Advancing early detection of suicide? A national study examining socio-demographic factors, antecedent stressors and long-term history of self-harm.

BACKGROUND: A range of factors including mental disorders, adverse events and history of self-harm are associated with suicide risk. Further examination is needed of the characteristics of suicides which occur without established risk factors, using national surveillance systems. METHODS: Data on all suicides in Ireland from 2015 to 2017 were drawn from the Irish Probable Suicide Deaths Study (IPSDS). Variables examined included socio-demographics, psychiatric history and precipitant stressors. Suicide data were linked with data on prior self-harm from the National Self-Harm Registry Ireland (NSHRI). Latent Class Analysis (LCA) was used to identify sub-groups of suicide cases. RESULTS: Of the 1809 individuals who died by suicide, 401 (22.2 %) had a history of hospital-treated self-harm. Four distinct profiles of suicides were identified. One group was marked by high levels of prior self-harm and mental health conditions. Two of the groups included few individuals with a history of self-harm but had notably high levels of mental health conditions. These two groups had relatively high levels of reported chronic pain or illness but differed in terms of socio-demographics. The final group, predominantly male, had markedly low levels of mental health conditions or self-harm but high levels of personal stressors and substance use. LIMITATIONS: The use of coronial data may be limited by bias in the collecting of information from the deceased's family members. CONCLUSIONS: A sub-group of suicide cases exists without any psychiatric or self-harm history but with salient occupational or health-related proximal stressors. Suicide prevention interventions should include occupational settings and should promote mental health literacy.

A 2-year longitudinal evaluation of the impact of the COVID-19 pandemic on individuals with pre-existing anxiety disorders.

OBJECTIVES: To examine if the COVID-19 pandemic is associated with a differential effect over a 2-year time period in relation to its psychological and social impact on patients with established anxiety disorders. METHODS: Semi-structured interviews were conducted with 21 individuals attending the Galway-Roscommon Mental Health Services in Ireland with an ICD-10 diagnosis of an anxiety disorder. Interviews occurred at three time-points over a 2-year period to determine the impact of the COVID-19 pandemic and associated restrictions on anxiety and depressive symptoms, social and occupational functioning, and quality of life. RESULTS: No statistical difference in symptomatology was noted between the three time-points in relation to anxiety symptoms as measured utilising psychometric rating scales (Beck Anxiety Inventory (BAI), Hamilton Anxiety Rating Scale (HARS) or Likert Scale measures). The greatest impact of COVID-19 at all time-points related to social functioning and quality of life. Significant variability was noted for individual participants. Qualitative analysis noted a tentative optimism for the future in the setting of vaccination and societal re-opening. Fear of re-emerging anxiety symptoms with the removal of societal restrictions was noted. CONCLUSIONS: No significant overall change in symptomatology or functioning over time was noted for individuals with pre-existing anxiety disorders, however variability was demonstrated, with some individuals describing ongoing anxiety, social isolation and concern for their future. A strong theme of hope for the future and less concern regarding the COVID-19 pandemic was evident; however tailored supports including the utilisation of tele-psychiatry is suggested, particularly for those experiencing increased anxiety with the removal of societal restrictions.

Providers' perspectives on the reproductive decision-making of BRCA-positive women.

BACKGROUND: Reproductive decision-making is difficult for BRCA-positive women. Our objective was to assess the complexities of decision-making and identify decisional supports for patients and providers when discussing reproductive options prior to risk-reducing salpingo-oophorectomy (RRSO). METHODS: This study was of qualitive design, using data collection via semi-structured interviews conducted from November 2018 to October 2020. Individuals were included if they were identified to provide care to BRCA-positive women. In total, 19 providers were approached and 15 consented to participate. Providers were recruited from three clinics in Toronto, Ontario located at academic centers: [1] A familial ovarian cancer clinic, [2] A familial breast cancer clinic and [3] A fertility clinic, all of which treat carriers of the BRCA1/BRCA2 genetic mutation. The interview guide was developed according to the Ottawa Decision Support Framework and included questions regarding reproductive options available to patients, factors that impact the decision-making process and the role of decisional support. Interviews were transcribed and transcripts were analyzed thematically using NVIVO 12. RESULTS: Providers identified three major decisions that reproductive-aged women face when a BRCA mutation is discovered: [1] "Do I want children?"; [2] "Do I want to take the chance of passing on this the mutation?"; and [3] "Do I want to carry a child?" Inherent decision challenges that are faced by both providers and patients included difficult decision type, competing options, scientifically uncertain outcomes, and challenging decision timing. Modifiable decisional needs included: inadequate knowledge, unrealistic expectations, unclear values and inadequate support or resources. Identified clinical gaps included counselling time constraints, lack of reliable sources of background information for patients or providers and need for time-sensitive, geographically accessible, and centralized care. CONCLUSION: Our study identified a need for a patient information resource that can be immediately provided to patients who carry a BRCA genetic mutation. Other suggestions for clinical practice include more time during consultation appointments, adequate follow-up, value-centric counseling, access to psychosocial support, and a specialized decisional coach.

Choosing Wisely Canada: Canadian fertility and andrology society's list of top items physicians and patients should question in fertility medicine.

PURPOSE: To create a Choosing Wisely Canada list of the top 5 diagnostic and therapeutic interventions that should be questioned in Reproductive Endocrinology and Infertility in Canada. METHODS: The Canadian Fertility and Andrology Society (CFAS) National Working Group developed an initial list of recommendations of diagnostic and therapeutic interventions that are commonly used, but are not supported by evidence, and could expose patients to unnecessary harm. These were chosen based on their prevalence, cost, potential for harm, and quality of supporting evidence. A modified Delphi consensus was used over 5 rounds to generate ideas, review supporting evidence, assess clinical relevance, estimate recommendation impact and narrow the recommendations list to 5 items. RESULTS: Fifty unique ideas were first proposed by the working group, and after 5 rounds including a survey of Canadian Fertility and Andrology Society (CFAS) members, the final list of recommendations was created, including topics related to unnecessary investigations and interventions for patients with infertility and recurrent pregnancy loss, and those undergoing IVF. In this article, we describe not only the Delphi process used to determine the list, but also provide a summary of the evidence behind each of the final recommendations. CONCLUSIONS: The list of five recommendations highlights opportunities to initiate conversations between clinicians and patients about the risks, benefits, harms and costs of unnecessary fertility treatments and procedures in a Canadian context.

COVID-19 and its effect on emergency presentations to a tertiary hospital with self-harm in Ireland.

OBJECTIVES: This study aimed to assess the impact of COVID-19 on presentations to an acute hospital with self-harm. METHODS: All presentations to University Hospital Galway with self-harm were assessed during the peak period of the coronavirus crisis in Ireland, over the 3 months from 1 March to 31 May 2020. These data were compared with presentations in the same months in the 3 years preceding (2017-2019). Data were obtained from the anonymised service database. RESULTS: This study found that in 2020, the rate of presentation with self-harm dropped by 35% from March to April and rose by 104% from April to May, peaking from mid-May. When trends over a 4-year period were examined, there was a significantly higher lethality of attempt (p < 0.001), and significant differences in diagnosis (p = 0.031) in 2020 in comparison with the three previous years. The increased lethality of presentations remained significant after age and gender were controlled for (p = 0.036). There were also significant differences in the underlying psychiatric diagnoses (p = 0.018), notably with a significant increase in substance misuse disorders presenting during the 2020 study period. CONCLUSIONS: COVID-19 showed a reduction in self-harm presentations initially, followed by a sharp increase in May 2020. If a period of economic instability follows as predicted, it is likely that this will further impact the mental health of the population, along with rates of self-harm and suicidal behaviours. There is a need for research into the longer-term effect of COVID-19 and lockdown restrictions, especially with respect to self-harm.

Ghrelin receptor (GHS-R1A) antagonism alters preference for ethanol and sucrose in a concentration-dependent manner in prairie voles.

Ghrelin receptor (GHS-R1A) activity has been implicated in reward for preferred foods and drugs; however, a recent study in our laboratory indicated that GHS-R1A antagonism reduces early (after only four exposures) preference for 20% ethanol, but not 10% sucrose in prairie voles, a genetically diverse high alcohol-consuming species. The purpose of the present study was to determine if these effects of GHS-R1A antagonism depend on the concentration of the rewarding solution being consumed. We first characterized preference for varying concentrations of ethanol and sucrose. Two bottle tests of each ethanol concentration versus water indicated that 10% and 20% ethanol are less preferred than 3% ethanol, and a follow-up direct comparison of 10% vs. 20% showed that 10% was preferred over 20%. Direct two-bottle comparisons of 2% vs. 5%, 2% vs. 10%, and 5% vs. 10% sucrose showed that 10% sucrose was most preferred, and 2% sucrose was least preferred. The effects of JMV 2959, a GHS-R1A antagonist, on preference for each concentration of ethanol and sucrose were then tested. In a between groups design prairie voles were given four two-hour drinking sessions in which animals had access to ethanol (3, 10, or 20%) versus water, or sucrose (2, 5, or 10%) versus water every other day. Saline habituation injections were given 30 min before the third drinking session. JMV 2959 (i.p.; 9 mg/kg), a GHS-R1A antagonist, or saline was administered 30 min before the fourth drinking session. JMV 2959 reduced preference for 20% ethanol and 2% sucrose, but had no significant effect on preference for the other ethanol and sucrose concentrations. These data identify constraints on the role of GHS-R1A in early preference for ethanol and sucrose, and the concentration-dependent effects suggest strong preference for a reward may limit the importance of GHS-R1A activity.

Optimized administration regimen of lopinavir for a myocardial ischaemia reperfusion study in Sprague-Dawley rats.

Pharmacokinetics of drugs may differ between small and large mammals (including humans); therefore, drug testing in animal models must be carefully designed. Sprague-Dawley rats were used in cardiac experiments, during which the lopinavir concentration in serum had to match human therapeutic levels (4-10 µg/mL). Lopinavir was administered as a co-formulated drug of lopinavir and ritonavir. It was found that after a single administration of a standard human peroral dose (lopinavir 13.3 mg/kg of body weight), the serum concentration of lopinavir was only one-tenth of the target level. It remained below the minimum target level even after 10-fold the standard dose was administered. After initial pilot tests, a dose escalation study was conducted with oral doses 10- and 15-fold the standard clinical dose of lopinavir (i.e. 133 and 200 mg/kg, respectively). A second administration 2 h later effectively increased and maintained higher concentrations during the experimental ischaemia and reperfusion periods. A dose-dependent increase in serum concentration of the drug was observed. Thus, the target therapeutic serum level of lopinavir in the rats was achieved by administrating 10- to 15-fold the standard human dose twice, separated by a 2 h interval.

Mental illness training on the Internet for nurse aides: a replication study.

Internet training courses for nurse aides (NAs) in long-term care facilities (LTCs) have been shown to be effective. Little is known, however, about Internet training effects on NAs in a non-research context, or about continued utilization of an available training programme. In this research, a replication study was conducted with the Internet training programme Caring Skills: Working with Mental Illness. Three LTCs provided the training to all NAs, each within a 1-month interval scheduled during consecutive months. Supervisors were interviewed subsequently about their experiences organizing and supervising the training. Participants in all three LTCs showed positive pre-post-tests effects with large effect sizes on situational knowledge and self-efficacy, and knowledge about mental illness. Users rated the programme highly, and they indicated that it would improve quality of their resident care. Supervisors praised the training, and they said NAs were using recommended training behaviours. Although available to all staff, nursing and other staff made little use of the training in subsequent months. Training for NAs on the Internet thus appears feasible, and it is perceived to be beneficial for resident care. Plans for continued utilization and dissemination of best practices to other staff, however, should be integrated when planning for staff training on the Internet.

Factors associated with deliberate self-harm among Irish adolescents.

BACKGROUND: Deliberate self-harm (DSH) is a major public health problem, with young people most at risk. Lifetime prevalence of DSH in Irish adolescents is between 8% and 12%, and it is three times more prevalent among girls than boys. The aim of the study was to identify the psychological, life-style and life event factors associated with self-harm in Irish adolescents. METHOD: A cross-sectional study was conducted, with 3881 adolescents in 39 schools completing an anonymous questionnaire as part of the Child and Adolescent Self-harm in Europe (CASE) study. There was an equal gender balance and 53.1% of students were 16 years old. Information was obtained on history of self-harm life events, and demographic, psychological and life-style factors. RESULTS: Based on multivariate analyses, important factors associated with DSH among both genders were drug use and knowing a friend who had engaged in self-harm. Among girls, poor self-esteem, forced sexual activity, self-harm of a family member, fights with parents and problems with friendships also remained in the final model. For boys, experiencing bullying, problems with schoolwork, impulsivity and anxiety remained. CONCLUSIONS: Distinct profiles of boys and girls who engage in self-harm were identified. Associations between DSH and some life-style and life event factors suggest that mental health factors are not the sole indicators of risk of self-harm. The importance of school-related risk factors underlines the need to develop gender-specific initiatives in schools to reduce the prevalence of self-harm.

Expression of immune-related molecules is downregulated in twitcher mice following bone marrow transplantation.

Twitcher (twi/twi) is a murine model of a human genetic demyelinating disease, globoid cell leukodystrophy (Krabbe disease). The affected mice usually die before reaching age 45 days, having demyelination associated with extensive glial activation. The twi/twi mice that receive wild-type bone marrow transplantation (BMT) survive up to 3 times longer with improved pathology. We hypothesize that immune-related molecules such as cytokines and chemokines are partly responsible for the demyelination in twi/twi, and that the decrease in the expression of such molecules following BMT contributes to clinico-pathological improvement. Cells expressing TNF-alpha, MCP-1, and MIP-1beta were conspicuous in the twi/twi CNS accompanied by infiltration of Ia+ and CD8+/CD3- hematogenous cells. These cells decreased gradually after BMT TNF-alpha mRNA and mRNA of C-C chemokine families, including MCP-1, IP-10, MIP-1alpha, MIP-1beta, and RANTES, were upregulated in the twi/twi CNS but downregulated gradually following BMT. In twi/twi that survived to 20 wk of age, cells expressing TNF-alpha, MCP-1, MIP-1beta, Ia, or CD8 were hardly detected and pathology was clearly improved. These results are consistent with the hypothesis that cytokine expression in glial cells contributes (to some extent) to the pathogenesis of demyelinating lesions in the twi/twi mice.

Recent studies with eplerenone, a novel selective aldosterone receptor antagonist.

Activation of the renin-angiotensin-aldosterone system is associated with unsatisfactory outcomes in patients with hypertension and congestive heart failure, in that activation of this system is correlated strongly with both the incidence and extent of end-organ damage. Despite the availability of the angiotensin-converting enzyme inhibitors and the AT1 receptor antagonists, unblocked aldosterone levels remain an important risk factor for cardiovascular disease progression. New preclinical data generated over the past few years strongly support the hypothesis that aldosterone has important deleterious effects on the cardiovascular system independent of the classical action of this hormone on renal epithelial cells. The new selective aldosterone receptor antagonist eplerenone has been shown to produce significant cardioprotective effects in experimental models of cardiovascular disease. Early clinical testing suggests that eplerenone may have important therapeutic benefit in the treatment of hypertension and heart failure.

Absence of macrophage-inflammatory protein-1alpha delays central nervous system demyelination in the presence of an intact blood-brain barrier.

Chemokines are small chemotactic cytokines that modulate leukocyte recruitment and activation during inflammation. Here, we describe the role of macrophage inflammatory protein-1alpha (MIP-1alpha) during cuprizone intoxication, a model where demyelination of the CNS features a large accumulation of microglia/macrophage without T cell involvement or blood-brain barrier disruption. RNase protection assays showed that mRNA for numerous chemokines were up-regulated during cuprizone treatment in wild-type, C57BL/6 mice. RANTES, inflammatory protein-10, and monocyte chemoattractant protein-1 showed greatest expression with initiation of insult at 1-2 wk of treatment, whereas MIP-1alpha and beta increased later at 4-5 wk, coincident with peak demyelination and cellular accumulation. The function of MIP-1alpha during demyelination was tested in vivo by exposing MIP-1alpha knockout mice (MIP-1alpha(-/-)) to cuprizone and comparing pathology to wild-type mice. Demyelination at 3.5 wk of treatment was significantly decreased in MIP-1alpha(-/-) mice ( approximately 36% reduction), a result confirmed by morphology at the electron microscopic level. The delay in demyelination was correlated to apparent decreases in microglia/macrophage and astrocyte accumulation and in TNF-alpha protein levels. It was possible that larger effects of the MIP-1alpha deficiency were being masked by other redundant chemokines. Indeed, RNase protection assays revealed increased expression of several chemokine transcripts in both untreated and cuprizone-treated MIP-1alpha(-/-) mice. Nonetheless, despite this possible compensation, our studies show the importance of MIP-1alpha in demyelination in the CNS and highlight its effect, particularly on cellular recruitment and cytokine regulation.

Phagocytosis and clearance of apoptotic cells is mediated by MER.

Apoptosis is fundamental to the development and maintenance of animal tissues and the immune system. Rapid clearance of apoptotic cells by macrophages is important to inhibit inflammation and autoimmune responses against intracellular antigens. Here we report a new function for Mer, a member of the Axl/Mer/Tyro3 receptor tyrosine kinase family. mer(kd) mice with a cytoplasmic truncation of Mer had macrophages deficient in the clearance of apoptotic thymocytes. This was corrected in chimaeric mice reconstituted with bone marrow from wild-type animals. Primary macrophages isolated from mer(kd) mice showed that the phagocytic deficiency was restricted to apoptotic cells and was independent of Fc receptor-mediated phagocytosis or ingestion of other particles. The inability to clear apoptotic cells adequately may be linked to an increased number of nuclear autoantibodies in mer(kd) mice. Thus, the Mer receptor tyrosine kinase seems to be critical for the engulfment and efficient clearance of apoptotic cells. This has implications for inflammation and autoimmune diseases such as systemic lupus erythematosus.

HIPPA privacy regulations: practical information for physicians.

After much debate and controversy, the Bush administration announced on April 12, 2001, that it would implement the Health Insurance Portability and Accountability Act (HIPAA) privacy regulations issued by the Clinton administration in December of 2000. The privacy regulations became effective on April 14, 2001. Although the regulations are considered final, the Secretary of the Department of Health and Human Services has the power to modify the regulations at any time during the first year of implementation. These regulations affect how a patient's health information is used and disclosed, as well as how patients are informed of their privacy rights. As "covered entities," physicians have until April 14, 2003, to comply fully with the HIPAA privacy regulations, which are more than 1,500 pages in length. This article presents a basic overview of the new and complex regulations and highlights practical information about physicians' compliance with the regulations. However, this summary of the HIPAA privacy regulations should not be construed as legal advice or an opinion on specific situations. Please consult an attorney concerning your compliance with HIPAA and the regulations promulgated thereunder.

Growing pains: can any willing provider laws overcome the challenges of the teenage years?

Any willing provider laws were first enacted in the late 1980's as a way to combat the exclusion of providers from insurer and Health Maintenance Organization (HMO) network panels. Generally, the laws provided that insurers and managed care organizations had to admit to their provider panels any provider who was willing to accept the entity's terms and conditions for participation. These laws face two significant challenges today: how to overcome Employee Retirement Income Security Act (ERISA) preemption and the fact that the legislatures either failed to put limits on the terms and conditions that could be imposed or did not define what reasonable terms and conditions were. This article gives a basic overview of any willing provider laws, the ERISA statutory and case law that affects them, and the current problem of what terms and conditions imposed upon providers can be considered reasonable. It also summarizes many of the current any willing provider laws and notes which laws among those listed have been held by courts to be preempted by ERISA. Efforts have been taken to make this article current and accurate; however, they should not be construed as legal advice or an opinion on specific situations. Because of the rapid pace with which these laws and the cases affecting them change, you should consult an attorney concerning the existence and validity of any willing provider and similar laws in your state.

T-lymphocyte production of macrophage inflammatory protein-1alpha is critical to the recruitment of CD8(+) T cells to the liver, lung, and spleen during graft-versus-host disease.

To investigate the mechanism by which macrophage inflammatory protein-1alpha (MIP-1alpha) affects graft-versus-host disease (GVHD), the expression and function of MIP-1alpha in 2 murine models of GVHD were evaluated. In irradiated class I and class II disparate recipients, the expression of messenger RNA (mRNA) and protein for MIP-1alpha was significantly increased in GVHD target organs after transfer of allogeneic lymphocytes compared to syngeneic lymphocytes. When lymphocytes unable to make MIP-1alpha were transferred, there was a decrease in the production of MIP-1alpha in the liver, lung, and spleen of bm1 (B6.C-H2(bm1)/By) and bm12 (B6.C-H2(bm12)/KhEg) recipients compared to the transfer of wild-type splenocytes. At day 6 there was a 4-fold decrease in the number of transferred CD8(+) T cells in the lung and approximately a 2-fold decrease in the number of CD8(+) T cells in the liver and spleen in bm1 recipients after transfer of MIP-1alpha-deficient (MIP-1alpha(-/-)) splenocytes compared to wild-type (MIP-1alpha(+/+)) splenocytes. These differences persisted for 13 days after splenocyte transfer. In contrast, the number of donor CD4(+) T cells found in the liver and lung was significantly increased after the transfer of MIP-1alpha(-/-) compared to wild-type splenocytes in bm12 recipients from day 6 through day 10. Thus, the transfer of allogeneic T cells was associated with the enhanced expression of MIP-1alpha in both a class I and class II mismatch setting. However, the increased expression only led to enhanced recruitment of CD8(+), but not CD4(+), donor T cells. Production of MIP-1alpha by donor T cells is important in the occurrence of GVHD and functions in a tissue-dependent fashion.

Falsely elevated INRs in warfarin-treated patients with the lupus anticoagulant.

The Lupus Anticoagulant (L.A.) is an antibody that prolongs the clotting time of in-vitro laboratory tests by binding phospholipid in the test system. Patients with the L.A. are at increased risk for development of venous and arterial thrombosis but not hemorrhage. Therefore, many patients with the L.A. are being treated with warfarin sodium to prevent reoccurrence of thrombosis. This oral anticoagulant therapy is traditionally regulated by periodic determination of the Prothrombin Time (PT). This test is usually unaffected by the L.A. However, we have recently identified a small series of patients with the L.A. in whom the PT is affected by the L.A. This interference is manifest as an artifactually increased International Normalized Ratio (INR). These patients were identified by failure to achieve significant correction of the PT with addition of an equal volume of normal plasma to the patient plasma and a Factor X level discordant with the PT INR Interference in determination of the PT by the L.A. was found to occur in 6.5% of patients identified with the L.A. by our laboratory. It is suggested that patients with this complication of anticoagulant therapy be monitored by measurement of Factor X levels rather than the PT INR. Failure to recognize this complication may result in inadequate anticoagulation and recurrent thrombosis.

Development and comparison of two 3T3-L1 adipocyte models of insulin resistance: increased glucose flux vs glucosamine treatment.

Insulin resistance can be induced in vivo by intravenous infusion of glucosamine or in cells by incubation with glucosamine. However, a publication (Hresko, R. C., et al. (1998) J. Biol. Chem. 273, 20658-20668) suggests a trivial explanation of glucosamine-induced insulin resistance whereby intracellular ATP pools are depleted presumably due to the phosphorylation of glucosamine to glucosamine 6-phosphate, a hexosamine pathway intermediate. The reduced ATP level impaired insulin receptor (IR) autophosphorylation and tyrosine kinase activity toward substrates. The present work describes the development and comparison of two methods for inducing insulin resistance, by treating 3T3-L1 adipocytes overnight using either 25 mM glucose/5 nM insulin or 2 mM glucosamine. Under these conditions basal glucose transport rates were comparable with controls. Insulin-stimulated 2-deoxyglucose uptake, however, was reduced by approximately 45% in response to both high glucose/insulin and glucosamine treatment, relative to control cells. The total relative amounts of the insulin-responsive glucose transporter, Glut4, remained constant under both treatment conditions. The relative phosphotyrosine (Tyr(P)) contents of the insulin receptor and its substrate 1 (IRS-1) were assessed in whole cell homogenates. With both methods to induce insulin resistance, IR/IRS-1 Tyr(P) levels were virtually indistinguishable from those in control cells. Insulin-stimulated phosphorylation of Akt on Ser(473) was not impaired in insulin-resistant cells. Furthermore, the relative Tyr(P) content of the PDGF receptor was comparable in high glucose/insulin- or glucosamine-treated 3T3-L1 adipocytes upon subsequent challenge with PDGF. Finally, the relative amounts of glutamine:fructose-6-phosphate amidotransferase and O-linked N-acetylglucosamine transferase, two important hexosamine pathway enzymes, were similar in both treatments when compared with controls. Thus, 3T3-L1 adipocytes can be used as a model system for studying insulin resistance induced by increased influx of glucose. Under appropriate experimental conditions, glucosamine treatment can mimic the effects of increased glucose flux without impairment of tyrosine phosphorylation-based signaling.

Distribution and characterization of GFP(+) donor hematogenous cells in Twitcher mice after bone marrow transplantation.

The twitcher mouse is a murine model of globoid cell leukodystropy, a genetic demyelinating disease caused by a mutation of the galactosylceramidase gene. Demyelination of the central nervous system commences around 20 postnatal days. Using GFP-transgenic mice as donors, the distribution of hematogenous cells after bone marrow transplantation was investigated in the twitcher mice. Bone marrow transplantation was carried out at 8 postnatal days. In twitcher chimeric mice examined before 30 postnatal days, numerous GFP(+) cells were detected in spleen and peripheral nerve but only a few were detected in the liver, lung, and spinal white matter. In contrast, at 35 to 40 postnatal days when demyelination is evident, many GFP(+) cells with ameboid form were detected in the white matter of the spinal cord, brainstem, and cerebrum. Approximately half of these GFP(+) cells were co-labeled with Mac-1. In twitcher chimeric mice examined after 100 postnatal days, the majority of GFP/Mac-1 double-positive cells displayed the morphological features of ramified microglia with fine delicate processes and was distributed diffusely in both gray and white matter. These results suggest that a significant number of donor hematogenous cells are able to infiltrate into the brain parenchyma, repositioning themselves into areas previously occupied by microglia, and to ameliorate lethality.