Increased TGF-beta 1 protein expression in patients with advanced colorectal cancer

INTRODUCTION: There is evidence that TGF-beta 1 plays a role as a tumor suppressor in early disease and has pro-oncogenic effects in advanced tumor stage. The aim of the study was to correlate TGF-beta 1 in plasma and tissue to clinical and pathological parameters in patients with various stages of disease progression. METHODS: One hundred sixty-nine patients who underwent surgery for a colorectal carcinoma were prospectively included. Blood samples, tumor free mucosa and tumor biopsies were assayed. RESULTS: TGF-beta 1 protein expression in tumors increased with increasing T-stage regardless of whether patients with metastatic disease were included or not (P = 0.0006). Patients with metastatic disease showed elevated TGF-beta 1 protein expression in both tumor tissue (P = 0.004) and plasma (P = 0.001) compared to those without metastatic disease. TGF-beta 1 protein expression was higher in the colon compared with the rectum in both tumor tissue and tumor-free bowel (P = 0.03), regardless of whether patients with metastatic disease were included or not. This difference was mainly attributable to a higher TGF-beta 1 protein expression in non-metastatic patients with lymph node positivity (P = 0.005). CONCLUSIONS: Higher TGF-beta 1 protein expression is associated with increasing T-stage and metastatic disease, indicating that TGF-beta 1 is of importance in tumor progression. The localization of the tumor seems to influence the TGF-beta 1 protein expression in patients with tumor cell-positive lymph nodes.     

Medulla oblongata volume: a biomarker of spinal cord damage and disability in multiple sclerosis

BACKGROUND AND PURPOSE: While brain MR imaging is routinely performed, the MR imaging assessment of spinal cord pathology in multiple sclerosis (MS) is less frequent in clinical practice. The purpose of this study was to determine whether measurements of medulla oblongata volume (MOV) on routine brain MR imaging could serve as a biomarker of spinal cord damage and disability in MS.MATERIALS AND METHODS: We identified 45 patients with MS with both head and cervical spinal cord MR imaging and 29 age-matched and sex-matched healthy control subjects with head MR imaging. Disability was assessed by the expanded disability status scale (EDSS) and ambulation index (AI). MOV and upper cervical cord volume (UCCV) were manually segmented; semiautomated segmentation was used for brain parenchymal fraction (BPF). These measures were compared between groups, and linear regression models were built to predict disability.RESULTS: In the patients, MOV correlated significantly with UCCV (r = 0.67), BPF (r = 0.45), disease duration (r = −0.64), age (r = −0.47), EDSS score (r = −0.49) and AI (r = −0.52). Volume loss of the medulla oblongata was −0.008 cm³/year of age in patients with MS, but no significant linear relationship with age was found for healthy control subjects. The patients had a smaller MOV (mean ± SD, 1.02 ± 0.17 cm³) than healthy control subjects (1.15 ± 0.15 cm³), though BPF was unable to distinguish between these 2 groups. MOV was smaller in patients with progressive MS (secondary- progressive MS, 0.88 ± 0.19 cm³ and primary-progressive MS, 0.95 ± 0.30 cm³) than in patients with relapsing-remitting MS (1.08 ± 0.15 cm³). A model including both MOV and BPF better predicted AI than BPF alone (P = .04). Good reproducibility in MOV measurements was demonstrated for intrarater (intraclass correlation coefficient, 0.97), interrater (0.79), and scan rescan data (0.81).CONCLUSION: MOV is associated with disability in MS and can serve as a biomarker of spinal cord damage.

Multiple sclerosis (MS) is a multifactorial disease with a strong neurodegenerative component associated with progressive atrophy of the brain and spinal cord.¹ Previous studies have shown involvement of the spinal cord in more than 80% of the patients with clinically definite MS.^2–5 Atrophy of the spinal cord is thought to originate mainly from neurodegenerative changes, especially of the cervical segment,^4,6–10 which results in impairment of motor function.^11–16 In contrast, brain atrophy correlates well with neuropsychologic impairment.¹ The most severe and debilitating physical disability in MS seems to be of spinal origin. Therefore, it has been suggested that measurements of upper spinal cord volume provides information regarding disease progression that is complementary to the assessment of brain atrophy.Although head MR imaging is routinely performed in patients with MS, spinal cord MR imaging takes additional time and is therefore performed only on specific indications, both in the clinic and research.The medulla oblongata is the most caudal part of the brain stem and is continuous with the spinal cord. It contains nuclei that are important for autonomic control such as respiration, heart rate, blood pressure and reflexes, and white matter (WM) tracts that connect the rostral and caudal parts of the central nervous system (CNS). Ventral, dorsal, and lateral funiculi in the lower medulla oblongata are continuous with those of the spinal cord.The medulla oblongata is generally included in the field of view (FOV) of routine brain MR images of patients with MS. We set out to explore the feasibility and clinical relevance of volumetric measures of the lower medulla oblongata and hypothesized that these measures will reflect spinal cord atrophy. The relative ease to obtain such measurements from routinely performed clinical MR imaging examinations of the head makes this a potentially strong candidate for a biomarker of spinal cord damage and disability. In this work we present the results of a retrospective analysis of MR imaging-derived medulla oblongata volume (MOV) in MS to establish the relationship to spinal cord, its correlation with clinical disability and the reproducibility of this metric.     

Lingual thyroid in children: a rare clinical entity

Objectives/Hypothesis: To study the presentation, management, and long‐term outcome of children presenting with lingual thyroid. Study Design: Institutional review board approved, retrospective study (1993–2004). Methods: The study was conducted at a tertiary care pediatric medical center. The main outcomes measured were initial presentation, radiographic findings, endocrine evaluation, surgical outcome, pathologic features, complications, need for hormonal replacement. Results: Four patients presented to the Department of Otolaryngology and Communications Enhancement, Children's Hospital Boston with lingual thyroid between 1993 and 2004. All patients were female, with an age range of 2 to 12 years (x = 6). All patients presented with a mass (1.4–3.5 cm) and most with respiratory or feeding difficulty. Magnetic resonance imaging was obtained in three patients and revealed a mass consistent with lingual thyroid. Thyroid scan confirmed the lingual thyroid as the only functioning thyroid in all four patients. None of the patients responded to hormonal replacement, and all underwent surgical excision of the mass. Surgical approach included midline glossotomy (n = 2) and CO₂ laser excision (n = 2). Pathologic evaluation confirmed lingual thyroid in all four patients. No evidence of malignancy was seen in any patient. All four patients require lifelong hormonal replacement. Conclusions: Lingual thyroid is a rare condition, with an incidence of 1:100,000. This infrequent congenital anomaly is often asymptomatic until a pathologic stress such as systemic disease or physiologic stress such as puberty causes enlargement of the ectopic tissue, leading to dysphagia, dysphonia, and dyspnea. The work‐up should include routine blood work including thyroid function tests thyrotropin, thyroxine, and thyroid hormone binding ratio; iodine thyroid scintigraphy; and computerized tomography or magnetic resonance imaging. The majority of patients require surgical excision of the symptomatic mass and, in case of absence of orthotopic thyroid tissue, long‐term thyroid hormone replacement.     

Novel and highly recurrent chromosomal alterations in Sézary syndrome

This study was designed to identify highly recurrent genetic alterations typical of Sézary syndrome (Sz), an aggressive cutaneous T-cell lymphoma/leukemia, possibly revealing pathogenetic mechanisms and novel therapeutic targets. High-resolution array-based comparative genomic hybridization was done on malignant T cells from 20 patients. Expression levels of selected biologically relevant genes residing within loci with frequent copy number alteration were measured using quantitative PCR. Combined binary ratio labeling-fluorescence in situ hybridization karyotyping was done on malignant cells from five patients. Minimal common regions with copy number alteration occurring in at least 35% of patients harbored 15 bona fide oncogenes and 3 tumor suppressor genes. Based on the function of the identified oncogenes and tumor suppressor genes, at least three molecular mechanisms are relevant in the pathogenesis of Sz. First, gain of cMYC and loss of cMYC antagonists (MXI1 and MNT) were observed in 75% and 40% to 55% of patients, respectively, which were frequently associated with deregulated gene expression. The presence of cMYC/MAX protein heterodimers in Sézary cells was confirmed using a proximity ligation assay. Second, a region containing TP53 and genome maintenance genes (RPA1/HIC1) was lost in the majority of patients. Third, the interleukin 2 (IL-2) pathway was affected by gain of STAT3/STAT5 and IL-2 (receptor) genes in 75% and 30%, respectively, and loss of TCF8 and DUSP5 in at least 45% of patients. In sum, the Sz genome is characterized by gross chromosomal instability with highly recurrent gains and losses. Prominent among deregulated genes are those encoding cMYC, cMYC-regulating proteins, mediators of MYC-induced apoptosis, and IL-2 signaling pathway components.     

Disclosure of minor mental health problems: an exploratory theoretical study

AIM: The aim of this study was to explore people's experiences, concerns and beliefs about disclosing minor mental health problems by focusing on the ways in which such disclosures are interpreted. BACKGROUND: Approximately half of people with mental health problems do not seek help. The decision to consult represents just one aspect of the process of revealing one's illness to others. People with mental health problems are known to be reluctant to reveal the existence of those problems through fear of how others might then view them. DESIGN: A qualitative approach was employed. In-depth interviews were carried out with 47 users and nonusers of community mental health services. Interviews were tape-recorded, transcribed and analysed. RESULTS: The data suggest that when people reveal minor mental health problems others interpret these in relation to a number of perceived contextual factors. These include perceptions of the severity and duration of any possible causes, the inner 'strength' of the person, the expected ability of the person to either solve or suppress the experience, and the form and context of the expression itself. The data presented included individuals who were seeking help for relatively 'minor' mental health problems (primarily depression and anxiety) and individuals who had no current mental health problems but routinely managed expressions of their own emotions. Throughout the data there appeared to be no distinct difference between these two groups other than one of the severity of psychological experience. CONCLUSION: The key elements involved in the interpretation of people's expressions of sadness were essentially the same as those involved in the interpretation of expressions of depression. An appreciation of these contextual factors influencing the interpretation and disclosure of minor mental health problems may aid the development of more person-centred mental health services and inform the content of health education in the mental health field.     

Investigation of mechanisms underlying the T-cell response to the hapten 2,4-dinitrochlorobenzene

T-cell mediated contact sensitization by small molecular weight xenobiotics results in significant morbidity and absences from work. To be recognized by T-cells, xenobiotics must act as haptens, becoming protein-bound. At present, the requirement for processing and presentation of xenobiotics, the nature of the T-cell responses to them and the mechanisms that confer individual susceptibility in humans are unclear. We have investigated the T-cell response to the hapten 2,4-dinitrochlorobenzene (DNCB) which can sensitize all immunocompetent people. Fourteen healthy adults were sensitized with DNCB; 11 demonstrated positive T-cell responses to the chemical in vitro. Responding cells were of both CD4+ and CD8+ subsets, of Th1 and Tc1 phenotypes, producing high levels of IFN-gamma and low levels of IL-10. DNCB-specific T-cell clones were raised from 2 subjects, which in the presence of fixed and unfixed autologous Epstein-Barr virus transformed B cells as antigen-presenting-cells (APC), demonstrated that the chemical requires metabolic processing by the APC in order to initiate the T-cell response. Intracellular-reduced glutathione is consumed in detoxication of DNCB, leaving residual non-detoxified DNCB free to bind to proteins. The results suggest that DNCB forms multiple haptens with intracellular and extracellular proteins leading to Th1 and Tc1 responses in individuals exposed to this compound.     

Routine positron emission tomography and positron emission tomography/computed tomography in melanoma staging with positive sentinel node biopsy is of limited benefit

Positron emission tomography (PET) is increasingly used for the staging and management of melanoma. The aim of this study was to evaluate the role of PET or PET/ computed tomography (CT) as a routine procedure in patients with positive sentinel node biopsy (SNB). Thirty patients with melanoma of Breslow thickness greater than 1 mm who had PET or PET/CT scans performed within 100 days after a positive SNB were reviewed retrospectively. Two patients (6%) had a positive PET scan, none of which were melanoma related. The first patient had a synchronous neuroendocrine thyroid tumour and the second patient had increased uptake in the chest wall, which proved to be old trauma. Lymph node dissection was positive in five cases (16%). With a median follow-up of 24 months, 21 patients remained disease free. In none of the 30 cases did the early PET scan after a positive SNB alter subsequent melanoma management. The role of PET scanning soon after a positive sentinel node biopsy seems to be of limited benefit. It is questionable whether any imaging is beneficial at this stage. The results of this review suggest that PET scanning might not be indicated for this group of patients.     

Growing up ready: a shared management approach

In order to help youth with physical disabilities and their families to plan for the transition to adulthood, well-planned service delivery is essential. This paper provides an account of the work of a children's rehabilitation centre to develop a transition framework reflecting evidence-based practice. Examination of current transition practices, a review of the literature, and site visits to health care facilities and universities were conducted to identify promising practices in the field of transition to adult services. A transition framework was designed to facilitate the adoption of a shared management approach for helping families and their children to grow up ready. Key elements of the transition framework are described and future plans discussed.     

Inpatient Diabetes Education Is Associated With Less Frequent Hospital Readmission Among Patients With Poor Glycemic Control

OBJECTIVE

To explore the relationship between inpatient diabetes education (IDE) and hospital readmissions in patients with poorly controlled diabetes.

RESEARCH DESIGN AND METHODS

Patients with a discharge diagnosis of diabetes (ICD-9 code 250.x) and HbA_1c >9% who were hospitalized between 2008 and 2010 were retrospectively identified. All-cause first readmissions were determined within 30 days and 180 days after discharge. IDE was conducted by a certified diabetes educator or trainee. Relationships between IDE and hospital readmission were analyzed with stepwise backward logistic regression models.

RESULTS

In all, 2,265 patients were included in the 30-day analysis and 2,069 patients were included in the 180-day analysis. Patients who received IDE had a lower frequency of readmission within 30 days than did those who did not (11 vs. 16%; P = 0.0001). This relationship persisted after adjustment for sociodemographic and illness-related factors (odds ratio 0.66 [95% CI 0.51–0.85]; P = 0.001). Medicaid insurance and longer stay were also independent predictors in this model. IDE was also associated with reduced readmissions within 180 days, although the relationship was attenuated. In the final 180-day model, no IDE, African American race, Medicaid or Medicare insurance, longer stay, and lower HbA_1c were independently associated with increased hospital readmission. Further analysis determined that higher HbA_1c was associated with lower frequency of readmission only among patients who received a diabetes education consult.

CONCLUSIONS

Formal IDE was independently associated with a lower frequency of all-cause hospital readmission within 30 days; this relationship was attenuated by 180 days. Prospective studies are needed to confirm this association.Hospital readmission is an important contributor to total medical expenditures and is an emerging indicator of quality of care. The Affordable Care Act is placing increasing focus on medical homes and accountable care organizations, and transition programs for hospitalized patients have garnered increasing attention (1). In addition, the Medicare Payment Advisory Commission has reduced reimbursement rates for patients who have early rehospitalizations for certain conditions such as congestive heart failure (CHF) (2). Diabetes, similar to other chronic medical conditions, is associated with increased risk of hospital readmission (3). Robbins et al. (4) showed that rehospitalizations within 30 days of discharge occurred in 20% of patients with diabetes, which is more than the 5–14% estimated for all hospital discharges. Among patients with diabetes who had been hospitalized, Jiang et al. (5) showed that 30% of these patients were hospitalized more than once within 1 year, and these patients accounted for a majority of the inpatient costs for patients with diabetes. These findings are particularly relevant because hospital stays for patients with diabetes numbered >7.7 million in 2008, accounting for 20% of hospitalizations and $83 billion (23% of total hospital costs) in the U.S. (6).Rehospitalizations occur disproportionately among socioeconomically disadvantaged groups, including Hispanics and African Americans (AAs), those living in lower income zip codes, and those without private insurance (5,7). Other risk factors include previous hospitalization, extremes of age, and socioeconomic barriers. Failure to acknowledge diabetes at discharge is associated with increased 30-day readmissions, suggesting that suboptimal diabetes management may be an important factor for successful transitions in care (4).The involvement of a diabetes specialist team may reduce readmissions according to limited data from some (8,9) but not all (10) studies. Results may depend on the individual components of the program and attention to discharge needs. Inpatient diabetes management teams generally incorporate some component of diabetes education (11). In the outpatient setting, nursing education has resulted in improved HbA_1c and adherence to medication and glucose monitoring, so the potential benefits are not limited to readmission (12–14). In the case of heart failure, self-management education has been associated with improved readmission rates (15), so such a relationship in patients with diabetes would not be unprecedented.The objective of the study was to determine whether diabetes education, conducted by a dedicated trained diabetes educator during hospitalization, improves the frequency of readmission in patients with poorly controlled diabetes (HbA_1c >9%).