Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation in patients with acute myeloid leukemia (AML)

Strategies that augment a GVL effect without increasing the risk of GVHD are required to improve the outcome after allogeneic stem cell transplantation (SCT). Azacitidine (AZA) up-regulates the expression of tumor Ags on leukemic blasts in vitro and expands the numbers of immunomodulatory T regulatory cells (Tregs) in animal models. Reasoning that AZA might selectively augment a GVL effect, we studied the immunologic sequelae of AZA administration after allogeneic SCT. Twenty-seven patients who had undergone a reduced intensity allogeneic transplantation for acute myeloid leukemia were treated with monthly courses of AZA, and CD8(+) T-cell responses to candidate tumor Ags and circulating Tregs were measured. AZA after transplantation was well tolerated, and its administration was associated with a low incidence of GVHD. Administration of AZA increased the number of Tregs within the first 3 months after transplantation compared with a control population (P = .0127). AZA administration also induced a cytotoxic CD8(+) T-cell response to several tumor Ags, including melanoma-associated Ag 1, B melanoma antigen 1, and Wilm tumor Ag 1. These data support the further examination of AZA after transplantation as a mechanism of augmenting a GVL effect without a concomitant increase in GVHD.     

Efficient detection of hereditary nonpolyposis colorectal cancer gene carriers by screening for tumor microsatellite instability before germline genetic testing

BACKGROUND & AIMS: The optimal strategy for the detection of hereditary nonpolyposis colorectal cancer (HNPCC) gene carriers remains uncertain. We evaluated whether microsatellite instability (MSI) analysis or MSH2 and MLH1 protein immunostaining of tumors will screen individuals efficiently for germline MSH2 and MLH1 testing. METHODS: We performed a case-series study of 114 eligible families enrolled in our high-risk colorectal cancer (CRC) registry. Medical history data were collected on probands and relatives. MSI analysis was performed on proband tumors, and MSH2 and MLH1 protein immunostaining was assessed. Denaturing gradient gel electrophoresis was used to identify germline MSH2 or MLH1 mutations in probands found to have tumors with high-frequency MSI. RESULTS: Tumor tissue and adequate clinical data were available in 109 of the 114 families. Amsterdam criteria and Bethesda guidelines were met by 23% and 70% of the families, respectively. High-frequency MSI was identified in the proband tumors in 47 of the 109 families (43%). Germline MSH2 and MLH1 gene testing was carried out in the probands of 32 of 47 families with MSI-H tumors. Mutations were detected in 16 families (9 in MSH2 and 7 in MLH1) and sequence variants of uncertain significance in 5 families (1 in MSH2 and 4 in MLH1). Germline mutations or sequence variants of uncertain significance were detected in 15 of 19 (79%) of our Amsterdam families and in 6 of 13 (46%) of our non-Amsterdam families with MSI-H tumors. MSH2 and MLH1 protein immunostaining was assessed in 38 of the 47 MSI-H tumors. Unequivocal loss of hMLH1 expression was found in 20 tumors and loss of MSH2 expression in 9 tumors. Corresponding loss of protein expression was seen in 17 of 18 (94%) of tumors from probands with germline mutations or variants. CONCLUSIONS: The detection of high-frequency MSI or the loss of MSH2 or MLH1 immunostaining in CRCs are both useful criteria for selecting high-risk patients who should be tested for germline mutations in MSH2 or MLH1.     

Allogeneic hematopoietic stem cell transplantation for chronic myeloid leukemia in Europe 2006: transplant activity, long-term data and current results. An analysis by the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT)

The introduction of imatinib mesylate has changed attitudes towards hematopoietic stem cell transplantation (HSCT) for chronic myeloid leukemia (CML). Information on the current use and results of HSCT is warranted. Data from 592 teams in 42 European countries described their use of HSCT for CML from 1990 to 2004. Outcomes were analyzed for 13,416 patients, with a median age of 36 years (range 1-71 years); 60% were male. The analysis considered three time cohorts, 1980 to 1990, 1991 to 1999 and 2000 to 2003. Survival, transplant-related mortality and relapse incidence were assessed at 20 years for the first cohort and compared at 2 years between the three cohorts. The numbers of HSCT for CML increased from 540 allogeneic HSCT in 1990 to 1,396 HSCT in 1999 and declined to 802 in 2004. One third of all patients and half of those with a low risk were alive at 20 years. Survival at 2 years has improved from 53% to 61% in the most recent years due to a reduction in transplant-related mortality from 41% to 30% in all patients and from 31% to 17% in low-risk patients. Stage, donor type, time interval, age and donor-recipient sex combination remain the main risk factors; patients with a risk score of 0 or 1 have a survival probability of 80% at 2 years. HSCT remains an important treatment option for patients with CML. The data describe the current status of this option and the outcome a patient can expect today. They provide an objective basis for decision making.     

Susac's syndrome: Intratympanic therapy for hearing loss and a review of the literature

Two cases of Susac's Syndrome are presented with a discussion of treatment modalities for the associated severe sensorineural deafness. Patients were managed with high dose oral steroids, anticoagulants and immunosuppressive drugs. The addition of intratympanic methylprednisolone injections were added to one patient's regimen with initial improvement but subsequent relapse and progression to profound deafness. The management of Susac's syndrome is difficult and still in need of innovative methods as the standard treatment continues to be ineffective in the long term. Laryngoscope, 119:141–144, 2009     

Postnatal lesion evidence against a primary role for the corpus callosum in mouse sociability

The BTBR T+tf/J (BTBR) strain is an inbred strain of mice that displays prominent social deficits and repetitive behaviors analogous to the defining symptoms of autism, along with complete congenital agenesis of the corpus callosum (CC). The BTBR strain is genetically distant from the widely used C57BL/6J (B6) strain, which exhibits high levels of sociability, a low level of repetitive behaviors, and an intact CC. Emerging evidence implicates compromised interhemispherical connectivity in some cases of autism. We investigated the hypothesis that the disconnection of CC fiber tracts contributes to behavioral traits in mice that are relevant to the behavioral symptoms of autism. Surgical lesion of the CC in B6 mice at postnatal day 7 had no effect on juvenile play and adult social approaches, and did not elevate repetitive self-grooming. In addition, LP/J, the strain that is genetically closest to the BTBR strain but has an intact CC, displayed juvenile play deficits and repetitive self-grooming similar to those seen in BTBR mice. These corroborative results offer evidence against the hypothesis that the CC disconnection is a primary cause of low sociability and a high level of repetitive behaviors in inbred mice. Our findings indicate that genes mediating other aspects of neurodevelopment, including those whose mutations underlie more subtle disruptions in white matter pathways and connectivity, are more likely to contribute to the aberrant behavioral phenotypes in the BTBR mouse model of autism.     

Inbred strain differences in prepulse inhibition of the mouse startle response

 Prepulse inhibition is the phenomenon in which a weak prepulse stimulus suppresses the response to a startling stimulus. Patients with schizophrenia have impaired prepulse inhibition which is thought to reflect dysfunctional sensorimotor gating mechanisms. To investigate the potential genetic basis for differences in sensorimotor gating, the responses of 13 inbred strains of mice were evaluated using the prepulse inhibition paradigm. Ten male mice from A/J, AKR/J, BALB/cByJ, BUB/BnJ, C3H/HeJ, C57BL/6J, C57BL/10J, DBA/2J, FVB/NJ, ST/bJ, 129/J, 129/SvJ, 129/SvEvTac inbred strains were tested for acoustic prepulse inhibition of acoustic and tactile startle responses. There was a wide range of responses among the inbred strains of mice. Exact strain distributions were determined for each combination of prepulse sound level and startle stimulus. In general, mice from the 129/SvEvTac, AKR/J, 129/J, and 129/SvJ strains displayed high levels of prepulse inhibition of both the acoustic and tactile startle responses. C57BL/6J, C57BL/10J and BUB/BnJ mice showed low levels of prepulse inhibition. There was also a wide range in the amplitude of the acoustic and tactile startle responses. C57BL/10J and FVB/NJ mice displayed the greatest startle responses and DBA/2J, 129/J and 129/SvJ had the poorest startle responses. There was no correlation between the level of prepulse inhibition and the amplitude of the startle response. These findings indicate that inbred strains of mice may be a useful tool to study the genetic basis of sensorimotor gating. Received:8 October 1996 / Final version: 10 December 1996     

Social deficits in BTBR T + tf/J mice are unchanged by cross-fostering with C57BL/6J mothers

Inbred strains of mice are useful model systems for studying the interactions of genetic and environmental contributions during neurodevelopmental stages. We recently reported an inbred strain, BTBR T + tf/J (BTBR), which, as compared to the commonly used C57BL/6J (B6) strain, displays lower social interactions as juveniles, lower social approach in adult ages, and higher levels of repetitive self-grooming throughout developmental stages. The present study investigated whether the early postnatal maternal environment contributes substantially to the unusually low expression of social behaviors and high self-grooming in BTBR as compared to B6. Within 24 h of birth, entire litters of pups were cross-fostered to either a dam of the same strain or a dam of the opposite strain. Control litters were left with their own mothers. Offspring were tested for juvenile play at postnatal day 21 ± 1, for sociability at 8 weeks of age in an automated three-chambered social approach test, and for self-grooming at 9–11 weeks of age. Results indicate that deficits in play behaviors in juvenile BTBR pups were not rescued by a B6 maternal environment. Similarly, a BTBR maternal environment did not induce play deficits in B6 pups. Cross-fostering had no effect on sociability scores in adults. The high self-grooming in BTBR and low self-grooming in B6 were not affected by maternal environment. These findings favor a genetic interpretation of the unusual social behaviors and self-grooming traits of BTBR, and support the use of the BTBR inbred strain as a mouse model to study genetic mechanism of autism.     

Intracranial pressure in childhood cerebral malaria

Lumbar punctures were performed in 40 Gambian children with acute cerebral malaria aged between 18 months and 10 years. The mean opening pressure was elevated in 32 (80%) of the children, but was not significantly different in the 14 fatal cases compared with survivors: 110 (standard deviation 71) versus 131 (58) mm of cerebrospinal fluid respectively. Cerebral perfusion pressures were also similar in the 2 groups: 64 (20) mm Hg versus 64 (11) mm Hg respectively. There was no clear clinical evidence of raised intracranial pressure, and no evidence of deterioration immediately following lumbar puncture. Nevertheless brain swelling, and consequent brain-stem compression, may contribute to a fatal outcome in cerebral malaria--particularly in those children who die from sudden respiratory arrest. A prospective evaluation of osmotic agents in childhood cerebral malaria seems to be justified.     

Burden, features, and outcome of neurological involvement in acute falciparum malaria in Kenyan children

Context  Plasmodium falciparum appears to have a particular propensity to involve the brain but the burden, risk factors, and full extent of neurological involvement have not been systematically described. Objectives  To determine the incidence and describe the clinical phenotypes and outcomes of neurological involvement in African children with acute falciparum malaria. Design, Setting, and Patients  A review of records of all children younger than 14 years admitted to a Kenyan district hospital with malaria from January 1992 through December 2004. Neurological involvement was defined as convulsive seizures, agitation, prostration, or impaired consciousness or coma. Main Outcome Measures  The incidence, pattern, and outcome of neurological involvement. Results  Of 58 239 children admitted, 19 560 (33.6%) had malaria as the primary clinical diagnosis. Neurological involvement was observed in 9313 children (47.6%) and manifested as seizures (6563/17 517 [37.5%]), agitation (316/11 193 [2.8%]), prostration (3223/15 643 [20.6%]), and impaired consciousness or coma (2129/16 080 [13.2%]). In children younger than 5 years, the mean annual incidence of admissions with malaria was 2694 per 100 000 persons and the incidence of malaria with neurological involvement was 1156 per 100 000 persons. However, readmissions may have led to a 10% overestimate in incidence. Children with neurological involvement were older (median, 26 [interquartile range {IQR}, 15-41] vs 21 [IQR, 10-40] months; P<.001), had a shorter duration of illness (median, 2 [IQR, 1-3] vs 3 [IQR, 2-3] days; P<.001), and a higher geometric mean parasite density (42.0 [95% confidence interval {CI}, 40.0-44.1] vs 30.4 [95% CI, 29.0-31.8] x 10³/µL; P<.001). Factors independently associated with neurological involvement included past history of seizures (adjusted odds ratio [AOR], 3.50; 95% CI, 2.78-4.42), fever lasting 2 days or less (AOR, 2.02; 95% CI, 1.64-2.49), delayed capillary refill time (AOR, 3.66; 95% CI, 2.40-5.56), metabolic acidosis (AOR, 1.55; 95% CI, 1.29-1.87), and hypoglycemia (AOR, 2.11; 95% CI, 1.31-3.37). Mortality was higher in patients with neurological involvement (4.4% [95% CI, 4.2%-5.1%] vs 1.3% [95% CI, 1.1%-1.5%]; P<.001). At discharge, 159 (2.2%) of 7281 patients had neurological deficits. Conclusions  Neurological involvement is common in children in Kenya with acute falciparum malaria, and is associated with metabolic derangements, impaired perfusion, parasitemia, and increased mortality and neurological sequelae. This study suggests that falciparum malaria exposes many African children to brain insults.      

Evaluation of expressive writing for postpartum health: a randomised controlled trial

Pregnancy, birth and adjusting to a new baby is a potentially stressful time that can negatively affect the health of women. There is some evidence that expressive writing can have positive effects on psychological and physical health, particularly during stressful periods. The current study aimed to evaluate whether expressive writing would improve women’s postpartum health. A randomized controlled trial was conducted with three conditions: expressive writing (n?=?188), a control writing task (n?=?213), or normal care (n?=?163). Measures of psychological health, physical health and quality of life were measured at baseline (6–12 weeks postpartum), 1 and 6 months later. Ratings of stress were taken before and after the expressive writing task. Intent-to-treat analyses showed no significant differences between women in the expressive writing, control writing and normal care groups on measures of physical health, anxiety, depression, mood or quality of life at 1 and 6 months. Uptake and adherence to the writing tasks was low. However, women in the expressive writing group rated their stress as significantly reduced after completing the task. Cost analysis suggest women who did expressive writing had the lowest costs in terms of healthcare service use and lowest cost per unit of improvement in quality of life. Results suggest expressive writing is not effective as a universal intervention for all women 6–12 weeks postpartum. Future research should examine expressive writing as a targeted intervention for women in high-risk groups, such as those with mild or moderate depression, and further examine cost-effectiveness.Clinical trial registration number ISRCTN58399513 www.isrctn.com