Sociodemographic and cultural determinants of mood disorders.

PURPOSE OF REVIEW: The present review aims to examine, summarize and update information on the sociodemographic and cultural determinants of mood disorders. RECENT FINDINGS: Known sociodemographic and cultural determinants continue to be good predictors of the risk of developing a mood disorder over the lifetime. Polygenic risk scores do not appear to offer any advantages over these determinants at present. There is also new and emerging understanding of the role of lifestyle and environmental factors in mediating vulnerability to mood disorder. The influence of ethnicity and migration, on the other hand, is far more complex than initially envisaged. SUMMARY: Recent evidence on sociodemographic determinants of mood disorders confirms associations derived from existing literature. There is also new and emerging evidence on how quality of sleep, diet and the environment influence risk of mood disorders. Culture and ethnicity, depending on context, may contribute to both vulnerability and resilience. Socioeconomic deprivation may be the final common pathway through which several sociodemographic and cultural determinants of mood disorders act.

Does Alice Live Here Anymore? Autonomy and Identity in Persons Living and Dying With Dementia.

Conventional scientific definitions of dementia, or its newer proposed alternate-neurocognitive disorders place emphasis upon cognitive function, particularly memory. The changes in thought, emotion, behavior, personality, and biological function are usually considered only of secondary importance. At the core of the illness, however, lies a progressive loss of self, and by extension, of personhood, identity, autonomy, and agency. The identity of the person living with dementia, and the deterioration of a sense of self assumes significance in planning end of life care, including palliative care. A consideration of self and identity is also significant where physician assisted death, incorporating euthanasia, has legal sanctity. As dementia progresses, there is usually a progressive loss of personal decision making capacity and legal competence. Shared decision making, advance care directives and proxy representatives are options available to safeguard autonomy and agency in such cases. Advance care directives are often treated as static documents. The loss of self and deterioration of identity in persons with dementia means, that there is a psychological discontinuity across time and space, though biological continuity is retained. The discontinuity in self and identity however, imply that the person with dementia changes considerably and so too may values and beliefs. A document which best reflected the wishes of the person with dementia in the past, may not always do so now. Advance directives and proxy representatives may need to be dynamic and evolve over time, particularly where end of life care and physician assisted death is being invoked.

A phase III clinical trial of a mixture agent of plasma-derived factor VIIa and factor X (MC710) in haemophilia patients with inhibitors.

INTRODUCTION: MC710, a 1:10 protein weight ratio mixture of plasma-derived activated factor VII (FVIIa) and factor X (FX), is a novel bypassing agent for haemostasis in haemophilia patients with inhibitors. We evaluated the haemostatic efficacy and safety of one to two administrations of MC710 in 21 joint, muscle, and subcutaneous bleeding episodes in 14 male patients, in a multi-centre, open-label, non-randomized clinical trial. METHODS: Subjects were intravenously administered one or two doses of 60 or 120 µg kg-1 MC710 (as FVIIa) once or twice (to a maximum of 180 µg kg-1 ) over up to five bleeding episodes per subject. The haemostatic efficacy of MC710 was determined for each episode by investigator evaluation, using changes in visual analogue scale (VAS) for pain relief, and/or knee joint or muscle circumference for swelling reduction, and range of motion (ROM) for improvement of joint mobility. RESULTS: In 21 treatments for bleeding episodes, 19 were rated "excellent" or "effective" 8 h after the last treatment. VAS significantly decreased over time, and ROM significantly improved over time compared with the values before treatment. One mild adverse reaction, decreased blood potassium, and two serious adverse events, both knee joint bleeding, were observed within 1 week after first administration, with no significant effect on safety. Furthermore, diagnostic markers did not show any signs of disseminated intravascular coagulation (DIC). CONCLUSION: These results show that MC710 has sufficient haemostatic efficacy and safety, and can be used as a potential bypassing agent to control bleeding in haemophilia patients with inhibitors.

A Phase II clinical trial of a mixture of plasma-derived factor VIIa and factor X (MC710) in haemophilia patients with inhibitors: haemostatic efficacy, safety and pharmacokinetics/pharmacodynamics.

MC710, a mixture of plasma-derived activated factor VII and factor X at a protein weight ratio of 1:10, is a novel bypassing agent for haemostasis in haemophilia patients with inhibitors. In a Phase II trial, we evaluated the haemostatic efficacy and safety of single doses of MC710, and investigated pharmacokinetic and pharmacodynamic parameters in nine joint bleeding episodes in six male haemophilia patients with inhibitors. This trial was a multi-centre, open-label, non-randomized study of two doses (60 and 120 µg kg(-1) as FVIIa dose), allowing the re-administration of different MC710 dosages to the same subjects. Haemostatic efficacy was assessed by evaluating reduction in pain and swelling, as well as increase in range of motion in a bleeding joint. The results of the study showed that in nine bleeding episodes, seven treatments were rated as 'excellent' or 'effective' according to investigator's rating system of efficacy at 8 h after administration. No serious or severe adverse events were observed after administration; furthermore, measurement of several diagnostic markers revealed no signs or symptoms of disseminated intravascular coagulation (DIC). The haemostatic potential of MC710 was confirmed at doses of 60 and 120 µg kg(-1) in this trial. MC710 is thus expected to be a safe and efficacious novel bypassing agent for controlling bleeding in haemophilia patients with inhibitors.

Urinary ß-2-microglobulin as an alternative marker for fetal inflammatory response and development of bronchopulmonary dysplasia in premature infants.

OBJECTIVE: To evaluate the clinical utility of urinary ß-2-microglobulin (B2M) at birth, an alternative to proinflammatory cytokines, as an indicative marker of fetal inflammatory response and subsequent higher risk of bronchopulmonary dysplasia (BPD) in premature infants. STUDY DESIGN: The relationship between urinary B2M at birth and the occurrence of BPD was examined in 96 premature infants with a description of perinatal backgrounds. Constructing a receiver-operating characteristic curve to determine the cutoff value of urinary B2M at birth for the development of BPD, a multivariate logistic regression analysis was performed to evaluate whether elevated urinary B2M at birth can be used as a predictor of BPD. RESULTS: BPD was diagnosed in 34% (33/96) of the infants. Neonates with BPD had a significantly higher occurrence rate of chorioamnionitis and greater levels of median urinary B2M at birth than did those without BPD. The selected cutoff value of urinary B2M at birth correlated with the development of BPD, even after adjusting for gestational age and other confounding factors. CONCLUSIONS: Elevated urinary B2M levels at birth can be used as an alternative marker of fetal inflammatory response and subsequent higher risk of BPD in premature infants.

Little evidence of transdifferentiation of bone marrow-derived cells into pancreatic beta cells.

AIMS/HYPOTHESIS: Bone marrow cells contain at least two distinct types of stem cells which are haematopoietic stem cells and mesenchymal stem cells. Both cells have the ability to differentiate into a variety of cell types derived from all three germ layers. Thus, bone marrow stem cells could possibly be used to generate new pancreatic beta cells for the treatment of diabetes. In this study, we investigated the feasibility of bone marrow-derived cells to differentiate into beta cells in pancreas. METHODS: Using green fluorescent protein transgenic mice as donors, the distribution of haematogenous cells in the pancreas was studied after bone marrow transplantation. RESULTS: In the pancreas of green fluorescent protein chimeric mice, green fluorescent protein-positive cells were found in the islets, but none of these cells expressed insulin. Previous data has suggested that tissue injury can recruit haematopoietic stem cells or their progeny to a non-haematopietic cell fate. Therefore, low-dose streptozotocin (30 or 50 mg/kg on five consecutive days) was injected into the mice 5 weeks after bone marrow transplantation, but no green fluorescent protein-positive cells expressing insulin were seen in the islets or around the ducts of the pancreas. CONCLUSIONS/INTERPRETATION: Our data suggests that bone marrow-derived cells are a distinct cell population from islet cells and that transdifferentiation from bone marrow-derived cells to pancreatic beta cells is rarely observed.

Congenital fibrosarcoma of the jejunum in a premature infant with meconium peritonitis.

We report an unusual case of perforation of a congenital fibrosarcoma of the jejunum in utero and secondary meconium peritonitis. Prenatal ultrasound showed polyhydramnios and fetal ascites from 25 gestational weeks in the absence of other fetal congenital anomalies. A 2200 g baby girl was born at 34 weeks gestation, presenting with severe generalized edema and respiratory distress immediately after birth. Plain radiography revealed progressive abdominal distension and pneumoperitoneum. The baby subsequently underwent surgery at the age of one day. A perforation of the upper jejunum, which had resulted in meconium peritonitis, was discovered intraoperatively and the perforated section of the intestine was resected and anastomosed successfully. The postoperative course was uneventful. Pathological examination confirmed that the perforation was caused by rupture of a congenital fibrosarcoma originating from the jejunum. Rupture of a malignant tumor is an extremely rare cause of peritonitis in the fetus and neonate.

Migration of enhanced green fluorescent protein expressing bone marrow-derived microglia/macrophage into the mouse brain following permanent focal ischemia.

Brain ischemia induces a marked response of resident microglia and hematopoietic cells including monocytes/macrophages. The present study was designed to assess the distribution of microglia/macrophages in cerebral ischemia using bone marrow chimera mice known to express enhanced green fluorescent protein (EGFP). At 24 h after middle cerebral artery occlusion (MCAO), many round-shaped EGFP-positive cells migrated to the ischemic core and peri-infarct area. At 48-72 h after MCAO, irregular round- or oval-shaped EGFP/ionized calcium-binding adapter molecule 1 (Iba 1)-positive cells increased in the transition zone, while many amoeboid-shaped or large-cell-body EGFP/Iba 1-positive cells were increased in number in the innermost area of ischemia. At 7 days after MCAO, many process-bearing ramified shaped EGFP/Iba 1-positive cells were detected in the transition to the peri-infarct area, while phagocytic cells were distributed in the transition to the core area of the infarction. The distribution of these morphologically variable EGFP/Iba 1-positive cells was similar up to 14 days from MCAO. The present study directly showed the migration and distribution of bone marrow-derived monocytes/macrophages and the relationship between resident microglia and infiltrated hematogenous element in ischemic mouse brain. It is important to study the distribution of intrinsic and extrinsic microglia/macrophage in ischemic brain, since such findings may allow the design of appropriate gene-delivery system using exogenous microglia/macrophages to the ischemic brain area.

Two cases of influenza with impaired ocular movement.

Complications of influenza include respiratory disorders (pneumonia, bronchitis and croup) and occasionally myocarditis, myositis, encephalitis, encephalopathy and Reye's syndrome, which may be life-threatening and cause various sequelae. We report two patients who developed unusual complications of influenza infection: one had ptosis and impaired ocular movement, and the other suffered from Guillain-Barré syndrome with paralysis of the extraocular muscles.

An AAV-derived Apaf-1 dominant negative inhibitor prevents MPTP toxicity as antiapoptotic gene therapy for Parkinson's disease.

Adeno-associated virus (AAV) vector delivery of an Apaf-1-dominant negative inhibitor was tested for its antiapoptotic effect on degenerating nigrostriatal neurons in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. The wild-type caspase recruitment domain of Apaf-1 was used as a dominant negative inhibitor of Apaf-1 (rAAV-Apaf-1-DN-EGFP). An AAV virus vector was used to deliver it into the striatum of C57 black mice, and the animals were treated with MPTP. The number of tyrosine hydroxylase-positive neurons in the substantia nigra was not changed on the rAAV-Apaf-1-DN-EGFP injected side compared with the noninjected side. We also examined the effect of a caspase 1 C285G mutant as a dominant negative inhibitor of caspase 1 (rAAV-caspase-1-DN-EGFP) in the same model. However, there was no difference in the number of tyrosine hydroxylase-positive neurons between the rAAV-caspase-1-DN-EGFP injected side and the noninjected side. These results indicate that delivery of Apaf-1-DN by using an AAV vector system can prevent nigrostriatal degeneration in MPTP mice, suggesting that it could be a promising therapeutic strategy for patients with Parkinson's disease. The major mechanism of dopaminergic neuronal death triggered by MPTP seems to be the mitochondrial apoptotic pathway.

A neonate with Löffler syndrome.

We report a neonate-boy with pulmonary infiltrates and peripheral blood eosinophilia. He was noted to have abnormal pulmonary infiltrates on a chest X-ray film taken on day 8 after birth when he had vomiting. He had not such symptoms as cough or dyspnea. In routine laboratory studies, eosinophilia was noted. Radiographic changes were transient and disappeared by day 25. Eosinophilia was also transient and gradually returned to normal level by 2 months. Löffler syndrome is very rare in neonates and its diagnosis is often made fortuitously likely in this case.

Usefulness of bronchoalveolar lavage for the diagnosis and treatment of refractory pneumonia in a patient with Kostmann syndrome, a severe congenital neutropenia.

UNLABELLED: An 11-year-old girl with Kostmann syndrome developed refractory pneumonia. Culture of oral discharge, throat-swab specimens, and blood could not identity the causative organism, and systemic antimicrobial therapy failed to achieve improvement. We then performed diagnostic bronchoalveolar lavage (BAL) and culture of BAL fluid (BALF) yielded Pseudomonas aeruginosa. Therapeutic BAL using gentamicin produced a striking improvement of her pneumonia. CONCLUSION: In immunocompromised children with pneumonia, BAL helps to identify the causative organism. If the patient is unresponsive to systemic antimicrobial therapy, BAL using antimicrobial agents is also worth trying.

Differentiation of transplanted bone marrow cells in the adult mouse brain.

BACKGROUND: Bone marrow transplantation is reportedly effective in preventing the progression of neurological deterioration in lysosomal storage disorders, although the mechanism underlying the therapeutic effects remains to be elucidated. Recent research on stem cell biology suggests that bone marrow cells contain nonhematopoietic stem cells, including brain precursor cells. To evaluate the contribution of bone marrow cells as carriers for cell and gene therapy of neurological disorders, we studied the fate of transplanted bone marrow cells in the adult mouse brain. METHODS: Bone marrow cells were genetically marked with a retroviral vector containing the green fluorescence protein gene and then transplanted into irradiated mice by either systemic infusion or direct injection. To identify cell types, brain sections were stained with specific antibodies against neuronal cell markers-neuron specific enolase for neurons, glial fibrillary acidic protein (GFAP) for astrocytes, carbonic anhydrase II (CAII) for oligodendrocytes, and ionized calcium binding adaptor molecule 1 (Iba1) for microglia-and then examined under a confocal microscope. RESULTS: Twenty-four weeks after systemic infusion, transplanted cells expressed Iba1 but none of the other brain cell markers. Conversely, 12 weeks after direct injection, transplanted cells were stained with antibodies against GFAP, CAII, and Iba1. CONCLUSIONS: Bone marrow contains cells capable of differentiating into oligodendrocytes, astrocytes, and microglia when exposed to the brain microenvironment. Autologous bone marrow cells may be useful as carriers for ex vivo gene therapy for lysosomal disorders with neurological symptoms.

Transduction of fibroblasts and CD34+ progenitors using a selectable retroviral vector containing cDNAs encoding arylsulfatase A and CD24.

Metachromatic leukodystrophy (MLD) is an autosomal recessive, inherited, lysosomal storage disease caused by a deficiency in arylsulfatase A (ASA). This disease is characterized by progressive demyelination leading to severe neurological symptoms. Allogenic bone marrow transplantation at an early stage of clinical course is only effective treatment currently available. Accordingly the corrective transfer of the ASA gene into hematopoietic stem cells is thought to be an important option for curative treatment for MLD. We have recently developed a selectable vector system based on ex vivo sorting of transduced cells (Migita et al. 1995). In this study, we applied this selectable system for development of MLD gene therapy. A bicistronic retroviral vector containing ASA cDNA and CD24 cDNA as a selectable marker gene was constructed. This vector was successfully transduced on fibroblasts from MLD patients, ASA activity was increased 7-fold compared to normal untransduced cells. PCR Southern analysis of hematopoietic colonies showed that transduction efficiency of CD34+ cells was 11-22%. However, after fluorescence-activated cell sorting using anti-CD24 antibody, 75-100% of colonies became vector positive. The sorting raised the ASA activity several fold compared to untransduced CD34+ progenitors. These results suggest that a bicistronic ASA vector containing a CD24 selectable marker could be a useful component of gene therapy for MLD.

Temporal criterion for behavior: orientation of the young Japanese flounder Paralichthys olivaceus.

When considering a behavioral pattern as a specific type of mechanism, an inherent problem is that it is difficult to determine to what extent the mechanism is programmed to behave selectively in individual situations. To probe this question further, we investigated the orientation of the body axis of the young Japanese flounder Paralichthys olivaceus. The pattern of the substrate and the orientation of neighboring fish were recognized as the determining factors for orientation in P. olivaceus. It was expected, therefore, that a group of individuals would exhibit a definite orientation pattern with respect to the striped pattern. However, the global orientation patterns on the striped substrate based on ten individuals could be classified into two categories: perpendicular and cross to the stripe pattern. This suggests that the substrate pattern and the surrounding individuals operated as distinct temporal criteria as stimuli for orientation. Analysis based on the local and global viewpoints reveals the temporality quantitatively.