Trajectory of criterion symptoms of major depression under newly started antidepressant treatment: sleep disturbances and anergia linger on while suicidal ideas and psychomotor symptoms disappear early.

OBJECTIVE: In modern psychiatry, depression is diagnosed with the diagnostic criteria; however, the trajectory of each of the criterion symptoms is unknown. This study aims to examine this. METHODS: We made repeated assessments of the nine diagnostic criterion symptoms with the Patient Health Questionnaire-9 (PHQ-9) among 2011 participants of a 25-week pragmatic randomised controlled trial of sertraline and/or mirtazapine for hitherto untreated major depressive episodes. The changes from baseline were estimated with the mixed-effects model with repeated measures. The time to disappearance of each symptom was modeled using the Kaplan-Meier survival analysis. RESULTS: The total score on PHQ-9 was 18.5 (SD = 3.9, n = 2011) at baseline, which decreased to 15.3 (5.2, n = 2011) at week 1, to 11.5 (5.9, n = 1953) at week 3, to 7.8 (6.0, n = 1927) at week 9, and to 6.0 (5.9, n = 1910) at week 25. Suicidal ideas, psychomotor symptoms decreased rapidly, while anergia and sleep disturbance also decreased but only slowly. The survival analyses confirmed the primary analyses. CONCLUSIONS: Upon initiation of antidepressant treatment, patients with newly treated major depressive episodes can expect their suicidal ideas and psychomotor symptoms to disappear first but sleep disturbances and anergia to linger on.

Association of thalamic hyperactivity with treatment-resistant depression and poor response in early treatment for major depression: a resting-state fMRI study using fractional amplitude of low-frequency fluctuations.

Despite novel antidepressant development, 10-30% of patients with major depressive disorder (MDD) have antidepressant treatment-resistant depression (TRD). Although new therapies are needed, lack of knowledge regarding the neural mechanisms underlying TRD hinders development of new therapeutic options. We aimed to identify brain regions in which spontaneous neural activity is not only altered in TRD but also associated with early treatment resistance in MDD. Sixteen patients with TRD, 16 patients with early-phase non-TRD and 26 healthy control (HC) subjects underwent resting-state functional magnetic resonance imaging. To identify brain region differences in spontaneous neural activity between patients with and without TRD, we assessed fractional amplitude of low-frequency fluctuations (fALFF). We also calculated correlations between the percent change in the Hamilton Rating Scale for Depression (HRSD17) scores and fALFF values in brain regions with differing activity for patients with and without TRD. Patients with TRD had increased right-thalamic fALFF values compared with patients without TRD. The percent change in HRSD17 scores negatively correlated with fALFF values in patients with non-TRD. In addition, patients with TRD showed increased fALFF values in the right inferior frontal gyrus (IFG), inferior parietal lobule (IPL) and vermis, compared with patients with non-TRD and HC subjects. Our results show that spontaneous activity in the right thalamus correlates with antidepressant treatment response. We also demonstrate that spontaneous activity in the right IFG, IPL and vermis may be specifically implicated in the neural pathophysiology of TRD.

Loss of WT1 expression in the endometrium of infertile PCOS patients: a hyperandrogenic effect?

CONTEXT: In fertile patients the endometrial Wilms tumor suppressor gene (WT1) is expressed during the window of implantation. Polycystic ovary syndrome (PCOS) patients suffer from hyperandrogenemia and infertility and have elevated endometrial androgen receptor (AR) expression. WT1 is known to be down-regulated by AR. Therefore, the expression of WT1 and its targets may be altered in PCOS endometrium. OBJECTIVE: The objective of the study was to assess the expression and regulation of WT1 and selected downstream targets in secretory endometrium from ovulatory PCOS (ovPCOS) and fertile women. DESIGN AND PATIENTS: Endometrial samples were obtained from 25 ovPCOS and 25 fertile patients. MAIN OUTCOME MEASURE: Endometrial expression of WT1 and selected downstream targets were assessed by immunohistochemistry and RT-PCR. The androgen effect on WT1 expression was determined in vitro by immunoblots and RT-PCR. The expression of WT1 and its targets was quantified in fertile and ovPCOS stromal cells in the presence of androgens by RT-PCR. Caspase-3/7 activity was measured to evaluate sensitivity to drug-induced apoptosis. RESULTS: WT1 expression was down-regulated in secretory-phase ovPCOS endometrium. Stromal expression of Bcl-2 and p27 was higher, and epidermal growth factor receptor was lower in ovPCOS than in fertile patients. Endometrial stromal expression of WT1, Bcl-2, Bcl-2-associated X protein, and ß-catenin was regulated by androgens. Apoptosis levels were reduced in ovPCOS samples and androgen-treated fertile samples. CONCLUSION: WT1 expression is down-regulated in ovPCOS endometrium during the window of implantation. Androgens regulate the expression of WT1 and its targets during endometrial decidualization. The altered balance between WT1 and AR in the endometrium of PCOS patients may jeopardize the success of decidualization and endometrial receptivity.

Expression of Wilms' tumor suppressor gene (WT1) in human endometrium: regulation through decidual differentiation.

The Wilms' tumor suppressor gene (WT1) encodes a zinc-finger containing transcription factor that is selectively expressed in the developing urogenital tract and functions as a tissue-specific developmental regulator. In addition to its gene-regulatory function through DNA binding properties, WT-1 also regulates transcription by formation of protein-protein complexes. These properties place WT-1 as a major regulator of cell growth and differentiation. In view of these observations, we studied WT1 mRNA and protein in human endometrial extracts and in endometrial stromal cells (ESCs) differentiating into decidual cells in vitro, by RT-PCR and Western blotting, respectively. WT1 protein expression was also studied in situ in the proliferative and the secretory phase of the menstrual cycle in the early pregnant state. Analysis by PCR of total RNA prepared from human ESCs demonstrated the presence of WT1 mRNA and four WT1 mRNA splice variants. Western blot analysis of nuclear protein extracts from ESCs yielded one immunoreactive protein of the expected size (approximately 52-54 kDa) recognized by the WT1 antibody. Immunohistochemical staining showed that WT1 protein is localized only to nuclei of human endometrial stromal cells. It remains constant in the proliferative and the secretory phase of the menstrual cycle and is increased remarkably during decidualization in early pregnancy. ESCs decidualized in vitro were investigated for WT-1 expression, which confirmed that decidualizing stimuli (E2, medroxy-progesterone-acetate, and relaxin for 12 d or cAMP and progesterone for 1-4 d) induced WT-1 mRNA (P < 0.05) and increased protein levels (P < 0.05). These data indicate that in humans the WT1 gene is expressed in ESCs and its mRNA and protein levels remain constant in the proliferative and the secretory phase of the menstrual cycle and that WT1 mRNA and protein expression increases significantly in ESCs when these cells differentiate into decidual cells.

A novel transgenic technique that allows specific marking of the neural crest cell lineage in mice.

Neural crest cells are embryonic, multipotent stem cells that give rise to various cell/tissue types and thus serve as a good model system for the study of cell specification and mechanisms of cell differentiation. For analysis of neural crest cell lineage, an efficient method has been devised for manipulating the mouse genome through the Cre-loxP system. We generated transgenic mice harboring a Cre gene driven by a promoter of protein 0 (P0). To detect the Cre-mediated DNA recombination, we crossed P0-Cre transgenic mice with CAG-CAT-Z indicator transgenic mice. The CAG-CAT-Z Tg line carries a lacZ gene downstream of a chicken beta-actin promoter and a "stuffer" fragment flanked by two loxP sequences, so that lacZ is expressed only when the stuffer is removed by the action of Cre recombinase. In three different P0-Cre lines crossed with CAG-CAT-Z Tg, embryos carrying both transgenes showed lacZ expression in tissues derived from neural crest cells, such as spinal dorsal root ganglia, sympathetic nervous system, enteric nervous system, and ventral craniofacial mesenchyme at stages later than 9.0 dpc. These findings give some insights into neural crest cell differentiation in mammals. We believe that P0-Cre transgenic mice will facilitate many interesting experiments, including lineage analysis, purification, and genetic manipulation of the mammalian neural crest cells.

Id gene expression as a key mediator of tumor cell biology.

Id genes encode members of the helix-loop-helix (HLH) family of transcription factors that inhibit transcription by forming inactive heterodimers with basic HLH (bHLH) proteins. There are four members of the Id gene family recognized in mammals, and the proteins they encode share homology primarily in their HLH domain. bHLH proteins typically form heterodimers with other bHLH proteins, and their basic domain binds to a DNA sequence element, the E-box, activating transcription. Products of Id genes lack the basic DNA binding domain of the bHLH transcription factors, and when they heterodimerize with bHLH proteins, the complexes are inactive. Generally, high levels of Id mRNA are detected in proliferative undifferentiated, embryonal cells and lower levels are detected in well-differentiated, mature, adult tissues. In vitro, these genes are generally expressed at lower levels in cells after the induction of differentiation. Recently, high levels of expression of Id genes have been identified in cell lines derived from a wide variety of different tumors and in tumor tissues as well. These findings suggest that not only the inappropriate proliferation of tumors but also the anaplastic characteristics that contribute to their malignant behavior may be regulated by Id gene expression.

The mouse Id2 and Id4 genes: structural organization and chromosomal localization.

The Id proteins belong to a family of nuclear HLH proteins lacking a basic region and thought to function as dominant-negative regulators of bHLH proteins during cell growth and differentiation. In this paper, we report the genomic organization of the mouse Id2 and Id4 genes. These genes each span approximately 3 kb of the mouse genome and are each organized as three exons with recognizable splice donor and acceptor consensus sequences. Their genomic organization is very similar, consistent with their having evolved from a common, ancestral Id-like gene. Using FISH analysis, we have localized the mouse Id2 and Id4 genes to mouse chromosome 12 and 13, respectively.

Multiple cerebral arterial occlusions in a young patient with Sjögren's syndrome: case report.

We describe a case of a young patient with multiple occlusions of major cerebral arteries and Sjögren's syndrome. This 17-year-old female patient experienced repeated transient ischemic attacks of right hemiparesis, speech disturbance, and unconsciousness. Angiography revealed progressive occlusion of the bilateral carotid and vertebral arteries. Examinations, including a serological test, a rose bengal test, Ga scintigraphy, and a biopsy of the parotid gland, indicated Sjögren's syndrome. The patient was successfully managed with bypass surgery. Patients with Sjögren's syndrome may experience progressive occlusion of the major cerebral arteries resembling that of moyamoya disease.

Modulation of hematopoiesis in mice with a truncated mutant of the interleukin-2 receptor gamma chain.

The interleukin-2 (IL-2) receptor gamma chain is indispensable for IL-2-, IL-4-, IL-7-, IL-9-, and IL-15-mediated signaling. Mutations of the human gamma chain cause the X-linked severe combined immunodeficiency (XSCID), showing that T and natural killer cells absolutely require the gamma chain for their development in humans. To elucidate the roles of the gamma chain in hematopoiesis, we have generated mice, by gene targeting, that express a form of the gamma chain lacking the cytoplasmic region. Male mice carrying the truncated gamma-chain mutant, which mimics mutations in patients with XSCID, showed a decrease in the number of lymphocytes and an increase in monocytes; the number of T cells was profoundly reduced and no natural killer cells were detected, which is similar to the characteristic of human XSCID. Unlike human XSCID, the levels of B cells were also reduced. In spite of the severe decrease in CD45R+/sIgM+ B cells, the level of IgM in serum of the 8-week-old mutant mice was higher than that of control littermates. Interestingly, the stem cell population with surface phenotypes of CD34, c-kit, and Sca-1 was significantly increased. Furthermore, the colony-forming assay showed that the mutant mice had 15-fold higher numbers of hematopoietic progenitor cells in the spleen as compared with that of controls. These results indicate that functional loss of the gamma chain causes significant effects on the immunological system in mice.

A novel isoform of the neurofibromatosis type-1 mRNA and a switch of isoforms during murine cell differentiation and proliferation.

Four types of cDNAs encoding the GTPase-activating protein-related domain (GRD) of the mouse neurofibromatosis type-1 gene (NF1) have been cloned. One of these isoforms was a newly identified form termed type IV. Analysis of the genomic structure of the mouse NF1-GRD revealed two exons (23A and 23B) between exons 23 and 24, leading to the production of four types of NF1-GRD cDNAs by an alternative splicing mechanism. Amino-acid sequences encoded by NF1-GRD are highly conserved between human and mouse. Analysis of the expression of these transcripts in various tissues of adult mouse revealed that the type-I transcript is predominantly expressed in neural tissues such as brain and spinal cord. Other forms, termed types II, III and IV, are also expressed in various tissues. The type-I and type-II transcripts are expressed equivalently in undifferentiated P19 mouse teratocarcinoma cells, whereas type-I expression becomes predominant during neuronal differentiation by retinoic acid treatment. Expression of type I is also shown to be correlated with cessation of cell proliferation in P19 cells, but not in NIH3T3 cells. These, together with other results, suggest that the four types of NF1-GRD transcripts generated by alternative splicing have some important biological roles in cell differentiation and proliferation.