Female germline mosaicism in tuberous sclerosis confirmed by molecular genetic analysis

We have investigated a family in which three siblings with the autosomal dominant disorder tuberous sclerosis had unaffected parents. The family were typed for polymorphic markers spanning the two genes known to cause tuberous sclerosis located at 9q34 (TSC1) and 16p13.3 (TSC2). TSC1 markers showed different maternal and paternal haplotypes in affected children, excluding a mutation in TSC1 as the cause of the disease. For the TSC2 markers all the affected children had the same maternal and paternal haplotypes, as did three of their unaffected siblings. Mutation screening by RT-PCR and direct sequencing of the TSC2 gene identified a 4 bp insertion TACT following nucleotide 2077 in exon 18 which was present in the three affected children but not in five unaffected siblings or the parents. This mutation would cause a frameshift and premature termination at codon 703. Absence of the mutation in lymphocyte DNA from the parents was consistent with germline mosaicism and this was confirmed by our finding of identical chromosome 16 haplotypes in affected and unaffected siblings, providing unequivocal evidence of two different cell lines in the gametes. Molecular analysis of the TSC2 alleles present in the affected subjects showed that the mutation had been inherited from the mother. This is the first case of germline mosaicism in tuberous sclerosis proven by molecular genetic analysis and also the first example of female germline mosaicism for a characterized autosomal dominant gene mutation apparently not associated with somatic mosaicism.      

Follistatin and activin A in extra-embryonic coelomic and amniotic fluids and maternal serum in early pregnancy

Follistatin is a specific binding protein which controls bioavailability of activins and inhibins which have an important role in fetal development. In the first trimester of pregnancy bioactive dimeric inhibins are found at high concentrations in the extra- embryonic coelomic fluid, but the distribution of follistatin and activins is not known. We have used recently developed immunoassays for follistatin, activin A and activin AB to determine their presence in the intrauterine compartments during early pregnancy. Follistatin was present in highest concentrations in the extra-embryonic coelomic fluid (11.72 +/- 1.70 ng/ml; median +/- SEM), with less in maternal serum (6.35 +/- 4.58) and lowest amounts in amniotic fluid (0.97 +/- 0.52). Follistatin concentrations in extra-embryonic coelomic fluid were highly correlated with both dimeric inhibin isoforms. Activin A was present in only barely detectable amounts in some samples of extra- embryonic coelomic fluid (41% of samples) and maternal serum (26%) and was undetectable in all amniotic fluid samples. Activin AB was undetectable in all compartments. The presence of follistatin in the amniotic and extra-embryonic coelomic fluids may regulate the availability of bioactive activins and inhibins which are released into the intrauterine compartments during the development of the fetus and placenta in early pregnancy.      

Clinical frailty and its effect on the septuagenarian population after emergency laparotomy

IntroductionThe UK has an ageing population with an increased prevalence of frailty in the over 70s. Emergency laparotomy for acute intra-abdominal pathology is increasingly offered to this population. This can challenge decision making and information given to patients should not only be based on mortality outcomes but on relative expected quality of life and change to frailty syndromes.Materials and methodsThis was a single site National Emergency Laparotomy Audit (NELA)-based retrospective cohort audit for consecutive cases in the septuagenarian population assessing mortality, length of stay outcome and subjective postoperative functioning. Follow-up was conducted between one and two years postoperatively to determine this.ResultsSome 153 patients were identified throughout the single site NELA database. Median age was 79 years with a ratio of 1.7 men to women. Median rate of all-cause mortality was 35.3% at the median follow-up of 19 months. Median time from admission to death was 120 days. Of those who had died by the time of follow-up, significant preoperative indicators included clinical frailty scale (p < 0.0001), preoperative P-POSSUM (mortality). At follow-up, 35% responded to a quality of life follow-up. This revealed a decline in mid-term physical functioning, lower energy, higher fatigue and reduction in social functioning. There was also an increase in pre- and postoperative clinical frailty scale score.ConclusionIn the septuagenarian-plus population it is important to consider not only risk stratification with mortality scoring (P-POSSUM or NELA-adjusted risk), but to take into account frailty. Postoperative rehabilitation and careful recovery is paramount. Where possible, during the counselling and consent for emergency laparotomy, significant postoperative long-term deterioration in physical, emotional and social function should be considered.     

Myocardial and liver iron status using a fast T*2 quantitative MRI (T*2qMRI) technique.

This work demonstrates the use of a fast and precise methodology for evaluating myocardial and liver iron status in multitransfused thalassemic patients by means of a fast T(2) (*) quantitative MRI (T(2) (*)qMRI) technique. Myocardial and liver T(2) (*) values were calculated in 48 thalassemic patients and 21 normal subjects on a 1.5T MRI system using a breath-hold 2D single-slice multiecho gradient-echo (MEGRE) sequence (16 echoes, TR/TE1/TE16/FA = 160/2.7/37.65 ms/25 degrees ). No ECG gating was used. Myocardial T(2) (*), liver T(2) (*), and myocardial to muscle (CR/MS) and liver to muscle (LV/MS) T(2) (*) ratios were correlated with serum ferritin concentration (SFC) levels for all patients. Significant differences in myocardial and liver mean T(2) (*), CR/MS, and LV/MS T(2) (*) values between patients and normal subjects were found (P < 0.0005). Differences in paraspinous muscle mean T(2) (*) values between patients and normal subjects were not significant. Myocardial T(2) (*) and CR/MS T(2) (*) values were not correlated with SFC levels. Liver T(2) (*) and LV/MS T(2) (*) values were significantly correlated with SFC (r = 0.540, P < 0.0005). Myocardial T(2) (*) and CR/MS T(2) (*) values were not correlated with either liver T(2) (*) or LV/MS T(2) (*) values, respectively. We conclude that myocardial and liver iron deposition can be evaluated using the fast non-ECG-gated T(2) (*)qMRI technique.     

Determination of normal splenic volume on computed tomography in relation to age, gender and body habitus

The purpose of our study was to examine variations in normal splenic size in relation to age, gender and body habitus in vivo, and to determine normative data for splenic volume on CT. The width (W), length (L), thickness (Th), cross-sectional areas and volume (Vol) of the spleen were obtained from abdominal CT examinations of 140 patients who underwent CT for indications unrelated to splenic disease. Splenic volume did not vary significantly (–0.04 < r < 0.05, p > 0.10) with the patient's age, gender, height, weight, body mass index or the diameter of the first lumbar vertebra, the latter considered as representative of body habitus on CT. The mean value of the measured splenic volume (S Vol) was 214.6 cm³ with a range from 107.2 to 314.5 cm³. S Vol correlated well with all the linear and the maximal cross-sectional area measurements and could be calculated using the formula: S Vol = 30 + 0.58 (W × L × Th.). Employing the same formula splenic volume was reliably assessed in 47 patients with clinically evident splenomegaly. Quantitative assessment of splenic volume might be of value in assessing mild variations in splenic size, because splenomegaly is the most common manifestation of splenic involvement in many disorders. Received 29 January 1996; Revision received 24 June 1996; Accepted 15 July 1996     

Computed tomography of the normal appendix and acute appendicitis

The aim of this article is to present pictorially the spectrum of appearances of the appendix and appendicitis on CT. The images presented were selected from the database of our hospitals. The various appearances of the normal appendix on CT are shown. Appendicitis can be divided into four categories on the basis of CT findings. Examples of each category are shown. Received 17 June 1996; Revision received 27 September 1996; Accepted 8 November 1996     

Determination of dose-area product from panoramic radiography using a pencil ionization chamber: normalized data for the estimation of patient effective and organ doses

The aims of the present study were (a) to investigate the potential of pencil ionization chamber to be used for the determination of dose-width product (DWP) and dose-area product (DAP) from panoramic radiographic exposures and (b) to provide data normalized to DAP for the determination of patient effective and gonadal dose from panoramic radiography performed in any laboratory. A pencil ionization chamber commonly used to measure CT dose index (CTDI) in CT scanners was employed to determine DWP for various combinations of panoramic exposure settings at the beam exit slit of a Cranex Tome panoramic x-ray unit (Soredex, Helsinki, Finland). DWP values were also measured using an array of thermoluminescence dosimeters. Reproducibility of the DWP measurement was tested. The effect of milliamperage and kilovoltage of panoramic exposures on DWP was investigated. DAP was estimated using the value of DWP measured using the pencil ionization chamber and the beam exit slit length measured using dosimetric film attached on the beam exit slit. A Rando anthropomorphic phantom appropriately loaded with thermoluminescent dosimeters (TLDs) was used to obtain organ dose and effective dose values from panoramic radiography. Reproducibility of DWP determination using the proposed method was better than 1.5%. DWP was found to be linearly related to milliamperage (r>0.999, p<0.001) and to kilovoltage raised in a power ranging from 2.18 to 2.55. DWP measured using the pencil chamber was found to be up to 11% higher than the corresponding values determined using TLD array. The panoramic exposure obtained with settings appropriate for the typical adult patient was found to result in 0.008 mSv patient effective dose, 0.0002 mGy gonadal dose, and 11.3 cGy cm2 DAP. The use of a pencil ionization chamber is proposed for the determination of DWP and DAP from panoramic radiographic exposures. Normalized data over DAP were provided for the determination of patient effective and gonadal dose from panoramic radiography.