The role of lysosomes and autophagosomes in frontotemporal lobar degeneration.

INTRODUCTION: Cell biological and genetic evidence implicate failures in degrading aggregating proteins, such as tau and TDP-43, through the autophagy or lysosomal pathways in the pathogenesis of frontotemporal lobar degeneration (FTLD). METHODS: We investigated changes in the degradative pathways in 60 patients with different pathological or genetic forms of FTLD employing immunohistochemistry for marker proteins such as lysosomal-associated membrane proteins 1 (LAMP-1) and 2 (LAMP-2), cathepsin D (CTSD) and microtubule-associated protein 1 light chain 3 alpha (LC3A). Immunostained sections were qualitatively and semi-quantitatively assessed for the appearance, distribution and intensity of staining in neurones of the dentate gyrus (DG) and CA4 region of the hippocampus, and the temporal cortex (Tcx). RESULTS: Lower levels of neuronal LAMP-1 immunostaining were present in the DG and Tcx in FTLD-tau compared to FTLD-TDP. There was less LAMP-1 immunostaining in FTLD-tau with MAPT mutations, and FTLD-tau with Pick bodies, compared to FTLD-TDP types A and B, and less LAMP-1 immunostaining in FTLD-TDP type C than in FTLD-TDP types A and B. There was greater LAMP-1 immunostaining in GRN mutation which may reflect the underlying type A histology rather than mutation. There were no differences in neuronal LAMP-2, CTSD, EEA-1 or LC3A immunostaining between any of the five FTLD histological or four genetic groups, nor between FTLD-TDP and FTLD-tau. CONCLUSIONS: The underlying pathological mechanism in FTLD-tau may lie with a relative deficiency of lysosomes, or defective vesicular transport, whereas the failure to clear TDP-43 aggregates may lie with lysosomal dysfunction rather than a lack of available lysosomes or degradative enzymes.

Development of consensus-based national antimicrobial stewardship competencies for UK undergraduate healthcare professional education.

BACKGROUND: Healthcare professionals are involved in an array of patient- and medicine-related stewardship activities, for which an understanding and engagement with antimicrobial stewardship (AMS) is important. Undergraduate education provides an ideal opportunity to prepare healthcare professionals for these roles and activities. AIM: To provide UK national consensus on a common set of antimicrobial stewardship competencies appropriate for undergraduate healthcare professional education. METHODS: A modified Delphi approach comprising two online surveys delivered to a UK national panel of 21 individuals reflecting expertise in prescribing and medicines management with regards to the education and practice of nurses and midwives, pharmacists, physiotherapists, and podiatrists; and antimicrobial prescribing and stewardship. Data collection took place between October and December 2017. FINDINGS: A total of 21 participants agreed to become members of the expert panel, of whom 19 (90%) completed round 1 questionnaire, and 17 (89%) completed round 2. Panelists reached a consensus, with consistently high levels of agreement reached, on six overarching competency statements (subdivided into six domains), and 55 individual descriptors essential for antimicrobial stewardship by healthcare professionals. CONCLUSION: Due to the consistently high levels of agreement reached on competency statements and their associated descriptors, this competency framework should be used to direct education for undergraduate healthcare professionals, and those working in new clinical roles to support healthcare delivery where an understanding of, and engagement with, AMS is important. Although the competencies target basic education, they can also be used for continuing education.

How adaptations of substrate utilization regulate body composition.

OBJECTIVE: To elucidate the mathematical relationship between longitudinal changes of body composition and the adaptations of substrate utilization required to produce those changes. DESIGN: We developed a simple mathematical model of macronutrient balance. By using an empirical relationship describing lean body mass as a function of fat mass, we derived a mathematical expression for how substrate utilization adapts to changes of diet, energy expenditure and body fat such that energy imbalances produced the required changes of body composition. RESULTS: The general properties of our model implied that short-term changes of dietary fat alone had little impact on either fat or non-fat oxidation rates, in agreement with indirect calorimetry data. In contrast, changes of non-fat intake caused robust adaptations of both fat and non-fat oxidation rates. Without fitting any model parameters, the predicted body composition changes and oxidation rates agreed with experimental studies of overfeeding and underfeeding when the measured food intake, energy expenditure and initial body composition were used as model inputs. CONCLUSION: This is the first report to define the quantitative connection between longitudinal changes of body composition and the required relationship between substrate utilization, diet, energy expenditure and body fat mass. The mathematical model predictions are in good agreement with experimental data and provide the basis for future study of how changes of substrate utilization impact body composition regulation.

Treatment of Staphylococcus aureus endocarditis using moxifloxacin.

The conventional treatment of staphylococcal endocarditis requires in-patient administration, is inconvenient, and is potentially toxic. Increasing experience with well-absorbed, well-tolerated and highly active agents such as the new quinolones has prompted interest in their use as therapeutic alternatives for the treatment of such infections. We describe a case of staphylococcal endocarditis which failed to respond to conventional therapy, but where the addition of moxifloxacin, an 8-methoxyquinolone, was curative.

Photo-induced synthesis of tomatidenol-based glycoalkaloids in Solanum phureja tubers.

The effect of light exposure on the steroidal glycoalkaloid content of Solanum phureja tubers has been investigated and compared with that in domesticated potato (Solanum tuberosum) tubers. The results indicated that the increase in the concentration of solanidine-based glycoalkaloids, alpha-solanine and alpha-chaconine was broadly similar in both species. However, in the S. phureja tubers, light exposure also induced the synthesis of tomatidenol-based glycoalkaloids. These have been identified as alpha- and beta-solamarine. These glycoalkaloids were not detected in tubers continually stored in darkness.

Infective endocarditis in children following dental extraction and appropriate antibiotic prophylaxis.

Infective endocarditis is a rare but important complication of certain types of dental treatment. Antibiotic prophylaxis is routinely prescribed for patients with known congenital heart disease. In this report we describe two patients in whom endocarditis developed within 3 months of the dental procedure, despite appropriate antibiotics. Endocarditis should be actively excluded if patients develop a fever associated with non-specific symptoms following an 'at risk' dental procedure.

Diagnosis of infected modified Blalock-Taussig shunt by computed tomography.

Accurate localization of infection after pediatric cardiac operation is essential for correct decisions regarding treatment. We report a case of infection and endocarditis of a Blalock-Taussig shunt. Localization by computed tomography led to successful surgical intervention.

Lactoferrin cDNA. Expression and in vitro mutagenesis.

The full length copy DNA (cDNA) for human lactoferrin has been synthesised by the polymerase chain reaction (PCR) using sequence specific primers. The template was first strand cDNA, synthesised from human bone marrow RNA using oligo(dT) to prime DNA synthesis by MMLV reverse transcriptase. The full-length human lactoferrin cDNA has been expressed in baby hamster kidney (BHK) cells using the expression vector pNUT. The protein expressed from the cloned cDNA is secreted into the culture medium and yields of up to 40 mg per litre have been obtained. A mutant protein corresponding to the N-lobe of human lactoferrin (LfN) has also been expressed in BHK cells. The cDNA coding for this protein was produced by the introduction of stop codons into the region of the cDNA corresponding to the helix linking the N- and C-lobes of the native protein. LfN is also expressed as a secreted protein and has been obtained in high yield. LfN binds iron and has UV/Vis and ESR spectra which are virtually identical to the native protein. However, the pH at which iron is released from LfN is quite different to the pH of iron release from the native and the full-length recombinant protein. A number of mutations have been introduced into LfN by site-directed mutagenesis and the mutant proteins expressed in BHK cells. These mutations involve the iron binding ligands and have been designed to introduce some of the changes found in the C-lobe of melanotransferrin into LfN. An attempt has been made to express a protein corresponding to the C-lobe of human lactoferrin (LfC) by attaching the sequence for the signal peptide of lactoferrin to the cDNA sequences coding for the C-lobe.

End-on aortogram: improved identification of important coronary artery anomalies in tetralogy of Fallot.

OBJECTIVE: To identify coronary artery anomalies in patients with tetralogy of Fallot with an aortogram taken with steep caudal and left oblique angulation ("end-on" aortogram). DESIGN: Prospective evaluation of end-on aortogram in the preoperative angiographic assessment of consecutive patients with tetralogy of Fallot. SETTING: Regional paediatric cardiology centre. PATIENTS: 34 patients, aged 3 months to 12 years (median age 9 months). METHODS: An aortogram was performed with steep caudal (38 degrees-45 degrees) and left oblique (0 degrees-30 degrees) angulation under general anaesthetic as part of routine preoperative angiographic assessment. RESULTS: The origins and courses of the coronary arteries were visualised in all patients and important coronary artery anomalies were identified in four patients: single left coronary artery; single right coronary artery (two patients); separate high origin of left anterior descending. These anomalous coronary vessels crossed the right ventricular outflow tract. CONCLUSIONS: It is important to identify preoperatively coronary arteries that may interfere with right ventricular outflow tract reconstruction. An aortogram with steep caudal and left oblique angulation is useful in identifying anomalous coronary arteries and more importantly it defines the relation of these vessels to the right ventricular outflow tract.

A prospective cytogenetic study of 36 cases of DiGeorge syndrome.

Cytogenetic analysis was carried out in a prospective series of 36 children with DiGeorge syndrome. High-resolution banding (> 850 bands/haploid set) was achieved in 30 cases. Monosomy 22q11.21-->q11.23 was found in 9 of these 30 cases. In each of these cases monosomy 22q11.21-->q11.23 resulted from an interstitial deletion and not from a translocation. No other chromosome abnormalities were seen.

Unusual complication after pelvic surgery: unilateral lower limb crush syndrome and bilateral common peroneal nerve paralysis.

We present a patient who developed a right anterior leg compartment syndrome and bilateral common peroneal nerve paralysis following radical hysterectomy in the lithotomy position. We describe the physiopathology of the syndrome, its various etiologies, the treatment, and prevention of this complication.

DiGeorge syndrome with isolated aortic coarctation and isolated ventricular septal defect in three sibs with a 22q11 deletion of maternal origin.

DiGeorge syndrome was diagnosed in an infant who had an interrupted aortic arch, hypoparathyroidism, and low T lymphocyte numbers. Two siblings had heart defects that are not commonly described in DiGeorge syndrome (a membranous ventricular septal defect and coarctation of the aorta respectively). These siblings did not have evidence of thymic dysfunction or hypoparathyroidism. Chromosome analysis showed that the mother, whose cardiovascular examination was normal, and her three offspring with heart defects had a 22q11 interstitial deletion, which was confirmed by molecular analysis. This family suggests that 22q11 deletions can cause apparently isolated heart defects and that the range of these defects may be wider than previously recognised. Once the genes that are deleted in this family are characterised they will be useful candidate genes in the investigation of isolated cardiac malformations.

Fetal and infantile hypertension caused by unilateral renal arterial disease.

Three children who presented with heart failure in infancy caused by severe hypertension as a result of unilateral renal arterial disease are described. One presented at 3 days of age with persistent fetal circulation and heart failure. He had abnormal great vessels that indicated that the hypertension was of long standing and therefore fetal; this has not been described previously. The other two children failed to thrive because of unrecognised hypertension and subsequently presented with heart failure. All three underwent unilateral nephrectomy which cured their hypertension, and all were thriving at the time of writing. The benefits of nephrectomy outweighed the operative risks and loss of renal function. Blood pressure should be measured in children who are failing to thrive as part of routine clinical practice.

Idiopathic infantile arterial calcification in two siblings: failure of treatment with diphosphonate.

Two siblings with idiopathic infantile arterial calcification are reported. The fetal and postnatal echocardiographic features were a large pericardial effusion, thickened pulmonary and aortic valves, poor pulsation of the descending aorta, and calcification of the great vessels. In one patient calcification was first detected at 33 weeks' gestation. Despite treatment with disodium etidronate both children died.

[Acute maternal anterior poliomyelitis in a non-endemic zone]. / Poliomyélite antérieure aiguë maternelle en zone non endémique.

The authors report the case of a 26 year old woman with acute anterior poliomyelitis contracted during the vaccination of her baby. Despite having been herself vaccinated in infancy she was not protected against the poliovirus. The clinical interest of this uncommon case is a severe paralytic state with definitive paraplegia. The authors suggest serologic testing of patients born before 1967 especially if they are at risk of encountering the virus.

Balloon dilatation of the aortic valve for congenital aortic stenosis in childhood.

Balloon dilatation of the aortic valve was attempted in 34 consecutive children aged 16 months to 17 years (median 7 years), weight range 9-60 (median 22) kg. Previous surgical valvotomy had been performed in two patients (twice in one of them). The valve was not crossed in one patient. In the remaining 33 patients the pressure difference between the left ventricle and the ascending aorta during systole was reduced from 71 (30) to 28 (19) mm Hg. In 24 patients recatheterisation 2-19 (mean 9) months later showed gradients that were similar to those immediately after balloon dilatation (35 (20) v 31 (20) mm Hg). The two patients with the highest residual gradients immediately after balloon dilatation showed a spontaneous reduction in gradient at repeat catheterisation, whereas the patient who had twice had previous surgical valvotomy showed an increase in gradient from 37 to 99 mm Hg over nine months and required aortic root replacement. Balloon dilatation was repeated in two patients and this caused a further reduction in gradient. New aortic regurgitation occurred in nine (27%) patients (grade I, 8; grade II, 1) and aortic regurgitation was exacerbated (grade I to II) in two of the nine with pre-existing aortic regurgitation. External iliac artery avulsion occurred in one (3%) patient and two (6%) required intravenous streptokinase because the femoral artery became occluded. There were no other complications. Open valvotomy was performed in the child in whom the valve was not crossed, but no other child required aortic valve operation. Balloon dilatation of the aortic valve gave reasonable short term palliation and was well tolerated. It is an alternative to surgical valvotomy for initial palliation of congenital aortic stenosis in many children.