Chromosome aberrations in coeliac and non-coeliac enteropathies

The frequency of chromosomal aberrations in peripheral blood lymphocytes was assessed in three groups of children: untreated coeliac disease (n = 20); non-coeliac disease enteropathies (n = 15); controls (n = 15). The mean frequency of aberrant cells and the total number of aberrations per 100 metaphases was increased in the coeliac disease group compared with controls by factors of 5 and 6, respectively (p < 0.01 for both). Aberrant cells and total aberrations were similarly increased in the non-coeliac disease enteropathy group by a factor of 3.7 in each case (p < 0.05). However, the frequency of aberrations in the two enteropathy groups was not significantly different. Children with coeliac disease, similar to affected adults, have evidence of increased chromosomal instability. However, similarly increased chromosomal aberrations are seen in children with non-coeliac disease enteropathies, indicating that the abnormality is not specific for coeliac disease.     

Does a single plasma phenylalanine predict quality of control in phenylketonuria?

A 1993 MRC working group on phenylketonuria suggested standardising blood phenylalanine measurements by taking blood samples at the same time each day. Since it is not known how representative of a 24 hour period a single phenylalanine concentration is, the aim of this study was to investigate the 24 hour variability of plasma phenylalanine in well controlled children with phenylketonuria. Sixteen subjects, 12 girls and four boys aged 1 to 18 years, had hourly venous blood samples collected for 13 hours between 09.00 and 21.00 on one day. Serial skin puncture blood specimens were then collected at 24.00, 03.00, and 06.00 within the same 24 hour period. All food and drink was weighed. The median variation in plasma phenylalanine concentration was 155 mumol/l/day, with a minimum of 80 and a maximum of 280. The highest concentration occurred in the morning between 6.00 and 9.00 in 63% of subjects; the lowest occurred between midday and midnight in 94%. Concentrations < 100 mumol/l occurred in 46% of children below 11 years, three having concentrations < 30 mumol/l for two, six, and seven hours respectively. Three of five subjects had concentrations above the MRC guidelines for 24% of the period studied. Except in two subjects, the blood concentrations did not rise in response to phenylalanine consumption. However, the greater the quantity of protein substitute taken between waking and the 16.00 specimen, the larger the decrease in daytime phenylalanine concentration (r = -0.7030) (p < 0.005). There is therefore wide variability in phenylalanine concentrations in a 24 hour period in children with phenylketonuria which is not reflected in a single observation. Further study is needed to investigate the effects of timing of protein substitute on the stability of phenylalanine concentrations.     

Pharmacodynamic Profiling of a Siderophore-Conjugated Monocarbam in Pseudomonas aeruginosa: Assessing the Risk for Resistance and Attenuated Efficacy

The objective of this study was to investigate the risk of attenuated efficacy due to adaptive resistance for the siderophore-conjugated monocarbam SMC-3176 in Pseudomonas aeruginosa by using a pharmacokinetic/pharmacodynamic (PK/PD) approach. MICs were determined in cation-adjusted Mueller-Hinton broth (MHB) and in Chelex-treated, dialyzed MHB (CDMHB). Spontaneous resistance was assessed at 2× to 16× the MIC and the resulting mutants sequenced. Efficacy was evaluated in a neutropenic mouse thigh model at 3.13 to 400 mg/kg of body weight every 3 h for 24 h and analyzed for association with free time above the MIC (fT>MIC). To closer emulate the conditions of the in vivo model, we developed a novel assay testing activity mouse whole blood (WB). All mutations were found in genes related to iron uptake: piuA, piuC, pirR, fecI, and pvdS. Against four P. aeruginosa isolates, SMC-3176 displayed predictable efficacy corresponding to the fT>MIC using the MIC in CDMHB (R² = 0.968 to 0.985), with stasis to 2-log kill achieved at 59.4 to 81.1%. Efficacy did not translate for P. aeruginosa isolate JJ 4-36, as the in vivo responses were inconsistent with fT>MIC exposures and implied a threshold concentration that was greater than the MIC. The results of the mouse WB assay indicated that efficacy was not predictable using the MIC for JJ 4-36 and four additional isolates, against which in vivo failures of another siderophore-conjugated β-lactam were previously reported. SMC-3176 carries a risk of attenuated efficacy in P. aeruginosa due to rapid adaptive resistance preventing entry via the siderophore-mediated iron uptake systems. Substantial in vivo testing is warranted for compounds using the siderophore approach to thoroughly screen for this in vitro-in vivo disconnect in P. aeruginosa.     

Admission inflammatory markers and isolation of a causative organism in patients with spontaneous spinal infection

Introduction

The purpose of this study was to investigate the significance of the inflammatory markers on admission in the isolation of a causative pathogen in patients with spinal infection. Spinal infection is treated frequently at spinal units and can encompass a broad range of clinical entities. Its diagnosis is often delayed because of the difficulty of identifying the responsible pathogen.

Methods

Patients with spinal infection treated in our institution over a period of eight years were identified and their notes studied retrospectively. Admission C-reactive protein (CRP), white cell count (WCC) as well as co-morbidities and mode of pathogen identification were recorded. Overall, 96 patients were included in the study.

Results

The CRP levels on admission were correlated significantly with the overall potential for isolation of a pathogen (p<0.0001) and positive biopsy cultures (p=0.0016). Admission WCC levels were associated significantly with the overall potential for isolation of a pathogen (p=0.0003) and positive biopsy cultures (p=0.0023). Both CRP and WCC levels were significantly negatively correlated with the duration of the preceding symptoms (p=0.0003 and p<0.0001 respectively). Delay in presentation was significantly negatively correlated with organism isolation (p=0.0001). Multivariate analyses identified the delay in presentation as the strongest independent variable for organism isolation (p=0.014) in cases of spontaneous spinal infection when compared with the admission CRP level (p=0.031) and WCC (p=0.056).

Conclusions

In spontaneous spinal infection, delay in presentation is the strongest independent variable for organism isolation. High inflammatory marker levels on admission are a useful prognostic marker for the overall potential of isolating a causative organism either by blood cultures or by biopsy in patients with negative blood cultures. Furthermore, the admission inflammatory marker levels allow for treating surgeons to counsel their patients of the likelihood of achieving a positive microbiological yield from biopsy.     

Remission following an elemental diet or prednisolone in Crohn's disease

The short- and long-term effects of an elemental diet in children with acute Crohn's disease were compared with those of prednisolone in historical controls. Clinical remission was induced in 25 of 30 and in 18 of 28 episodes treated for six weeks with an elemental diet and prednisolone. Patients with proximal disease had longer remission after treatment with an elemental diet (p < 0.05) than did patients with colonic disease after treatment with prednisolone (p < 0.01). Disease activity index score improved in both groups compared with the pretreatment scores (p < 0.05). However, the improvement in the elemental diet group was significantly better than in the prednisolone group (p < 0.001). Changes in linear growth were better after treatment with an elemental diet compared with steroids (p < 0.001). Serum albumin and haematocrit concentrations all improved significantly in the children treated with an elemental diet (p < 0.001) but not in those treated with steroids. Thus an elemental diet was better than prednisolone in proximal disease and confirmed improved growth and nutritional status.     

Comparison of an elemental with a hydrolysed whey formula in intolerance to cows' milk

In a double blind study, 40 infants with cows' milk intolerance of various causes were randomised to receive a nutritionally complete formula in which nitrogen was supplied either as whey hydrolysate or amino acids. The median age of infants was 10 weeks (range 36 weeks' gestation to 108 weeks' postnatal age). After a median follow up period of 25 weeks there was no significant difference in dietary intake between the formulas. Twenty four weeks after entry, weight and weight for length improved equally on both formulas. Plasma albumin improved significantly on the hydrolysed whey formula but not in the amino acid group. Both milks were palatable and normal intakes of formula were maintained. Biochemical and haematological indices remained within normal limits. There was no difference in stool frequency and vomiting between the two formulas. Two infants developed a probable allergic colitis while receiving hydrolysed whey. Amino acid formula may have a role in the management of atopic infants with severe cows' milk intolerance who have already reacted to whey or casein hydrolysate formula.     

A Comparison of Circulating Immune Complexes, Pregnancy Associated β1-Macroglobulin and Galactosyltransferase as Tumour Markers for Ovarian Cancer

Serial blood samples have been obtained from 12 patients with ovarian cancer who were treated by surgery and, generally, chemotherapy or radiotherapy. Some achieved clinical remission, but the majority relapsed after variable time interval. Three potential tumour markers (Circulating Immune Complexes, Pregnancy Associated beta 1-Macroglobulin and Galactosyltransferase) have been studied longitudinally in serum for clinical correlation, predictive value, and biochemical 'lead time' to clinically detectable progression. None of the 3 offered any signal advantage over the others, and each showed an inconsistent relationship to observed disease status, with high levels indicating a poor outlook and the converse not true. Thus, since the 'lead time' is short, and reliability low, none of the compounds can be strongly commended as individual markers for ovarian cancer.     

Feeding problems in young PKU children

Behavioural feeding problems were found to be more prevalent in a group of 15 PKU children aged 1-5 years when compared to non-PKU controls. The parents of PKU children identified poorer appetites ( p < 0.01), a more limited range of foods consumed ( p < 0.03) and more gastrointestinal symptoms such as vomiting and constipation ( p < 0.03) than control children. The children were slower to feed ( p < 0.03), were more likely to dislike sweet foods and some ate separately from the rest of the family at mealtime ( p < 0.03). The effects on normal feeding behaviour should be considered when advocating strict diet therapy for young PKU children.     

Conservative surgery to preserve ovarian function in patients with malignant ovarian germ cell tumors. A review of 74 cases

BACKGROUND: Effective combination chemotherapy has improved the previously dismal prognosis for malignant ovarian germ cell tumors (MOGCT) dramatically. In young patients, conservative surgery with adjuvant chemotherapy has made the preservation of fertility possible, even in patients with advanced disease. The increase in cure rates has shifted the focus of recent studies to the long term menstrual, reproductive, and gynecologic outcomes in these patients. METHODS: The current study is a retrospective review of 74 patients with MOGCT treated by conservative surgery, retaining the uterus and contralateral ovary to preserve ovarian function, with or without chemotherapy. RESULTS: The mean age of the patients was 20.9 years (range, 10-35 years). The histologic subtypes included 31 dysgerminomas (41.9%), 16 immature teratomas (21.6%), 13 endodermal sinus tumors (17.6%), 11 mixed germ cell tumors (14.9%), and 3 embryonal cell tumors (4.1%). There were 56 International Federation of Gynecology and Obstetrics (FIGO) Stage I tumors (75.7%), 3 Stage II tumors, (4.1%), 11 Stage III tumors (14.9%), and 4 Stage IV tumors (5.4%). Adjuvant chemotherapy was administered in 47 patients (63.5%). The overall mean follow-up period was 52.1 months. There were 7 recurrences (9.5%) and 2 deaths (2.7%). Survival for patients with Stage I disease was 98.2% and that for patients with advanced disease stages was 94.4%. During chemotherapy 61.7% of patients developed amenorrhea but 91.5% of these women resumed normal menstrual function on completion of chemotherapy. Fourteen healthy live births were recorded in the chemotherapy group and there were no documented birth defects. There was 1 case of infertility (1.4%). CONCLUSIONS: The surgical approach in young patients with MOGCT confined to a single ovary should aim to preserve fertility. Advanced disease is not usually accompanied by contralateral ovarian disease and should not necessarily contraindicate conservative surgery. The majority of these patients who have received combination chemotherapy resume normal ovarian function and can expect a normal fertility rate and healthy offspring.     

Patterns of recurrence and disease-free survival in advanced squamous cell carcinoma of the vulva

OBJECTIVE: To compare patterns of recurrence and disease-free survival (DFS) of node-positive and node-negative patients with advanced vulval squamous cell carcinoma (SCC). METHODS: Fifty-five patients with FIGO stage III/IVA vulval SCC who had surgery at the Queensland Centre for Gynaecological Cancer from 1989 to 1999 were included. Patients were grouped as follows: Group A, pT3 N0; Group B, pT3 N1; Group C, pT4 N2. Treatment included surgery +/- postoperative radiotherapy. Multivariate Cox models were calculated to identify independent prognostic factors. RESULTS: After a median follow-up of 96 months, 25 patients (45.5%) experienced recurrence at the vulva (n = 2), pelvis (n = 8), or distant sites (n = 15). Recurrence in the pelvis and at distant sites was more likely for patients in groups B and C (P 0.003). At 5 years the probability of DFS was 66.6%, 35.3%, and 39.8% for patients in groups A, B, and C, respectively (P 0.085). Patients with negative nodes (n = 15), one microscopic positive node (n = 11), and two or more positive nodes (n = 29) had a probability of DFS of 66.6%, 67.3%, and 26.1% at 5 years, respectively (P 0.005). CONCLUSION: Patients with > or =2 positive groin nodes are at risk for distant failure. The DFS of patients with negative groin nodes and those with only one microscopic positive node is very similar. The prognosis of patients with > or =2 positive unilateral or bilateral groin nodes is similar. The current FIGO staging system inaccurately reflects prognosis for patients with advanced vulval cancer. Clinical trials are warranted to investigate the benefit of systemic treatment.