Clinical evidence for utilization of the A3 adenosine receptor as a target to treat rheumatoid arthritis: data from a phase II clinical trial

OBJECTIVE: Adenosine exerts antiinflammatory effects via activation of the A3 adenosine receptor (A3AR), a Gi protein-associated cell-surface receptor, overexpressed in synovial tissue and peripheral blood mononuclear cells (PBMC) in patients with active rheumatoid arthritis (RA). CF101 is a highly specific orally bioavailable A3AR agonist. METHODS: This was a multicenter study, blinded to dose, designed to assess the clinical activity and safety of CF101 in active RA. Seventy-four patients were randomized to receive 0.1, 1.0, or 4.0 mg CF101 bid for 12 weeks. The primary efficacy endpoint was American College of Rheumatology 20% response (ACR20) at Week 12. A3AR expression levels were analyzed in PBMC from 18 patients. RESULTS:. Maximal responses were observed with 1.0 mg bid, lower at 0.1 and 4.0 mg bid. At 12 weeks, 55.6%, 33.3%, and 11.5% of the patients receiving 1.0 mg CF101 achieved ACR20%, 50%, and 70% responses, respectively. CF101 was generally well tolerated, with mild headache (4.1%), nausea (2.7%), and rash (2.7%) being the most common treatment-related adverse events. Statistically significant correlations between A3AR overexpression at baseline and ACR50 and ACR70 responses were observed. CONCLUSION: CF101 administered bid for 12 weeks resulted in improvement in signs and symptoms of RA that did not achieve statistical significance, and was safe and well tolerated. The expression level of A3AR was directly correlated with patient responses to CF101, suggesting its utilization as a biomarker for the pharmacodynamic and therapeutic effects of this novel agent. These findings require confirmation in a double-blind randomized placebo-controlled trial, currently under way.     

A multicenter retrospective study defining the clinical and hematological manifestations of brucellosis and pancytopenia in a large series: Hematological malignancies, the unusual cause of pancytopenia in patients with brucellosis

The aim of the study is to review the clinical manifestations and the hematological findings of brucellosis and pancytopenia, with or without hematological malignancies. The records of 202 patients with brucellosis were evaluated retrospectively. Among these cases of brucellosis seen in a 6 year period between April 1999 and June 2005, 30 patients with pancytopenia were identified. The most common manifestation was fever, followed by weight loss, anorexia, malaise, arthralgia, and hepatosplenomegaly. Bone marrow biopsies revealed hypercellularity or normocellularity. The most common findings in the bone marrow evaluation were histiocytic hemophagocytosis and granulomas. Among all cases, we diagnosed 5 hematological malignancies (1 acute myelogenous leukemia, 2 acute lymphoblastic leukemia, and 2 multiple myeloma) concurrently with brucellosis. The clinical symptoms and findings were similar in patients with and without malignancies. In cases with malignancies, the bone marrow biopsy revealed predominant primary disease involvement. Significant increases in ESR and CRP, severe anemia and thrombocytopenia were observed in patients with malignancies. Peripheral blood counts in patients without malignancies returned to normal after antibiotic treatment for brucellosis. However, pancytopenia in two patients with malignancies did not recover because of primary resistant disease. We conclude that while histiocytic hemophagocytosis may be considered as a major cause of pancytopenia, leukemic infiltration can also be an extreme and unusual cause of pancytopenia in patients in whom brucellosis was concurrently diagnosed with hematological malignancies.     

Levels of plasma fibrinogen and d-dimer in patients with impaired fasting glucose.

BACKGROUND: Cardiovascular risk associated with impaired fasting glucose has been examined in various studies with conflicting results. During the last 10 years, several risk markers for atherosclerosis such as fibrinogen and D-dimer have been identified. The present study was designed to evaluate plasma fibrinogen and D-dimer levels in patients with impaired fasting glucose compared with normal subjects and those with type 2 diabetes mellitus. METHODS: Age-, sex-, and body mass index-matched 30 normal subjects, 30 patients with impaired fasting glucose (fasting glucose 110 to 125 mg/dl), and 30 patients with type 2 diabetes mellitus (fasting glucose >/= 126 mg/dl) were included in the study. RESULTS: The levels of plasma fibrinogen in patients with type 2 diabetes mellitus, impaired fasting glucose, and normal subjects were 449 (306 - 605) mg/dl, 348 (264 - 468) mg/dl, and 216 (179 - 260) mg/dl, respectively. Patients with impaired fasting glucose had significantly lower plasma fibrinogen levels than patients with type 2 diabetes mellitus (p < 0.05). There were significantly higher plasma fibrinogen levels in patients with impaired fasting glucose than in normal subjects (p < 0.05). The levels of plasma D-dimer in patients with type 2 diabetes mellitus, impaired fasting glucose, and normal subjects were 615 (505 - 768) mg/l, 518 (412 - 664) mg/l, and 424 (356 - 557) mg/l, respectively. Patients with impaired fasting glucose had significantly lower plasma D-dimer levels than patients with type 2 diabetes mellitus (p < 0.05). There were significantly higher plasma D-dimer levels in patients with impaired fasting glucose than in normal subjects (p < 0.05). The levels of plasma fibrinogen and D-dimer were related to fasting glucose in type 2 diabetes mellitus and impaired fasting glucose groups (p < 0.05). We also detected positive correlation between plasma fibrinogen levels and age in study groups (p < 0.05). CONCLUSION: Our data suggest that patients with impaired fasting glucose pose a hypofibrinolytic status and cardiovascular risk, although this was lower than in patients with type 2 diabetes mellitus.     

Leptin response to oral glucose tolerance test in obese and nonobese premenopausal women

The objective of this study was to investigate the serum leptin response to oral glucose stimulation in a group of obese and nonobese normotensive, normolipidemic, and glucose-tolerant premenopausal women. Twenty-one obese (BMI: 37.7 +/- 6.3 kg/m2) and 14 nonbese (BMI: 21.5 +/- 1.0 kg/m2) age-matched, healthy premenopausal women were included in the study. Serum glucose, insulin, and leptin levels were measured at 30 min intervals during the 120 min of an oral glucose tolerance test (OGTT). Mean serum glucose, insulin, and leptin levels were significantly higher in the obese group compared to nonobese subjects during OGTT. Except for a 120 min decrement noted in obese women, no changes occurred in serum leptin levels during oral glucose stimulation in both groups. As a conclusion, absence of a significant elevation in serum leptin levels during OGTT in our obese subjects compared to nonobese subjects may be related to their normal metabolic variables despite being abdominally obese and insulin resistant.     

Effect of dopamine infusion on thyroid hormone tests and prolactin levels in very low birth weight infants

Objective: To evaluate the effect of dopamine on thyroid hormone tests and prolactin (PRL) and to assess requirement for L-thyroxin (LT4).

Methods: The infants (n?=?102) were divided into three groups (Group 1; received no dopamine, Group 2 received ≤25?mg/kg cumulative dose and Group 3; received >25?mg/kg cumulative dose). Blood samples were taken at 6–8 days (timepoint 1), 13–15 days (timepoint 2), and 4–6 weeks of life (timepoint 3).

Results: Respiratory distress syndrome was higher in group 2 and 3. Patnet ductus arteriosus was higher in group 3 than in groups 1 and 2. Duration and cumulative dose in group 3 were higher than group 2. There was no difference between thyroid hormones that were taken after stopping infusion at timepoint 3 among all groups. No therapy with LT4 was needed. PRL levels were higher at timepoint 1 in group 1 than compared to group 2 and 3 (p?p?>?0.05). This difference was disappeared at following timepoints.

Conclusions: The release of TSH, FT3, FT4 and PRL were not inhibited and prophylactic thyroid hormone treatment was not required in VLBW infants receiving dopamine infusions.     

The association between stereotyping and interprofessional collaborative practice

Objective

This study aimed to identify the association between stereotyping and professional intercollaborative practice.

Quantitative assessment of thyroid gland elasticity with shear-wave elastography in pediatric patients with Hashimoto’s thyroiditis

Objective

Hashimoto’s thyroiditis is the most common autoimmune thyroid disorder in the pediatric age range. Measurement of thyroid gland size is an essential component in evaluation and follow-up of thyroid pathologies. Along with size, tissue elasticity is becoming a more commonly used parameter in evaluation of parenchyma in inflammatory diseases. The aim of the current study was to assess thyroid parenchyma elasticity by shear-wave elastography in pediatric patients with Hashimoto’s thyroiditis; and compare the elasticity values to a normal control group.

Materials and methods

In this study; thyroid glands of 59 patients with a diagnosis of Hashimoto’s thyroiditis based on ultrasonographic and biochemical features, and 26 healthy volunteers without autoimmune thyroid disease and thyroid function disorders, were evaluated with shear-wave elastography. Patients with Hashimoto thyroiditis were further subdivided into three categories based on gray-scale ultrasonography findings as focal thyroiditis (grade 1), diffuse thyroiditis (grade 2), and fibrotic thyroid gland (grade 3).

Results

Patients with Hashimoto’s thyroiditis (n = 59) had significantly higher elasticity values (14. 9 kPa; IQR 12.9–17.8 kPa) than control subjects (10.6 kPa; IQR 9.0–11.3 kPa) (p < 0.001). Of the 59 patients with Hashimoto’s thyroiditis, 23 patients had focal thyroiditis involving less than 50% of the gland categorized as grade 1, 24 patients had diffuse involvement of the thyroid gland categorized as grade 2, and 12 patients had marked hyperechoic septations and pseudonodular appearance categorized as grade 3 on gray-scale ultrasound. Based on elastography, grade 3 patients had significantly higher elasticity values (19.7 kPa; IQR 17.8–21.5 kPa) than patients with grade 2 (15.5 kPa; IQR 14.5–17.8 kPa) and grade 1 thyroiditis (12.8 kPa; IQR 11.9–13.1 kPa) (p < 0.05). Patients with grade 2 thyroiditis had significantly higher elasticity values than those with grade 1 thyroiditis (p < 0.05).

Conclusion

Gray-scale ultrasound findings of heterogeneous echotexture and hypoechoic echogenicity reflect a longer duration of inflammation and may not be found in the initial stages of thyroiditis. Our results indicate that shear-wave elastography could be used to evaluate the degree of fibrosis in Hashimoto’s thyroiditis.