Fat-bone interaction within the bone marrow milieu: Impact on hematopoiesis and systemic energy metabolism.

The relationship between fat, bone and systemic metabolism is a growing area of scientific interest. Marrow adipose tissue is a well-recognized component of the bone marrow milieu and is metabolically distinct from current established subtypes of adipose tissue. Despite recent advances, the functional significance of marrow adipose tissue is still not clearly delineated. Bone and fat cells share a common mesenchymal stem cell (MSC) within the bone marrow, and hormones and transcription factors such as growth hormone, leptin, and peroxisomal proliferator-activated receptor γ influence MSC differentiation into osteoblasts or adipocytes. MSC osteogenic potential is more vulnerable than adipogenic potential to radiation and chemotherapy, and this confers a risk for an abnormal fat-bone axis in survivors following cancer therapy and bone marrow transplantation. This review provides a summary of data from animal and human studies describing the relationship between marrow adipose tissue and hematopoiesis, bone mineral density, bone strength, and metabolic function. The significance of marrow adiposity in other metabolic disorders such as osteoporosis, diabetes mellitus, and estrogen and growth hormone deficiency are also discussed. We conclude that marrow adipose tissue is an active endocrine organ with important metabolic functions contributing to bone energy maintenance, osteogenesis, bone remodeling, and hematopoiesis. Future studies on the metabolic role of marrow adipose tissue may provide the critical insight necessary for selecting targeted therapeutic interventions to improve altered hematopoiesis and augment skeletal remodeling in cancer survivors.

Is the NHS best practice tariff for type 1 diabetes applicable in the Irish context?

The National Health Service in the UK has identified thirteen key standards of paediatric diabetes care. Funding depends on services meeting these standards. The aim of this study was to determine if these standards are applicable in an Irish setting. All patients attending the diabetes service during 2012 were included. Patient charts, electronic appointments, nursing notes and computerised results were used to ascertain relevant information for comparison with the NHS standards. Patients attended a mean 2.97 (SD 0.7) medical and 2.2 (SD 2.9) nursing appointments per year, with a median additional contacts of 8 nurse phone calls (range 0 - 125). Most standards were met by this service. In comparing our service to the NHS standard, we have identified a number of areas for improving our service provision. Limited resources and staff shortages make a number of these standards unachievable, namely annual dietetic review and three monthly outpatient appointments.

The evolving course of HNF4A hyperinsulinaemic hypoglycaemia--a case series.

BACKGROUND: Hepatocyte nuclear factor 4 alpha (HNF4A) gene mutations have a well-recognized role in maturity-onset diabetes of the young and have recently been described in congenital hyperinsulinism. A biphasic phenotype has been postulated, with macrosomia and congenital hyperinsulinism in infancy, and diabetes in young adulthood. In this case series, we report three children with HNF4A mutations (two de novo) and diazoxide-responsive congenital hyperinsulinism, highlighting the potential for ongoing diazoxide requirement and the importance of screening for these mutations even in the absence of family history. CASE REPORTS: All patients presented with macrosomia (mean birthweight 4.26 kg) and hyperinsulinaemic hypoglycaemia soon after birth (median age 1 day). All three (age range 7 months to 11 years 10 months) remain on diazoxide therapy, with dose requirements increasing in one patient. There was no prior family history of diabetes, neonatal hypoglycaemia or macrosomia. Parents were screened for HNF4A mutations post-diagnosis and one father was subsequently found to have maturity-onset diabetes of the young. CONCLUSIONS: This case series follows the evolving course of three patients with confirmed HNF4A-mediated congenital hyperinsulinism, highlighting (1) the variable natural history of these mutations, (2) the potential for prolonged diazoxide requirement, even into adolescence, and (3) the need for screening, regardless of family history.

Afferent and efferent immunological pathways of the brain. Anatomy, function and failure.

Immunological privilege appears to be a product of unique lymphatic drainage systems for the brain and receptor-mediated entry of inflammatory cells through the blood-brain barrier. Most organs of the body have well-defined lymphatic vessels that carry extracellular fluid, antigen presenting cells, lymphocytes, neoplastic cells and even bacteria to regional lymph nodes. The brain has no such conventional lymphatics, but has perivascular pathways that drain interstitial fluid (ISF) from brain parenchyma and cerebrospinal fluid (CSF) from the subarachnoid space to cervical lymph nodes. ISF and solutes drain along narrow, ∼100 nm-thick basement membranes within the walls of cerebral capillaries and arteries to cervical lymph nodes; this pathway does not allow traffic of lymphocytes or antigen presenting cells from brain to lymph nodes. Although CSF drains into blood through arachnoid villi, CSF also drains from the subarachnoid space through channels in the cribriform plate of the ethmoid bone into nasal lymphatics and thence to cervical lymph nodes. This pathway does allow the traffic of lymphocytes and antigen presenting cells from CSF to cervical lymph nodes. Efferent pathways by which lymphocytes enter the brain are regulated by selected integrins on lymphocytes and selective receptors on vascular endothelial cells. Here we review: (1) the structure and function of afferent lymphatic drainage of ISF and CSF, (2) mechanisms involved in the efferent pathways by which lymphocytes enter the brain and (3) the failure of lymphatic drainage of the brain parenchyma with age and the role of such failure in the pathogenesis of Alzheimer's disease.

Monitoring policy and actions on food environments: rationale and outline of the INFORMAS policy engagement and communication strategies.

The International Network for Food and Obesity/non-communicable diseases Research, Monitoring and Action Support (INFORMAS) proposes to collect performance indicators on food policies, actions and environments related to obesity and non-communicable diseases. This paper reviews existing communications strategies used for performance indicators and proposes the approach to be taken for INFORMAS. Twenty-seven scoring and rating tools were identified in various fields of public health including alcohol, tobacco, physical activity, infant feeding and food environments. These were compared based on the types of indicators used and how they were quantified, scoring methods, presentation and the communication and reporting strategies used. There are several implications of these analyses for INFORMAS: the ratings/benchmarking approach is very commonly used, presumably because it is an effective way to communicate progress and stimulate action, although this has not been formally evaluated; the tools used must be trustworthy, pragmatic and policy-relevant; multiple channels of communication will be needed; communications need to be tailored and targeted to decision-makers; data and methods should be freely accessible. The proposed communications strategy for INFORMAS has been built around these lessons to ensure that INFORMAS's outputs have the greatest chance of being used to improve food environments.

A proposed approach to monitor private-sector policies and practices related to food environments, obesity and non-communicable disease prevention.

Private-sector organizations play a critical role in shaping the food environments of individuals and populations. However, there is currently very limited independent monitoring of private-sector actions related to food environments. This paper reviews previous efforts to monitor the private sector in this area, and outlines a proposed approach to monitor private-sector policies and practices related to food environments, and their influence on obesity and non-communicable disease (NCD) prevention. A step-wise approach to data collection is recommended, in which the first ('minimal') step is the collation of publicly available food and nutrition-related policies of selected private-sector organizations. The second ('expanded') step assesses the nutritional composition of each organization's products, their promotions to children, their labelling practices, and the accessibility, availability and affordability of their products. The third ('optimal') step includes data on other commercial activities that may influence food environments, such as political lobbying and corporate philanthropy. The proposed approach will be further developed and piloted in countries of varying size and income levels. There is potential for this approach to enable national and international benchmarking of private-sector policies and practices, and to inform efforts to hold the private sector to account for their role in obesity and NCD prevention.

Short stature in child with early-onset diabetes.

We present a girl who initially presented at 12 weeks of age with antibody negative diabetes. Genetic screening for common mutations of monogenic diabetes was negative. She was noted to have short stature at 8 years of age (height <0.4 centile), as well as overlapping toes and distal abnormalities of her fingers. On reevaluation, further investigation revealed an EIF2AK3 mutation, and a diagnosis of Wolcott Rallison syndrome was made. This case highlights the importance of close follow up of patients with neonatal diabetes for the development of syndromic features that may lead to a unifying diagnosis.

Equine paranasal sinus disease: a long-term study of 200 cases (1997-2009): ancillary diagnostic findings and involvement of the various sinus compartments.

REASONS FOR PERFORMING STUDY: There is a lack of objective information on the value of ancillary diagnostic techniques used to investigate equine sinus disease, and also on which sinus compartments are commonly affected in this disorder. OBJECTIVES: To record the ancillary diagnostic findings used to investigate equine sinus disease and to document which compartments are affected. MATERIALS AND METHODS: The clinical case records of 200 consecutive cases of sinus disease, including subacute (<2 months' duration) primary (n = 52); chronic (>2 months' duration) primary (n = 37); dental (n = 40); traumatic (n = 13); sinus cyst (n = 26); sinus neoplasia (n = 10); dental related oromaxillary fistula (n = 8); mycotic sinusitis (n = 7) and intra-sinus progressive ethmoid haematoma (n = 7) were retrospectively examined. RESULTS: Nasal endoscopy showed exudate draining from the sino-nasal ostia in 88% of cases and a sino-nasal fistula was present in 15% of cases. Sinoscopy was performed in 79% of cases and was of great diagnostic value. More recently, 22% of cases had fenestration of the ventral conchal bulla performed to allow sinoscopy of the rostral sinus compartments. Radiography was performed in 97% of cases and showed intra-sinus fluid lines to be common (69% prevalence) in subacute primary sinusitis. Radiographic dental apical changes were not specific to dental sinusitis, e.g. 29% of chronic primary sinusitis cases had radiographic dental changes. Scintigraphy was performed in 20% of cases and was helpful in identifying dental apical changes when radiography was inconclusive. Overall, the caudal maxillary (78% involvement) and rostral maxillary (61%) sinuses were most commonly affected, with the ventral conchal sinus (VCS) (54% involvement) and conchofrontal sinuses (48%) less so. The VCS showed the greatest tendency to contain inspissated pus (present in 46% of all affected VCS). CONCLUSIONS: Nasal endoscopy, sinoscopy and skull radiography are of great value in diagnosing the presence and causes of equine sinus disease.

Equine paranasal sinus disease: a long-term study of 200 cases (1997-2009): treatments and long-term results of treatments.

REASONS FOR PERFORMING STUDY: There is limited objective information available on the treatment and the long-term response to treatment of the different types of equine sinus disease. OBJECTIVES: To document the treatments and long-term response to these treatments in 200 cases of equine sinus disease (1997-2009). METHODS: The treatments of horses affected with subacute primary sinusitis (n = 52); chronic primary sinusitis (n = 37); dental sinusitis (n = 40); sinus cyst (n = 26); traumatic (n = 13); dental-related oromaxillary fistula (n = 8); sinus neoplasia (n = 10); mycotic sinus disease (n = 7); and intrasinus progressive ethmoid haematoma (n = 7) and the long-term response to these treatments were retrospectively reviewed. RESULTS: Treatments evolved throughout the study and latterly were as conservative as possible, including sinoscopic lavage and standing sinusotomy, with a maxillary sinusotomy approach preferred for the mainly mature horses treated in this study. Removal of intrasinus inspissated pus, including transendoscopically (by sinusotomy and via existing sinonasal fistulae), was the main treatment for chronic primary sinusitis and sinonasal fistulation was seldom performed latterly. Attempted oral extraction of infected cheek teeth, even if unsuccessful, facilitated subsequent dental repulsion, resulting in few post operative problems. Sinus cyst removal carried an excellent prognosis. Except for cases of sinus neoplasia (only 22% cured), an excellent long-term response to treatment (91% fully cured, 7% partially cured) was obtained for all other types of sinus disease following a median of one treatment. CONCLUSIONS: More conservative treatments, including removal of intrasinus inspissated pus by sinoscopy, pre-existing sinonasal fistula or sinusotomy, are effective for chronic primary sinus disease. Standing sinusotomy, mainly using a small maxillary site, was suitable for most cases of sinus disease in mature horses.

Historical and clinical features of 200 cases of equine sinus disease.

The historical and clinical findings in 200 referred cases of equine sinus disease were reviewed retrospectively. Univariable and multivariable analyses were performed to detect significant differences in historical or clinical features between various categories of sinus disease. The causes of sinus disease were classified as subacute primary (less than two months duration) (n=52), chronic primary (more than two months duration) (n=37), dental (n=40), sinus cyst (n=26), traumatic (n=13) or mycotic sinusitis (n=7), sinus neoplasia (n=10), dental-related oromaxillary fistula (n=8) and intrasinus progressive ethmoid haematoma (n=7). The majority of sinus disorders were of chronic duration at the time of referral and most (including 97 per cent of chronic primary sinusitis cases) had not responded to previous antibiotic therapy and/or sinus lavage in some cases. Clinical signs included unilateral nasal discharge in most cases, including purulent or mucopurulent discharge in all horses with primary, dental and mycotic sinusitis. Haemorrhagic nasal discharge was a feature of traumatic sinusitis and intrasinus progressive ethmoid haematomas. Firm facial swellings and nasal airflow obstruction were features of sinus cysts and neoplasms. Ipsilateral lymphadenitis was a more prominent feature of sinus disease with active infections such as primary, dental or mycotic sinusitis.

Investigation of the sensitivity and specificity of radiological signs for diagnosis of periapical infection of equine cheek teeth.

REASONS FOR PERFORMING STUDY: Radiography is commonly used for the diagnosis of equine cheek teeth (CT) infection but, to our knowledge, no study to date has evaluated the relative values of individual specific radiographic signs when making a diagnosis. OBJECTIVES: To investigate the sensitivity and specificity of individual radiographic signs identified from the literature for the diagnosis of CT apical infection using a retrospective case-control study. METHODS: Cropped radiographs taken using computed radiography of 41 apically infected CT and 41 control CT were independently blindly evaluated by 3 clinicians for the presence of 12 predetermined radiographic signs associated with CT apical infection. A final diagnosis of either noninfected or infected was made. Sensitivity and specificity were calculated for the presence or absence of each radiographic sign for each clinician. Uni- and multivariable conditional logistic regression were used to determine strength of association of the 12 radiographic signs with apical infection. RESULTS: Median sensitivity and specificity for the diagnosis of CT apical infection were 76 and 90%, respectively. Periapical sclerosis, clubbing of one or 2 roots, degree of clubbing and periapical halo formation had the highest sensitivities (73-90%), with moderate specificity (61-63%). Multivariable conditional logistic regression revealed that severity of periapical sclerosis and extensive periapical halo were strongly associated with CT apical infection. CONCLUSIONS: The presence of periapical sclerosis and formation of a periapical halo were strongly associated with CT apical infection. Computed radiography appears to have a higher sensitivity but similar specificity to previously published results using film radiography to detect CT apical infection. POTENTIAL RELEVANCE: These findings may aid practitioners when interpreting radiographs of equine CT as to the relative significance of their findings.

Precise measurement of the e+e- --> pi+pi-(gamma) cross section with the initial state radiation method at BABAR.

A precise measurement of the cross section of the process e(+)e(-) --> pi(+)pi(-)(gamma) from threshold to an energy of 3 GeV is obtained with the initial state radiation (ISR) method using 232 fb(-1) of data collected with the BABAR detector at e(+)e(-) center-of-mass energies near 10.6 GeV. The ISR luminosity is determined from a study of the leptonic process e(+)e(-) --> mu(+)mu(-)gamma(gamma). The leading-order hadronic contribution to the muon magnetic anomaly calculated using the pipi cross section measured from threshold to 1.8 GeV is (514.1 +/- 2.2(stat) +/- 3.1(syst)) x 10(-10).

Observation of tree-level B decays with ss production from gluon radiation.

We report on our search for decays proceeding via a tree-level b-->c quark transition in which a gluon radiates into an ss[over ] pair. We present observations of the decays B;{-}-->D_{s};{+}K;{-}pi;{-} and B[over ];{0}-->D_{s};{+}K_{S};{0}pi;{-} and evidence for B;{-}-->D_{s};{+}K;{-}K;{-} and set upper limits on the branching fractions for B[over ];{0}-->D_{s};{+}K_{S};{0}pi;{-} and B;{-}-->D_{s};{+}K;{-}K;{-} using 383x10;{6} Upsilon(4S)-->BB[over ] events collected by the BABAR detector at SLAC. We present evidence that the invariant mass distributions of D_{s};{+}K;{-} pairs from B;{-}-->D_{s};{+}K;{-}pi;{-} decays are inconsistent with the phase-space model, suggesting the presence of charm resonances lying below the D_{s};{+}K;{-} threshold.

Smoking is a risk factor for multiple sclerosis: a metanalysis.

Several case control studies have probed a link between cigarette smoking and subsequent multiple sclerosis (MS). Data collection and statistical methods have varied, and frequently, case numbers have been small. Publications relating to MS and smoking are reviewed and combined where comparable methods have been used. Metanalysis of six informative studies show significantly elevated odds or rate ratios, ranging from 1.22 to 1.51, depending on the method of analysis, confirming that the risk of MS is increased for those who smoke prior to disease onset, as measured by commencement of symptoms. A variety of direct causative mechanisms are discussed, but an indirect association through health adverse conduct is favoured.

Are multiple sclerosis patients risk-takers?

Several factors appear to be associated with multiple sclerosis (MS), and each has a postulated immune or environmental explanation, but a common theme is lacking. This article suggests that a unifying premise could be risk-associated behaviour. Evidence is reviewed for associations with smoking, alcohol, recreational drug use, oral contraception, cholesterol intake, risk attitude and behaviour, ultraviolet light and vitamin D exposure, frequency of MS in healthy societies, and viral infection. The evidence associated with smoking, not taking vitamin D supplements and Epstein-Barr viral infection appears good. There may be a pattern of risk-associated behaviour that characterizes patients with MS and brings them into contact with one or more causative agents. Of the possible agents, viral infection seems the most likely.

The insulin-like growth factor-II/mannose-6-phosphate receptor: structure, distribution and function in the central nervous system.

The insulin-like growth factor-II/mannose-6-phosphate (IGF-II/M6P) receptor is a multifunctional single transmembrane glycoprotein which, along with the cation-dependent M6P (CD-M6P) receptor, mediates the trafficking of M6P-containing lysosomal enzymes from the trans-Golgi network (TGN) to lysosomes. Cell surface IGF-II/M6P receptors also function in the degradation of the non-glycosylated IGF-II polypeptide hormone, as well as in the capture and activation/degradation of extracellular M6P-bearing ligands. In recent years, the multifaceted role of the receptor has become apparent, as several lines of evidence have indicated that in addition to its role in lysosomal enzyme trafficking, clearance and/or activation of a variety of growth factors and endocytosis-mediated degradation of IGF-II, the IGF-II/M6P receptor may also mediate transmembrane signal transduction in response to IGF-II binding under certain conditions. However, very little is known about the physiological significance of the receptor in the function of the central nervous system (CNS). This review aims to delineate what is currently known about IGF-II/M6P receptor structure, its ligand binding properties and role in lysosomal enzyme transport. It also summarizes the recent data regarding the role of the receptor in the CNS, including its distribution, possible importance for normal and activity-dependent functioning as well as its implications in neurodegenerative disorders such as Alzheimer's disease (AD).

Early extubation for adult cardiac surgical patients.

BACKGROUND: Over 30 studies reported that early extubation (within eight hours) appears to be safe without an increased incidence of morbidity. A benefit of the practice may be cost savings associated with shorter Intensive Care Unit and hospital length of stays. OBJECTIVES: To assess the effects of early extubation and the impact of the extubating clinician's profession on morbidity, mortality, intensive care unit and hospital length of stay, with a subgroup analysis for extubation within four hours or four to eight hours. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL)(issue 1, 2003), MEDLINE (January 1966 to June 2003), EMBASE (January 1980 to June 2003), CINAHL (January 1982 to December 2002), SIGLE(January 1980 to December 2002). We searched reference lists of articles and contacted researchers in the field. SELECTION CRITERIA: Randomized controlled trials and controlled clinical trials of adult cardiac surgical patients (coronary artery bypass grafts, aortic valve replacement, mitral valve replacement, aortic aneurysm repair). DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. Study authors were contacted for additional information. A meta-analysis for most outcomes was conducted. MAIN RESULTS: Six trials were included in the review. There was no evidence of a difference between early and conventionally extubated patients shown in the relative risk and 95% confidence interval for the following outcomes: mortality in intensive care was 0.8 (0.42 to 1.52); thirty day mortality was 1.2 (0.63 to 2.27); myocardial ischaemia was 0.96 (0.71 to 1.30); reintubation within 24 hours of surgery was 5.93 (0.72 to 49.14). Time spent in intensive care and in hospital were significantly shorter for patients extubated early (7.02 hours (- 7.42 to - 6.61) and 1.08 days ( - 1.35 to - 0.82) respectively). REVIEWER'S CONCLUSIONS: There is no evidence of a difference in mortality and morbidity rates between the study groups. Early extubation reduces intensive care unit and hospital length of stay. Studies were underpowered and designed to show differences between study groups rather than equivalence between the groups. Suggested future areas of investigation: establishing the safety and efficacy of immediate extubation compared with early extubation; establishing the most effective means of pain control and reducing anxiety for patients; systematic reviews of the evidence for different parts of the patients journey through a cardiac surgery episode; and the impact of the profession of the clinician making the decision to extubate.

Selective increases in HIV-specific neutralizing antibody and partial reconstitution of cellular immune responses during prolonged, successful drug therapy of HIV infection.

Because the immune response to HIV depends on viral gene expression, we examined the HIV-specific immune responses in persons whose viral load after highly active antiretroviral therapy (HAART) was <400 on at least 3 occasions over a 12-month interval. Eleven patients were identified. While there was little change in mean HIV-binding antibody (Ab) titers in this group, two persons mounted increases in HIV envelope-specific binding antibody. Neutralizing antibody (NAb) titers against a panel of HIV-1 primary isolates (BZ167, US1, and CM237) increased post-HAART (80% neutralization titer against US1, p = 0.06; against CM237, p = 0.04). The two persons with large increases in binding antibody also had increases in primary isolate NAb. Roughly half of HAART recipients had significant increases in neutralizing antibody to the primary isolates US1 and CM237. Compared with CD4-matched, non-HAART controls, there were significant increases in NAb against the subtype B primary isolate US1 (p < 0.0009); no increases were seen against more easily neutralized primary isolate BZ167. There were no differences after HAART in antibody-directed cellular cytotoxicity (ADCC). HAART resulted in a partial restoration of lymphoproliferative responses to recall antigens (tetanus and diphtheria). New responses developed to HIV Gag p24. No patient responded to HIV Env gp160 or gp120 either before or after HAART. The data underscore the lack of functional reconstitution of HIV-specific, CD4-mediated responses despite durable suppression of viral replication. In the setting of stable anti-HIV Ab levels, the development of increased NAb in certain individuals suggests that control of the virus by HAART may assist in immune control of HIV.

Factitious halothane detection during trigger-free anesthesia in a malignant hyperthermia susceptible patient.

PURPOSE: To discuss the problems encountered when halothane was detected in a presumed 'clean' patient circuit during the 'trigger-free' anesthetic management of a known Malignant Hyperthermia Susceptible (MHS) patient for routine orthopedic surgery. CLINICAL FEATURES: A 29-yr-old MHS woman had a wrist arthroscopy/exploration/fusion under general anesthesia. During the course of the 'trigger-free' anesthetic the respiratory gas analyser detected end-tidal halothane in the patient circuit. The patient was disconnected from the circuit as attempts to identify the source of the readings were undertaken. After ruling out the presence of halothane by various clinical manoeuvre the patient was reconnected to the circuit without sequelae. CONCLUSION: By exclusion the problem was presumed to be a factitious reading resulting from the respiratory gas analyser incorrectly identifying patient-expired methane as halothane.