Seasonal variation of serotonin turnover in human cerebrospinal fluid,depressive symptoms and the role of the 5-HTTLPR

Studying monoaminergic seasonality is likely to improve our understanding of neurobiological mechanisms underlying season-associated physiological and pathophysiological behavior. Studies of monoaminergic seasonality and the influence of the serotonin-transporter-linked polymorphic region (5-HTTLPR) on serotonin seasonality have yielded conflicting results, possibly due to lack of power and absence of multi-year analyses. We aimed to assess the extent of seasonal monoamine turnover and examined the possible involvement of the 5-HTTLPR. To determine the influence of seasonality on monoamine turnover, 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were measured in the cerebrospinal fluid of 479 human subjects collected during a 3-year period. Cosine and non-parametric seasonal modeling were applied to both metabolites. We computed serotonin (5-HT) seasonality values and performed an association analysis with the s/l alleles of the 5-HTTLPR. Depressive symptomatology was assessed using the Beck Depression Inventory-II. Circannual variation in 5-HIAA fitted a spring-peak cosine model that was significantly associated with sampling month (P=0.0074). Season of sampling explained 5.4% (P=1.57 × 10⁻⁷) of the variance in 5-HIAA concentrations. The 5-HTTLPR s-allele was associated with increased 5-HIAA seasonality (standardized regression coefficient=0.12, P=0.020, N=393). 5-HIAA seasonality correlated with depressive symptoms (Spearman''s rho=0.13, P=0.018, N=345). In conclusion, we highlight a dose-dependent association of the 5-HTTLPR with 5-HIAA seasonality and a positive correlation between 5-HIAA seasonality and depressive symptomatology. The presented data set the stage for follow-up in clinical populations with a role for seasonality, such as affective disorders.     

A case of sparsely granulated growth hormone cell adenoma associated with lymphocytic hypophysitis.

Lymphocytic hypophysitis is in itself rare and usually occurs in the postpartum period or the last trimester of pregnancy. It has not been described in combination with a pituitary tumor. A twenty-two year old woman, who had never been pregnant, presented with a history of nine months amenorrhea and spontaneous galactorrhea. She was not taking any medication and had never used oral contraceptives. Physical examination was unremarkable except that whitish fluid could be expressed from both breasts. Her visual fields were normal. Her serum PRL levels was high at 105.7 micrograms/l and increased to 138.4 micrograms/l at 60 minutes in a triple bolus test. GH values were normal and there was no evidence of overproduction of other pituitary hormones. CT scan showed an intrasellar mass with suprasellar extension. A tumor was selectively removed transsphenoidally. Morphologic examination revealed a clinically silent sparsely granulated growth hormone cell adenoma with lymphocytic infiltration of the adjacent pituitary tissue. Postoperatively her menstrual periods resumed and she conceived despite a slightly elevated PRL level. Three months after an uneventful pregnancy and full term delivery her PRL level was 69.9 micrograms/l and increased to 102.2 micrograms/l at 60 min. Basal GH and cortisol levels were normal. She remains well without replacement fourteen months after delivery. This case is of interest because it is the first reported simultaneous occurrence of a pituitary adenoma and lymphocytic hypophysitis and also because the hypophysitis preceded her first pregnancy.     

Amino acid variations at a single residue in an autoimmune peptide profoundly affect its properties: T-cell activation, major histocompatibility complex binding, and ability to block experimental allergic encephalomyelitis.

Myelin basic protein (MBP) or helper T cells reactive against MBP induce an autoimmune disease, experimental allergic encephalomyelitis, in B10.PL and PL/J inbred mice. In both strains, virtually the entire repertoire of MBP-specific T cells recognize an N-terminal peptide fragment in the context of the I-Au molecule encoded by the major histocompatibility complex (MHC) and utilize a very limited set of T-cell receptor genes. To delineate the nature of the trimolecular complex, consisting of the T-cell receptor, MBP-peptide fragment, and MHC molecule (I-Au), we have synthesized 13 variants of the 9-mer N-terminal immunodominant peptide differing at residue 4 and studied their immune recognition in vitro and in vivo. These substitutions have a striking range of effects on T-cell activation, ability to bind to the MHC molecule, and initiation of immune responses in vivo. An understanding of the autoimmune peptide/MHC/T-cell receptor interactions allowed us to design variant 9-mer peptides that have high affinity for an MHC molecule and are effective in blocking experimental allergic encephalomyelitis, possibly through two distinct mechanisms, peripheral T-cell tolerance and the inhibition of binding of the encephalitogenic peptide to the MHC molecules.     

Morphine tolerance attenuates the resolution of postoperative pain and enhances spinal microglial p38 and extracellular receptor kinase phosphorylation

Persistent postoperative pain is a very common phenomenon which severely affects the lives of patients who develop it following common surgical procedures. Opioid analgesics are of limited efficacy in the treatment of persistent pain states because of side effects including antinociceptive tolerance. We have previously shown that surgical incision injury and morphine tolerance share similar mechanisms, including a CNS role of spinal cord glia. We therefore hypothesized that prior chronic morphine exposure would inhibit the resolution of postoperative allodynia through increased glial ionized calcium-binding adaptor protein 1 (Iba1) and glial fibrillary acidic protein (GFAP) protein expression and mitogen activated protein kinase (MAPK) activation. To test this hypothesis, rats were implanted with s.c. osmotic minipumps on day zero, releasing saline or morphine for 7 days preceding or 7 days preceding and following paw incision surgery, which was completed on day seven. Thermal hyperalgesia and mechanical allodynia were assessed postoperatively every 3 days. Chronic morphine attenuated the resolution of postoperative thermal hyperalgesia and mechanical allodynia through day 20. However, no changes in Iba1 or GFAP expression were observed in the spinal cord dorsal horn between groups. Assessment of MAPK protein phosphorylation revealed that chronic morphine administration enhanced both p38 and extracellular receptor kinase (pERK) phosphorylation compared to saline on day 20. p-p38 and pERK immunofluorescence were only observed to colocalize with a marker of microglial cells and not with markers of astrocytes or neurons. Together, these data demonstrate that chronic morphine administration attenuates the resolution of postoperative allodynia in association with microglial p38 and extracellular receptor kinase (ERK) phosphorylation, independent of changes in Iba1 and GFAP expression.