Activation of natural regulatory T cells by IgG Fc-derived peptide "Tregitopes"

We have identified at least 2 highly promiscuous major histocompatibility complex class II T-cell epitopes in the Fc fragment of IgG that are capable of specifically activating CD4(+)CD25(Hi)FoxP3(+) natural regulatory T cells (nT(Regs)). Coincubation of these regulatory T-cell epitopes or "Tregitopes" and antigens with peripheral blood mononuclear cells led to a suppression of effector cytokine secretion, reduced proliferation of effector T cells, and caused an increase in cell surface markers associated with T(Regs) such as FoxP3. In vivo administration of the murine homologue of the Fc region Tregitope resulted in suppression of immune response to a known immunogen. These data suggest that one mechanism for the immunosuppressive activity of IgG, such as with IVIG, may be related to the activity of regulatory T cells. In this model, regulatory T-cell epitopes in IgG activate a subset of nT(Regs) that tips the resulting immune response toward tolerance rather than immunogenicity.     

Unexpected discovery of 2 cases of hepatocyte nuclear factor 1α-mutated infracentimetric adenomatosis

We present 2 cases of hepatocyte nuclear factor 1α （HNF1α）-mutated adenomatosis, discovered for reasons unrelated to this disease, and identified using immunohistochemical methods. These new tools may further our understanding of the link between adenomas/adenomatosis subtypes and their complications, and their association with other abnormalities.     

Flt3-ligand induces adhesion of haematopoietic progenitor cells via a very late antigen (VLA)-4- and VLA-5-dependent mechanism

The adhesion of haematopoietic progenitor cells (HPC) to the bone marrow microenvironment is a process regulated by cytokines. In this study, we have shown that flt3-ligand (FL), a growth factor that controls early haematopoiesis, regulated the function and expression of the beta-1 integrins, very late antigen (VLA)-4 and VLA-5 on HPC. The modulation of the adhesiveness of HPC by FL was studied by adhesion assays on umbilical vein endothelial cells (HUVEC). Stimulation by FL induced two peaks of increased adhesiveness of HPC. The first peak was at around 30 min and was mechanistically related to an activation of the beta-1 integrins, mainly VLA-4 and VLA-5. The second peak was at around 12 h and was related to increased expression of VLA-4 and VLA-5. The control of HPC adhesiveness by FL is a previously unreported property of FL that may be important for the homing and the retention of flt3-expressing HPC within the bone marrow microenvironment.     

The molecular epidemiology of HIV type 1 among Vietnamese Australian injecting drug users in Melbourne, Australia

The proportion of human immunodeficiency virus type 1 (HIV-1) among Vietnamese injecting drug users (IDUs) in Melbourne, Australia exceeds that of the background population. To investigate the molecular epidemiology of HIV-1 among this group, the C2-V4 region of the HIV-1 envelope was directly sequenced from 11 Vietnamese Australians and 19 non-Vietnamese Australian controls. A significant difference in the distribution of the HIV-1 subtypes was demonstrated, with greater than 50% of Vietnamese Australian IDU shown to be infected with CRF01_AE-the predominant subtype in Southeast Asia, rather than subtype B, which dominates the Australian epidemic and which was found in 89.5% of the non-Vietnamese controls. The genetic diversity of the CRF01_AE epidemic in Vietnamese Australian IDUs was substantially lower that that of the background subtype B, consistent with a more recent introduction of a limited number of viral strains from Vietnam. These results support public health policy targeting Australian IDUs of Vietnamese ethnicity as a distinct vulnerable population.     

Diagnostic dilemmas in patients with cystic neoplasms of the pancreas

Summary Cystic neoplasms of the pancreas (CNP) are rare lesions that can be difficult to diagnose preoperatively. Twenty patients with cystic neoplasms of the pancreas including five microcystic adenomas, six benign mucinous cystic neoplasms, three malignant mucinous cystic neoplasms, two solid and papillary epithelial neoplasms, and four cystic neuroendocrine tumors were treated at a single institution between 1962 and 1987. The average duration of symptoms prior to diagnosis was 10 months. Five patients were asymptomatic. Forty percent of patients presented with an abdominal mass. Plain abdominal x-rays and UGI barium contrast studies were never diagnostic. Ultrasonography, computerized tomography (CT) and visceral angiography aided in the correct diagnosis in 28%, 36%, and 75% of patients studied, respectively. Overall a correct diagnosis was made preoperatively in only 35% of patients. Twelve of 13 patients were correctly diagnosed at laparotomy with intraoperative biopsy. Without biopsy the mass was misdiagnosed at laparotomy in five of six cases. CNP must be suspected inany patients who present with an upper abdominal mass with or without abdominal pain and no history of pancreatitis. CT may be diagnostic in up to one third of cases and should be obtained routinely to demonstrate the proximity of the lesion to other structures. Visceral angiography should also be obtained prior to operation. A generous incisional biopsy should be obtained of all pancreatic cysts that are not to be resected.     

Cardiovascular Assessment of Falls in Older People

Falls in older people can be caused by underlying cardiovascular disorders, either because of balance instability in persons with background gait and balance disorders, or because of amnesia for loss of consciousness during unwitnessed syncope. Pertinent investigations include a detailed history, 12-lead electrocardiography, lying and standing blood pressure, carotid sinus massage (CSM), head-up tilt, cardiac electrophysiological tests, and ambulatory blood pressure and heart rate monitoring, which includes external and internal cardiac monitoring. The presence of structural heart disease predicts an underlying cardiac cause. Conversely, the absence of either indicates that neurally mediated etiology is likely. CSM and tilt-table testing should be considered in patients with unexplained and recurrent falls. Holter monitoring over 24 hours has a low diagnostic yield. Early use of an implantable loop recorder may be more cost-effective. A dedicated investigation unit increases the likelihood of achieving positive diagnoses and significantly reduces hospital stay and health expenditure.     

Acute heart failure syndromes: Potential strategies to improve post-discharge outcomes

Hospitalization for acute heart failure syndromes (AHFS) is a significant negative predictor of prognosis. Although patients' presenting symptoms generally improve throughout hospitalization in response to therapy, post-discharge event rates, defined as rehospitalization and/or mortality, remain unacceptably high. In the past decade, many lifesaving therapies for heart failure, such as beta-blockers, aldosterone antagonists, and cardiac resynchronization therapy (CRT), have been defined. Hospitalization presents a unique opportunity to implement these and other lifesaving therapies. However, these opportunities are often missed, perhaps because the traditional focus of hospitalization has been on symptom relief, not improvement of post-discharge outcomes. Although many therapies are now available, each needs to be tailored to each patient based on a proper assessment (eg, revascularization for those with severe coronary artery disease, CRT for those with wide QRS). Thorough cardiac assessment combined with tailored implementation may improve post-discharge outcomes. New strategies are needed to improve uptake of current best-evidence therapies to decrease the morbidity and mortality of AHFS.     

Incidence and prognosis of c-KIT and FLT3 mutations in core binding factor (CBF) acute myeloid leukaemias

DNA from 110 adult de novo acute myeloid leukaemia (AML) patients exhibiting either inv(16) (n = 63) or t(8;21) (n = 47) was screened for mutations in the c-KIT (exon 8 and Asp816) and FLT3 (ITD and Asp835) genes. c-KIT exon 8 mutations were found in 15/63 (23.8%) inv(16) patients and 1/47 (2.1%) t(8;21) patients. c-KIT Asp816 mutations were present in 5/63 (7.9%) inv(16) AML and 5/47 (10.6%) t(8;21) AML. FLT3 mutations were identified in five patients (7.9%) with inv(16) and three patients (5.6%) with t(8;21) AML. All mutations were mutually exclusive; 40% of inv(16) AML patients possessed either a c-KIT or FLT3 mutation. c-KIT exon 8 mutations were shown to be a significant factor adversely affecting relapse rate.     

The Prevalence and Symptom Profile of Asthma–COPD Overlap: The HUNT Study

The concept of asthma and COPD as separate conditions has been questioned, and the term asthma–COPD overlap syndrome has been introduced. We assessed the prevalence, symptoms, and lifestyle factors of asthma–COPD overlap (ACO) in a large Norwegian population-based study.

From 2006 to 2008, a total of 50,777 residents of Nord-Trøndelag participated in the Nord-Trøndelag Health Study, Norway. They completed questionnaires regarding respiratory symptoms, disease status, and medication use. We estimated the prevalence and 95% confidence intervals of ACO. Additionally, spirometry was used to estimate the prevalence of ACO in a subgroup.

The prevalence of self-reported ACO was 1.9%, and in age groups <40, 40–60 and ≥60 years it was 0.7%, 1.4%, and 3.2%, respectively. Among those reporting COPD, the proportion of ACO was 0.56. In the spirometry subgroup when ACO was defined as doctor diagnosed asthma ever and FEV₁/FVC < 0.70, the prevalence of ACO was 2.0%. All respiratory symptoms, separately or in combination, as well as medication use were reported most frequently in those with ACO compared to the other groups. Strikingly, we observed a two-fold higher proportion of allergic rhinitis in ACO compared to COPD only.

In this Norwegian population, the prevalence of self-reported ACO was 1.9%, and the corresponding proportion of ACO among those with COPD was 0.56. Participants with ACO generally had the highest proportions of respiratory symptoms compared to asthma or COPD.     

Increased fracture rates in Turner's syndrome: a nationwide questionnaire survey

BACKGROUND AND OBJECTIVES: Reduced bone mineral content (BMC) and bone mineral density (BMD) have previously been reported in Turner's syndrome, although appropriate GH treatment and early induction of puberty seem to permit normal bone mass accumulation. Furthermore, an increased risk of fractures and osteoporosis have been reported in a registry study. The aim of the present study was to further characterize the risk of fractures in TS and to explore risk factors, in a historical follow-up survey based on a self-administered questionnaire. STUDY GROUPS: The questionnaire was issued to all females with TS (n = 632) in Denmark and to 1888 randomly selected controls (C) matched for age and geographical region. A total of 322 patients (51%) and 1169 controls (62%) returned the questionnaire. RESULTS: TS women were younger than C (30 years, range: 1-73 years vs. 34 years, range 2-82 years, P < 0.0005), smoked less often (17%vs. 27%, P < 0.0005), and had less frequent spontaneous menstruation (18%vs. 86%, P < 0.0005). In contrast, they used hormonal replacement therapy (HRT) more often (71%vs. 7%, P < 0.0005). The median age at start of HRT was 16 years (range 8-59 years) in TS vs. 42 years (range 12-53 years) in C (P < 0.0005). Above the age of 15 years, 83% of TS and 8% of C used HRT. GH had been used by 37% of TS but only 0.2% of C. Both type 1 and 2 diabetes were increased sevenfold among TS. Altogether, 77 individuals with TS had 109 fractures. The fracture risk was increased in TS [hazard ratio (HR, status) 1.35, confidence interval (CI) 1.04-1.75, P = 0.025]. Time to first fracture was reduced in TS (53 +/- 2 vs. 63 +/- 1; log-rank P = 0.03). Spontaneous menstruation was protective in females above 13 years of age (HR: 0.70, CI 0.54-0.93, P = 0.012). A history of parental fractures increased the risk (HR 1.92, CI 1.62-2.27, P < 0.001). Fractures of the forearm was more frequent among TS (P = 0.02). CONCLUSION: The present nationwide survey, based on questionnaires, confirms an increased risk of early fractures in TS, especially in those without ovarian function and with a positive family history of fracture and osteoporosis. It thereby emphasizes the need for being vigilant with respect to BMD measurements in these patients.