Combination antiretroviral therapy and recent declines in AIDS incidence and mortality

The reasons for recent declines in AIDS incidence and mortality may include advances in treatment, but these may be confounded by earlier declines in the incidence of human immunodeficiency virus (HIV) infection. To determine whether the declines in AIDS and mortality may, in part, stem from wider use of combination antiretroviral therapy, 622 HIV-positive men with well-characterized dates of seroconversion were followed. In this group, combination therapy came into widespread use in only 1996. In a Cox proportional hazards model, the 1996 calendar period was significantly associated with slower progression to AIDS (relative hazard [RH]=0. 19, 95% confidence interval [CI], 0.05-0.69, P=.01) and death (RH=0. 45, 95% CI, 0.21-0.95, P=.04). Declines in incidence of HIV infection, changes in HIV virulence, and end-point underreporting cannot fully explain the decline in AIDS and death in 1996. The introduction of combination antiretroviral therapy as the standard of care may already have had measurable effects.     

Concept analysis of trust: a coronary care perspective

The presence in serum of adenylate kinase isoenzyme originating from erythrocyte can be useful as a marker for detecting hemolysis. We have presented preliminary evidence for identifying hemolytic anemia patients earlier by determining erythrocyte AK isoenzyme activity in serum (or plasma) rather than using measurement of plasma hemoglobin concentration. This test being quite specific for hemolysis should find use as a quick method for estimating the extent of in vivo hemolysis in hemolytic patients earlier than heretofore possible.     

Developmental aspects of dendritic cells in vitro and in vivo

Our knowledge in immunology has been dramatically increased by several excellent investigations elucidating the role of the Fas (Apo-1/CD95) receptor/ligand (FasL) system in complex immunological processes such as the acquisition of self tolerance in T cells, progression of autoimmunity, clonal deletion of activated T cells, B-cell regulation and the establishment of "immune privileged" sites such as testis or retina. In addition to these regulatory immunological activities, Fas/FasL interaction was also shown to participate in active defense mechanisms of the host against infected or transformed cells thereby inducing apoptosis in target cells. However, the same mechanism seems also to be part of an escape strategy utilized by tumor cells in various neoplastic malignancies of both hematopoetic as also non-hematopoetic origin. We ourselves were able to demonstrate that neoplastic plasma cell lines, as well as native malignant myeloma cells constitutively express FasL mRNA and protein. The FasL molecule is functionally active and able to induce programmed cell death in Fas sensitive target T cells in vitro. These target T cells were protected from programmed cell death by preincubation of T cells with a Fas-blocking monoclonal antibody (mAb) or of myeloma cells with a FasL-neutralizing mAb. respectively. Furthermore, overexpression of the caspase inhibitor, cowpoxvirus protein CrmA, also protected target T cells from being killed by myeloma cells, identifying Fas/FasL mediated signaling as the effector pathway utilized by malignant plasma cells. Our observations strongly suggest the engagement of Fas/FasL interaction in the escape strategy of this malignancy. The molecular basis of this evasive mechanism differs in essential respects from those described in melanoma, lung cancer, hepatocellular carcinoma, or astrocytoma, since downregulation of Fas or instrinsic insensitivity towards Fas-mediated signaling were not prerequisites for the occurrence of this phenomenon in Fas-sensitive multiple myeloma cell lines. However, myeloma cell lines resisted cocultivation with FasL-expressing target T cells in vitro. The aim of this review is to discuss the role of Fas/FasL interaction in the establishment of malignant disease, in the light of our findings on myeloma cells and also by drawing upon similar observations of other investigators on different kinds of tumor cells and cell lines and further to consider its possible relevance in formulating novel approaches to cancer therapy.     

Professional drivers: protection needed for a high-risk occupation

"On the job" motor vehicle deaths number more than 4,000 annually in the U.S. and comprise nearly one-third of all work-related deaths. Yet the Department of Labor has set no standards relating to on-the-road safety of the millions of workers whose jobs entail large amounts of driving, and Department of Transportation standards affecting occupational safety cover only drivers in interstate commerce. Drivers of some commercial vehicles, such as heavy trucks, are at special risk of injury because trucks have usually been exempted for many years from federal motor vehicle safety standards--such as standards for brakes and seatbelts--designed to prevent crashes or protect occupants in crashes. Observations based on a series of 150 fatal crashes involving tractor trailers illustrate the need for better protection of this large population of high-risk workers. Clarification of responsibility within the various federal agencies and application of available knowledge and technology are essential.     

Brain stem integration of vocalization: role of the nucleus retroambigualis

1. The descending pathways that mediate the periaqueductal gray (PAG)-evoked coordination of respiratory, laryngeal, and orofacial activity for vocalization have yet to be delineated. Two hypotheses have been offered. One theory is that this activity is mediated by a diffuse descending projection to parvocellular reticular interneurons, adjacent to the relevant laryngeal and orofacial motoneuronal pools. The second hypothesis is that the motor activity for vocalization is integrated via a projection from the PAG to a caudal medullary column of neurons, the nucleus retroambigualis (NRA). These hypotheses were tested with the use of a series of medullary transections combined with PAG stimulation. Transections that eliminated, in a series of caudal-to-rostral steps, the NRA, also eliminated the PAG-evoked cricothyroid and most of the thyroarytenoid laryngeal motor activity. These results indicate that the final common pathway for much of the laryngeal activity in PAG-evoked vocalization includes un initial synapse in the caudal medulla, presumably in the NRA. 2. The electromyographic changes evoked by microinjection of D,L-homocysteic acid (DLH) in the NRA of the unanesthetized, precollicular decerebrate cat were analyzed in order to delineate the NRA contribution to the coordinated respiratory, laryngeal, and oral muscle changes in vocalization. A total of 415 DLH injection sites were located at or caudal to the level of the obex. Vocalization was evoked at 46 of these sites, which were all confined to a restricted region of the ventrolateral medulla 1-3 mm caudal to the obex. This region corresponded to the rostral half of the NRA and the immediately adjacent medullary tegmentum. 3. In all experiments evidence was obtained that variable muscle activation, rather than functional and integrated muscle patterns, was represented within the NRA. Vocalization evoked by DLH microinjection in the NRA was usually associated with excitation of the cricothyroid, thyroarytenoid, external oblique, internal oblique, internal intercostal, and diaphragm muscles that occurred in a different manner from site to site. That is, injection at sites separated by 0.3-0.5 mm evoked quite different responses. 4. NRA-evoked vocalization was compared with PAG-evoked vocalization using small injections (1.5-4.5 nl) into each region. As well, larger microinjections (15-120 nl) into NRA were made for comparison with previous results from the PAG using similar doses. Within the PAG, stereotyped and relatively "fixed" patterns of muscle activity are represented, whereas within the NRA there was no representation of specific muscle patterns, but rather a partial topographic separation of "premotor neurons" regulating different muscles. Correspondingly, stereotyped vocalizations were never evoked from the NRA. Further, most NRA-evoked vocalizations were unusual in quality and would not be identified generally as feline. 5. Evidence was obtained for a separation of pathways from the PAG regulating sound production and orofacial modulation of that sound. In contrast to the results from the PAG, excitation of NRA neurons rarely evoked activity in the oral muscles (genioglossus or anterior belly of digastric) or orofacial modulation of sound production. 6. Our finding suggests that the NRA serves as an important substrate for the generation of respiratory pressure and larynges adduction, which are two essential aspects of not only vocalization but also several behaviors involving Valsava maneuvers such as coughing, vomiting, and defecation.