The importance of evidence-based supportive care practice guidelines in childhood cancer-a plea for their development and implementation.

As cure rates in pediatric oncology have improved substantially over the last decades, supportive care has become increasingly important to reduce morbidity and mortality and improve quality of life in children with cancer. Currently, large variations exist in pediatric oncology supportive care practice, which might negatively influence care. This plea underlines the importance of development and implementation of trustworthy supportive care clinical practice guidelines, which we believe is the essential next step towards better supportive care practice, and thus a higher quality of care. To facilitate international development and endorsement, the International Pediatric Oncology Guidelines in Supportive Care Network has been established.

Single hospital visit elective day-case laparoscopic cholecystectomy without prior outpatient attendance.

INTRODUCTION: Eighty percent of all UK elective laparoscopic cholecystectomies (LC) are performed as day-case procedures, but the pre-operative patient pathway has received little attention. In response to local patient feedback, we aimed to introduce a single hospital visit pathway for day-case LC. METHODS: A single hospital visit pathway for elective LC was piloted alongside standard services. Following telephone consultation, a pack containing procedure information, knowledge questionnaire and consent form were sent. Patients were not excluded on age, BMI or co-morbidity criteria, but recent ultrasonography and liver function tests were required. Patients were operated without attending any clinic or pre-operative service. There was no restriction on surgical or anaesthetic technique. Early surgeon-led telephone follow-up was made post-operatively and patient satisfaction assessed at 3 months. RESULTS: One hundred and sixty-six patients were referred with 92% transferred to day-case waiting lists following telephone consultation. One hundred and six patients underwent LC without previously visiting the hospital with 85% discharged the same day. Nine percent required post-operative primary care review primarily for wound reviews. Median patient-reported time to normal activities was 4 weeks (range 1-12). Ninety-nine percent reported being satisfied with the single-stop pathway. CONCLUSIONS: Single hospital visit LC is feasible, safe and acceptable for primary care referral patients with symptomatic gallstone disease without evidence of common bile duct or LFT abnormalities.

Enhanced recovery after anterior resection: earlier leak diagnosis and low mortality in a case series.

INTRODUCTION: Early detection and treatment of anastomotic leak may mitigate its consequences. Within an enhanced recovery setting, the subtle signs of a leak can be more apparent. There are multiple treatment options for anastomotic leak following anterior resection. This study aimed to determine when leaks are diagnosed in enhanced recovery, and whether the choice of intervention affects outcomes. MATERIALS AND METHODS: We conducted a retrospective study of a prospectively maintained database of complications of anterior resections for rectal cancer in a district general hospital in the UK. Data were extracted on day of leak diagnosis, length of stay, intensive care admission, mortality and ileostomy reversal rate. Statistical analysis was performed using Student's t, Mann-Whitney U and chi square tests. RESULTS: A total of 323 patients underwent anterior resection for colorectal cancer between 1 January 2007 and 1 October 2015. The leak rate was 10.8% (35/323). Patients were diagnosed in hospital with leaks on median day 4 compared with day 11 for patients diagnosed with leaks after readmission from home (P < 0.001). Defunctioned patients diagnosed with a leak had a longer median length of stay (24 vs 18.0 days, P = 0.31) but were more frequently managed non-operatively (100% vs 19.0%, P < 0.001) and had a lower admission rate to intensive care (9.5% vs 42.9%, P = 0.02) than patients who were not defunctioned at time of resection. Overall mortality from anastomotic leak was 2.9% (1/35). Ileostomies were reversed in 73.5% of patients (25/34). DISCUSSION: Enhanced recovery enables early diagnosis of leaks following anterior resection. Defunctioning of patients with anastomotic leak lowers mortality.

Abnormal preschool Lung Clearance Index (LCI) reflects clinical status and predicts lower spirometry later in childhood in cystic fibrosis.

BACKGROUND: Clinical and prognostic value of preschool Multiple Breath Washout (MBW) remains unclear. METHODS: Initial MBW results (Exhalyzer® D, EcoMedics AG) in preschool Cystic Fibrosis (CF) subjects (age 2-6 years) at a time of clinical stability were compared to (1) concurrent clinical status measures and (2) later spirometry outcomes. Abnormal Lung Clearance Index (LCI) was defined using published reference data (ULN for LCI 8.0). RESULTS: LCI was abnormal in 56% (28/50), with mean (SD) LCI 8.61(1.85) at age 4.71(1.3) years. Abnormal LCI was associated with higher dornase alfa use, previous positive bacterial cultures and pF508.del homozygous genotype. Later spirometry (n = 44; mean (SD) 2.3(0.5) years after MBW) demonstrated that abnormal initial preschool LCI was a strong predictor of lower later spirometry outcomes. CONCLUSION: Abnormal preschool LCI was associated with concurrent measures of clinical status and later spirometry deficits, suggesting early prognostic utility of MBW testing in this age range.

Are children just small adults? The differences between paediatric and adult sleep medicine.

Several important physiological and maturational changes occur in sleep development during the paediatric age range, particularly during infancy and in early childhood. As the pathology of sleep apnoea is superimposed onto a developing and often plastic physiological system, children often show a different pathophysiology to their adult counterparts. These factors need to be incorporated into the evaluation of a child's sleep problems. Particular attention should be paid to the developmental stage of the child. Investigation, interpretation and subsequent management provide further unique challenges and during successive reviews predicted normal changes must also be taken into account. This review article discusses the important physiological and maturational changes that occur in sleep during childhood, some common paediatric sleep conditions and their presentation and the appropriate evaluation and management of these conditions. In the course of the discussion, we have stressed important differences between paediatric and adult sleep medicine.

Utility of single versus multiple breath washout in adult asthma.

Nitrogen multiple breath washout (N2 MBW) is a sensitive method to identify peripheral airway involvement in asthma, but is a time-consuming test. The N2 vital capacity single breath (VC SBW) test offers greater time efficiency, but concordance with N2 MBW is poorly understood. The prevalence of peripheral airway abnormality was determined by N2 MBW and N2 SBW tests in 194 asthmatic subjects aged 18-1 years. N2 MBW data were related to findings in 400 healthy controls, aged 17-71 years, while N2 SBW data were compared to findings in 224 healthy controls, aged 15-65 years, to derive equipment-specific reference values. Amongst asthmatic subjects, relationships between N2 SBW and N2 MBW outcomes were studied. N2 SBW relationship with clinical history, spirometry, blood eosinophils and fraction exhaled nitric oxide (FENO) data was also explored. The prevalence of peripheral airway involvement (i.e. abnormal ventilation distribution) determined by N2 SBW-derived phase III slope (N2 SIII ) was 24·7%, compared to 44% determined by N2 MBW-derived lung clearance index (LCI) (P<0·001). Predictors of abnormal N2 SIII were older age, smoking history and lower FEV1. N2 SBW offers lower sensitivity than N2 MBW to detect small airway dysfunction in adult asthma, but may be a marker of more severe disease.

Pharmacologic interventions for fatigue in cancer and transplantation: a meta-analysis.

Background: Our objective was to determine whether, compared with control interventions, pharmacologic interventions reduce the severity of fatigue in patients with cancer or recipients of hematopoietic stem-cell transplantation (hsct). Methods: For a systematic review, we searched medline, embase, the Cochrane Central Register of Controlled Trials, cinahl, and Psychinfo for randomized trials of systemic pharmacologic interventions for the management of fatigue in patients with cancer or recipients of hsct. Two authors independently identified studies and abstracted data. Methodologic quality was assessed using the Cochrane Risk of Bias tool. The primary outcome was fatigue severity measured using various fatigue scales. Data were synthesized using random-effects models. Results: In the 117 included trials (19,819 patients), the pharmacologic agents used were erythropoietins (n = 31), stimulants (n = 19), l-carnitine (n = 6), corticosteroids (n = 5), antidepressants (n = 5), appetite stimulants (n = 3), and other agents (n = 48). Fatigue was significantly reduced with erythropoietin [standardized mean difference (smd): -0.52; 95% confidence interval (ci): -0.89 to -0.14] and with methylphenidate (smd: -0.36; 95% ci: -0.56 to -0.15); modafinil (or armodafinil) and corticosteroids were not effective. Conclusions: Erythropoietin and methylphenidate significantly reduced fatigue severity in patients with cancer and in recipients of hsct. Concerns about the safety of those agents might limit their usefulness. Future research should identify effective interventions for fatigue that have minimal adverse effects.

Novel methodology to perform sulfur hexafluoride (SF6)-based multiple-breath wash-in and washout in infants using current commercially available equipment.

Multiple-breath inert gas washout (MBW) is ideally suited for early detection and monitoring of serious lung disease, such as cystic fibrosis, in infants and young children. Validated commercial options for the MBW technique are limited, and suitability of nitrogen (N2)-based MBW is of concern given the detrimental effect of exposure to pure O2 on infant breathing pattern. We propose novel methodology using commercially available N2 MBW equipment to facilitate 4% sulfur hexafluoride (SF6) multiple-breath inert gas wash-in and washout suitable for the infant age range. CO2, O2, and sidestream molar mass sensor signals were used to accurately calculate SF6 concentrations. An improved dynamic method for synchronization of gas and respiratory flow was developed to take into account variations in sidestream sample flow during MBW measurement. In vitro validation of triplicate functional residual capacity (FRC) assessments was undertaken under dry ambient conditions using lung models ranging from 90 to 267 ml, with tidal volumes of 28-79 ml, and respiratory rates 20-60 per minute. The relative mean (SD, 95% confidence interval) error of triplicate FRC determinations by washout was -0.26 (1.84, -3.86 to +3.35)% and by wash-in was 0.57 (2.66, -4.66 to +5.79)%. The standard deviations [mean (SD)] of percentage error among FRC triplicates were 1.40 (1.14) and 1.38 (1.32) for washout and wash-in, respectively. The novel methodology presented achieved FRC accuracy as outlined by current MBW consensus recommendations (95% of measurements within 5% accuracy). Further clinical evaluation is required, but this new technique, using existing commercially available equipment, has exciting potential for research and clinical use.

Clinical characteristics of adult asthma associated with small airway dysfunction.

Suboptimal asthma control is common despite modern asthma therapy. The degree of peripheral airway involvement remains unclear and poor medication delivery to these regions might be a contributing reason for this failure in obtaining adequate symptom control. A cohort of 196 adults (median (range) age 44 (18-61) years, 109 females, 54 ex-smokers, six current smokers) with physician-diagnosed asthma were recruited from primary care. Subjects were characterized clinically by interviews, questionnaires, skin prick tests (SPT) and blood eosinophil counts. Lung function was assessed by spirometry, impulse oscillometry (IOS) and nitrogen multiple breath washout (N2 MBW). IOS assessed peripheral airway resistance (FDR, frequency dependence of resistance). N2 MBW assessed global ventilation inhomogeneity (LCI, lung clearance index), specific indices of peripheral airway function (Scond × VT and Sacin × VT; VT, tidal volume), and inter-regional inhomogeneity (specific ventilation ratio). Never-smoking healthy cohorts of 158 and 400 adult subjects provided local reference values for IOS and N2 MBW variables, respectively. Peripheral airway dysfunction was detected in 31% (FDR or specific ventilation ratio) to 47% (Scond x VT) of subjects. Risk factors for peripheral airway dysfunction were identified. Among subjects with low FEV1 and either positive smoking history and/or blood eosinophilia (>4.0%), 63% had abnormality across all peripheral airway outcomes, whilst only one subject was completely normal. Abnormal peripheral airway function was present in a large proportion of adult asthmatics at baseline. Reduced FEV1, a positive smoking history, and/or blood eosinophilia identified "a small airway asthma subtype" that might benefit from peripheral airway targeted therapy.

Treatment of chronic sclerosing osteomyelitis of the mandible with calcitonin: a report of two cases.

We report two patients with diffuse sclerosing osteomyelitis in the mandible in whom management with non-steroidal anti-inflammatory drugs, long-term antibiotics, and surgical debridement failed to resolve the symptoms of pain and swelling, which subsequently improved when the patients were given calcitonin.

Epithelioid Haemangioendothelioma of the mandibular gingiva: case report and literature review.

INTRODUCTION: Epithelioid hemangioendothelioma (EHE) is a rare vascular neoplasm that exhibits the potential for recurrence and metastasis but rarely involves the oral cavity. PRESENTATION OF CASE: We report the management and long term follow up of recurrent EHE in a 23- year-old woman. The lesion initially presented as a small area of erythematous gingival swelling with localised bone loss around the lower anterior teeth. It was treated by buccal and lingual stripping of the gingival tissues. The patient suffered local recurrence after 7 years and was treated with a wider surgical excision of the buccal and lingual gingivae, conserving the adjacent teeth and bone with an excellent cosmetic outcome. Over 21 years later, there have been no further recurrences. DISCUSSION: This case highlights the management challenges of EHE and is the only case in the literature to have reported a case of mandibular gingivae with a long review period of 21 years. CONCLUSION: Oral EHE is an unpredictable lesion with a relatively benign course, unlike non-oral EHE where up to one third of cases may metastasise. Because of the propensity to recur locally after excision and curettage, a wide local excision with close clinical follow has been suggested in the literature as the treatment of choice for oral lesions. However, the lack of metastases from oral lesions, the small size, mandibular site and bland histology in this case suggests that a limited soft tissue excision and bone curettage, with long term follow-up would be appropriate for similar gingival lesions in future.

Effect of a chemical modification on the hydrated adenosine intermediate produced by adenosine deaminase and a model reaction for a potential mechanism of action of 5-aminoimidazole ribonucleotide carboxylase.

Using the hydrated adenosine intermediate (6R)-6-amino-1, 6-dihydro-6-hydroxy-9-(beta-D-ribofuranosyl)purine (2) produced by adenosine deaminase (ADA, EC 3.5.4.4) as a starting point, the active site probe and inhibitor platform 5-(formylamino)imidazole riboside (FAIRs, 4) was designed by removal of the-C6(OH)(NH2)-molecular fragment of 2 generated by the early events of the enzyme-catalyzed hydrolysis. FAIRs was synthesized directly from the sodium salt of 5-amino-1-(beta-D-ribofuranosyl)imidazole-4-carboxylic acid (CAIR) along a reaction sequence involving a tandem N-formylation/decarboxylation that may have a mechanistic connection to the Escherichia coli purE-catalyzed constitutional isomerization of N5-CAIR to CAIR. The physical and spectral properties of FAIRs were elucidated, its X-ray crystal and NMR solution structures were determined, and its interaction with ADA was investigated. Crystalline FAIRs exists solely as the Z-formamide rotamer and exhibits many of the same intramolecular hydrogen bonding events known to contribute to the association of Ado to ADA. In water and various organic solvents, however, FAIRs exists as NMR-distinct, slowly interconverting Z and E rotamers. This truncated enzymatic tetrahedral intermediate analog was determined to be a competitive inhibitor of ADA with an apparent Ki binding constant of 40 microM, a value quite close to that (33 microM) of the natural substrate's K(m). The actual species selected for binding by ADA, though, is likely the minor hydroxyimino prototropic form of Z-FAIRs possessing a far lower true Ki value. As the structural features of FAIRs appear well-suited to support its use as a template for constructing active site probes of both ADA and AIR carboxylases, a variety of carbohydrate-protected versions of FAIRs suitable for facile aglycon elaborations were synthesized. The N3-alkylation, N3-borane complexation, and C4-iodination of some of these were investigated in order to assess physicochemical properties that may assist in the elucidation of mechanisms for the AIR carboxylases. The survey of these properties taken together with a reasonable mechanism for the model CAIRs-->FAIRs synthetic transformation is interpreted to support a mechanism for the purE-catalyzed N5-CAIR-->CAIR biosynthetic one that involves a carboxylative sp3-rehybridization of the imidazole C4 atom rather than one possessing a dipole-stabilized C4 sp2 carbanionic intermediate.

Genetically determined low maternal serum dopamine beta-hydroxylase levels and the etiology of autism spectrum disorders.

Autism, a neurodevelopmental disability characterized by repetitive stereopathies and deficits in reciprocal social interaction and communication, has a strong genetic basis. Since previous findings showed that some families with autistic children have a low level of serum dopamine beta-hydroxylase (DbetaH), which catalyzes the conversion of dopamine to norepinephrine, we examined the DBH gene as a candidate locus in families with two or more children with autism spectrum disorder using the affected sib-pair method. DBH alleles are defined by a polymorphic AC repeat and the presence/absence (DBH+/DBH-) of a 19-bp sequence 118 bp downstream in the 5' flanking region of the gene. There was no increased concordance for DBH alleles in affected siblings, but the mothers had a higher frequency of alleles containing the 19-bp deletion (DBH-), compared to an ethnically similar Canadian comparison group (chi(2) = 4.20, df = 1, P = 0.02 for all multiplex mothers; chi(2) = 4.71, df = 1, P < 0.02 for mothers with only affected sons). Although the odds ratios suggested only a moderate relevance for the DBH- allele as a risk allele, the attributable risk was high (42%), indicating that this allele is an important factor in determining the risk for having a child with autism. DBH genotypes also differed significantly among mothers and controls, with 37% of mothers with two affected sons having two DBH- alleles, compared to 19% of controls (chi(2) = 5.81, df = 2, P = 0.03). DbetaH enzyme activity was lower in mothers of autistic children than in controls (mean was 23.20 +/- 15.35 iU/liter for mothers vs. 33.14 +/- 21.39 iU/liter for controls; t = - 1.749, df = 46, P = 0.044). The DBH- allele was associated with lower mean serum DbetaH enzyme activity (nondeletion homozygotes: 41.02 +/- 24.34 iU/liter; heterozygotes: 32.07 +/- 18.10 iU/liter; and deletion homozygotes: 22.31 +/- 13.48 iU/liter; F = 5.217, df = 2, P = 0.007) in a pooled sample of mothers and controls. Taken together, these findings suggest that lowered maternal serum DbetaH activity results in a suboptimal uterine environment (decreased norepinephrine relative to dopamine), which, in conjunction with genotypic susceptibility of the fetus, results in autism spectrum disorder in some families.

Regional localization of an X-linked mental retardation gene to Xp21.1-Xp22.13 (MRX38).

A gene responsible for X-linked mental retardation with macrocephaly and seizures (MRX38) in a family with five affected males in three generations was localized to Xp21.1-p22.13 by linkage analysis. Recombination events placed the gene between DXS1226 distally and DXS1238 proximally, defining an interval of approximately 14 cM. A peak lod score of 2.71 was found with several loci in Xp21.1 (DXS992, DXS1236, DXS997, and DXS1036) at a recombination fraction of zero. The map intervals of 5 X-linked mental retardation loci, MRX2 (Xp22.1-p22.2), MRX19 (Xp22), MRX21 (Xp21.1-p22.3), MRX29 (Xp21.2-p22.1), and MRX32 (Xp21.2-p22.1), and two syndromal mental retardation loci, Partington syndrome (PRTS; Xp22) and Coffin-Lowry syndrome (CLS; Xp22.13-p22.2), overlap this region. As none of these display the same phenotype seen in the family reported here, this X-linked mental retardation locus may represent a new entity.

Absolute structure determination of the highly biologically active bisdehydrodoisynolic acids.

In a project designed to relate the unexpected in vivo and in vitro properties exhibited by (+)- and (-)-bisdehydrodoisynolic acid with their absolute stereochemical structure, an X-ray crystal-structure analysis was undertaken of the highly estrogenic, poorly binding (-) enantiomer. (1) and (13)C NMR spectra are also reported for the first time. The crystal structure shows the cis juxtaposition of the carboxyl and ethyl groups, which are separated by a large torsion angle, and that only the carbon atom holding the carboxyl group is out of the plane in which the remainder of the fused three-ring moiety lies. The crystal structure, which unequivocally characterizes the (-) enantiomer as cis-13(S),14(R) and, implicitly, the (+) enantiomer as cis-13(R),14(S), will be useful in continued studies aimed at explaining the selective estrogen receptor modulation (SERM) of these enantiomers which, in some cases, produces significantly different end-organ effects compared to those of estradiol, in both males and females, affording the promise of a variety of therapeutic and pharmacologic applications.

Effects of local anesthesia on substance P and CGRP content of the human dental pulp.

The aim of the study was to determine immunoreactive Substance P (iSP) and immunoreactive calcitonin gene-related peptide (iCGRP) content in the human dental pulp and whether local anesthesia has an effect on the neuropeptide content. Dental pulps were obtained from patients, who underwent surgical extraction of all 4 impacted wisdom teeth under general isoflurane gas anesthesia. There was a very high interindividual variation in tissue content, with small variation in levels found in teeth from the same patient. Pulps obtained from lower teeth without local anesthesia contained an average of 131 +/- 62 fmol/mg protein of iCGRP and 15 +/- 9 fmol/mg iSP (n = 10). With additional mandibular block anesthesia the values were 194 +/- 71 fmol/mg iCGRP (statistically significant, p = 0.0356, Mann-Whitney-rank-sum-test) and 12 +/- 3.6 fmol/mg iSP. The results suggest that local anesthesia attenuates neuropeptide release in the human dental pulp during surgical extraction.

Bone scans and the timing of treatment for condylar hyperplasia.

Bone scintiscans comparing the uptake of technetium 99 in the normal and affected condyles of 10 patients with unilateral condylar hyperplasia were recorded at or after the time when overall growth had ceased. The scans of 6 patients demonstrated persisting increased growth activity at this time. In 2 of these cases where the abnormal condyles showed uptakes of 240% and 170% with respect to the normal side, the nature and timing of treatment were changed when the results of the scans were known.

Articular cartilage of the temporomandibular joint: can it regenerate?

Clinical evidence and previous experimental animal work suggest that mandibular condylar cartilage shows the capacity for repair, after trauma or degeneration, that can reconstitute a functional articular surface; a facility not shared by other synovial joints. This study aims to test the regenerative capability of condylar cartilage in the repair of standardised full-thickness articular defects, and thereby to test the hypothesis that the healed wounds comprise tissues identical in form and composition to those of similar, but uninjured areas. Articular defects were produced at open arthrotomy of the temporomandibular joints in the young adult cotton eared marmoset. After healing periods of between 3 days and 1 year, repairing wounds were examined using histological, autoradiographic and immunocytochemical methods in an attempt to identify tissue architecture, cell proliferation and cartilage matrix components. The results showed reconstitution of all tissue elements of condylar cartilage within 6 months of injury. Glycosaminoglycans reformed at an early stage and appeared to be associated with type I collagen fibrillogenesis. Subsequently, type II collagen and aggregated proteoglycans accumulated from 8 weeks postoperatively, coinciding with organisation of the cell layers of condylar cartilage. The reformed tissue was maintained intact for the period studied (up to 1 year).