Mcl-1 antagonizes Bax/Bak to promote effector CD4(+) and CD8(+) T-cell responses.

Members of the Bcl-2 family have critical roles in regulating tissue homeostasis by modulating apoptosis. Anti-apoptotic molecules physically interact and restrain pro-apoptotic family members preventing the induction of cell death. However, the specificity of the functional interactions between pro- and anti-apoptotic Bcl-2 family members remains unclear. The pro-apoptotic Bcl-2 family member Bcl-2 interacting mediator of death (Bim) has a critical role in promoting the death of activated, effector T cells following viral infections. Although Bcl-2 is an important Bim antagonist in effector T cells, and Bcl-xL is not required for effector T-cell survival, the roles of other anti-apoptotic Bcl-2 family members remain unclear. Here, we investigated the role of myeloid cell leukemia sequence 1 (Mcl-1) in regulating effector T-cell responses in vivo. We found, at the peak of the response to lymphocytic choriomeningitis virus (LCMV) infection, that Mcl-1 expression was increased in activated CD4(+) and CD8(+) T cells. Retroviral overexpression of Mcl-1-protected activated T cells from death, whereas deletion of Mcl-1 during the course of infection led to a massive loss of LCMV-specific CD4(+) and CD8(+) T cells. Interestingly, the co-deletion of Bim failed to prevent the loss of Mcl-1-deficient T cells. Furthermore, lck-driven overexpression of a Bcl-xL transgene only partially rescued Mcl-1-deficient effector T cells suggesting a lack of redundancy between the family members. In contrast, additional loss of Bax and Bak completely rescued Mcl-1-deficient effector T-cell number and function, without enhancing T-cell proliferation. These data suggest that Mcl-1 is critical for promoting effector T-cell responses, but does so by combating pro-apoptotic molecules beyond Bim.

Responses of bone marrow gamma-glutamyltranspeptidase and alkaline phosphatase in vitro to tumor-elaborated granulocytopoietic factors.

Evidence has been obtained for the humoral mediation of the recently noted tumor-induced rise of the host bone marrow gamma-glutamyltranspeptidase (gamma GT) and alkaline phosphatase (AP) content in vivo: normal rat bone marrow suspensions, if incubated for 18 hr to 3 days with serum from mammary carcinoma hosts, show 2- to 8-fold elevations (per cell) of the same 2 enzymes. The active substance(s) is in the acid-stable, HCI-ethanol-soluble polypeptide fraction of the mammary carcinoma extract, and of the hosts' blood serum. The larger the size of the neoplasm, and the faster its growth rate, the greater the effect of the host serum on the gamma GT and AP of the normal bone marrow cells. In host rats in vivo, this response is followed by increases in the number (as well as the gamma GT and AP content) of circulating granulocytes. Therefore, a positive response on the part of these enzymes in the bone marrow suspension was also sought, and found, upon incubation with preparations which enhance granulocyte colony formation in agar cultures (i.e., colony-stimulating factor and serum from endotoxin-treated rats). The results indicate: (a) that the increase in gamma GT and AP is a necessary prelude to stimulation of granulocyte multiplication by appropriate growth factors; and (b) that measurement of these enzymes in the short-term liquid culture offers a biochemical test for such factors elaborated by cancers or in nonneoplastic conditions.

Regional cerebral metabolic alterations in dementia of the Alzheimer type: positron emission tomography with [18F]fluorodeoxyglucose.

Alzheimer disease is the most common cause of dementia in adults. Despite recent advances in our understanding of its anatomy and chemistry, we remain largely ignorant of its pathogenesis, physiology, diagnosis, and treatment. Dynamic positron emission tomography using [18F]fluorodeoxyglucose (FDG) was performed on the Donner 280-crystal ring in 10 subjects with dementia of the Alzheimer type and six healthy age-matched controls. Ratios comparing mean counts per resolution element in frontal, temporoparietal, and entire cortex regions in brain sections 10 mm thick obtained 40-70 min following FDG injection showed relatively less FDG uptake in the temporoparietal cortex bilaterally in all the Alzheimer subjects (p less than 0.01). Left-right alterations were less prominent than the anteroposterior changes. This diminished uptake was due to lowered rates of FDG use and suggests that the metabolic effects of Alzheimer disease are most concentrated in the temporoparietal cortex. Positron emission tomography is a most powerful tool for the noninvasive in vivo assessment of cerebral pathophysiology in dementia.

Central auditory processing. III. The "cocktail party" effect and anterior temporal lobectomy.

The capacity to selectively attend to only one of multiple, spatially separated. simultaneous sound sources--the "cocktail party" effect--was evaluated in normal subjects and in those with anterior temporal lobectomy using common environmental sounds. A significant deficit in this capacity was observed for those stimuli located on the side of space contralateral to the lobectomy, a finding consistent with the hypothesis that within each anterior temporal lobe is a mechanism that is normally capable of enhancing the perceptual salience of one acoustic stimulus on the opposite side of space, when other sound sources are present on that side. Damage to this mechanism also appears to be associated with a deficit of spatial localization for sounds contralateral to the lesion.

Central auditory processing. IV. Ear dominance--spatial and temporal complexity.

Ear dominance for dichotically presented tones was measured in 63 righthanded subjects when the frequency difference (delta f) was small compared to the center frequency (fc) and again when it was large. Although two-thirds of the population exhibited a left-ear dominance in both conditions, a shift toward right-ear dominance occurred when the delta f was increased. An additional study, employing the alternating tone illusion described by Deutsch, revealed the same general effect, i.e., a shift toward right-ear dominance with increasing values of delta f/fc. The results of these experiments, coupled with a review of previously published data of other dichotic experiments, indicate that as the ratio of delta f/fc increases, the subjective complexity of the sound image increases, and there is a progressive emergence of a "right-ear advantage" (or ear dominance). A tentative explanation relates these results to the effects of anatomical asymmetries of primary and auditory association cortex and the efferent temporal lobe enhancement mechanism described by R. Efron, P.H. Crandall, B. Koss, P.L. Divenyi, and E.W. Yund (Brain and Language, 1983, 19, 254-263.

Saccadic intrusions in Alzheimer-type dementia.

Horizontal eye-movement responses of four patients with Alzheimer-type dementia were recorded using the infrared oculographic technique. Abnormally frequent saccadic intrusions occurred during the fixation and slow, smooth pursuit tasks in all four patients. Saccadic intrusions have previously been reported in the literature to occur in normals, in strabismus, in patients with certain neurological disorders, and in schizophrenic patients. This is the first report of a group of Alzheimer-type dements with an eye movement abnormality which cannot be regarded as an ocularmotor reflection of diffuse cerebral dysfunction.

Effect of neoplasms on the content and activity of alkaline phosphatase and gamma-glutamyl transpeptidase in uninvolved host tissues.

In rats carrying s.c. or i.p. neoplasms, there were striking (3- to 20-fold) rises in the gamma-glutamyl transpeptidase and alkaline phosphatase activity of several tissues. These included liver, lung, spleen, bone marrow, and circulating granulocytes but not lymphocytes. In response to mammary carcinoma 5A, for example, the gamma-glutamyl transpeptidase activity changed from 0.27 to 1.18 units/g lung and from 0.3 to 4.0 milliunits/million granulocytes; from 2.3 to 17 units and from 2.4 to 46 milliunits were the accompanying increases in alkaline phosphatase. These abnormalities in each host tissue were reversible in that 3 to 7 days after tumor resection the enzymes returned to control levels. Among the secondary factors which might have been responsible for the host tissue changes, it was possible to exclude stimulated adrenocortical secretion, tissue necrosis, and transplantation trauma. Comparisons of the effects of two mammary carcinomas, a fibrosarcoma, and two hepatomas on the gamma-glutamyl transpeptidase and alkaline phosphatase of various "noninvolved" tissues indicate that the faster the growth rate of the tumors, the more striking is this host syndrome.