Disproportionate Reduction of Serotonin Transporter May Predict the Response and Adherence to Antidepressants in Patients with Major Depressive Disorder: A Positron Emission Tomography Study with 4-[18F]-ADAM

Background:

Many lines of evidence suggest the role of serotonin transporter (SERT)-mediated reuptake of serotonin in the pathophysiology and treatment of major depressive disorder (MDD). This study aimed to examine whether the pretreatment of SERT binding potential or SERT binding ratio between terminal projection regions relative to the midbrain raphe nuclei was associated with treatment outcomes to SERT-targeted antidepressants.

Methods:

We recruited 39 antidepressant-naïve patients with MDD and 39 heathy controls. Positron emission tomography with N,N-dimethyl-2-(2-amino-4-[¹⁸F]fluorophenylthio)benzylamine (4-[¹⁸F]-ADAM) was used to measure in vivo SERT availability prior to antidepressant treatment. The 21-item Hamilton Depression Rating Scale (HDRS) was use to assess the severity of depression from baseline to week 6. All the patients with MDD had HDRS scores of 18 or more.

Results:

Pretreatment SERT binding in the thalamus and striatum positively correlated with an early reduction in HDRS scores at week 3. Nonresponders and dropout patients showed a proportionate reduction in SERT binding in the terminal projection regions and midbrain compared to healthy controls. In contrast, a disproportionate reduction in SERT binding in the terminal projection regions relative to midbrain was observed in responders.

Conclusions:

The results of this study suggested that a disproportionate reduction in SERT binding between terminal projection regions and midbrain may predict better treatment outcomes in patients with MDD.     

Ezrin regulates NHE3 translocation and activation after Na+-glucose cotransport

Initiation of Na(+)-glucose cotransport in intestinal epithelial cells leads to activation of the apical Na(+)-H(+) exchanger NHE3 and subsequent increases in cytoplasmic pH (pH(i)). This process requires activation of p38 mitogen-activated protein (MAP) kinase, but additional signaling intermediates have not been identified. One candidate is the cytoskeletal linker protein ezrin, which interacts with NHE3 via specific regulatory proteins. The data show that initiation of Na(+)-glucose cotransport resulted in rapid increases in both apical membrane-associated NHE3 and cytoskeletal-associated ezrin and occurred in parallel with ezrin phosphorylation at threonine 567. Phosphorylation at this site is known to activate ezrin and increase its association with actin. Consistent with a central role for ezrin activation in this NHE3 regulation, an N-terminal dominant negative ezrin construct inhibited both NHE3 recruitment and pH(i) increases after Na(+)-glucose cotransport. Ezrin phosphorylation occurred in parallel with p38 MAP kinase activation, and the latter proceeded normally in cells expressing dominant negative ezrin. In contrast, inhibition of p38 MAP kinase prevented increases in ezrin phosphorylation after initiation of Na(+)-glucose cotransport. Thus, ezrin phosphorylation after Na(+)-glucose cotransport requires p38 MAP kinase activity, but p38 MAP kinase activation does not require ezrin function. These data describe a specific role for ezrin in the coordinate regulation of Na(+)-glucose cotransport and Na(+)-H(+) exchange. Intact ezrin function is necessary for NHE3 recruitment to the apical membrane and NHE3-dependent pH(i) increases triggered by Na(+)-glucose cotransport. The data also define a pathway of p38 MAP kinase-dependent ezrin activation.     

Failure Analysis of a C-276 Alloy Pipe in a Controlled Decomposition Reactor

Failure analysis was carried out on a ruptured C-276 pipe heated externally at 1050 °C, which had been used for a few months in a controlled decomposition reactor (CDR) system. To catch the decomposed perfluorinated compounds (PFCs, e.g., CF₄, SF₆, NF₃, C₃F₈ and C₄F₈) present in the exhaust gas, the C-276 reactor was periodically purged with water mist, which caused a temperature gradient from the external to the inner surface of the pipe. The precipitation of large amounts of intermetallic compounds along the grain boundaries were found to be corroded preferentially. The internal surface of the used pipe was covered with many fine cracks. The corrosion and cracking of grain boundary precipitates accounted for the short service life of the C-276 pipe. Compositional measurements by electron probe micro-analyzer (EPMA) and phase identification by electron backscatter diffraction (EBSD) confirmed the presence of δ and μ phases in the ruptured pipe. The coarse intergranular precipitates were the δ phase (Mo₇Ni₇), which were enriched in Mo and Cr. Moreover, the fine precipitates dispersed intergranularly and intragranularly were the μ phase (Mo₆Ni₇), which were abundant in Mo and W. The numerous precipitates present in the matrix and along the grain boundaries were responsible for an obvious loss in the strength and ductility of the used C-276 pipe.     

Associations between Plasma Folate and Vitamin B12, Blood Lead,and Bone Mineral Density among Adults and Elderly Who Received a Health Examination

This study hypothesized that plasma folate and vitamin B₁₂ levels modified the association between blood lead and cadmium and total urinary arsenic levels and bone loss. A total of 447 study subjects who received a physical examination at the Wanfang Hospital Medical Center were recruited. Bone loss was defined as a calcaneus bone mineral density T-score less than −1. Blood cadmium and lead concentrations were measured by ICP-MS. Urinary arsenic species were determined using HPLC-HG-AAS. A SimulTRAC-SNB radioassay was used to measure plasma folate, vitamin B₁₂, and homocysteine levels. Total urinary arsenic and blood lead concentration were positively correlated with the odds ratio (OR) for bone loss in a dose–response manner. The OR and 95% confidence interval (CI) for bone loss in participants with blood lead concentrations > 56.14 versus ≤33.82 μg/dL were 1.82 and 1.10–3.01. No correlation between plasma folate and vitamin B₁₂ levels alone and bone loss was observed. However, this study is the first observational study to find that blood lead concentrations tend to increase the OR of bone loss in a low plasma folate and plasma vitamin B₁₂ group with multivariate ORs (95% CI) of 2.44 (0.85–6.96).     

Synthesis and evaluation of (S)-2-(2-[18F]fluoroethoxy)-4-([3-methyl-1-(2-piperidin-1-yl-phenyl)-butyl-carbamoyl]-methyl)-benzoic acid ([18F]repaglinide): a promising radioligand for quantification of pancreatic beta-cell mass with positron emission tomography (PET)

18F-labeled non-sulfonylurea hypoglycemic agent (S)-2-(2-[(18)F]fluoroethoxy)-4-((3-methyl-1-(2-piperidin-1-yl-phenyl)-butylcarbamoyl)-methyl)-benzoic acid ([(18)F]repaglinide), a derivative of the sulfonylurea-receptor (SUR) ligand repaglinide, was synthesized as a potential tracer for the non-invasive investigation of the sulfonylurea 1 receptor status of pancreatic beta-cells by positron emission tomography (PET) in the context of type 1 and type 2 diabetes. [(18)F]Repaglinide could be obtained in an overall radiochemical yield (RCY) of 20% after 135 min with a radiochemical purity higher than 98% applying the secondary labeling precursor 2-[(18)F]fluoroethyltosylate. Specific activity was in the range of 50-60 GBq/micromol. Labeling was conducted by exchanging the ethoxy-moiety into a 2-[(18)F]fluoroethoxy group. To characterize the properties of fluorinated repaglinide, the affinity of the analogous non-radioactive (19)F-compound for binding to the human SUR1 isoform was assessed. [(19)F]Repaglinide induced a complete monophasic inhibition curve with a Hill coefficient close to 1 (1.03) yielding a dissociation constant (K(D)) of 134 nM. Biological activity was proven via insulin secretion experiments on isolated rat islets and was comparable to that of repaglinide. Finally, biodistribution of [(18)F]repaglinide was investigated in rats by measuring the concentration of the compound in different organs after i.v. injection. Pancreatic tissue displayed a stable accumulation of approximately 0.12% of the injected dose from 10 min to 30 min p.i. 50% of the radioactive tracer could be displaced by additional injection of unlabeled repaglinide, indicating that [(18)F]repaglinide might be suitable for in vivo investigation with PET.     

The development of bladder tumors and contralateral upper urinary tract tumors after primary transitional cell carcinoma of the upper urinary tract

BACKGROUND: Contralateral, metachronous upper urinary tract (UUT) tumors after primary transitional cell carcinoma (TCC) of the UUT are reported rarely, and to the authors' knowledge the risk factors have not been determined to date. In addition, few reports have described the characteristics of recurrent bladder tumors and contralateral UUT tumors and any relation between theses tumor types. METHODS: Statistical analysis of data from 223 patients with documented primary UUT-TCC was undertaken. After excluding bilateral involvement and distant metastases, 12 variables were analyzed by multivariate analysis in 189 patients to determine the risk factors for recurrent urothelial tumors. RESULTS: The incidence rates of recurrent bladder tumors and contralateral UUT tumors were 31.2% and 5.8%, respectively. Multiplicity was determined as a risk factor for recurrent bladder tumors. Renal insufficiency, uremia, and concurrent bladder tumors significantly predisposed patients to develop contralateral UUT tumors after primary UUT-TCC. The time intervals and stage distributions differed significantly between recurrent bladder tumors and contralateral UTT tumors. Patients who had recurrent bladder tumors had earlier stage tumors and had a shorter time to recur compared with patients who had contralateral, metachronous UUT tumors. CONCLUSIONS: For patients with primary UUT-TCC, regular follow-up by cystoscopy is necessary to detect recurrent bladder tumors. Intravenous urography or retrograde pyelography should be performed for patients who have a high risk of developing contralateral UUT tumors.     

A reduced ratio of dietary carbohydrate to protein improves body composition and blood lipid profiles during weight loss in adult women

Claims about the merits or risks of carbohydrate (CHO) vs. protein for weight loss diets are extensive, yet the ideal ratio of dietary carbohydrate to protein for adult health and weight management remains unknown. This study examined the efficacy of two weight loss diets with modified CHO/protein ratios to change body composition and blood lipids in adult women. Women (n = 24; 45 to 56 y old) with body mass indices >26 kg/m(2) were assigned to either a CHO Group consuming a diet with a CHO/protein ratio of 3.5 (68 g protein/d) or a Protein Group with a ratio of 1.4 (125 g protein/d). Diets were isoenergetic, providing 7100 kJ/d, and similar amounts of fat ( approximately 50 g/d). After consuming the diets for 10 wk, the CHO Group lost 6.96 +/- 1.36 kg body weight and the Protein Group lost 7.53 +/- 1.44 kg. Weight loss in the Protein Group was partitioned to a significantly higher loss of fat/lean (6.3 +/- 1.2 g/g) compared with the CHO Group (3.8 +/- 0.9). Both groups had significant reductions in serum cholesterol ( approximately 10%), whereas the Protein Group also had significant reductions in triacylglycerols (TAG) (21%) and the ratio of TAG/HDL cholesterol (23%). Women in the CHO Group had higher insulin responses to meals and postprandial hypoglycemia, whereas women in the Protein Group reported greater satiety. This study demonstrates that increasing the proportion of protein to carbohydrate in the diet of adult women has positive effects on body composition, blood lipids, glucose homeostasis and satiety during weight loss.     

Effects of chronic cocaine abuse on postsynaptic dopamine receptors

To assess the effects of chronic cocaine intoxication on dopamine receptors in human subjects, the authors evaluated [18F]N-methylspiroperidol binding using positron emission tomography in 10 cocaine abusers and 10 normal control subjects. Cocaine abusers who had been detoxified for 1 week or less showed significantly lower values for uptake of [18F]N-methylspiroperidol in striatum than the normal subjects, whereas the cocaine abusers who had been detoxified for 1 month showed values comparable to those obtained from normal subjects. The authors conclude that postsynaptic dopamine receptor availability decreases with chronic cocaine abuse but may recover after a drug-free interval.     

In vitro and in vivo evaluation of novel glibenclamide derivatives as imaging agents for the non-invasive assessment of the pancreatic islet cell mass in animals and humans.

Pancreatic islet cell mass (PICM) is a major determinant of the insulin secretory capacity in humans. Currently, the only method for accurate assessment of the PICM is an autopsy study. Thus, development of a technique allowing the non-invasive quantification of PICM is of great interest. The aim of this study was to develop such a non-invasive technique featuring novel fluorine- and (99m)Tc-labelled glibenclamide derivatives. Despite the structural modifications necessary to introduce fluorine into the glibenclamide molecule, all derivatives retained insulin stimulating capacity as well as high affinity binding to human SUR1 when compared to the original glibenclamide. Contrastingly, the lipophilicity of the fluorine-labelled derivatives was altered depending on the particular modification. In the human PET-study a constant but weak radioactive signal could be detected in the pancreas using a fluorine-labelled glibenclamide derivative. However, a reliable assessment and visualisation of the PICM could not be obtained. It can be assumed that the high uptake of the fluorine-labelled tracer e.g. into the the liver and the high plasma protein binding leads to a relatively low signal-to-noise ratio. In case of the presented fluorine-labelled glibenclamide based compounds this could be the result of their invariably high lipophilicity. The development of a (99 m)Tc-labelled glibenclamide derivative with a lower lipophilicity and differing in vivo behaviour, glibenclamide based compounds for non-invasive imaging of the pancreatic islet cell mass may be possible.