Omega-3 polyunsaturated fatty acids and psychological intervention for workers with mild to moderate depression: A double-blind randomized controlled trial.

BACKGROUND: This study assessed whether a combined intervention of omega-3 polyunsaturated fatty acids (PUFAs) and psychoeducation better improved mild to moderate depression in workers compared to psychoeducation alone. METHODS: This study was a double-blinded, parallel group, randomized controlled trial that compared the intervention group, receiving omega-3 fatty acids, with a control group, receiving a placebo supplement. Participants receiving omega-3 fatty acids took 15 × 300 mg capsules per day for 12 weeks. The total daily dose of omega-3 PUFAs was 500 mg docosahexaenoic acid and 1000 mg eicosapentaenoic acid (EPA). The Beck Depression Inventory®-II (BDI-II) was used to assess the severity of depression after treatment. RESULTS: After 12 weeks of treatment, BDI-II scores were significantly lower in the placebo and omega-3 group, when compared to their respective baseline scores (Placebo: t = - 4.6, p < 0.01; Omega-3: t = - 7.3, p < 0.01). However, after 12 weeks of treatment, we found no significant difference between both groups with respect to changes in the BDI-II scores (0.7; 95% CI, - 0.7 to 2.1; p = 0.30). LIMITATIONS: This study did not measure blood omega-3 fatty acid concentration and presented a high-dropout rate. Moreover, our results may not be generalizable to other regions. CONCLUSIONS: The results show that a combination of omega-3 fatty acids and psychoeducation and psychoeducation alone can contribute to an improvement in symptoms in people with mild to moderate depression. However, there is no difference between the interventions in ameliorating symptoms of depression.

Disseminated Hormographiella aspergillata infection with involvement of the lung, brain, and small intestine following allogeneic hematopoietic stem cell transplantation: case report and literature review.

Disseminated infection by Hormographiella aspergillata is extremely rare and small intestine involvement has not been reported previously. A 51-year-old man with myelodysplastic syndrome developed pneumonia after cord blood cell transplantation. Fungal growth from the biopsied lung was identified as H. aspergillata by morphology and the gene analysis. Although antifungal agents including voriconazole and liposomal amphotericin B were administered, he died of disseminated H. aspergillata infection. We review the literature and discuss the treatment and prognosis.

Gonadotrophin-releasing hormone pulse generator activity in the hypothalamus of the goat.

Pulsatile release of gonadotrophin-releasing hormone (GnRH) is indispensable to maintain normal gonadotrophin secretion. The pulsatile secretion of GnRH is associated with synchronised electrical activity in the mediobasal hypothalamus (i.e. multiple unit activity; MUA), which is considered to reflect the rhythmic oscillations in the activity of the neuronal network that drives pulsatile GnRH secretion. However, the cellular source of this ultradian rhythm in GnRH activity is unknown. Direct input from kisspeptin neurones in the arcuate nucleus (ARC) to GnRH cell bodies in the medial preoptic area or their terminals in the median eminence could be the intrinsic source for driving the GnRH pulse generator. To determine whether kisspeptin signalling could be responsible for producing pulsatile GnRH secretion, we studied goats, measured plasma levels of luteinising hormone (LH) and recorded MUA in the posterior ARC, where the majority of kisspeptin neuronal cell bodies are located. Rhythmic volleys of MUA were found to be accompanied by LH pulses with regular intervals in the ARC, where kisspeptin neuronal cell bodies were found. Exogenous administration of kisspeptin stimulated a sustained increase in LH secretion, without influencing MUA, suggesting that the GnRH pulse generator, as reflected by MUA, originated from outside of the network of GnRH neurones, and could plausibly reflect the pacemaker activity of kisspeptin neurones, whose projections reach the median eminence where GnRH fibres project. These observations suggest that the kisspeptin neurones in the ARC may be the intrinsic source of the GnRH pulse generator.

Modulation of gonadotrophin-releasing hormone pulse generator activity by the pheromone in small ruminants.

In small ruminants, such as goats and sheep, a primer pheromone produced by males induces an out-of-seasonal ovulation in anoestrous females, a phenomenon known as the male effect. The male effect is unique in that an external chemical stimulus can immediately modulate the activity of the hypothalamic gonadotrophin-releasing hormone (GnRH) pulse generator. We have established a monitoring method of the GnRH pulse generator activity in Shiba goat. Using this method as a sensitive bioassay to assess the male effect pheromone activity, we have shown that the male effect pheromone is synthesised in an androgen-dependent manner in the sebaceous glands or their vicinity in specific body regions in goats. Although chemical identity of the pheromone is yet to be determined, analyses of male goat hair extracts by gas chromatography fractionation suggest that the male effect pheromone is a volatile substance with relatively small molecular weight. From morphological and molecular biological studies in goats, it is suggested that the pheromone molecule is detected by a member of the V1R family located on both the olfactory neurones and the vomeronasal sensory neurones, and the pheromone signal is conveyed to the medial nucleus of amygdala via the main olfactory and vomeronasal pathways and, subsequently, to the hypothalamic GnRH pulse generator to enhance its activity.

Antifeedant rings B and D opened limonoids from Khaya senegalensis.

Three new rings B and D opened limonoids, two mexicanolides named khayanone (1) and 2-hydroxyseneganolide (2) and one rearranged phragmalin limonoid of 1-O-acetylkhayanolide A (3), were isolated together with six known B,D-seco compounds from the acetone extract of the stem bark of Khaya senegalensis. Structures of new compounds were elucidated by spectroscopic means, and the absolute stereochemistry of 1 was established by CD study of the dibenzoate derivative. The insect antifeedant and antiviral activities of the new compounds were also determined.

A possible role of neuropeptide Y as a mediator of undernutrition to the hypothalamic gonadotropin-releasing hormone pulse generator in goats.

To understand central mechanisms for nutritional infertility, the activity of the GnRH pulse generator was directly assessed in ovariectomized (OVX) goats under several experimental conditions by recording characteristic increases in the multiple-unit activity (volleys). When estradiol (E(2))-treated animals were fasted for 4-5 days, the activity of the GnRH pulse generator was gradually suppressed, and the volley interval at the end of fasting was significantly prolonged, compared with that during the feeding period (67.4 vs. 49.3 min, n = 5, P < 0.01). On the other hand, such a significant effect on the pulse generator was not observed in OVX goats. In the second experiment, the animals received a bolus intracerebroventricular injection of several doses (0, 2, 5, and 20 microg/400 microl) of neuropeptide Y (NPY). Exogenous NPY dose-dependently inhibited the pulse generator activity. At the highest dosage, the 1st posttreatment volley interval was significantly longer than that of the pretreatment (112.4 vs. 32.6 min, n = 5, P < 0.01) in OVX goats. The suppressive effect of NPY was similarly observed in OVX+E(2) goats. Further, when NPY was infused (10 microg/200 microl.h for 6 h) into OVX goats, the activity of the GnRH pulse generator was almost completely inhibited during the infusion period. Hypothalamic sites responding to fasting were immunohistochemically evaluated using an antibody for Fos in castrated goats. Fos-immunoreactive neurons were found in areas adjacent to the third ventricle. Double-labeling immunohistochemistry revealed that a subpopulation of NPY neurons in the arcuate nucleus was activated in response to fasting. These results demonstrate that: 1) the activity of the GnRH pulse generator is suppressed by fasting in the presence of E(2); 2) exogenous NPY inhibits the activity of the GnRH pulse generator regardless of the presence of E(2); and 3) several hypothalamic neurons or regions, including those containing NPY in the arcuate nucleus, are activated by fasting. Collectively, these observations suggest that NPY acts as a mediator of undernutrition to the GnRH pulse generator.

Induction of early growth response protein-1 gene expression in the rat ovary in response to an ovulatory dose of human chorionic gonadotropin.

Granulosa cells in a mature ovarian follicle have an abundance of LH/hCG receptors that respond rapidly to an ovulatory surge in gonadotropins. Within minutes, membrane signal transduction sets in motion metabolic changes that lead to follicular rupture. This study provides evidence that the initial ovarian response to such an ovulatory stimulus includes induction of the immediate-early transcription factor gene for early growth response protein-1 (Egr-1). Immature Wistar rats were primed with 10 IU equine CG (eCG), sc, and 48 h later the 12-h ovulatory process was initiated by 10 IU hCG, sc. Ovarian RNA was extracted at 0, 0.5, 1, 2, 4, 8, 12, and 24 h after the primed animals were injected with hCG. The RNA extracts were used for RT-PCR differential display for random detection of gene expression in the stimulated ovarian tissue. Northern analysis of one of the differentially amplified complementary DNAs confirmed that it was part of a gene that was significantly up-regulated within 1 h after the ovaries had been stimulated by hCG. Maximum transcription was at 4 h after hCG, and expression declined to 0 h control levels by 24 h after hCG. Subcloning and sequence analysis revealed that the complementary DNA matched the gene for Egr-1. In situ hybridization indicated that the Egr-1 messenger RNA was in the granulosa layer of mature follicles. Western blotting confirmed the temporal pattern of Egr-1 expression detected by differential display, Northern analysis and in situ hybridization. The Egr-1 protein is approximately 84 kDa. In conclusion, the data show that expression of the zinc finger transcription factor Egr-1 is an early event in the cascade of inflammatory-like changes that occur in an ovulatory follicle in response to a trophic hormone.

Normal fetal brain development: MR imaging with a half-Fourier rapid acquisition with relaxation enhancement sequence.

PURPOSE: To analyze normal maturation of the fetal brain with half-Fourier rapid acquisition with relaxation enhancement (RARE) magnetic resonance (MR) imaging. MATERIALS AND METHODS: The normal brains of 25 fetuses of 12-38 weeks gestational age were examined in utero with half-Fourier RARE imaging. Gyrus maturation, gray and white matter differentiation, ventricle-to-brain diameter ratio, and subarachnoid space size were evaluated with respect to gestational age. RESULTS: At 12-23 weeks, the brain had a smooth surface, and two or three layers were differentiated in the cerebral cortex. At 24-26 weeks, only a few shallow grooves were seen in the central sulcus, and three layers, including the immature cortex, intermediate zone, and germinal matrix, were differentiated in all fetuses. At 27-29 weeks, sulcus formation was observed in various regions of the brain parenchyma, and the germinal matrix became invisible. Sulcation was seen in the whole cerebral cortex from 30 weeks on. However, the cortex did not undergo infolding, and opercular formation was not seen before 33 weeks. At 23 weeks and earlier, the cerebral ventricles were large; thereafter, they gradually became smaller. The subarachnoid space overlying the cortical convexities was slightly dilated at all gestational ages, most markedly at 21-26 weeks. CONCLUSION: Changes in brain maturation proceed through stages in an orderly and predictable fashion and can be evaluated reliably with half-Fourier RARE MR imaging.

Degeneration in vivo of rat hippocampal neurons by wild-type Alzheimer amyloid precursor protein overexpressed by adenovirus-mediated gene transfer.

In an attempt to elucidate the pathological implications of intracellular accumulation of the amyloid precursor protein (APP) in postmitotic neurons in vivo, we transferred APP695 cDNA into rat hippocampal neurons by using a replication-defective adenovirus vector. We first improved the efficiency of adenovirus-mediated gene transfer into neurons in vivo by using hypertonic mannitol. When a beta-galactosidase-expressing recombinant adenovirus suspended in 1 M mannitol was injected into a dorsal hippocampal region, a number of neurons in remote areas were positively stained, presumably owing to increased retrograde transport of the virus. When an APP695-expressing adenovirus was injected into the same site, part of the infected neurons in the hippocampal formation underwent severe degeneration in a few days, whereas astrocytes near the injection site showed no apparent degeneration. These degenerating neurons accumulated different epitopes of APP, and beta/A4 protein (Abeta)-immunoreactive materials were undetected in the extracellular space. A small number of degenerating neurons showed nuclear DNA fragmentation. Electron microscopic examinations demonstrated that degenerating neurons had shrunken perikarya along with synaptic abnormalities. Microglial cells/macrophages were often found in close proximity to degenerating neurons, and in some cases they phagocytosed these neurons. These results suggest that intracellular accumulation of wild-type APP695 causes a specific type of neuronal degeneration in vivo in the absence of extracellular Abeta deposition.

Bedside wellness--development of a virtual forest rehabilitation system.

The present study aims at the development of a new concept system that will contribute toward improving the quality of life for bedridden patients and the elderly. The results of a basic study showed the possibility of a virtual reality system reducing stress and pain, provided VR sickness does not occur. A Bedside Wellness System which lets a person experience a virtual forest walk and provides a facility of rehabilitation was proposed based on the basic study and developed. An experiment to assess the developed system using healthy subjects was executed. The data suggested the positive effects of the system; however, some points to be improved were also extracted. After a few improvements, the system will be available for clinical use.

Peptide expression in GABAergic neurons in rat suprachiasmatic nucleus in comparison with other forebrain structures: a double labeling in situ hybridization study.

We investigated the characteristics of GABAergic neurons in the rat suprachiasmatic nucleus (SCN) in normal untreated rats by examination of co-expressed peptides. We adopted double labeling in situ hybridization using a digoxigenin-labeled glutamic acid decarboxylase (GAD) riboprobe and 35S-labeled peptide riboprobes. GAD mRNA-positive neurons were distributed throughout the SCN from the rostal to the caudal pole. In the dorsomedial part of the SCN, most GAD mRNA-positive neurons co-expressed arginine vasopressin mRNA. In the ventrolateral part of the SCN, about two thirds of GAD mRNA-positive neurons co-expressed vasoactive intestinal peptide (VIP) mRNA. Co-expression of GAD and somatostatin mRNA was observed in virtually all neurons of the intermediate part of the SCN. In contrast, these peptidergic traits were poorly expressed in hypothalamic GABAergic neurons outside the SCN. Vasopressin mRNA-positive cells in the supraoptic nucleus did not express GAD mRNA, and co-expression of somatostatin mRNA and GAD mRNA was rare in the periventricular hypothalamic nucleus. Similarly, the VIP mRNA co-expression ratio of GABAergic neurons in the cerebral cortex was far lower than that in the SCN.

Metabolite changes with age measured by proton magnetic resonance spectroscopy in normal subjects.

To determine whether there are metabolite changes in the left medial temporal and frontal lobes with aging, we performed proton magnetic resonance spectroscopy in 36 normal subjects. The N-acetylaspartate/creatine-phosphocreatine ratio in the medial temporal lobe tended to be decreased in subjects over 60 years of age. The ratio decrease in the frontal lobe related to aging was lower than that in the medial temporal lobe. There were no significant differences in the metabolite ratios between males and females. These findings suggest that structures in the medial temporal lobe may be more susceptible to neuronal dysfunction associated with aging than those in the frontal lobe.

Self-injurious behavior and dopaminergic neuron system in neonatal 6-hydroxydopamine-lesioned rat: 1. Dopaminergic neurons and receptors.

Dopaminergic neuronal circuits underlying self-injurious behavior (SIB) were investigated in neonatal 6-hydroxydopamine (6-OHDA)-induced dopamine-depleted rats. The extent of damaged dopamine neuronal areas was investigated by quantitative analysis of tyrosine hydroxylase (TH) immunocytochemistry and the biochemical quantification of dopamine levels in three groups; neonatal 6-OHDA-treated rats showing SIB (the SIB(+) group), neonatal 6-OHDA-treated rats not showing SIB (SIB(-) group) and neonatal saline-treated controls (control group). In the SIB(+) group, both dorsal and ventral mesostriatal dopaminergic neuron systems were severely destroyed, but the mesocortical dopaminergic neuron system and intrahypothalamic dopaminergic neuron system remained intact. In SIB(-) group, the dorsal mesostriatal dopaminergic neuron system was severely destroyed, but the ventral mesostriatal dopaminergic neuron system was only partially impaired. The effect of neonatal 6-OHDA treatment on dopaminergic receptors was analyzed by quantitative in vitro receptor autoradiography using [3H]SCH-23390 for the D1 site and [3H]YM-09151-2 for the D2 site. Although D1 and D2 binding was not altered in the dorsal and ventral striatum, cerebral cortex and hypothalamus, the D1 binding in the substantia nigra pars reticulata was increased in the SIB(+) group compared with the SIB(-) or control groups. The D1 binding assay using the membrane preparation of the nigral homogenates, revealed that the KD did not change, but the Bmax in the SIB(+) group was higher than that in the SIB(-) or control groups (P < .05). These results suggest that the region-specific change of dopaminergic neurons and receptors underlies the manifestation of SIB.

Neurobiology of L-DOPAergic systems.

L-DOPA is proposed to be a neurotransmitter and/or neuromodulator in CNS. It is released probably from neurons, which may contain L-DOPA as an end-product, and/or from some compartment other than catecholamine-containing vesicles. The L-DOPA itself produces presynaptic and postsynaptic responses. All are stereoselective and most are antagonized by competitive antagonist. In striatum, L-DOPA is neuromodulator, mother of catecholamines, not only a precursor for dopamine but also a potentiator of children for presynaptic beta-adrenoceptors to facilitate dopamine release and postsynaptic D2 receptors, and ACh release inhibitor. All may cooperate for Parkinson's disease. Meanwhile, supersensitization of increase in L-glutamate release to nanomolar levodopa was seen in Parkinson's model rats, which may relate to dyskinesia or "on-off" during chronic therapy. In lower brainstem, L-DOPA tonically activates postsynaptic depressor sites of NTS and CVLM and pressor sites of RVLM. L-DOPA is probably a neurotransmitter of primary baroreceptor afferents terminating in NTS. GABA, the inhibitory neuromodulator for baroreflex in NTS, tonically functions to inhibit, via GABAA receptors, L-DOPA release and depressor responses to levodopa. Levodopa inversely releases GABA. L-DOPAergic monosynaptic relay from NTS to CVLM and from PHN to RVLM is suggested. Tonic L-DOPAergic baroreceptor-aortic nerve-NTS-CVLM relay seems to carry baroreflex information. Disturbance of neuronal activity to release L-DOPA in NTS, loss of the activity in CVLM, enhancement of the activity with decreased decarboxylation and increase in sensitivity to levodopa in RVLM may be involved in maintenance of hypertension in SHR. This is a story of "L-DOPAergic receptors" with extremely high affinity and low density.

Reserpine-induced immunocytochemical change of neuropeptide Y in the hypothalamic arcuate nucleus.

The effect of reserpine on neuropeptide Y immunoreactive (NPY-IR) neurons in the rat hypothalamic arcuate nucleus was examined by immunocytochemical techniques. Although only NPY-IR fibers and terminals were distributed in this nucleus in untreated and saline treated rats, single treatment of reserpine (10 mg/kg, i.p.) visualized abundant NPY-IR neuronal cell bodies: the increase began at 12 h of postinjection, reached its maximal level at 48 h, and returned to its normal level at 96 h. Pretreatment of nialamide, a monoamine oxidase inhibitor, prevented these acute reserpine-induced changes, suggesting reserpine acts on NPY neurons through monoaminergic mechanism. Chronic treatment of haloperidol (5 mg/kg, once daily for 5 days) a dopamine receptor antagonist, could induce the similar increase of NPY immunoreactivity. However, interruption of adrenergic and serotonergic neurotransmissions by chronic treatment of propranorol and methysergide, or chemical lesions of ascending noradrenergic and serotonergic pathways by 6-hydroxydopamine and 5,6-dihydroxytryptamine, could not induce any immunoreactive increase of NPY in arcuate neurons. These findings strongly suggest that reserpine-induced NPY increase occurs through dopaminergic afferents in hypothalamic arcuate neurons.

Effects of parathyroidectomy and calcium supplementation on the pressor response to angiotensin II in conscious rats.

OBJECTIVE: We evaluated the effect of parathyroidectomy (PTx) and of calcium supplementation on the pressor response to angiotensin II (Ang II) in conscious rats. STUDY DESIGN: PTx and sham surgery were performed on 10-week-old male Wistar rats. The mean arterial pressure (MAP), heart rate, and the effective pressor dose of Ang II (EPD) which defined as the dose of Ang II required to elicit a rise of 20 mmHg in MAP, were evaluated in PTx and sham operated rats. Intracellular free calcium in platelets was assessed with the fluorescent dye, fura-2 acetoxymethyl ester. In addition, after administering a dose of supplemental calcium chloride, a 10, 20, or 40 mg/rat, we determined the changes in the MAP, EPD, and serum calcium level. RESULTS: The EPD in the PTx rats was significantly lower than the sham operated rats. The serum concentration of calcium in PTx was also significantly lower than the sham operated rats. A statistically significant negative relationship was observed between the EPD and intracellular free calcium in PTx rats. Following administration of 20 mg of calcium chloride (7.4 mg of elemental calcium) to the PTx rats, the EPD returned to the level seen in sham operated rats. CONCLUSION: Results suggest that a depletion of parathyroid hormone is associated with the pressor response to Ang II, and is involved in the regulation of intracellular free calcium.

Activated (HLA-DR+) T-lymphocyte subsets in cervical carcinoma and effects of radiotherapy and immunotherapy with sizofiran on cell-mediated immunity and survival.

A prospective randomized trial on 312 patients with locally advanced cervical carcinoma (FIGO stages IB-IV) was carried out. The 5-year survival in 90 patients treated with radiotherapy and antitumor polysaccharide sizofiran, an extract from the culture broth of Schizophyllum commune Fries, in combination was significantly (P = 0.045) better than that in 82 patients treated with radiotherapy alone. Treatment with sizofiran and 5-fluorouracil in combination improved (P = 0.003) the 5-year survival in 60 patients treated with radiotherapy. In 244 cervical carcinoma patients, the percentage of activated CD8+ (CD8+HLA-DR+) T cells in the CD8+ T-cell subsets in peripheral lymphocytes increased significantly as the disease progressed. A similar tendency was observed in the percentage of activated CD4+ (CD4+HLA-DR+) T cells in the CD4+ T-cell subsets. These immunologic parameters were significantly increased by radiotherapy, but not by surgery. Sizofiran accelerated a recovery in the activated CD8+ T cells in the CD8+ T-cell subsets compared with that of sizofiran nontreated patients after radiotherapy. Our data show that possible immune impairment in cervical carcinoma may be caused by disturbances in cell-mediated immunity, and that sizofiran is an effective immunotherapeutic agent for cervical carcinoma because it stimulates a rapid recovery of the immunologic parameters impaired by radiotherapy.

Transient expression of estrogen receptor-immunoreactivity (ER-IR) in the layer V of the developing rat cerebral cortex.

Occurrence of estrogen receptor-immunoreactivity (ER-IR) in the cerebral cortex was examined in neonatal and adult rats. In newborn rats of postnatal day 1 (= day of birth) and postnatal day 5 (PD1 and PD5, respectively), ER-IR was not evident in the neocortex. On postnatal days 7, 10 and 13 (PD7, PD10 and PD13 respectively), a group of cells with distinct ER-IR appeared in the layer V of the auditory cortex. At the PD10, weak but specific ER-IR were also appeared in the somatosensory and the visual cortices. Among these areas, the ER-IR positive neurons occurred most frequently in the auditory cortex at PD10 rats. By examination of adjacent sections, one stained with Cresyl violet and the another stained with acethylcholinesterase (AChE) histochemistry, it was revealed that the region with ER-IR at PD7 to PD13 was limited to layer V of the neocortex. These signals, however, disappeared at PD15. In layer II of the neocortex, on the other hand, weak ER-IR signals were detected throughout the area sporadically at PD21 and in adults. The ER-IR detected transiently in the auditory cortex by the antiserum might contribute to maturation and establishment of the neurons of the rat auditory circuit.

In situ hybridization histochemistry of vghm1f mRNA in the rat suprachiasmatic nucleus: co-localization with vasopressin/neurophysin and VIP/PHI.

The expression of vgf gene, first isolated as a gene induced by nerve growth factor in PC12 cells, was investigated in neurons of the suprachiasmatic nucleus (SCN) by in situ hybridization. In the rat forebrain, the vgf mRNA was found most densely in the SCN. Neurons which express vgf mRNA were found both in the dorsomedial and ventrolateral subdivisions. Double-labeling of vgf in situ hybridization and peptide immunocytochemistry demonstrated that vgf mRNA was expressed in most vasopressin- and neurophysin-immunoreactive neurons in the dorsomedial part and in vasoactive intestinal peptide (VIP)- and peptide histidine isoleucine amide (PHI)-immunoreactive neurons in the ventrolateral part. These findings suggest that vgf is a highly expressed gene in both vasopressin/neurophysin neurons and VIP/PHI neurons which were speculated to be involved in the generation and entrainment of circadian rhythm.