCP plays an important role in the management of postpancreatic surgery problems including biliary and anastomotic strictures, and should be the modality of choice. However, surgical technique may make the afferent limb inaccessible, and the ductal anastomosis difficult to identify in patients with some types of pancreaticoduodenectomy. Closer collaboration between surgeon and endoscopist may allow alterations in surgical technique to improve postoperative ERCP success.

Radiation modifiers: treatment overview and future investigations.

Many radiosensitizers are in current clinical use. In addition, a myriad of potential new targeted therapies, which may also interact with radiation, are in clinical development. The clinical utility of new targeted therapies, in combination with existing radiation sensitizers (chemotherapies) requires further evaluation, as does the understanding of their acute and late radiation effects. Free radical scavengers appear to show promise as radioprotectors, but data for mucoprotection are less convincing.

Review article: the management of lower gastrointestinal bleeding.

Several recent advances have been made in the evaluation and management of acute lower gastrointestinal bleeding. This review focuses on the management of lower gastrointestinal bleeding, especially acute severe bleeding. The aim of the study was to critically review the published literature on important management issues in lower gastrointestinal bleeding, including haemodynamic resuscitation, diagnostic evaluation, and endoscopic, radiologic, and surgical therapy, and to develop an algorithm for the management of lower gastrointestinal bleeding, based on this literature review. Publications pertaining to lower gastrointestinal bleeding were identified by searches of the MEDLINE database for the years 1966 to December 2004. Clinical trials and review articles were specifically identified, and their reference citation lists were searched for additional publications not identified in the database searches. Clinical trials and current clinical recommendations were assessed by using commonly applied criteria. Specific recommendations are made based on the evidence reviewed. Approximately, 200 original and review articles were reviewed and graded. There is a paucity of high-quality evidence to guide the management of lower gastrointestinal bleeding, and current endoscopic, radiologic, and surgical practices appear to reflect local expertise and availability of services. Endoscopic literature supports the role of urgent colonoscopy and therapy where possible. Radiology literature supports the role of angiography, especially after a positive bleeding scan has been obtained. Limited surgical data support the role of segmental resection in the management of persistent lower gastrointestinal bleeding after localization by either colonoscopy or angiography. There is limited high-quality research in the area of lower gastrointestinal bleeding. Recent advances have improved the endoscopic, radiologic and surgical management of this problem. However, treatment decisions are still often based on local expertise and preference. With increased access to urgent therapeutic endoscopy for the management of acute upper gastrointestinal bleeding, diagnostic and therapeutic colonoscopy can be expected to play an increasing role in the management of acute lower gastrointestinal bleeding.

Treatment of bleeding colonic diverticula by endoscopic band ligation: an in-vivo and ex-vivo pilot study.

BACKGROUND AND STUDY AIMS: Angiographic and surgical therapy are standards of care for persistent diverticular bleeding. Colonoscopic intervention using epinephrine injection, multipolar electrocautery, and placement of an Endoclip has not gained widespread acceptance due to concerns about complications,and the widespread management of severe lower gastrointestinal bleeding by surgeons and interventional radiologists. The utility of colonoscopic band ligation for control of diverticular bleeding was evaluated both in vivo and ex vivo. PATIENTS AND METHODS: Endoscopic band ligation of diverticula was performed on surgical resection specimens and in patients with actively bleeding colonic diverticula. RESULTS: In the in-vivo study, active diverticular bleeding was completely controlled in four patients by endoscopic band ligation. In two cases, a visible vessel was seen on the everted and banded diverticulum. Procedure time ranged from 45 to 140 min. The total lengths of hospital stays for the four patients were 2, 6, 14, and 35 days. The long hospital stays (> 7 days)were associated with non-gastrointestinal co-morbidity. There were no acute complications of band ligation. No rebleeding or need for surgery occurred during a follow-up period of 12 months in any of the patients. In the ex-vivo study, 11 diverticula were successfully everted and banded in five of nine surgical specimens (one right colon and four left colons). Mucosa was identified in all of the "banded" segments. Ten of 11 ligated diverticula revealed evidence of blood vessels or submucosal tissue. The presence of subserosal fat was suggested in three of the 11 "banded" segments, and none of the ex-vivo ligated diverticula contained muscularis propria or serosal involvement. There was no evidence of perforation. CONCLUSIONS: Both in-vivo and ex-vivo data suggest that endoscopic band ligation may be a safe and effective therapy for actively bleeding colonic diverticula.

Intraductal papillary mucinous tumors of the pancreas.

Intraductal papillary mucinous tumor (IPMT) is an uncommon pancreatic neoplasm with characteristic histology and distinctive clinicobiologic behavior. It is characterized by proliferation of ductal epithelium associated with ductal dilatation and variable mucin production. Due to indolent nature of these tumors, IPMTs are frequently missed or misdiagnosed. Prompt recognition and differentiation from other tumors are essential because IPMT has a better prognosis than other pancreatic malignancies. The purpose of this article is to display the radiologic spectrum of IPMT.

The development of a Th1-type response and resistance to Leishmania major infection in the absence of CD40-CD40L costimulation.

CD40-CD40L interactions have been shown to be essential for the production of IL-12 and IFN-gamma and control of L. major infection. In contrast, C57BL/6 mice deficient in CD28 develop a dominant Th1-type response and heal infection. In this study, we investigate the effects of a deficiency in both CD40L and CD28 molecules on the immune response and the course of L. major infection. We compared infection in mice genetically lacking CD40L (CD40L(-/-)), CD28 (CD28(-/-)), or both (CD40L(-/-)CD28(-/-)), and in C57BL/6 mice, all on a resistant background. Although CD40L(-/-) mice failed to control infection, CD28(-/-) and CD40L(-/-)CD28(-/-) mice, as well as C57BL/6 mice, spontaneously resolved their infections. Healing mice had reduced numbers of lesion parasites compared with nonhealing CD40L(-/-) mice. At wk 9 of infection, we detected similar levels of IL-4, IFN-gamma, IL-12p40, and IL-12Rbeta2 mRNA in draining lymph nodes of healing C57BL/6, CD28(-/-), and CD40L(-/-)CD28(-/-) mice, whereas CD40L(-/-) mice had increased mRNA levels for IL-4 but reduced levels for IFN-gamma, IL-12p40, and IL-12Rbeta2. In a separate experiment, blocking of the CD40-CD40L pathway using Ab to CD40L led to an exacerbation of infection in C57BL/6 mice, but had little or no effect on infection in CD28(-/-) mice. Together, these results demonstrate that in the absence of CD28 costimulation, CD40-CD40L interaction is not required for the development of a protective Th1-type response. The expression of IL-12p40, IL-12Rbeta2, and IFN-gamma in CD40L(-/-)CD28(-/-) mice further suggests the presence of an additional stimulus capable of regulating IL-12 and its receptors in absence of CD40-CD40L interactions.

Rapid (0.5 degrees C/min) minimally invasive induction of hypothermia using cold perfluorochemical lung lavage in dogs.

OBJECTIVE: Demonstrate minimally invasive rapid body core and brain cooling in a large animal model. DESIGN: Prospective controlled animal trial. SETTING: Private research laboratory. SUBJECTS: Adult dogs, anesthetized, mechanically ventilated. INTERVENTIONS: Cyclic lung lavage with FC-75 perfluorochemical (PFC) was administered through a dual-lumen endotracheal system in the new technique of 'gas/liquid ventilation' (GLV). In Trial-I, lavage volume (V-lav) was 19 ml/kg, infused and withdrawn over a cycle period (tc) of 37 s. (effective lavage rate V'-lav=31 ml/kg/min.) Five dogs received cold (approximately 4 degrees C) PFC; two controls received isothermic PFC. In Trial-II, five dogs received GLV at V-lav=8.8 ml/kg, tc=16 s, V'-lav=36 ml/kg/min. MEASUREMENTS AND MAIN RESULTS: Trial-I tympanic temperature change was -3.7+/-0.6 degrees C (SD) at 7.5 min, reaching -7.3+/-0.6 degrees C at 18 min. Heat transfer efficiency was 60%. In Trial-II, efficiency fell to 40%, but heat-exchange dead space (VDtherm) remained constant. Lung/blood thermal equilibration half-time was <8 s. Isothermic GLV caused hypercapnia unless gas ventilation was increased. At necropsy after euthanasia (24 h), modest lung injury was seen. CONCLUSIONS: GLV cooling times are comparable to those for cardiopulmonary bypass. Heat and CO(2) removal can be independently controlled by changing the mix of lavage and gas ventilation. Due to VDtherm of approximately 6 ml/kg in dogs, efficient V-lav is >18 ml/kg. GLV cooling power appears more limited by PFC flows than lavage residence times. Concurrent gas ventilation may mitigate heat-diffusion limitations in liquid breathing, perhaps via bubble-induced turbulence.

IL-10 mediates susceptibility to Leishmania donovani infection.

Human visceral leishmaniasis (VL) results in a severe and potentially fatal systemic disease, accompanied by cellular immune depression. The production of IL-10 correlates with ongoing disease and it has been suggested that the cellular immune depression that accompanies active disease may be due to a predominance of IL-10 production rather than a lack of IFN-gamma production, which is essential for optimal macrophage activation and parasite elimination. To examine the role of IL-10 in resistance during L. donovani infection (a causative agent of VL), the course of infection was examined in mice lacking the gene for IL-10. BALB/c IL-10-/-, as well as C57BL/6 IL-10-/- mice, were highly resistant to L. donovani infection, as evidenced by liver parasite burdens which were tenfold lower than those in control mice after 14 days of infection. Enhanced resistance was accompanied by increased production of IFN-gamma and nitric oxide in BALB/c IL-10-/- mice. Susceptibility to infection in BALB/c IL-10-/- mice was enhanced following in vivo treatment with a neutralizing antibody to IFN-gamma or IL-12. Together these studies demonstrate for the first time that IL-10 is a critical component of the immune response that inhibits resistance to L. donovani.