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.

Effect of attention bias modification on event-related potentials in patients with irritable bowel syndrome: A preliminary brain function and psycho-behavioral study.

BACKGROUND: Attention bias modification normalizes electroencephalographic abnormalities in alpha and beta power percentages related to attention in patients with irritable bowel syndrome (IBS). Yet, it is unknown whether ABM contributes to the normalization of event-related potentials (ERP) in these patients. We hypothesized that ERP related to attention deficit would be normalized after ABM implementation in individuals with IBS. METHODS: Thirteen patients with IBS and 10 control subjects completed a 2-month intervention that included five ABM sessions. Each session included 128 trials, resulting in a total of 640 trials during the study period. Event-related potentials were measured at the first and fifth sessions. As per the international 10-20 system for electroencephalographic electrode placement, right parietal P4 was evaluated to measure the attention component of facial expression processing. KEY RESULTS: A group comparison of P100 latency at P4 revealed that latencies were significantly different between groups in session 1 (IBS vs control, 108 ± 8 vs 97 ± 14; t = -2.51, P = .0203). This difference was absent in session 5 (94 ± 11 vs 93 ± 11, respectively; t = -0.397, P = .6954, r = .09), indicating an effect of ABM in the IBS group. CONCLUSIONS AND INFERENCES: Attention bias modification may have clinical utility for normalizing brain function and specifically attentional abnormalities in patients with IBS.

Effect of attention bias modification on brain function and anxiety in patients with irritable bowel syndrome: A preliminary electroencephalogram and psycho-behavioral study.

BACKGROUND: Gastrointestinal symptoms of irritable bowel syndrome (IBS) show a reciprocal relationship with anxiety. In this intervention-based study, we investigated the utility of attention bias modification (ABM) therapy in patients with IBS. We hypothesized that IBS-related electroencephalographic abnormalities would be normalized after ABM therapy. METHODS: Seventeen patients with IBS and 13 healthy subjects completed five ABM intervention sessions over a 2-month period. Each session included 128 ABM trials, resulting in a total of 640 trials across the intervention period. For each trial, subjects viewed a pair of facial expression images and were instructed to indicate the position of the neutral face as quickly and accurately as possible by pressing one of two buttons on a button box. Electroencephalography data (alpha and beta power percentages) were collected during the 1st and 5th sessions. KEY RESULTS: Generalized estimating equations of relative alpha power revealed a significant effect of period was identified at O2 (P=.036). Paired t tests revealed that ABM significantly increased relative alpha power at O2 in patients with IBS. Generalized estimating equation of relative beta power revealed a significant effect of the group × period interaction was identified at Pz (P=.035). Paired t tests revealed that ABM significantly decreased relative beta power at Pz in patients with IBS. CONCLUSIONS & INFERENCES: Attention bias modification may normalize brain function related to attention and anxiety in patients with IBS.

Anti-cyclic citrullinated peptide antibody (anti-CCP antibody) is present in the sera of patients with dementia of Alzheimer's type in Asian.

BACKGROUND: In the hippocampi of Alzheimer's disease (AD) patients, aberrant expression of citrullinated proteins and peptidylarginase 2 (PADI2) has been identified. We explored the functional roles of these proteins by means of detection of serum anti-cyclic citrullinated peptide antibody (anti-CCP antibody) in patients with dementia of Alzheimer's type (DAT). METHODS: Sera were obtained from 42 patients with DAT, 30 patients with other neurological disorders and 42 healthy controls. Gender ratio and age were comparable among the three groups. The level of anti-CCP antibody in sera was examined by ELISA. FINDINGS: Anti-CCP antibody was not found in the 30 patients with other neurological disorders, and only one of the 42 healthy controls (2.4%) was positive. However, surprisingly, anti-CCP antibody was clearly detected in eight of the 42 DAT patients. INTERPRETATION: Anti-CCP antibody appears to be a simple and early serologic biomarker for DAT among dementia patients. Additionally, our data imply that citrullinated proteins accumulated in the astrocytes of AD patients acquire neo-antigenicity, inducing anti-CCP antibody production.

Resistance of CD4-positive T lymphocytes to etoposide-induced apoptosis mediated by upregulation of Bcl-xL expression in patients with HTLV-I-associated myelopathy.

Human T-lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM) is characterized by chronic inflammation of the spinal cord. The exact mechanisms that enhance the development of chronic myelopathy remain to be determined. One such mechanism could be an altered response of peripheral blood CD4(+) T lymphocytes to apoptotic stimuli. We examined the sensitivity of these cells to apoptosis in HAM patients and control. Apoptosis was induced by etoposide, which induces mitochondria-dependent apoptosis through the release of cytochrome c from the mitochondria. The percentage of apoptotic cells that expressed hypodiploid DNA among etoposide-treated CD4(+) T lymphocytes was significantly lower in HAM patients than in the control. Western blot analysis of cell lysates derived from CD4(+) T lymphocytes demonstrated that the expression level of Bcl-xL protein was significantly higher in HAM patients than in the control. Our results indicate that peripheral blood CD4(+) T lymphocytes of HAM patients are resistant to apoptosis triggered through mitochondrial death pathway through upregulation of expression of anti-apoptotic protein, Bcl-xL. This phenomenon might contribute to the prolongation and perpetuation of the chronic inflammatory process in the spinal cord of HAM patients.

Comparative molecular analysis of HTLV-I proviral DNA in HTLV-I infected members of a family with a discordant HTLV-I-associated myelopathy in monozygotic twins.

In order to elucidate the underlying mechanisms of a discordant case with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in monozygotic twins, we investigated HTLV-I tax sequences of 10 - 18 polymerase chain reaction-based clones each derived from peripheral blood mononuclear cells of the twins as well as their infected mother and an elder brother who also suffered from HAM/TSP. Sequence comparison revealed that three of the infected individuals including a twin with HAM/TSP shared the consensus tax sequence identical to the reference, ATK-1, but that of another healthy twin was different at five nucleotide positions including three nonsynonymous changes from ATK-1. This finding strongly suggested that different HTLV-I strains infected the monozygotic twins and the difference in infected proviral sequences determined the discordant clinical outcomes. Transfection and subsequent reporter assays failed to show a significant difference in transactivation activity on HTLV-I LTR and NF-kappaB elements between the products of the two sequences. Two HAM/TSP patients (a twin and elder brother) among three members infected with the ATK-1 type virus shared a paternal HLA allele which was absent in the healthy individual (mother). Genetic analysis of sequence variation in the tax sequences of the discordant twins showed that the Dn/Ds ratio was high in the healthy twin but low in the twin with HAM/TSP, implying the presence of more intense selection forces in the carrier. Our findings strongly suggested that a particular combination of HTLV-I strains with an HLA genotype would be a risk for HAM/TSP.

Importance of immune deviation toward Th1 in the early immunopathogenesis of human T-lymphotropic virus type I-associated myelopathy.

Although the principal neuropathological feature of human T-lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM) is chronic inflammation of the spinal cord, characterized by perivascular cuffing of mononuclear cells accompanied by parenchymal lymphocytic infiltration, the precise mechanisms by which HTLV-I infection causes chronic inflammation of the spinal cord are still obscure. In patients with HAM, peripheral blood CD4(+)T lymphocytes, particularly HTLV-I-infected CD4(+)T lymphocytes, have increased adherent activity to endothelial cells and transmigrating activity through basement membranes. In addition, the profile of cytokine expression suggests increased numbers of Th1 cells in peripheral blood CD4(+)T lymphocytes of patients with HAM. These findings strongly suggest that immune deviation toward Th1, which might be based on high viral load of HTLV-I, plays an important role in tissue damage in the central nervous system of patients with HAM. We herein emphasize the importance of activated Th1 cells as the first trigger in the immunopathogenesis of HAM.

[A case of herpes zoster encephalitis with Ramsay-Hunt syndrome, herpes zoster generalisatus and acute pancreatitis].

We describe here a 71-year-old man who had herpes zoster encephalitis. He developed high fever, headache and disturbance of consciousness on 1st, May, 1998. On admission, neurological examination revealed disturbance of consciousness with restlessness and meningeal signs. Brain MRI (T 1 and T 2 weighted images) demonstrated high signal lesions in the left temporal lobe and cerebellar vermis. VSV encephalitis was diagnosed based on CSF pleocytosis, high serum and CSF titers of VZV antibody and EEG abnormality. During hospitalization, Ramsay-Hunt syndrome, herpes zoster generalisatus and acute pancreatitis developed. To our knowledge, the characteristic combination of the clinical signs in this case is very rare. We discussed the pathogenic mechanisms of these conditions, and this case was considered to have VZV encephalitis, and to be associated with right facial nerve palsy and pancreatitis, in spite of the absence of immunological deficiency.

Vascular cell adhesion molecule-1-mediated matrix metalloproteinase-2 induction in peripheral blood T cells is up-regulated in patients with HTLV-I-associated myelopathy.

We investigated whether matrix metalloproteinase-2 (MMP-2) is induced in peripheral blood T cells after their contact with tumor necrosis factor-alpha (TNF-alpha)-stimulated glioblastoma cell line (T98G), expressing vascular cell adhesion molecule-1 (VCAM-1), in patients with HTLV-I-associated myelopathy (HAM) compared to control patients with other neurological disorders (OND). Gelatin zymography revealed that the incremental ratio of gelatinolytic activity of MMP-2 in culture supernatants derived from T cells cocultured with TNF-alpha-stimulated T98G to that of supernatants derived from cultures of T cells alone was significantly higher in HAM patients than in control patients with OND. Immunoblot analysis of immunoprecipitates of culture supernatant showed that increased gelatinolytic activity of MMP-2 was due to increased production of MMP-2 protein in T cells. Increased gelatinolytic activity of MMP-2 in T cells of HAM patients was blocked by pretreatment of TNF-alpha-stimulated T98G with anti-VCAM-1 antibody before coculture with T cells, indicating that MMP-2 induction was VCAM-1-mediated. Although no significant differences were noted in the percentage of VLA-4-positive cells in cultured T cells between HAM patients and control patients with OND, our results indicate that VCAM-1-mediated MMP-2 induction is up-regulated in T cells of HAM patients.

Relationship between the clinical efficacy of pentoxifylline treatment and elevation of serum T helper type 2 cytokine levels in patients with human T-lymphotropic virus type I-associated myelopathy.

OBJECT: Previously, we reported the efficacy of pentoxifylline (PTX) treatment in human T-lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM). Here, we clarify the relationship between the clinical efficacy of PTX treatment and elevation of T helper type 2 (Th2) cytokine levels in HAM patients. PATIENTS AND METHODS: PTX (300 mg) was administered daily by the oral route to 12 HAM patients for 4 weeks. We assessed the relationship between the changes in neurological status (motor disability scores, the degree of spasticity on neurological examination, and the time required to walk 10 m) and the changes in serum and cerebrospinal fluid (CSF) levels of interferon-gamma (IFN-gamma) as a Th1 cytokine and interleukin-4 and -10 (IL-4 and -10) as Th2 cytokines measured by an EASIA (enzyme-amplified sensitivity immunoassay) kit. RESULTS: PTX treatment induced incremental increases in the levels of IL-4 and IL-10 in both sera and CSF of 6 HAM patients. Clinical improvement was associated with this elevation in IL-4 and IL-10. PTX treatment also induced a decrease in IFN-gamma levels in the sera of 6 HAM patients, but this was not correlated with clinical improvement. CONCLUSION: These results suggest that the correction of the immunological imbalance in Th1 to Th2 cytokine responses, with upregulation of IL-4 and IL-10, may account for the clinical improvement in HAM patients treated with PTX.

[A case of hereditary ceruloplasmin deficiency with hemosiderosis].

We report a 49-year-old female with hereditary ceruloplasmin deficiency with hemosiderosis. There was a family history of the same symptoms; her brother showed hypoceruloplasminemia and decrease of the serum copper content. On physical examinations, dementia, dysarthria, downbeat nystagmus, sensorineural hearing disturbance, orthostatic hypotension, retinitis pigmentosa, diffuse goiter, and cerebellar ataxia were noted. Laboratory examinations disclosed leukopenia, diabetes mellitus, hypothyroidism, decrease of copper content in the serum and urine. Serum ferritin concentration was remarkably increased. Serum ceruloplasmin could not be detected. Biopsy of the liver showed that iron content in the liver was increased. On MRI study, dentate nucleus of the cerebellum, basal ganglia, and the liver showed low intensity in both T1 and T2 weighted images. A nonsense mutation in the ceruloplasmin gene was found in this patient. Systemic iron deposition and tissue damage were considered as caused by deficiency of function of ceruloplasmin as ferroxidase. To our knowledge, the characteristic combination of the clinical signs in this patient has not been reported.

[A case of juvenile Parkinson disease with vocal cord abductor paralysis in the course of malignant syndrome].

We report a 60-year-old woman with juvenile Parkinson disease (PD) with vocal cord abductor paralysis (VCAP). She had suffered from juvenile PD for 30 years. She was admitted in February 1998 to our clinical unit, because of malignant syndrome induced by dehydration. Neurological examination revealed disturbance of consciousness, hand tremor, dyskinesia of the trunk and all extremities, and rigidity. Laboratory examinations disclosed leukocytosis, renal dysfunction, hypermyoglobinemia, and elevation of the serum creatine kinase. Six days after admission, dyspnea and inspiratory stridor were noted, and the respiratory distress worsened. Endoscopy of the upper airways revealed that the vocal cord was in the midline or paramedian position. There are some cases of PD with VCAP, but such a case is very rare in Japan. We discussed the pathogenic mechanisms of these conditions, and speculated that VCAP was associated with malignant syndrome in our case.

A mouse prion protein transgene rescues mice deficient for the prion protein gene from purkinje cell degeneration and demyelination.

Disruption of both alleles of the prion protein gene, Prnp, renders mice resistant to prions; in a Prnp o/o line reported by some of us, mice progressively developed ataxia and Purkinje cell loss. Here we report torpedo-like axonal swellings associated with residual Purkinje cells in Prnp o/o mice, and we demonstrate abnormal myelination in the spinal cord and peripheral nerves in mice from two independently established Prnp o/o lines. Mice were successfully rescued from both demyelination and Purkinje cell degeneration by introduction of a transgene encoding wild-type mouse cellular prion protein. These findings suggest that cellular prion protein expression may be necessary to maintain the integrity of the nervous system.

Elevated levels of interleukin-12 and interferon-gamma in patients with human T lymphotropic virus type I-associated myelopathy.

The levels of interleukin-12 (IL-12) (p70 heterodimer), total IL-12 (p70 heterodimer plus p40 chains), interferon-gamma (IFN-gamma) as Th1 cytokine, and those of interleukin-4 (IL-4) and interleukin-10 (IL-10) as Th2 cytokines in sera and cerebrospinal fluid (CSF) from 22 patients with human T lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM) were compared with those of 22 patients with other neurological diseases (OND), including nine anti-HTLV-I-seropositive carriers. Both serum IL-12 (total and p70 heterodimer) and CSF IFN-gamma, measured by the enzyme-linked immunosorbent assay (ELISA), were significantly elevated in patients with HAM as compared to the patients with OND, including the anti-HTLV-I-seropositive carriers. Serum IFN-gamma also was significantly elevated in the HAM patients as compared to the controls. There was no significant difference in the CSF levels of IL-12 (total and p70 heterodimer) between the HAM patients and controls, whereas, for the Th2 cytokines IL-4 was detected in the CSF of four anti-HTLV-I-seropositive carriers of the 13 control patients but not in any of the patients with HAM. No significant difference was found in the serum levels of IL-4 and IL-10, nor in the CSF levels of IL-10 in the patients with HAM and in the controls. These findings indicate that in patients with HAM, the immunological balance of helper T lymphocytes between Th1 and Th2 is toward Th1 in the periphery and that Th1-mediated immunological status in the central nervous system is involved in the pathogenesis of HAM.

[A case of superficial siderosis of the central nervous system--findings of the neuro-otological tests and evoked potentials].

We report a 57-year-old woman with superficial siderosis of the central nervous system. On physical examination, sensorineural hearing impairment, cerebellar ataxia, pyramidal tract signs, dysarthria, and neurogenic bladder were seen. Brain and spinal cord MRI (T2 and proton weighted images) revealed cerebellar atrophy and marginal hypointensity of the Sylvian fissure and brain stem, cerebellum and spinal cord. We diagnosed this patient as superficial siderosis because of the clinical course and specific findings on MRI. We consider this case idiopathic superficial siderosis because the source of the bleeding was unknown. Neuro-otological tests and BAEP disclosed retrocochlear deafness. Her central motor conduction time on MEP was delayed. We discussed the pathogenic mechanism of these conditions, and we concluded that we must take notice of myelinopathy in superficial siderosis and that MEP was useful for detecting them.

[Beneficial effects of acetazolamide on paroxysmal attacks of girdle sensation in multiple sclerosis].

A 56-year-old woman with a 40-year history of multiple sclerosis (MS) developed paroxysmal attacks of girdle sensation in the Th5-6 dermatomes. The attacks lasted 20-60 minutes and occured up to three times per week. T2-weighted MR imaging of the spinal cord showed high intensity area from Th5 to Th8. Electrocardiography, echocardiography and laboratory findings did not indicate ischemic heart disease; therefore, the paroxysms were attributed to the spinal cord lesions. Attacks were successfully suppressed by acetazolamide 250 mg/day. Although carbamazepine is frequently used to treat paroxysmal attacks in MS, we would like to suggest that acetazolamide may also be beneficial in some patients with paroxysmal symptoms.

Apoptosis in labial salivary glands from Sjögren's syndrome (SS) patients: comparison with human T lymphotropic virus-I (HTLV-I)-seronegative and -seropositive SS patients.

Apoptosis is a type of cell death that occurs during morphogenesis and development of the immune system. One of the mechanisms is mediated through the Fas and Fas ligand (FasL) pathway. To determine the possible involvement of Fas and its ligand in salivary gland destruction, we analysed the appearance of nuclei with DNA fragmentation by using nick end labelling (TUNEL) and the expression of Fas and FasL by immunohistochemistry in labial salivary glands. Furthermore, we compared the features of apoptosis in labial salivary glands between HTLV-I- and HTLV-I+ SS. When the frozen sections of 10 primary SS patients in the absence of anti-HTLV-I antibody were examined, several apoptotic cells were found in the acinar and ductal epithelial cells as well as infiltrated mononuclear cells. Both Fas and FasL were detected in the infiltrated mononuclear cells. Acinar epithelial cells, which are surrounded by FasL+ mononuclear cells, were also double-positive with Fas and FasL, although the expression of FasL was localized at their apical border, suggesting that apoptosis of mononuclear cells was achieved by activation-induced mechanisms through Fas/FasL pathways, and that of acinar epithelial cells was mediated by FasL derived from either acinar epithelial cells themselves or infiltrated mononuclear cells. Interestingly, Fas expression in ductal epithelial cells was localized around the lumen side of the ducts, indicating that FasL secreted from acinar epithelial cells may induce Fas-mediated apoptosis of ductal epithelial cells. We also studied the labial salivary glands from nine SS patients with anti-HTLV-I antibodies. There was no significant difference in the occurrence of apoptotic cells or in the expression of Fas and FasL between HTLV-I+ and HTLV-I- SS patients. It was of note that neither the expression of Fas and FasL nor the presence of apoptotic cells were determined in labial salivary glands from subjects without SS. These findings indicate that Fas-mediated apoptosis in salivary glands could be involved in the pathological manifestations of SS, irrespective of HTLV-I seropositivity.

Increased Fas-mediated cytotoxicity of CD4-positive T cells in patients with human T-lymphotropic virus type I-associated myelopathy.

Using a 51Cr release assay, we investigated Fas-mediated cytotoxicity of peripheral blood CD4+ T cells of patients with human T-lymphotropic virus type-I (HTLV-I)-associated myelopathy (HAM) against T98G, a glioblastoma cell line which expresses Fas. Cytotoxic activity of CD4+ T cells against T98G was significantly higher in HAM patients than in controls. Moreover, when CD4+ T cells of HAM patients were preincubated with a monoclonal antibody to human Fas ligand (FasL), cytotoxic activity against T98G was significantly suppressed. These results suggest that damage to nervous tissues by the Fas/FasL system is involved in the pathogenesis of HAM.

HTLV-I-associated myelopathy associated with multi-organ inflammatory disease: a case report.

We report a 73-year-old man with human T-lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM) complicated with multi-organ inflammatory disease, including Sjögren's syndrome, interstitial cystitis, and uveitis. The presence of HTLV-I proviral DNA in peripheral blood mononuclear cells (PBMC), cerebrospinal fluid, salivary gland, mucosa of urinary bladder, and aqueous humor was confirmed by polymerase chain reaction using HTLV-I pX region primer. Western blot analysis revealed the presence of anti-HTLV-I antibodies in serum, CSF, saliva, and urine, suggesting replication of HTLV-I in each tissue. A high load of HTLV-I proviral DNA (20 copies out of 100 PBMC) was present, associated with increased spontaneous proliferation of peripheral blood lymphocytes (24,747 cpm). Our results suggest that the high load of HTLV-I in patients with HAM may potentially induce systemic inflammation in several organs.