Enhanced liver fibrosis score is stable after withdrawal in patients with heavy alcohol consumption: A pilot study.

BACKGROUND: Enhanced liver fibrosis (ELF) score is an accurate, noninvasive test for assessing the severity of liver fibrosis in chronic liver disease, including alcohol-related liver disease. However, whether the ELF score changes during alcohol withdrawal is unknown. This pilot study assessed changes in the ELF score during withdrawal in patients with a history of excessive alcohol intake. METHODS: In this prospective study, ELF was performed on day 0 (D0, at the beginning of hospitalization), at day 7 (D7, on discharge from hospital), and at follow-up visits on days 30 (D30) and 90 (D90). Transient elastography (TE) was also assessed on days 4 (D4) and D30. RESULTS: The study included 35 patients (71% male) with a mean alcohol intake of 139 g/day. On D30 and D90, 8 and 13 patients had resumed alcohol consumption (mean intake of 90 and 80 g/day, respectively). In patients who remained abstinent, the mean ELF score was 8.93 on D0, 9.14 on D30 (p = 0.32), and 9.27 on D90 (p = 0.14). In patients who resumed alcohol, mean ELF score was 9.7 on D0, 10.05 on D30 (p = 0.09), and 9.71 on D90 (p = 0.12). ELF score was comparable over the first months after withdrawal, although there was a slight increase in the first week (mean ELF score increased from 9.24 on D0 to 9.74 on D7, p < 0.001). Mean TE value was 7.9 kPa on D4 and 8.1 kPa on D30 (p = 0.84) in patients who resumed alcohol consumption, and 8.3 and 7.5 kPa (p = 0.03) on D4 and D30, respectively, in abstinent patients. CONCLUSION: The ELF score is stable during the first months after withdrawal and thus appears to be a useful tool to assess liver fibrosis or cirrhosis in this setting. Nevertheless, because in the first week there is a transient increase in ELF score, caution in interpretation is warranted.

Radiomics, a Promising New Discipline: Example of Hepatocellular Carcinoma.

Radiomics is a discipline that involves studying medical images through their digital data. Using "artificial intelligence" algorithms, radiomics utilizes quantitative and high-throughput analysis of an image's textural richness to obtain relevant information for clinicians, from diagnosis assistance to therapeutic guidance. Exploitation of these data could allow for a more detailed characterization of each phenotype, for each patient, making radiomics a new biomarker of interest, highly promising in the era of precision medicine. Moreover, radiomics is non-invasive, cost-effective, and easily reproducible in time. In the field of oncology, it performs an analysis of the entire tumor, which is impossible with a single biopsy but is essential for understanding the tumor's heterogeneity and is known to be closely related to prognosis. However, current results are sometimes less accurate than expected and often require the addition of non-radiomics data to create a performing model. To highlight the strengths and weaknesses of this new technology, we take the example of hepatocellular carcinoma and show how radiomics could facilitate its diagnosis in difficult cases, predict certain histological features, and estimate treatment response, whether medical or surgical.

Mid-Infrared Spectroscopy as a New Tool for Ruling Out Spontaneous Bacterial Peritonitis: A Proof-of-Concept Study.

BACKGROUND AND AIMS: A highly sensitive and specific point-of-care method for diagnosing spontaneous bacterial peritonitis (SBP) is currently lacking. The objective of the present study is to evaluate the diagnostic value of a rapid, easy-to-use, mid-infrared fiber evanescent wave spectroscopy (MIR-FEWS) method for ruling out SBP. PATIENTS AND METHODS: Cirrhotic patients (n = 256) at five centers in France were included for suspected SBP or for the scheduled evacuation of ascites fluid. The mid-infrared spectrum of 7 µL of an ascites fluid sample was recorded using a MIR-FEWS system. To define a model for the diagnosis of SBP, the patients were divided into a calibration group (n = 170) and a validation group (n = 86). RESULTS: Most of the patients were male (71%). The mean age was 60.25 years. Alcohol-related liver disease was the most common cause of cirrhosis. SBP was observed in 18% of the patients. For the diagnosis of SBP in the calibration and validation groups, respectively, the model gave areas under the receiver operating characteristic curves of 0.87 and 0.89, sensitivities of 90% and 87%, specificities of 78% and 80%, positive predictive values of 48% and 50%, negative predictive values of 97% and 96%, positive likelihood ratio of 4.09 and 4.35, negative likelihood ratio of 0.13 and 0.16, Youden index of 0.68 and 0.67, and correct classification rates of 80% and 81%. CONCLUSION: The results of this proof-of-concept study show that MIR-FEWS is a highly sensitive diagnostic method for ruling out SBP. The method warrants further investigation.

Documentation from trained medical students has a low rate of relative downcoding for emergency medicine encounters.

Background: Since 2018, the Centers for Medicare & Medicaid Services (CMS) guidelines have allowed teaching physicians to bill for evaluation and management services based on medical student documentation. Limited previous data suggest that medical student documentation suffers from a high rate of downcoding relative to faculty documentation. We sought to compare the coding outcomes of documentation performed by medical students, and not edited by faculty, with documentation edited and submitted by faculty. Methods: A total of 104 randomly selected notes from real patient encounters written by senior medical students were compared to the revised notes submitted by faculty. The note pairs were then split and reviewed by blinded professional coders and assigned level of service (LoS) codes 1-5 (corresponding to E&M CPT codes 99281-99285). Results: We found that the LoS agreement between student and faculty note versions was 63%, with 23% of all student notes receiving lower LoS compared to faculty notes (downcoded). This was found to be similar to baseline variability in professional coder LoS designations. Conclusions: Notes from medical students who have completed a focused documentation curriculum have less LoS downcoding than in previous reports.

Number of Patient Encounters in Emergency Medicine Residency Does Not Correlate with In-Training Exam Domain Scores.

INTRODUCTION: Emergency medicine (EM) residents take the American Board of Emergency Medicine (ABEM) In-Training Examination (ITE) every year. This examination is based on the ABEM Model of Clinical Practice (Model). The purpose of this study was to determine whether a relationship exists between the number of patient encounters a resident sees within a specific clinical domain and their ITE performance on questions that are related to that domain. METHODS: Chief complaint data for each patient encounter was taken from the electronic health record for EM residents graduating in three consecutive years between 2016-2021. We excluded patient encounters without an assigned resident or a listed chief complaint. Chief complaints were then categorized into one of 20 domains based on the 2016 Model. We calculated correlations between the total number of encounters seen by a resident for all clinical years and their ITE performance for the corresponding clinical domain from their third year of training. RESULTS: Available for analysis were a total of 232,625 patient encounters and 69 eligible residents who treated the patients. We found no statistically significant correlations following Bonferroni correction for multiple analyses. CONCLUSION: There was no correlation between the number of patient encounters a resident has within a clinical domain and their ITE performance on questions corresponding to that domain. This suggests the need for separate but parallel educational missions to achieve success in both the clinical environment and standardized testing.

Management of diabetes mellitus in patients with cirrhosis: An overview and joint statement.

Type 2 diabetes mellitus (T2DM) is a frequent comorbidity in patients with cirrhosis that is projected to rise in prevalence due to the worldwide burden of obesity, insulin-resistance and non-alcoholic fatty liver disease. The management of T2DM in patients with cirrhosis is complex given the requirement for accurate adaptation according to the level of liver function impairment, with lack of summary of the little evidence available in the literature. Here, we summarise the data available with respect to the epidemiology and the impact of T2DM in patients with cirrhosis, as well as those on the management of T2DM in these patients. We provide guidance for the diagnosis of T2DM and the monitoring of glycaemic control in patients with cirrhosis, and for the management of nutrition and pharmacological treatments in relation to the level of liver dysfunction.

Adrenomedullin interacts with VEGF in endometrial cancer and has varied modulation in tumours of different grades.

OBJECTIVE: Endometrial cancer, in developed countries, is the most common malignancy of the female genital tract. Surgery and radiotherapy are successful in many patients but systemic and recurrent diseases have no consistently effective treatments, and for high grade advanced disease the prognosis is poor. The study investigated characteristics of adrenomedullin in endometrial cancer to assist in identifying targets for developing treatments. METHODS: Endometrial samples of women with and without cancer, and the Ishikawa cell line were used to investigate adrenomedullin mRNA regulation, peptide expression, adrenomedullin secretion and effects of adrenomedullin on VEGF secretion. RESULTS: Expression of adrenomedullin mRNA was upregulated compared to that in healthy post-menopausal endometria. Adrenomedullin secretion was increased by cobalt chloride in this study. Secretion was reduced by the naturally-occurring compounds, (-)-epigallocatechin gallate (EGCG) and 3,4',5-trihydroxystilbene (resveratrol), which we have previously demonstrated to also suppress VEGF secretion in endometrial tumour tissue. We noted, for the first time, that adrenomedullin enhanced VEGF secretion from tumour cells. CONCLUSIONS: Increased adrenomedullin expression may result in amplifying both tumorigenic and angiogenic activities. A substantial impact on growth of tumours may result in vivo as a consequence of the synergism between adrenomedullin and VEGF. Adrenomedullin, which has altered cellular characteristics in tumour compared to healthy tissue, offers an understudied target with potential to modify endometrial cancer behaviour, complementing other treatments.

Outcomes of revision total knee arthroplasty after methicillin-resistant Staphylococcus aureus infection.

BACKGROUND: The incidence of infection by methicillin-resistant Staphylococcus aureus (MRSA) in total knee arthroplasty (TKA) is becoming a more frequent concern, as increased morbidity following TKA has been reported for infections by resistant organisms. This study investigates whether MRSA infections are associated with decreased functional scores. QUESTIONS/PURPOSES: We therefore compared the functional scores, operative times, and rates of reinfection of revision TKA following MRSA infection versus other indications for revision. METHODS: We retrospectively reviewed charts of 101 patients (103 knees) who underwent mobile bearing TKA revision from January 2003 to September 2006, with a minimum clinical followup of 2 years in 45 knees (44%). We obtained the following indices: WOMAC, Activities of Daily Living Score (ADLS), SF-36, and Knee Society scores (KSS). Three groups of revisions were compared: MRSA infection (n = 6), non-MRSA infection (n = 9), and aseptic failure (n = 30). The three groups were similar in demographics and comorbidities. RESULTS: The MRSA (166 minutes) and non-MRSA groups (149 minutes) had longer operative times than the aseptic group (121 minutes). With numbers available, there were no differences in ROM, WOMAC, ADLS, KSS, and SF-36, with MRSA separate or combined with all infections. Infection recurrence between MRSA-infected knees and non-MRSA-infected knees was similar. CONCLUSIONS: While our study was underpowered to detect functional differences between MRSA-infected knees and non-MRSA-infected knees it does add data to the literature. Knees revised for infection have longer operative times and more frequent infection after revision. The reason for increased operative times is unclear. LEVEL OF EVIDENCE: Level III, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.

Lack of emergency medical services documentation is associated with poor patient outcomes: a validation of audit filters for prehospital trauma care.

BACKGROUND: Our previous Delphi study identified several audit filters considered sensitive to deviations in prehospital trauma care and potentially useful in conducting performance improvement, a process currently recommended by the American College of Surgeons Committee on Trauma. This study validates 2 of those proposed audit filters. STUDY DESIGN: We studied 4,744 trauma patients using the electronic records of the Central Region Trauma registry and Emergency Medical Services (EMS) patient logs for the period January 1, 2002, to December 31, 2004. We studied whether requests by on-scene Basic Life Support (BLS) for Advanced Life Support (ALS) assistance or failure by EMS personnel to record basic patient physiology at the scene was associated with increased in-hospital mortality. We performed multivariate analyses, including a propensity score quintile approach, adjusting for differences in case mix and clustering by hospital. RESULTS: Overall mortality was 6.1%. A total of 28.2% (n = 1,337) of EMS records were missing patient scene physiologic data. Multivariate analysis revealed that patients missing 1 or more measures of patient physiology at the scene had increased risk of death (adjusted odds ratio = 2.15; 95% CI, 1.13 to 4.10). In 17.4% (n = 402) of cases BLS requested ALS assistance. Patients for whom BLS requested ALS had a similar risk of death as patients for whom ALS was initially dispatched (odds ratio = 1.04; 95% CI, 0.51 to 2.15). CONCLUSIONS: Failure of EMS to document basic measures of scene physiology is associated with increased mortality. This deviation in care can serve as a sensitive audit filter for performance improvement. The need by BLS for ALS assistance was not associated with increased mortality.

Geochemical evidence for magmatic water within Mars from pyroxenes in the Shergotty meteorite.

Observations of martian surface morphology have been used to argue that an ancient ocean once existed on Mars. It has been thought that significant quantities of such water could have been supplied to the martian surface through volcanic outgassing, but this suggestion is contradicted by the low magmatic water content that is generally inferred from chemical analyses of igneous martian meteorites. Here, however, we report the distributions of trace elements within pyroxenes of the Shergotty meteorite--a basalt body ejected 175 million years ago from Mars--as well as hydrous and anhydrous crystallization experiments that, together, imply that water contents of pre-eruptive magma on Mars could have been up to 1.8%. We found that in the Shergotty meteorite, the inner cores of pyroxene minerals (which formed at depth in the martian crust) are enriched in soluble trace elements when compared to the outer rims (which crystallized on or near to the martian surface). This implies that water was present in pyroxenes at depth but was largely lost as pyroxenes were carried to the surface during magma ascent. We conclude that ascending magmas possibly delivered significant quantities of water to the martian surface in recent times, reconciling geologic and petrologic constraints on the outgassing history of Mars.

The retinal ganglion cell layer and visual acuity of the camel.

We examined the retinal ganglion cell layer of the dromedary camel, Camelus dromedarius. We have estimated that there are 8 million neurons in the ganglion cell layer of this large retina (mean area of 2,300 mm(-2)). However, only approximately 1 million are considered to be ganglion cells. The ganglion cells are arranged as two areas of high cell density, one in the temporal and one in the nasal retina. Densities of ganglion cells between these two high density regions is much lower, often less than 100 per mm(-2). In between these two high density regions, on the nasal side of the optic nerve head, is a unique and dense vertical streak of mostly non-ganglion cells; the function of this specialization is unknown. On the basis of ganglion cell density we estimate that the peak acuity in the dromedary camel is about 10 and 9.5 cycles per degree in the temporal and nasal high density regions respectively and falls to 2-3 cycles per degree in the central retina. Behavioral acuity was estimated for one bactrian camel and was found to be approximately 10 cyc deg(-1). The camel has a retina with a mean thickness of 104 microm, less than the 143 microm thickness that has previously been thought to be necessary for a retinal vasculature. Nevertheless, there is an extensive vitreal vasculature that does not appear to spare any retinal region.

Evidence of a founder BRCA1 mutation in Scotland.

BRCA1 mutations have been identified in breast and ovarian cancer families from diverse ethnic backgrounds. We studied 17 different families with the BRCA1 2800delAA mutation; seven were ascertained in Scotland (Dundee, Edinburgh, Glasgow, St Andrews), five in Canada (Toronto, Victoria) and five in the United States (Chicago, Philadelphia, Seattle). Overall there was a clear preponderance of Scottish ancestry. Genotype analysis performed on key members from 17 families was consistent with a common haplotype, strongly suggesting a single ancestral origin. A possible link was established between two families by tracing their genealogies through the records of the Registrar General for Scotland. This is the first example of a BRCA1 mutation likely to be derived from a common founder in Scotland. Further studies will be necessary to estimate more accurately the population frequency of the BRCA1 2800delAA mutation among unselected cases of breast and ovarian cancer in Scotland and the UK.

Characterization and polyanion-binding properties of purified recombinant prion protein.

Certain polysulphated polyanions have been shown to have prophylactic effects on the progression of transmissible spongiform encephalopathy disease, presumably because they bind to prion protein (PrP). Until now, the difficulty of obtaining large quantities of native PrP has precluded detailed studies of these interactions. We have over-expressed murine recombinant PrP (recPrP), lacking its glycophosphoinositol membrane anchor, in modified mammalian cells. Milligram quantities of secreted, soluble and partially glycosylated protein were purified under non-denaturing conditions and the identities of mature-length aglycosyl recPrP and two cleavage fragments were determined by electrospray MS. Binding was assessed by surface plasmon resonance techniques using both direct and competitive ligand-binding approaches. recPrP binding to immobilized polyanions was enhanced by divalent metal ions. Polyanion binding was strong and showed complex association and dissociation kinetics that were consistent with ligand-directed recPrP aggregation. The differences in the binding strengths of recPrP to pentosan polysulphate and to other sulphated polyanions were found to parallel their in vivo anti-scrapie and in vitro anti-scrapie-specific PrP formation potencies. When recPrP was immobilized by capture on metal-ion chelates it was found, contrary to expectation, that the addition of polyanions promoted the dissociation of the protein.

Patient selection and education for use of the CapSure (Re/Stor) continence shield.

Stress urinary incontinence affects millions of women. Many treatment options are available, ranging from behavioral or nonsurgical therapies to surgical intervention. The clinical findings of a multicenter trial using the CapSure (Re/Stor) continence shield to evaluate the safety and efficacy of this device for treating women with stress urinary incontinence are reported here. Additionally, the role of patient education and selection is discussed.

Evidence for linkage to psychosis and cerebral asymmetry (relative hand skill) on the X chromosome.

The hypothesis that psychosis arises as a part of the genetic diversity associated with the evolution of language generates the prediction that illness will be linked to a gene determining cerebral asymmetry, which, from the evidence of sex chromosome aneuploidies, is present in homologous form on the X and Y chromosomes. We investigated evidence of linkage to markers on the X chromosome in 1) 178 families multiply affected with schizophrenia or schizoaffective disorder with a series of 16 markers spanning the centromere (study 1), and 2) 180 pairs of left-handed brothers with 14 markers spanning the whole chromosome (study 2). In study 1, excess allele-sharing was observed in brother-brother pairs (but not brother-sister or a small sample of sister-sister pairs) over a region of approximately 20 cM, with a maximum LOD score of 1.5 at DXS991. In study 2, an association between allele-sharing and degree of left-handedness was observed extending over approximately 60 cM, with a maximum lod score of 2.8 at DXS990 (approximately 20 cM from DXS991). Within the overlap of allele-sharing is located a block in Xq21 that transposed to the Y chromosome in recent hominid evolution and is now represented as two segments on Yp. In one of two XX males with psychosis we found that the breakpoint on the Y is located within the distal region of homology to the block in Xq21. These findings are consistent with the hypothesis that an X-Y homologous determinant of cerebral asymmetry carries the variation that contributes to the predisposition to psychotic illness.

Anatomical comparison of the macaque and marsupial visual cortex: common features that may reflect retention of essential cortical elements.

This study identifies fundamental anatomical features of primary visual cortex, area V1 of macaque monkey cerebral cortex, i.e., features that are present in area V1 of phylogenetically distant mammals of quite different lifestyle and features that are common to other regions of cortex. We compared anatomical constituents of macaque V1 with V1 of members of the two principal marsupial lines, the dunnart and the quokka, that diverged from the eutherian mammalian line over 135 million years ago. Features of V1 common to both macaque and marsupials were then compared with anatomical features we have previously described for macaque prefrontal cortex. Despite large differences in overall area and thickness of V1 cortex between these animals, the absolute size of pyramidal neurons is remarkably similar, as are their specific dendritic branch patterns and patterns of distribution of intrinsic axons. Pyramidal neuron patchy connections exist in the supragranular V1 in both the marsupial quokka and macaque as well as in macaque prefrontal cortex. Several specific types of aspinous interneurons are common to area V1 in both marsupial and macaque and are also present in macaque prefrontal cortex. Spiny stellate cells are a common feature of the thalamic-recipient, mid-depth lamina 4 of V1 in all three species. Because these similarities exist despite the very different lifestyles and evolutionary histories of the animals compared, this finding argues for a highly conserved framework of cellular detail in macaque primary visual cortex rather than convergent evolution of these features.

Dopaminergic amacrine cells in the retina of the possum, Trichosurus vulpecula.

The common brush-tailed possum Trichosurus vulpecula is a small diprotodont marsupial common to both urban and natural environments. This is the first analysis of the neurotransmitter content of its retinal cells and, as the possum is a nocturnal forager, it was appropriate to begin with the dopaminergic amacrine cells that form an essential link in the modulation of the rod pathways subserving nocturnal vision. These results were compared with those from another diprotodont, the marsupial wallaby or quokka (Dann, 1996) to establish whether the dopaminergic systems were similar between these two diprotodont marsupials and also to compare these findings with those of other mammals. This study describes a population of amacrine cells in the possum retina that were immunolabelled with an antibody raised against tyrosine hydroxylase (TH). These TH-immunoreactive (IR) cells were located within the inner nuclear layer (INL) and their dendrites predominantly ramified within the most sclerad layers of the inner plexiform layer (IPL). The TH-IR amacrines formed a sparse cell population, of around 2400 cells, distributed over the entire retina. There was little evidence of a concentration gradient except for a slight elevation in density in the naso-temporal axis in dorsal retina. The formation of rings within the dendritic plexus, a feature common to TH-IR cells in other species, was also present in the possum and these appeared relatively frequently. This latter finding was rather unexpected since, in the marsupial quokka (Dann, 1996), the TH-IR dendrites formed fewer rings despite having the same density of TH-IR amacrines as the possum. This suggests that there may be subtle differences in the way the rod pathways are interconnected even within the same marsupial group and may also be a reflection of relative rod dominance across species.

Results of a multicenter trial of the CapSure (Re/Stor) Continence shield on women with stress urinary incontinence.

OBJECTIVES: To prospectively study the impact of the CapSure (Re/Stor) Continence shield for the treatment of stress urinary incontinence. METHODS: One hundred women with pure stress urinary incontinence were enrolled in a 6-month study. Objective measures of urine loss included pad weight test (PdWt) and provocative stress test (PST). Subjective measures included incontinence diaries documenting the number of incontinence episodes per day (IEPD), quality of life questionnaires, and satisfaction surveys. Objective and subjective measures were performed prior to enrollment, during use of the CapSure shield, and after discontinuation of the device. RESULTS: During the 12-week device utilization period, PdWt measurements demonstrated a 96% reduction in urine loss by week 1 and 97% by week 12. Eighty-two percent of subjects were completely dry by week 12. PST demonstrated 100% reduction in urine loss at each visit, with 91% of subjects completely dry by week 12. IEPD also demonstrated a 91% reduction in incontinence episodes by week 12. Quality of life scores and patient satisfaction surveys demonstrated significant improvement. During the 6-week post device utilization period (PUP), subjects continued to demonstrate a reduction in urine loss compared to pre-enrollment data, despite discontinuation of use. PdWt measurements demonstrated a 73% and 79% reduction in urine loss at weeks 14 and 18, respectively. Measurements of PST and IEPD demonstrated significant reductions in urine loss at weeks 14 and 18. A 1.5% prevalence of positive urine cultures was noted during device use. Bothersome vaginal or urethral irritation occurred in 12% of patients. Adverse events were few and required no therapeutic intervention. CONCLUSIONS: The CapSure shield is a safe and efficacious method of managing stress urinary incontinence in women.

Outpatient oral and maxillofacial surgery: transition to a Surgicenter setting and outcome of the first 200 cases.

Advances in techniques for perioperative management have reduced the morbidity associated with major oral and maxillofacial surgery. Simultaneously, pressures for cost control have affected patient access to surgical services. This report details the steps undertaken to effect a transition of major maxillofacial surgical procedures to an outpatient setting. Protocols for surgical, anesthetic, and postoperative management are described. Treatment outcomes for the first 200 cases are reported. Only 1% of cases required subsequent inpatient care and a less than 1% major revision rate was experienced.

Inherited mutations in PTEN that are associated with breast cancer, cowden disease, and juvenile polyposis.

PTEN, a protein tyrosine phosphatase with homology to tensin, is a tumor-suppressor gene on chromosome 10q23. Somatic mutations in PTEN occur in multiple tumors, most markedly glioblastomas. Germ-line mutations in PTEN are responsible for Cowden disease (CD), a rare autosomal dominant multiple-hamartoma syndrome. PTEN was sequenced from constitutional DNA from 25 families. Germ-line PTEN mutations were detected in all of five families with both breast cancer and CD, in one family with juvenile polyposis syndrome, and in one of four families with breast and thyroid tumors. In this last case, signs of CD were subtle and were diagnosed only in the context of mutation analysis. PTEN mutations were not detected in 13 families at high risk of breast and/or ovarian cancer. No PTEN-coding-sequence polymorphisms were detected in 70 independent chromosomes. Seven PTEN germ-line mutations occurred, five nonsense and two missense mutations, in six of nine PTEN exons. The wild-type PTEN allele was lost from renal, uterine, breast, and thyroid tumors from a single patient. Loss of PTEN expression was an early event, reflected in loss of the wild-type allele in DNA from normal tissue adjacent to the breast and thyroid tumors. In RNA from normal tissues from three families, mutant transcripts appeared unstable. Germ-line PTEN mutations predispose to breast cancer in association with CD, although the signs of CD may be subtle.