Overexpression of Arginase 1 is linked to DNMT3A and TET2 mutations in lower-grade myelodysplastic syndromes and chronic myelomonocytic leukemia.

Immune dysregulation is a common feature of myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML), particularly in early stages. However, the genetic basis remains poorly understood. We recently reported that macrophages from mice deficient in tet methylcytosine dioxygenase 2 (Tet2), a model of MDS/CMML, are hyperinflammatory and have increased expression of arginase 1 (Arg1). In macrophages and myeloid derived suppressor cells (MDSCs) expression of Arg1 contributes to T-cell suppression and immune evasion by L-arginine depletion, in the setting of chronic inflammation and cancer. Since human MDS and CMML are driven by TET2 mutations and associated with chronic inflammation, we hypothesized that arginase enzymatic activity and ARG1 expression would be increased in human MDS/CMML bone marrow. Elevated arginase activity was observed in bone marrow mononuclear cells of MDS and CMML patients with lower-grade features. Immunohistochemical studies confirmed that myelomonocytic cells overexpress ARG1. Additionally, mutations in the epigenetic regulators TET2 and DNMT3A corresponded to high ARG1 expression and activity. These findings suggest ARG1 is a biomarker of immune dysregulation in early MDS and CMML. Recent murine findings have implicated Tet2 and Dnmt3a in regulation of innate immunity. Our study suggests similar changes may be driven by human TET2 and DNMT3A mutations.

Prolonged clinical remissions in patients with relapsed or refractory follicular lymphoma treated with autologous stem cell transplantation incorporating rituximab.

Three sequential phase II trials were conducted with different immunotherapy approaches to enhance the outcome of autologous transplant (high-dose therapy and autologous stem cell transplantation (HDT/ASCT)) for recurrent follicular lymphoma. Seventy-three patients were enrolled from 1996 to 2009. Patients received HDT/ASCT combined with (1) interferon-α 3 MU/m(2) subcutaneously (SC) three times per week (TIW) for 2 years post-ASCT, (2) rituximab (R) 375 mg/m(2) for in vivo purging 3-5 days pre-stem cell collection and 2 × 4 weekly R at 2 and 6 months post-ASCT, respectively, or (3) three infusions of R pre-stem cell collection followed by 6× R weekly and interferon-α 3 MU/m(2) SC TIW. Although not statistically significant, progression-free survival (PFS) for patients who received rituximab was 56.4 and 49.1% at 5 and 10 years compared to 36 and 21% in those who did not receive rituximab. Molecular relapse post-HDT/ASCT was the strongest predictor of PFS in a multivariate analysis. Molecular relapse was coincident with or preceded clinical relapses in 84% of patients who relapsed­median of 12 months (range 0-129 months). Adverse events included secondary malignancy, transformation to diffuse large B cell lymphoma, prolonged mostly asymptomatic hypogammaglobulinemia, and pulmonary fibrosis. The long-term toxicity profile must be considered when selecting patients for this treatment.

Livestock bedding effects on two species of parasitoid wasps of filth flies.

Choice of livestock bedding has been shown to affect density of filth fly maggots. Here, laboratory experiments indicate that bedding type can also affect natural enemies of the flies, specifically the parasitoid wasps Spalangia endius Walker and Urolepis rufipes (Ashmead) (Hymenoptera: Pteromalidae) parasitizing a natural host, the house fly Musca domestica L. (Diptera: Muscidae). For both parasitoid species, when females parasitized hosts under bedding, cedar shavings resulted in fewer parasitoids compared with pine shavings, but pine shavings did not differ from wood pellets and corn cob pellets. In the absence of exposure to hosts, longevity of adult females was reduced in cedar shavings compared with pine shavings and pellets. In contrast to the effects on parasitization and on adult survival, shavings treatment had no significant effect on the number of parasitoids or flies that emerged when hosts were not exposed to shavings until after parasitization.

Validation of a scoring system to establish the probability of myelodysplastic syndrome in patients with unexplained cytopenias or macrocytosis.

Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders primarily seen in the elderly that are characterized by ineffective hematopoiesis and a propensity to develop AML. Clinicians may be hesitant to refer older patients with unexplained cytopenias and/or macrocytosis for a bone marrow biopsy (BM), and consequently undiagnosed patients may be deprived access to effective treatments. Previously, we described factors which were independently predictive of a diagnosis of MDS at time of bone marrow: age ≥65, mean cell volume (MCV), red cell distribution width (RDW), and lactate dehydrogenase (LDH), and suggested a scoring system to calculate the post-test probability of MDS [1]. In this study we validate this scoring system in a cohort of 313 individuals who underwent bone marrow examinations for the investigation of unexplained cytopenias and or macrocytosis over a 3 year period at our institution (2006-2008). Thirty-two percent of all patients were diagnosed with MDS and 9% had suspected MDS. The post-test likelihood of a diagnosis of MDS increased from 12% when none of the four identified factors were present to 48% when 3 or more factors were present. This scoring system can be used to guide the diagnostic testing of patients presenting with unexplained cytopenias or macrocytosis.

Discordance between receptor status in primary and metastatic breast cancer: an exploratory study of bone and bone marrow biopsies.

AIMS: The treatment of bone metastases in breast cancer is traditionally based upon the receptor status of the primary tumour. However, retrospective studies have shown significant discordance in receptor expression between primary and metastatic tumours. Therefore, the aim of this study was to prospectively assess the incidence of discordant receptor status in primary and metastatic disease and evaluate the role of bone marrow biopsies for the reassessment of receptor status. MATERIALS AND METHODS: Nine patients with known bone metastases were assessed with both a radiologically guided bone biopsy and a bone marrow aspirate and trephine. The oestrogen receptor and progesterone receptor status of these samples was assessed and compared with the primary breast cancer. Bone and bone marrow samples were also evaluated for HER2/neu status and compared with the status of the primary tumour if available. RESULTS: Tumour cells were found in six of the nine bone metastasis specimens and five of the nine bone marrow samples. A discordance rate for the oestrogen receptor was seen in five of nine patients (56%) and for the progesterone receptor in four patients (44%). There seemed to be a correlation between bone and bone marrow biopsies. CONCLUSION: The receptor discordance rate in this study was similar to previous retrospective studies. It seems that bone marrow biopsy may be a simple, safe and well-tolerated way to obtain tissue to reassess the receptor status of metastatic breast cancer.

Perceived adverse effects of antiretroviral therapy.

Adverse effects from antiretroviral therapy (ARV) for HIV are associated with medication nonadherence. The purposes of this study were to explore group differences in the reporting of adverse effects, identify individual adverse effects that are linked to nonadherence, and to explore the role of coping in the relationship between adverse effects and adherence. Cross-sectional interviews of 2,765 HIV-positive adults on ARV therapies in four U.S. cities were performed using a computerized assessment of self-reported adverse effects, coping self-efficacy, and adherence. There were no gender differences in the rate or severity of adverse effects reported. Latino respondents reported more adverse effects than either White or African Americans. Those taking a protease inhibitor (PI) reported a higher rate and greater severity of adverse effects. Older participants reported fewer adverse effects despite being more likely to be on a regimen containing a PI. Respondents with less than 90% adherence reported greater numbers and severity of adverse effects overall. In multivariate analyses, nausea, skin problems, vomiting, and memory adverse effects were independently related to less than 90% adherence over the prior three days. Coping moderated the relationship between nausea and adherence such that individuals who reported lower coping self-efficacy and experienced nausea were at increased risk for nonadherence, regardless of the length of time on the current ARV regimen. Women and men are similar in their overall reports of adverse effects, and Latinos report more adverse effects to ARVs than White or African American patients. Specific adverse effects (skin problems, memory problems, vomiting, and nausea) are more likely than others to be associated with missing ARV medications. Increasing adaptive coping self-efficacy among patients experiencing nausea may be a particularly effective strategy in increasing medication adherence.

Synthesis and trapping of transient 1,2-diselones to yield 1,4-diselenin derivatives: calculated structures of 1,2-diselones, 1,2-diselenetes and their sulfur analogues

Two conceptually different routes to transient 1,2-diselones are reported: 1) via ring fragmentation of the 1,4,2-diselenazine system 6, and 2) by the tributylphosphane-induced depolymerisation of the shelf-stable organoselenium polymer 15. Evidence for the intermediacy of 1,2-diselone species 7 and 16 is provided in both cases by in situ trapping with dimethyl acetylenedicarboxylate (DMAD) to yield 1,4-diselenin derivatives. The route via 15 is especially expedient and trapping of 16 is efficient. Subsequent reactions of adduct 17 afford [1,2-ethanediylbis(diphenylphosphane)] [5,6-bis(methoxycarbonyl)-1,4-diselenin-2,3-dithiolato]nickel(IV) (20). Theoretical calculations at Hartree-Fock (HF) and Moller-Plesset electron-correlated levels (MP2) suggest that the cyclic 1,2-diselenete structure 7c is significantly more stable than the acyclic 1,2-diselone structure 7a. For the bicyclic system 16, the difference in energy between the cyclic and acyclic structures is considerably reduced due to the conformational rigidity imposed by the fused 1,3-dithiole ring. In contrast, the acyclic structures of the 1,2-dithione analogues 13a and 25a are computed to be more stable than their corresponding cyclic 1,2-dithiete structures 13c and 25c.

Partial splenectomy in children with sickle cell disease and repeated episodes of splenic sequestration.

Twenty-five children with sickle cell disease and repeated episodes of splenic sequestration crises underwent partial splenectomy. They have been followed for 12 to 75 months (median 48 months) after surgery. During this period we have not observed any episode of splenic sequestration and the need for hospitalization and transfusions has been greatly reduced. We believe this is a useful and safe procedure for treating patients with this condition.

The organization zoo: a fable.

In the parable that follows, we have exaggerated animal behavior to show the importance of ego niches that people make for themselves in organizations. The parable illustrates the difficulty supervisors have in juggling individual egos, organizational needs, and change. We are all familiar with the moral of this fable: ¿The more things change, the more they stay the same.¿

Organizational moles: information control and the acquisition of power and status.

All organizations have moles or informants who seek to acquire informal power and status within the organization by keeping supervisors and the chief executive officer informed about employees and their activities. If the leaders of an organization are insecure and distrustful, they value the information about the organization that moles provide. Moles survive organizational change because they are loyal first to themselves. Moles often are hardworking, productive people, but their net effect on the organization's moral is negative because they foster distrust and defensiveness among employees. Guidelines are offered to help identify possible moles so they can be avoided lest one become a victim to moles' methods.

Diagnosing the health of organizations.

The concept of a healthy organization is idealistic. Organizations are never fully stable, they never maximize their potential, and they never achieve complete harmony. It is a common myth that the leader determines an organization's health. It is how the psychodynamics of an organization are managed and the capacity of leaders and followers to repair broken relationships that influence an organization's health.

Barriers to medical care of Mexican-Americans: the role of social class, acculturation, and social isolation.

Literature on medical care utilization by Mexican-Americans suggests that patterns of utilization can be explained, in part, by acculturation, social class and social isolation. The relative importance of these variables is explored in a survey of a rural Mexican-American community in Southern Texas. Data on 152 families are analyzed using a logit analysis, with utilization as the outcome variable. The results suggest that acculturation has a direct effect, while social class and social isolation interact to have a weak effect independent of acculturation. These results confirm the importance of understanding all three variables in planning and implementing medical care programs in Mexican-American communities.

Habitual anger-coping styles: I. Effect on mean blood pressure and risk for essential hypertension.

In this study we examined the effect(s) of race, sex socioecological stress, and habitual anger-coping systolic/diastolic blood pressure levels and risk for being classified hypotensive. A total of 495 black/white males and 511 black/white females, residing in high/low stress areas of Detroit, were classified in terms of high, medium, and low levels of anger expression to various provocative interpersonal situations. Results indicated that: 1) race and anger expression were major determinants of diastolic pressure; 2) race and sex influence systolic pressure; 3) anger expression was related to systolic pressure, but only for female respondents; 4) all four behavioral factors were independently related to one's relative risk of being labeled hypertensive; and 5) the odds of being hypertensive by a multiple 1.56 with the addition of each behavioral risk factor. These findings extended our understanding of both the important role played by sociodemographic factors and socioecological niche in predisposing humans to vascular disease and the magnitude of difference in mean blood pressure and risk for hypertension attributable to chronic suppressed anger. The present finding also provide a basis for identifying subgroups of individuals who are especially at risk for hypertension and, similarly, a basis on which to calculate the amount of potential therapeutic benefit resulting from attempts at modifying one or more risk factors.

Student reactions to a community-based experience for health professions education.

Student responses to a community health program in a rural Mexican-American town are presented. Off-campus training was provided for 104 health professions students, during which health evaluations were made of 741 elementary school children. The students reported that the program allowed them to apply clinical skills, that they were more interested in rural practice, and that their reaction to working in teams was overwhelmingly positive. The students reported that teaming offered as advantages greater knowledge and appreciation of other disciplines, more comprehensive patient care, increased knowledge of communication processes, and exposure to relevant clinical skills from other disciplines. Their perceptions of the advantages of teaming varied among the disciplines. The program provided a learning experience for the students and resulted in improved health care for the town.

The impact of sex therapy on sexual behaviors and marital communication.

The evaluation results of a short term intensive sex dysfunction workshop are presented. The evaluation research design involves before and after measures of sexual behaviors, sexual expectations, sexual communication, and marital communication. The results indicate that participants changed with regard to each of these variables. The workshop appears to impact couples in three ways: (1) there is a narrowing of the gap between actual and desired sexual behaviors, (2) there is improved sexual communication, and (3) there is improved marital communication. The results indicate that a combination of group instruction and individual therapy is an effective intervention technique in treating couples with sexual problems.