Joelle Singer

Anti-inflammatory properties of omega-3 fatty acids in critical illness: novel mechanisms and an integrative perspective

IntroductionFish oil-based nutrition is protective in severe critical care conditions. Regulation of the activity of transcription factor NF-κB is an important therapeutic effect of the major omega-3 fatty acids in fish oil, eicosapentaenoic and docosahexaenoic acid (EPA and DHA).Methods and resultsUsing the articles obtained by a Pubmed research, this article reviews three aspects of NF-κB/inflammatory inhibition by fish oil. (1) Inhibition of the NF-κB pathway at several subsequent steps: extracellular, free omega-3 inhibits the activation of the Toll-like receptor 4 by endotoxin and free saturated fatty acids. In addition, EPA/DHA blocks the signaling cascade between Toll-like/cytokine receptors and the activator of NF-κB, IKK. Oxidized omega-3 also interferes with the initiation of transcription by NF-κB. (2) The altered profile of lipid mediators generated during inflammation, with production of the newly identified, DHA-derived inflammation-resolving mediator classes (in addition to the formation of less pro-inflammatory eicosanoids from EPA). Resolvin D1 and Protectin D1 are potent, endogenous, DHA-derived lipid mediators that attenuate neutrophil migration and tissue injury in peritonitis and ischemia-reperfusion injury. Their production is increased in the later stages of an inflammatory response, at which time they enhance the removal of neutrophils. (3) Modulation of vagal tone with potential anti-inflammatory effects: vagal fibers innervating the viscera down-regulate inflammation by activating nicotinic receptors upon infiltrating and resident macrophages. Stimulation of the efferent vagus is therapeutic in experimental septic shock. Fish oil supplementation increases vagal tone following myocardial infarction and in experimental human endotoxinemia.ConclusionIt remains to be shown whether these pleiotropic actions of EPA/DHA contribute to fish oil’s therapeutic effect in sepsis.

Monitoring of Individual Needs in Diabetes (MIND): Baseline Data From the Cross-National Diabetes Attitudes, Wishes, and Needs (DAWN) MIND Study

OBJECTIVE To test the feasibility and impact of implementing the computer-assisted Monitoring of Individual Needs in Diabetes (MIND) procedure, which is aimed at improving recognition and management of the psychological needs of diabetic patients in routine care. RESEARCH DESIGN AND METHODS The MIND study was implemented in diabetes clinics across eight countries as part of the annual review. The computerized assessment covered emotional well-being (World Health Organization 5 Well-Being Index), diabetes-related distress (Problem Areas in Diabetes), life events, and the patient’s agenda. Medical data were retrieved from the charts, and agreed-upon actions were recorded. RESULTS Of 1,567 patients monitored using the MIND, 24.9% had either likely depression or high diabetes-related distress; 5.4% had both. Over 80% of these patients were newly identified cases, and 41% of patients with depression were referred to a mental health professional. CONCLUSIONS Monitoring of well-being and diabetes-related distress as part of routine diabetes care is feasible and helps to identify and discuss unmet psychosocial needs.

Telomere dynamics in arteries and mononuclear cells of diabetic patients: effect of diabetes and of glycemic control.

Telomeres serve as a mitotic clock and biological marker of senescence. Diabetes mellitus (DM) is associated with damage to target organs and premature aging. We assessed the effect of glycemic control on telomere dynamics in arterial cells of 58 patients undergoing coronary artery bypass and in mononuclear blood cells of other diabetic (32 type I and 47 type II) patients comparing well controlled to uncontrolled patients. All were compared to age-dependent curve of healthy controls. Telomeres were significantly shorter in the arteries of diabetic versus non-diabetic patients (p=0.049) and in mononuclear cells of both type I and type II diabetes. In all study groups good glycemic control attenuated shortening of the telomeres. In arterial cells good glycemic control attenuated, but not abolished, the telomere shortening. In type II DM the mononuclear telomere attrition was completely prevented by adequate glycemic control. Telomere shortening in mononuclear cells of type I diabetic patients was attenuated but not prevented by good glycemic control. Results of this study suggest that diabetes is associated with premature cellular senescence which can be prevented by good glycemic control in type II DM and reduced in type I DM.

Clinical Characteristics and Outcome of Familial Nonmedullary Thyroid Cancer: A Retrospective Controlled Study

BACKGROUND Familial nonmedullary thyroid cancer (FNMTC) is a disease defined by clustering of thyroid cancers of follicular cell origin, and it is estimated to account for 5% of all thyroid cancers. Several studies found FNMTC to be more aggressive than sporadic disease, whereas others found them to have a similar course and outcome. The purpose of this study was to determine whether FNMTC is more aggressive than sporadic thyroid cancer. METHODS A retrospective controlled study of FNMTC versus sporadic nonmedullary thyroid cancers was conducted using a registry of patients with thyroid cancer. Data on disease severity at presentation, treatment modalities, and outcome were collected. RESULTS Sixty-seven patients with FNMTC and 375 controls with sporadic disease were included. Follow-up period was 8.6 ± 10 years for patients with FNMTC and 8.4 ± 9.1 years for sporadic cases. Patients with FNMTC had comparable disease severity at diagnosis as sporadic patients, underwent similar surgical and radioiodine treatments, and had similar long-term disease-free survival. Long-term outcome in families with three or more affected relatives was similar to families with only two affected relatives. CONCLUSIONS Our results suggest that FNMTC is not more aggressive than sporadic thyroid cancer within our studied population. After a similar therapeutic strategy, FNMTC and sporadic cases had comparable prognosis, including in families with three or more affected members.

Monitoring of Individual Needs in Diabetes (MIND)-2

OBJECTIVE To test the effects of implementing computer-assisted Monitoring of Individual Needs in Diabetes (MIND) in routine diabetes care on psychological status and glycemic control, identify predictors of poor psychological outcomes, and evaluate care providers’ experiences. RESEARCH DESIGN AND METHODS The MIND procedure was implemented as part of the annual review in diabetes clinics across eight countries in a prospective observational study with a 1-year follow-up. MIND encompasses well-being (World Health Organization Five Well-Being Index [WHO-5]), diabetes-related distress (Problem Areas in Diabetes [PAID]), a Life Event Inventory, and the patient’s agenda for their consultation. Medical data and agreed case-management actions were retrieved from the charts. RESULTS Of the total 1,567 patients, 891 patients (57%) were monitored at a 1-year follow-up. Twenty-eight percent of the patients screened positive for depression and/or diabetes distress at baseline and considered cases, 17% of whom were receiving psychological care. Cases were significantly more often female and had type 2 diabetes and worse glycemic control compared with noncases. Clinically relevant improvements in WHO-5 and PAID were observed over time in cases, irrespective of referral (effects sizes 0.59 and 0.48, respectively; P < 0.0001). Glycemic control did not change. Female sex, life events, and concomitant chronic diseases were predictors of poor psychological outcomes. MIND was well received by patients and staff. CONCLUSIONS MIND appears suitable for screening and discussion of emotional distress as part of the annual review. Broader dissemination in diabetes care is recommendable, but sustainability will depend on reimbursement and availability of support services.

Impact of Pregnancy on Outcome and Prognosis of Survivors of Papillary Thyroid Cancer

BACKGROUND Papillary thyroid cancer (PTC) commonly affects women of child-bearing age. During normal pregnancy, several factors may have a stimulatory effect on normal and nodular thyroid growth. The aim of the study was to determine whether pregnancy in thyroid-cancer survivors poses a risk of progression or recurrence of the disease. METHODS The files of 63 consecutive women who were followed at the Endocrine Institute for PTC in 1992-2009 and had given birth at least once after receiving treatment were reviewed for clinical, biochemical, and imaging data. Thyroglobulin levels and neck ultrasound findings were compared before and after pregnancy. Demographic and disease-related characteristics and levels of thyroid-stimulating hormone (TSH) during pregnancy were correlated with disease persistence before conception and disease progression during pregnancy using Pearsons analysis. RESULTS Mean time to the first delivery after completion of thyroid-cancer treatment was 5.08 ± 4.39 years; mean duration of follow up after the first delivery was 4.84 ± 3.80 years. Twenty-three women had more than one pregnancy, for a total of 90 births. Six women had evidence of thyroid cancer progression during the first pregnancy; one of them also showed disease progression during a second pregnancy. Another two patients had evidence of disease progression only during their second pregnancy. Mean TSH level during pregnancy was 2.65 ± 4.14 mIU/L. There was no correlation of disease progression during pregnancy with pathological staging, interval from diagnosis to pregnancy, TSH level during pregnancy, or thyroglobulin level before conception. There was a positive correlation of cancer progression with persistence of thyroid cancer before pregnancy and before total I-131 dose was administered. CONCLUSIONS Pregnancy does not cause thyroid cancer recurrence in PTC survivors who have no structural or biochemical evidence of disease persistence at the time of conception. However, in the presence of such evidence, disease progression may occur during pregnancy, yet not necessarily as a consequence of pregnancy. The finding that a nonsuppressed TSH level during pregnancy does not stimulate disease progression suggests that it may be an acceptable therapeutic goal in this setting.

The psychosocial and financial impact of non-severe hypoglycemic events on people with diabetes: two international surveys

Abstract Objectives: To understand the impact of nocturnal and daytime non-severe hypoglycemic events on healthcare systems, work productivity and quality of life in people with type 1 or type 2 diabetes. Methods: People with diabetes who experienced a non-severe hypoglycemic event in the 4 weeks prior to the survey were eligible to participate in a nocturnal and/or daytime hypoglycemia survey. Surveys were conducted in Argentina, Australia, Brazil, Israel, Mexico and South Africa. Results: In total, 300 respondents were included in nocturnal/daytime hypoglycemia surveys (50/participating country/survey). All respondents with type 1 diabetes and 68%/62% (nocturnal/daytime) with type 2 diabetes were on insulin treatment. After an event, 25%/30% (nocturnal/daytime) of respondents decreased their insulin dose and 39%/36% (nocturnal/daytime) contacted a healthcare professional. In the week after an event, respondents performed an average of 5.6/6.4 (nocturnal/daytime) additional blood glucose tests. Almost half of the respondents (44%) reported that the event had a high impact on the quality of their sleep. Among nocturnal survey respondents working for pay, 29% went to work late, 16% left work early and 12% reported missing one or more full work days due to the surveyed event. In addition, 50%/39% (nocturnal/daytime) indicated that the event had a high impact on their fear of future hypoglycemia. Conclusions: The findings suggest that nocturnal and daytime non-severe hypoglycemic events have a large financial and psychosocial impact. Diabetes management that minimizes hypoglycemia while maintaining good glycemic control may positively impact upon the psychological wellbeing of people with diabetes, as well as reducing healthcare costs and increasing work productivity.

Inhaled Aerosolized Insulin: A “Topical” Anti-inflammatory Treatment for Acute Lung Injury and Respiratory Distress Syndrome?

Acute lung injury (ALI) and the more severe acute respiratory distress syndrome (ARDS) are forms of pulmonary edema that result from robust local and systemic inflammatory states, such as sepsis. The morbidity and mortality associated with ALI and ARDS are significant and the treatment of these conditions presents a formidable challenge. Controlling hyperglycemia with insulin is a core component of patient management in the critically ill. Insulin treatment also exerts beneficial metabolic effects beyond glucose control, as well as non-metabolic effects, in insulin-resistant states. For instance, insulin inhibits NF-κB—dependent synthesis of pro-inflammatory factors and attenuates production of ROS. Indeed, intravenous administration of insulin ameliorates pulmonary injury and dysfunction in the LPS model of ALI. Most recently, an inhalable insulin formulation was shown to effectively reduce glucose concentrations with minimal impact on long-term pulmonary function. We propose that administering inhalable insulin to hyperglycemic ALI/ARDS patients could directly reduce alveolar inflammation while reducing circulating glucose levels.

Well-differentiated thyroid carcinoma: comparison of microscopic and macroscopic disease.

BACKGROUND The rapid increase in the incidence of well-differentiated thyroid cancer in recent years is the result of smaller thyroid tumors (1 cm or less) being diagnosed more frequently. Few studies are available regarding the appropriate approach to this previously known postmortem incidental finding, and their results remain controversial. METHODS In 2005, our center started a registry of all patients with nonmedullary thyroid carcinoma who were followed at our institute. In the present study, data on the background, clinical, and outcome characteristics were collected from the registry for 225 patients with microscopic disease and 543 patients with macroscopic disease. RESULTS Patients with microscopic disease were slightly older (51 vs. 47.5 years, p = 0.003), had a higher female to male ratio (189:37 vs. 419:123; p = 0.06), and were affected more by papillary carcinoma (98.2% vs. 85.5%; p < 0.001). Multifocal disease was documented in 50.2% of the patients with microscopic disease and 46.8% of the patients with macroscopic disease (NS), and bilateral disease, in 42.6% and 36.8%, respectively (NS). Corresponding rates for the two groups for other tumor-related factors were as follows: lymph node involvement at initial treatment, 25.7% and 30% (NS); distant metastases, 2.4% and 5.1% (p = 0.16); persistent/recurrent disease, 11% and 32% (p < 0.001); and new distant metastases, 2.65% and 6.5% (p = 0.07). At a median follow-up of 5 years, 96% of the microscopic carcinoma group were disease free compared to 77% of the macroscopic group (p < 0.001). CONCLUSION The differences between patients with microscopic and macroscopic well-differentiated thyroid carcinoma may not justify a different therapeutic approach.

Effect of intensive glycemic control on platelet reactivity in patients with long-standing uncontrolled diabetes

BACKGROUND It has been previously shown that platelets of patients with diabetes are more reactive and less responsive to anti-platelet drugs compared with platelets from subjects without diabetes. Studies examining the effect of glycemic control on platelet reactivity have yielded conflicting data. Thus, in this study, we sought to explore the effect of tight glycemic control on platelet reactivity in patients with long standing uncontrolled diabetes. METHODS The study included 30 patients with long-standing treated diabetes and a baseline HbA1c level of ≥ 8.5%. All patients were treated with aspirin and statins. Patients were tested at baseline and after 3 months of intensive glycemic and metabolic control. The treatment goal was to achieve a HbA1c level of ≤ 7%. Platelet reactivity was assessed by light transmission aggregation in response to 5 and 10 μM ADP and to 0.5mg/ml arachidonic acid (AA). Additonally, platelet activation was assessed by plasma levels of soluble P-selectin using an enzyme-linked immunosorbent assay. RESULTS The mean duration of diabetes from the time of diagnosis was 20.46 ± 9.31 years. Baseline HbA1c was 9.4 ± 0.8%. Following the intensive glycemic control period, the HbA1C level decreased to 8.1 ± 0.8% (P < 0.0001). Other laboratory parameters did not change significantly except for triglyceride levels, which decreased. None of the platelet aggregation studies nor P-selectin levels differed between baseline and after 3 months of intensive glycemic control. CONCLUSIONS Intensive glycemic control in patients with longstanding uncontrolled diabetes does not seem to result in a reduction in platelet reactivity.