Thy-1+ and Thy-1- natural killer cells. Only Thy-1- natural killer cells suppress dendritic cells.

Cells enriched for NK activity (poly I:C induced, x-ray resistant, and nonadherent), include two phenotypically and functionally different populations. Both populations of NK cells are AGM1+, Ly-1.1-, Ly-2.1-, Ia-, and have the morphology of large granular lymphocytes. One population, however, is Thy-1+ while the second population is Thy-1-. Thy-1+ NK cells lyse YAC-1 and P815 target cells; Thy-1- NK cells lyse YAC-1 but not P815 target cells. The FACS was used to obtain homogeneous populations of Thy-1+ and Thy-1- NK cells, which retain high cytotoxicity. While Thy-1- NK cells suppress the antibody response in vitro by suppressing or eliminating DC, Thy-1+ NK cells do not suppress antibody responses in vitro.

Dendritic cells that have interacted with antigen are targets for natural killer cells.

Natural killer (NK) cells (poly I:C induced, x-ray resistant, nonadherent, Thy-1-, Ly-1.1-, Ly-2.1-, anti-asialo GM1-positive, and cytotoxic for YAC-1) suppressed T lymphocyte proliferation in mixed lymphocyte reaction (MLR) and autologous MLR cultures. Dendritic cells (DC) were required for proliferation of lymphocytes in both responses. The question whether lymphocytes or DC were the targets for NK cells was resolved by taking advantage of the fact that NK cells, but not DC, lose activity after 24 h in culture. Three findings indicate that DC, not lymphocytes, are targets for NK cells. First, responses suppressed by NK cells were fully restored by adding small numbers of DC to cultures 24 h after NK cells had been added. Second, DC incubated alone with NK cells and antigen for 24 h did not stimulate proliferation of lymphocytes. Third, lymphocytes incubated alone with NK cells for 24 h proliferated normally when DC were added. Additional experiments showed that DC became targets only after interaction with antigen. Thus, we suggest that NK cells may regulate lymphocyte proliferation by monitoring antigen presentation by DC.

Challenges to bonnet monkey (Macaca radiata) social groups: Mother-infant dyad and infant social interactions.

The mother-infant dyad is crucial to early development in a variety of species. The complexity of social groupings in nonhuman primates makes this relationship resilient as well as susceptible to early challenges associated with environmental chaos. Quantitative behavior observations of bonnet monkey mother-infant interactions were collected from 28 mother-infant dyads between one and twelve months of age. Social groups were subjected to several prenatal and/or postnatal housing relocations within a single year resulting in two study groups. One group experienced relocations (ATYPICAL, n = 14) and the second group (TYPICAL, n = 14) was conceived and reared in the same location. Behaviors in the ethogram included mother-infant interactions and infant social interactions with other members of the group. Observations between ages of two to four months were analyzed by a mixed model analysis of variance including fixed effects of per and postnatal history (TYPICAL, ATYPICAL), age, and history by age interaction and random effects of mother and infant nested within mother. A significant effect of relocation history was noted on a number of infant behaviors. ATYPICAL infants were out of direct contact with their mother at an earlier age but remained in her proximity. Control of proximity shifted to offsrping in the ATYPICAL group compared to the TYPICAL group. Furthermore, greater social interactions between two and four months of age with other members of the social group as well as the ir mother were observed in the ATYPICAL group. It is suggested that continuous challenge associated with relocation may affect the infant at later developmental ages due to these early differences in ways that are yet unclear.

Induction of leukemia-associated inhibitory activity and bone marrow granulocyte-macrophage progenitor cell alterations during infection with Abelson virus.

Neonatal and adult BALB/c mice were investigated in a longitudinal study for the acquisition of leukemia-associated inhibitory activity (LIA) interactions after inoculation with Abelson virus in vivo. Within 2 to 4 days after virus infection, the granulocyte-macrophage colony-forming cells from the bone marrow and spleen of the infected mice became insensitive to inhibition by LIA, even though colony morphology appeared normal. Shortly after, or simultaneously with, the detection of the colony-forming cell resistance phenomenon, LIA was found in bone marrow, spleen, and thymus cells. The abnormal interactions appeared to be related to induction of lymphoma in BALB/c neonates and to a lymphoproliferative disease in adult BALB/c mice. In contrast, normal cellular interactions were noted in adult C57BL/6 mice which were not susceptible to the Abelson disease after virus inoculation and in untreated neonatal and adult BALB/c and adult C57BL/6 mice. Their colony-forming cells were sensitive to inhibition by LIA, and no LIA was detected in their bone marrow, spleen, and thymus cells. The abnormal cellular interactions are similar to those noted in human leukemia, lymphoma, and "preleukemia." This suggests that Abelson virus-infected mice can serve as a model for the study of LIA interactions.

A randomized control trial of a psychosocial intervention for caregivers of allogeneic hematopoietic stem cell transplant patients: effects on distress.

Caregivers of patients receiving allogeneic hematopoietic stem cell transplants (allo-HSCT) serve a pivotal role in patient care but experience high stress, anxiety and depression as a result. We theorized that stress management adapted for allo-HSCT caregivers would reduce distress compared with treatment as usual (TAU). Of 267 consecutive caregivers of allo-HSCT patients approached, 148 (mean=53.5 years, 75.7% female) were randomized to either psychosocial intervention (i=74) or TAU (n=74). Eight one-on-one stress management sessions delivered across the 100-day post-transplant period focused on understanding stress, changing role(s) as caregiver, cognitive behavioral stress management, pacing respiration and identifying social support. Primary outcomes included perceived stress (psychological) and salivary cortisol awakening response (CAR) (physiological). Randomized groups were not statistically different at baseline. Mixed models analysis of covariance (intent-to-treat) showed that intervention was associated with significantly lower caregiver stress 3 months post transplant (mean=20.0, 95% confidence interval (95% CI)=17.9-22.0) compared with TAU (mean=23.0, 95% CI=21.0-25.0) with an effect size (ES) of 0.39 (P=0.039). Secondary psychological outcomes, including depression and anxiety, were significantly reduced with ESs of 0.46 and 0.66, respectively. Caregiver CAR did not differ from non-caregiving controls at baseline and was unchanged by intervention. Despite significant caregiving burden, this psychosocial intervention significantly mitigated distress in allo-HSCT caregivers.

Constant intraperitoneal 5-fluorouracil infusion through a totally implanted system.

Five-day continuous intraperitoneal (ip) infusions of 5-fluorouracil (FU) were injected into five patients as part of a phase I clinical pharmacology study. They received 20 courses through a totally implanted catheter/injection port system. Six courses are evaluable for kinetic parameters and all courses are evaluable for toxicity. In each course a 2 to 3 log FU concentration differential in favor of the peritoneal cavity was achieved and maintained. Steady-state venous plasma FU concentrations averaged 0.34 microM, whereas steady-state ip FU concentrations averaged 697 microM. Mean total body clearance (TBC) in these patients was 18.4 l/min and mean permeability-area (PA) product for diffusion from the peritoneum was 13.7 ml/min. Mean TBC of 20 l/min with ip FU infusion was observed in one patient who also received a 24-hr IV FU infusion for comparison. The TBC during the later infusion was 5.9 l/min. In this patient, calculations indicate 75% extraction of drug during the passage from the peritoneum to the systemic circulation, presumably representing in large part hepatic extraction of FU taken into the portal venous circulation. Ip constant infusion and bolus kinetics were compared in one patient. TBC for the ip bolus was 14.3 l/min, which was approximately half of the TBC of 29.5 l/min determined during the 5-day constant ip infusion. Thus constant ip infusion of FU (l gm/day) can provide an improved regional advantage over bolus ip FU because of an increased TBC. Toxicity was acceptable in all courses. Dose limiting toxicity was regional, namely moderate chemical peritonitis seen in two of the five patients on repeated courses. There was no myelosuppression, alopecia, nausea, or vomiting.(ABSTRACT TRUNCATED AT 250 WORDS)

Kinetic Resolution of Diiron Acyl Complexes-An Approach to Asymmetric Bicyclic ß-Lactams.

Kinetic resolution is achieved in the reaction of racemic diiron complexes like 1 with the chiral nitrone (-)-2. Oxidative removal of the metal and reductive cleavage of the N-O bond provides ß-amino acids. This sequence was used in the synthesis of ß-amino acids as well as the corresponding ß-lactams 4 (via 3).

Kinetic resolution in palladium-catalyzed asymmetric allylic alkylations by a P,O ligand system.

[reaction: see text] Through the investigation of peptide-based phosphine oxazoline ligands, a simple P,O ligand system was developed. This system provides palladium complexes that are capable of a very high degree of kinetic resolution of 1,3-diphenylprop-2-enyl acetate. The isolated palladium complex was synthesized, characterized, and determined to be an effective procatalyst.

Chiral P,N-ligands based on ketopinic acid in the asymmetric Heck reaction.

[figure: see text] Novel chiral P,N-ligands were synthesized from (1S)-(+)-ketopinic acid using palladium-catalyzed coupling reaction of a vinyl triflate and either a diarylphosphine or a dialkylphosphine as the key step. Palladium complexes of these ligands are efficient catalysts for asymmetric Heck reaction between aryl or alkenyl triflates and cyclic alkenes. Products were obtained with good to excellent enantioselectivity from arylation and alkenylation of 1,2-dihydrofuran, cyclopentene, and 4,7-dihydro-1,3-dioxepin.

Synthesis of new bicyclic P-N ligands and their application in asymmetric Pd-catalyzed pi-allyl alkylation and Heck reaction.

[structure: see text] The synthesis of phosphine oxazoline ligands based on P-chiral 1-phosphanorbornadienes is reported. The use of these ligands in palladium catalyzed asymmetric allylation and Heck reaction is described.

Mate similarity for substance dependence and antisocial personality disorder symptoms among parents of patients and controls.

UNLABELLED: Substance dependence (SD) and antisocial personality disorder (ASPD) are highly comorbid and aggregate in families. Mating assortment may be an important process contributing to this familial aggregation. HYPOTHESIS: Symptom counts of substance dependence, antisocial personality disorder, and retrospectively assessed conduct disorder (CD) will be correlated significantly among parents of youth in treatment for substance use and conduct problems and, separately, among parents of community controls. METHODS: We examined SD, ASPD, and CD among 151 pairs of parents of adolescents in treatment for substance use and conduct problems, and in 206 pairs of parents of control subjects. RESULTS: For average dependence symptoms (ADS) (the sum of across-drug substance dependence symptoms divided by the number of substance categories meeting minimum threshold use) mother-father correlations were 0.40 for patients and 0.28 for controls. Mother--father correlations for ASPD symptom count were 0.33 for patients and 0.26 for controls and for CD symptom count were 0.31 for patients (all P < 0.01) and 0.10 for controls (P = 0.14). CONCLUSIONS: Spousal correlations for ADS and ASPD, suggest substantial non-random mating. Results support gender differences in homogamy for SD. Behavior genetic studies of these disorders need to account for assortment to avoid biases in estimates of genetic and environmental effects.

Merging pathways: music therapy in neurosurgical rehabilitation.

Relatively few departments of Music Therapy are found within neurosurgical rehabilitation clinics. In institutions where these departments exist, music therapy has become an integral part of multi-professional treatment and research activities (Gilbertson 1999). The diverse intervention strategies in Music Therapy focus upon auditory, motor, visual, cognitive and affective processing which are all involved in receptive and expressive musical behaviour and which affect related non-musical behaviour. A clear differentiation is made between primary and adjunct therapy roles. The related fields of neuromusicology, neuroanatomy, neuropsychology, music psychology and humanistic psychology are primary sources in the development of models of clinical application (Hodges 1996). Our main interests are focussed on the following issues and areas of clinical application: The initialisation of contact with patients in vegetative status Communicative interaction with patients who can not (initially) use verbal communication (aphasic disorders) Temporal motor organisation with patients with sensomotor disorders Cognitive organisation and mnemonic framework with patients with neuropsychological functional disorders (concentration, memory, perception) Treatment of spatial perception disorders (neglect) Enhancing personal and social integration following individual isolation, social withdrawal. These topics will be discussed and highlighted with clinical examples.

Clinical, morphologic, and chemical studies on copper toxicosis of Bedlington Terriers.

In a study of 90 Bedlington Terriers, 68 had a defect that resulted in the accumulation of toxic excesses of copper in the liver. Concentrations of copper were 5 to 50 times that of clinically normal mongrel dogs. The bulk of this excess copper was sequestered in lysosomes. When copper concentrations exceeded 2,000 micrograms/g dry liver, progressive signs of functional and morphologic disturbance appeared as focal hepatitis, chronic active hepatitis, and ultimately cirrhosis. The disorder, which appears to be inherited, could only be diagnosed by liver biopsy. It was latent for many years in some dogs but led early in life to acute or chronic hepatic disease and death in others.

Chronic active hepatitis in Doberman pinschers.

Eleven Doberman Pinschers were affected with a disease that had clinical signs, serum biochemical abnormalities, and histologic features of chronic active hepatitis. Intrahepatic cholestasis and accumulations excess hepatic copper were prominent features. Most of the dogs deteriorated within weeks to months, and 6 died within 9 months after the 1st signs of disease were noticed.

Plasma cortisol response to exogenous ACTH in 22 dogs with hyperadrenocorticism caused by adrenocortical neoplasia.

The plasma cortisol response to exogenous ACTH (ACTH stimulation test) was evaluated in 22 dogs with hyperadrenocorticism caused by adrenocortical neoplasia. The mean basal cortisol concentration (6.3 microgram/dl) was high, but 7 dogs had basal cortisol concentrations that were within normal range. Administration of exogenous ACTH increased the plasma cortisol concentrations in each dog. Normal post-ACTH cortisol concentrations were found in 9 (41%) of the 22 dogs; 13 (59%) had an exaggerated increase in cortisol concentrations after ACTH administration. In 9 of 13 dogs with carcinoma and in 4 of 9 with adenoma, the cortisol response was exaggerated. The mean post-ACTH cortisol concentration in the dogs with carcinoma was approximately 4 times that of the dogs with adenoma; the 7 dogs with the highest concentrations had carcinoma. Repeat studies were performed in 6 dogs 2 to 8 weeks after initial testing. In 5 of the 6 dogs, repeat testing yielded data of similar diagnostic significance. One dog, however, had an abnormally high post-ACTH cortisol concentration at initial evaluation, but had only a minimal response to ACTH administration, with a normal post-ACTH cortisol concentration, at time of resting. Although ACTH stimulation testing is useful in diagnosing hyperadrenocorticism, it can not reliably separate dogs with hyperfunction adrenocortical tumors from clinically normal dogs or from dogs with pituitary-dependent hyperadrenocorticism (bilateral adrenocortical hyperplasia).

Cutaneous lesion caused by Mycobacterium tuberculosis in a dog.

A 5-month-old female mixed-breed dog was examined because of nonhealing wounds in the right submandibular region. Treatment with antibiotics and surgical excision was ineffective. Specimens of the right mandibular lymph node and surrounding tissues were submitted for bacteriologic culturing, and Mycobacterium tuberculosis was isolated. The dog was euthanatized. The risk of infection of human beings who associate with dogs that have cutaneous wounds caused by mycobacteria is unknown.

Interpretation of canine liver biopsy. A clinician's perspective.

Proper evaluation of hepatic biopsies is essential for the proper management of dogs with liver disease. The clinician must have some basic knowledge of hepatic anatomy and histopathologic nomenclature in order to establish an accurate prognosis and therapeutic plan.

Insula and orbitofrontal cortical morphology in substance dependence is modulated by sex.

BACKGROUND AND PURPOSE: Frontolimbic circuits are involved in learning and decision-making processes thought to be affected in substance-dependent individuals. We investigated frontolimbic cortical morphometry in substance-dependent men and women and determined whether morphometric measurements correlated with decision-making performance. MATERIALS AND METHODS: Twenty-eight abstinent SDI (17 men/11 women) were compared with 28 controls (13 men/15 women). Cortical thicknesses and volumes were computed by using FreeSurfer. After controlling for age and intracranial volume, group and sex effects were analyzed in 3 a priori regions of interest: the insula, orbitofrontal cortex, and anterior cingulate cortex by using analysis of covariance. A secondary whole-brain analysis was conducted to verify region-of-interest results and to explore potential differences in other brain regions. RESULTS: Region-of-interest analyses revealed a main effect of group on the left insula cortex, which was thinner in SDI compared with controls (P = .02). There was a group by sex interaction on bilateral insula volume (left, P = .02; right, P = .001) and right insula cortical thickness (P = .007). Compared with same-sex controls, female SDI had smaller insulae, whereas male SDI had larger insulae. Neither ACC nor OFC significantly differed across group. Performance on a decision-making task was better in controls than SDI and correlated with OFC measurements in the controls. CONCLUSIONS: SDI and controls differed in insula morphology, and those differences were modulated by sex. No group differences in OFC were observed, but OFC measurements correlated with negative-reinforcement learning in controls. These preliminary results are consistent with a hypothesis that frontolimbic pathways may be involved in behaviors related to substance dependence.

Ceramide synthase 6 modulates TRAIL sensitivity and nuclear translocation of active caspase-3 in colon cancer cells.

We have previously shown that the death receptor ligand TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) induces an increase of intracellular C(16)-ceramide in sensitive SW480 but not in resistant SW620 cells. Resistance in SW620 cells was overcome by exogenous ceramide, leading us to propose that defective ceramide signaling contributes to TRAIL resistance. In this study we found that the increase in C(16)-ceramide in SW480 cells was inhibited by fumonisin B1, an inhibitor of ceramide synthases (CerS). Protein analysis revealed that TRAIL-resistant SW620 cells expressed lower levels of ceramide synthase 6 (CerS6, also known as longevity assurance homologue 6), which prompted us to investigate the effect of CerS6 modulation on TRAIL phenotype. RNAi against CerS6 resulted in a specific and significant decrease of the C(16)-ceramide species, which was sufficient to inhibit TRAIL-induced apoptosis. In cells with decreased levels of CerS6, caspase-3 was activated but failed to translocate into the nucleus. CerS6 localized primarily to the perinuclear region, suggesting this enzyme may be important in regulation of nuclear permeability. Moderate elevation in CerS6 expression was sufficient to reverse TRAIL resistance in SW620 cells. These results suggest that modulation of CerS6 expression may constitute a new therapeutic strategy to alter apoptotic susceptibility.