A statistical analysis of murine stem cell suicide techniques

The clinical application of soft agar cloning techniques for granulocyte-macrophage stem cells (CFU-C) has resulted in a number of contradictory reports that may in part be due to an inadequate data base. Growth of murine CFU-C is more reproducible and less variable than that of human CFU-C. We utilized in vivo hydroxyurea suicide of murine marrow CFU-C to address the question of how many experiments are needed to detect a specific difference with a p of less than 0.05. In 66 experiments the mean marrow CFU-C hydroxyurea kill was 23.3%; 6-9 separate experiments were necessary to detaect differences of 25%-30%. In order to be sure that a 25%-30% difference is not present, 15-21 experiments were required. Using a Dec-20 computer, 1000 samples of sample size 3, 4, or 10 were drawn from the 66 experiments; it was found that with 3 experiments and a true value of 23%, the actually observed value was below 10%, 17% of the time, and was over 40% in 10% of the samplings. In a smaller number of experiments similar results were obtained analyzing 3HTdR suicide of pluripotent stem cells and CFU- C. These data could provide a base from which to judge the validity of studies utilizing the CFU-C technique.     

小唾液腺癌治疗新进展

该文旨在对小唾液腺癌的治疗进行回顾。小唾液腺癌可发生在头颈部很多位置,通常表现为黏膜下肿块。影像学检查是对肿瘤发病部位及病变范围内解剖结构的关系进行评估的基础。切取活检或穿吸活检可以决定肿瘤的病理类型和分级。随着分子生物学技术的不断进步,小唾液腺癌的诊断     

Orofacial neuralgia associated with a middle cerebral artery aneurysm

Chronic orofacial pain of neuropathic origin can present diagnostic and management dilemmas to dental practitioners and also affects the patient's quality of life. Intracranial aneurysms are a potential cause of stroke (e.g. sub‐arachnoid haemorrhage) that is usually associated with, high rates of mortality and morbidity. A patient who had been previously managed for symptoms of temporomandibular joint disorder (TMD) presented with sharp, shooting pain of moderate intensity. It was precipitated by swallowing, and radiated to the right throat, posterior border of the mandible, ear and temporomandibular joint. Clinical and radiological investigations ruled out odontogenic pain, TMD and other more common types of facial pain. Magnetic resonance imaging revealed a 7 × 6 mm aneurysm in the right middle cerebral artery (MCA) which was subsequently surgically clipped. Interestingly, the facial pain resolved after this procedure. Compression of the insular region of the brain innervated by the trigeminal, glossopharyngeal and vagus nerves provides a plausible explanation for the pain reported. To our knowledge, this is the first case of facial neuralgia associated with an aneurysm in the MCA which emphasizes the importance of a multidisciplinary approach in the diagnosis and management of unusual cases of chronic orofacial pain.     

Economic Evaluation of a Web-Based Tailored Lifestyle Intervention for Adults: Findings Regarding Cost-Effectiveness and Cost-Utility From a Randomized Controlled Trial

Background

Different studies have reported the effectiveness of Web-based computer-tailored lifestyle interventions, but economic evaluations of these interventions are scarce.

Objective

The objective was to assess the cost-effectiveness and cost-utility of a sequential and a simultaneous Web-based computer-tailored lifestyle intervention for adults compared to a control group.

Methods

The economic evaluation, conducted from a societal perspective, was part of a 2-year randomized controlled trial including 3 study groups. All groups received personalized health risk appraisals based on the guidelines for physical activity, fruit intake, vegetable intake, alcohol consumption, and smoking. Additionally, respondents in the sequential condition received personal advice about one lifestyle behavior in the first year and a second behavior in the second year; respondents in the simultaneous condition received personal advice about all unhealthy behaviors in both years. During a period of 24 months, health care use, medication use, absenteeism from work, and quality of life (EQ-5D-3L) were assessed every 3 months using Web-based questionnaires. Demographics were assessed at baseline, and lifestyle behaviors were assessed at both baseline and after 24 months. Cost-effectiveness and cost-utility analyses were performed based on the outcome measures lifestyle factor (the number of guidelines respondents adhered to) and quality of life, respectively. We accounted for uncertainty by using bootstrapping techniques and sensitivity analyses.

Results

A total of 1733 respondents were included in the analyses. From a willingness to pay of €4594 per additional guideline met, the sequential intervention (n=552) was likely to be the most cost-effective, whereas from a willingness to pay of €10,850, the simultaneous intervention (n=517) was likely to be most cost-effective. The control condition (n=664) appeared to be preferred with regard to quality of life.

Conclusions

Both the sequential and the simultaneous lifestyle interventions were likely to be cost-effective when it concerned the lifestyle factor, whereas the control condition was when it concerned quality of life. However, there is no accepted cutoff point for the willingness to pay per gain in lifestyle behaviors, making it impossible to draw firm conclusions. Further economic evaluations of lifestyle interventions are needed.

Trial Registration

Dutch Trial Register NTR2168; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2168 (Archived by WebCite at http://www.webcitation.org/6MbUqttYB).     

Detecting myocardial infarction in critical illness using screening troponin measurements and ECG recordings

Introduction

To use screening cardiac troponin (cTn) measurements and electrocardiograms (ECGs) to determine the incidence of elevated cTn and of myocardial infarction (MI) in patients admitted to the intensive care unit (ICU), and to assess whether these findings influence prognosis. This is a prospective screening study.

Materials and methods

We enrolled consecutive patients admitted to a general medical-surgical ICU over two months. All patients underwent systematic screening with cTn measurements and ECGs on ICU admission, then daily for the first week in ICU, alternate days for up to one month and weekly thereafter until ICU death or discharge, for a maximum of two months. Patients without these investigations ordered during routine clinical care underwent screening for study purposes but these results were unavailable to the ICU team. After the study, all ECGs were interpreted independently in duplicate for ischaemic changes meeting ESC/ACC criteria supporting a diagnosis of MI. Patients were classified as having MI (elevated cTn and ECG evidence supporting diagnosis of MI), elevated cTn only (no ECG evidence supporting diagnosis of MI), or no cTn elevation.

Results

One hundred and three patients were admitted to the ICU on 112 occasions. Overall, 37 patients (35.9 per cent) had an MI, 15 patients (14.6 per cent) had an elevated cTn only and 51 patients (49.5 per cent) had no cTn elevation. Patients with MI had longer duration of mechanical ventilation (p < 0.0001), longer ICU stay (p = 0.001), higher ICU mortality (p < 0.0001) and higher hospital mortality (p < 0.0001) compared with those with no cTn elevation. Patients with elevated cTn had higher hospital mortality (p = 0.001) than patients without cTn elevation. Elevated cTn was associated with increased hospital mortality (odds ratio 27.3, 95 per cent CI 1.7 – 449.4), after adjusting for APACHE II score, MI and advanced life support. The ICU team diagnosed 18 patients (17.5 per cent) as having MI on clinical grounds; four of these patients did not have MI by adjudication. Thus, screening detected an additional 23 MIs not diagnosed in practice, reflecting 62.2 per cent of MIs ultimately diagnosed. Patients with MI diagnosed by the ICU team had similar outcomes to patients with MI detected by screening alone.

Conclusion

Systematic screening detected elevated cTn measurements and MI in more patients than were found in routine practice. Elevated cTn was an independent predictor of hospital mortality. Further research is needed to evaluate whether screening and subsequent treatment of these patients reduces mortality.     

Epstein-Barr virus lymphoproliferation after bone marrow transplantation

We review 15 cases of secondary B-cell lymphoproliferative disorders that occurred among 2,475 patients who received allogeneic bone marrow transplants (BMTs) at the Fred Hutchinson Cancer Research Center (Seattle) between 1969 and 1987. The histopathologic findings in 14 of the 15 patients spanned a wide spectrum of lymphoproliferative lesions. One patient had features characteristic of angioimmunoblastic lymphadenopathy. Epstein-Barr virus (EBV) genomic sequences were identified by Southern blot analysis in each of the 13 patients evaluated. Ten of the 12 lesions evaluated originated in donor cells. In two patients, who had mixed chimerism after transplantation, the lesions originated in host cells. The combined evidence from immunoglobulin light chain staining and the analysis of immunoglobulin heavy chain gene rearrangement indicated that the lesions in most patients represented polyclonal proliferations that gave rise to clonal subpopulations. The results indicate an overall actuarial incidence of 0.6% for this complication in BMT recipients. Anti-CD3 monoclonal antibody (MoAb) treatment of acute graft-v-host disease (GVHD) and T cell depletion of the donor marrow were statistically significant risk factors, and GVHD appeared to play a contributing role, particularly in the setting of human leukocyte antigen (HLA) disparity. Two patients had no identifiable risk factors. Prophylaxis or treatment with acyclovir had no detectable effect in the patients; all but two died with uncontrolled lymphoproliferation.     

Costs, charges, and reimbursements for persons with sickle cell disease.

PURPOSE: The aims of this study were to describe health care costs and charges for patients with sickle cell disease (SCD) and identify predictors of high use. PATIENTS AND METHODS: Patients with SCD were identified by International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM) codes from a university hospital's administrative databases from January 1, 1996, to September 30, 1997. Clinical and administrative data were gathered on each patient for all hospital admissions and ambulatory clinic visits. Logistic regression models were used to determine predictors of high health care use. RESULTS: A total of 947 patients with SCD were identified, 73% of whom resided within three South Carolina counties. On average, there were 0.9 admissions per patient per year and 8.0 outpatient visits per patient per year. Mean inpatient hospital charges, physician charges, and direct hospital costs per admission were $7290, $1589, and $5405, respectively, and the average length of stay was 4.5 days. Mean hospital charges, physician charges, and direct hospital costs per outpatient visit were $305, $169, and $688, respectively. Forty percent of the inpatient hospital charges were accounted for by only 4.2% of the patients. Residing in a distant county and being admitted with a diagnosis of painful respiration were found to be predictors of excessive charges and expenses beyond expected reimbursements. CONCLUSIONS: Patients with SCD are frequent users of health care services. Charges and costs are distributed disproportionately across these patients. Predictors of excessive hospital charges include living geographically distant from the hospital and being admitted with a diagnosis of painful respiration.     

X-linked liver glycogenosis type II (XLG II) is caused by mutations in PHKA2, the gene encoding the liver alpha subunit of phosphorylase kinase

X-linked liver glycogenosis type II (XLG II) is a recently described X- linked liver glycogen storage disease, mainly characterized by enlarged liver and growth retardation. These clinical symptoms are very similar to those of XLG I. In contrast to XLG I patients, however, XLG II patients do not show an in vitro enzymatic deficiency of phosphorylase kinase (PHK). Recently, mutations were identified in the gene encoding the liver alpha subunit of PHK (PHKA2) in XLG I patients. We have now studied the PHKA2 gene of four unrelated XLG II patients and identified four different mutations in the open reading frame, including a deletion of three nucleotides, an insertion of six nucleotides and two missense mutations. These results indicate that XLG II is due to mutations in PHKA2. In contrast to XLG I, XLG II is caused by mutations that lead to minor structural abnormalities in the primary structure of the liver alpha subunit of PHK. These mutations are found in a conserved RXX(X)T motif, resembling known phosphorylation sites that might be involved in the regulation of PHK. These findings might explain why the in vitro PHK enzymatic activity is not deficient in XLG II, whereas it is in XLG I.      

Diffusion MRI detects early brain microstructure abnormalities in 2‐month‐old 3×Tg‐AD mice

The 3×Tg‐AD mouse is one of the most studied animal models of Alzheimer's disease (AD), and develops both amyloid beta deposits and neurofibrillary tangles in a temporal and spatial pattern that is similar to human AD pathology. Additionally, abnormal myelination patterns with changes in oligodendrocyte and myelin marker expression are reported to be an early pathological feature in this model. Only few diffusion MRI (dMRI) studies have investigated white matter abnormalities in 3×Tg‐AD mice, with inconsistent results. Thus, the goal of this study was to investigate the sensitivity of dMRI to capture brain microstructural alterations in 2‐month‐old 3×Tg‐AD mice. In the fimbria, the fractional anisotropy (FA), kurtosis fractional anisotropy (KFA), and radial kurtosis (K_┴) were found to be significantly lower in 3×Tg‐AD mice than in controls, while the mean diffusivity (MD) and radial diffusivity (D_┴) were found to be elevated. In the fornix, K_┴ was lower for 3×Tg‐AD mice; in the dorsal hippocampus MD and D_┴ were elevated, as were FA, MD, and D_┴ in the ventral hippocampus. These results indicate, for the first time, dMRI changes associated with myelin abnormalities in young 3×Tg‐AD mice, before they develop AD pathology. Morphological quantification of myelin basic protein immunoreactivity in the fimbria was significantly lower in the 3×Tg‐AD mice compared with the age‐matched controls. Our results demonstrate that dMRI is able to detect widespread, significant early brain morphological abnormalities in 2‐month‐old 3×Tg‐AD mice.