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State of the art in cholesterol management: targeting multiple pathways.

The relationship between increased serum levels of total cholesterol and increased risk of coronary heart disease (CHD) is widely accepted, as is the corollary that lowering elevated levels of low-density lipoprotein (LDL) cholesterol, a significant risk factor, reduces CHD mortality. Although statins are the most widely used agents to lower LDL cholesterol levels and demonstrate significant clinical benefits, alternate and/or additional treatment strategies are also being studied. One such approach for which several classes of agents are available is the nonspecific inhibition of intestinal cholesterol and bile acid absorption. Although all of these inhibitors-which include bile acid sequestrants, cholesterol absorption blockers, and plant stanols-reduce cholesterol concentrations within liver cells and increase the expression of LDL receptors, they are limited in their effectiveness because of poor tolerability and compensatory effects by the liver that blunt their ability to lower LDL. Ideally, the combination of a statin and another agent that specifically targets cholesterol absorption and promotes excretion while simultaneously decreasing synthesis may provide the greatest therapeutic benefit. The recent development of selective cholesterol inhibitors, including ezetimibe, provides an approach to lowering LDL that has significant potential both as monotherapy and in combination therapy.

Anticholesteremic Agents↗

Anti-CD40L monoclonal antibodies can replace anti-CD4 monoclonal antibodies for the nonmyeloablative induction of mixed xenogeneic chimerism.

BACKGROUND: We have previously demonstrated that xenogeneic bone marrow engraftment and donor-specific tolerance can be induced in mice receiving anti-CD4, -CD8, -Thy-1.2, and -NK1.1 monoclonal antibodies (mAbs) on Days -6 and -1, 3 Gy total body irradiation (TBI), and 7 Gy thymic irradiation on Day 0, followed by injection of T-cell depleted (TCD) rat bone marrow cells. We have recently demonstrated that anti-CD40L mAb treatment is sufficient to completely overcome CD4 cell-mediated resistance to allogeneic marrow engraftment and rapidly induce CD4 cell tolerance in an allogeneic combination. METHODS: We investigated the ability of anti-CD40L mAb to promote mixed xenogeneic chimerism and donor-specific tolerance in B6 mice receiving anti-CD8, -Thy1.2 and -NK1.1 mAbs and 3 Gy TBI followed by TCD bone marrow transplantation (BMT) from F344 rats. RESULTS: Administration of anti-CD4 mAb in this model could be completely replaced by one injection of anti-CD40L mAb. Evidence for deletional tolerance was obtained in mixed chimeras prepared with this anti-CD40L-based regimen. However, anti-NK1.1 and anti-Thy1.2 mAb could not be replaced by anti-CD40L mAb. CONCLUSIONS: These results demonstrate that anti-CD40L in combination with xenogeneic BMT can tolerize preexisting peripheral and intrathymic CD4 cells to xenoantigens. However, anti-CD40L does not prevent NK cell and/or gammaDelta cell-mediated rejection of xenogeneic bone marrow.

Animals↗

An improved map of conserved regulatory sites for Saccharomyces cerevisiae.

BACKGROUND: The regulatory map of a genome consists of the binding sites for proteins that determine the transcription of nearby genes. An initial regulatory map for S. cerevisiae was recently published using six motif discovery programs to analyze genome-wide chromatin immunoprecipitation data for 203 transcription factors. The programs were used to identify sequence motifs that were likely to correspond to the DNA-binding specificity of the immunoprecipitated proteins. We report improved versions of two conservation-based motif discovery algorithms, PhyloCon and Converge. Using these programs, we create a refined regulatory map for S. cerevisiae by reanalyzing the same chromatin immunoprecipitation data. RESULTS: Applying the same conservative criteria that were applied in the original study, we find that PhyloCon and Converge each separately discover more known specificities than the combination of all six programs in the previous study. Combining the results of PhyloCon and Converge, we discover significant sequence motifs for 36 transcription factors that were previously missed. The new set of motifs identifies 636 more regulatory interactions than the previous one. The new network contains 28% more regulatory interactions among transcription factors, evidence of greater cross-talk between regulators. CONCLUSION: Combining two complementary computational strategies for conservation-based motif discovery improves the ability to identify the specificity of transcriptional regulators from genome-wide chromatin immunoprecipitation data. The increased sensitivity of these methods significantly expands the map of yeast regulatory sites without the need to alter any of the thresholds for statistical significance. The new map of regulatory sites reveals a more elaborate and complex view of the yeast genetic regulatory network than was observed previously.

Algorithms↗

Combination of 22-oxa-1,25-dihydroxyvitamin D(3), a vitamin D(3) derivative, with vitamin K(2) (VK2) synergistically enhances cell differentiation but suppresses VK2-inducing apoptosis in HL-60 cells.

We originally reported that vitamin K(2) (VK2) effectively induces apoptosis in various types of primary cultured leukemia cells and leukemia cell lines in vitro. In addition, VK2 was shown to induce differentiation of leukemia cells when the cells were resistant against VK2-inducing apoptosis. A novel synthetic vitamin D(3)derivative, 22-oxa-1,25-dihydroxyvitamin D(3) (OCT: oxacarcitriol) shows a more potent differentiation-inducing ability among myeloid leukemia cells in vitro with much lesser extent of the induction of hypercalcemia in vivo as compared to the effects of 1alpha,25(OH)(2)D(3). In the present study, we focused on the effects of a combination of OCT plus VK2 on leukemia cells. Treatment of HL-60 cells with OCT for 72 h induces monocytic differentiation. A combination of OCT plus VK2 dramatically enhances monocytic differentiation as assessed by morphologic features, positivity for non-specific esterase staining, and cell surface antigen expressions. This combined effect far exceeds the maximum differentiation induction ability at the optimal concentrations of either OCT or VK2 alone. In addition, pronounced accumulation of the cells in the G0/G1 phase is observed by combined treatment with OCT plus VK2 as compared with each vitamin alone. In contrast to cell differentiation, caspase-3 activation and apoptosis induction in response to VK2 are significantly suppressed in the presence of OCT in HL-60 cells. These data suggest that monocytic differentiation and apoptosis induction of HL-60 cells are inversely regulated. Furthermore, pronounced induction of differentiation by combined treatment with VK2 plus OCT was also observed in four out of six cases of primary cultured acute myeloid leukemia cells in vitro, suggesting that VK2 plus OCT might be a potent combination for the differentiation-based therapy for acute myeloid leukemias.

Acute Disease↗

Combined alpha 2-adrenergic/D2 dopamine receptor blockade fails to reproduce the ability of clozapine to reverse phencyclidine-induced deficits in prepulse inhibition of startle.

RATIONALE: The combination of idazoxan, a specific alpha(2)-adrenoceptor antagonist with raclopride, a selective D(2)/D(3) receptor antagonist, has been recently proposed to produce an "atypical" antipsychotic profile comparable to that of clozapine, based on an animal study which analysed dopamine efflux in the medial prefrontal cortex and the preclinical test of conditioned avoidance response (CAR) for evaluation of antipsychotic potential. Accordingly, the combination of a "typical" antipsychotic with idazoxan has been proposed as an augmentation strategy in treatment-resistant schizophrenia, although its therapeutic potential remains difficult to predict. OBJECTIVES: Given the momentum stimulated by these reports, the present study investigated whether the combination of idazoxan with raclopride is indeed sufficient to mimic the ability of clozapine to reverse prepulse inhibition (PPI) deficits in rats, a behavioral paradigm that models PPI deficits observed in the schizophrenia spectrum, and currently the only test which reliably appears to distinguish between "typical" antipsychotics and compounds with "atypical" antipsychotic potential. METHODS: The effects of the combination idazoxan/raclopride were examined in two PPI paradigms: 1) phencyclidine (PCP)-induced disruption of PPI, which has been shown to be preferentially reversed by "atypical" antipsychotics; 2) apomorphine-induced disruption of PPI which can be reversed by either "typical" high-potency D(2) dopamine antagonists or "atypical" antipsychotics. RESULTS: In contrast to clozapine, combining idazoxan with raclopride failed to reverse PCP-induced deficits in PPI. In addition, there was no evidence of an enhancing effect of idazoxan on the blockade of apomorphine-induced disruption of PPI by raclopride. CONCLUSION: The present results challenge the hypothesis that simple alpha(2)/D(2) blockade is sufficient to produce clozapine-like "atypical" antipsychotic activities, and support the consensus that the PPI paradigm represents the most sophisticated behavioral preclinical test for detecting selective "atypical" profile of antipsychotics.

Adrenergic alpha-2 Receptor Antagonists↗

Monoclonal anti-idiotypic antibodies that recognize the binding site for nicotine on rat brain receptor.

Anti-idiotypic monoclonal antibodies have been prepared that represent the internal image of nicotine and are specific for the nicotine binding site on rat brain receptor. Specificity of these antibodies for the combining site on anti-nicotine was demonstrated by their ability to inhibit binding of monoclonal anti-nicotine to immobilized nicotine-polylysine. Furthermore, purified rat brain nicotine receptor but not acetylcholine receptor from fish electric organ effectively competed with anti-nicotine for immobilized nicotine and for immobilized anti-idiotype. Only 9 pmoles of naturally occurring (-)-nicotine inhibited idiotype-anti-idiotype binding by 50% whereas 11 times more (+)-nicotine was required. Acetylcholine, several cholinergic agonists and antagonists, nicotine metabolites, and other structurally related compounds were poor inhibitors.

Animals↗

Developmentally regulated tissue-associated cues influence axon sprouting and outgrowth and may contribute to target specificity.

The heart circuitry of the medicinal leech (Hirudo medicinalis) is a highly stereotyped circuit in the adult, but selection of the heart tube (HT) as a definitive target by heart excitor (HE) motor neurons during embryogenesis involves redirection of axonal arbors. In the present study we have confirmed the specificity of mature innervation using a retrograde marker and have used a combination of tissue/organ coculture and in situ manipulations to test the ability of HT and body wall to support axon outgrowth compared to CNS associated tissue. We also examined the temporal limits of target influence and the specificity of its action. Embryonic and young juvenile HT and body wall, but not adult HT, support or stimulate marked axon outgrowth from CNS ganglia, including those that would not innervate these tissues in vivo. Outgrowth support/stimulation by young tissue is largely contact based with little or no overt selectivity. Thus, outgrowth-supporting cues are developmentally regulated in the periphery, decreasing in efficacy with age while adult CNS-derived tissues consistently provide effective substrates supporting extensive axon outgrowth and regrowth. The HE motor neuron was very discriminating in that it showed little axon extension onto the HT compared to that of other neurons generally. These studies support a role for bidirectional communication in target selection. We suggest a working hypothesis that the HE motor neuron may initially select HT in response to a hierarchy of outgrowth supporting cues that have very broad influence and subsequently responds to selective signals for slowing or stopping growth and terminating on the functionally appropriate target.

Animals↗

The immunologic consequences of laparoscopy in oncology.

The last decade has seen the publication of many studies regarding the impact of both traditional open methods and minimally invasive techniques on a variety of immune function parameters. Clearly, major surgery results in period of cell-mediated immunosuppression that can have an impact on the patient's recovery that would best be avoided. Although there are conflicting data among studies regarding some immune parameters there is general agreement in regards to other variables. The DTH and LPA studies uniformly have shown that open methods result in significantly more immunosuppression than laparoscopic techniques. It seems that the choice of surgical approach does not impact on the absolute number of lymphocytes or lymphocyte subpopulations. There is evidence of a short-lived (less than 1 day) greater shift towards Th2 function, mainly through suppression of the Th1 lymphocyte population, after open surgery than after closed procedures. Regarding circulating monocytes, laparotomy seems to result in greater decreases in HLA-DR expression and monocyte-mediated cytotoxicity while at the same time activating monocytes to elaborate more TNF-alpha and superoxide anion than laparoscopic methods. The data regarding peritoneal macrophages is most confusing; however, most studies do agree that laparotomy results in increased release of cytokines and respiratory burst mediators. The degree to which CO2 pneumoperitoneum suppresses macrophage function is uncertain because, although some studies have shown that CO2 pneumoperitoneum suppresses macrophage function in regards to control animal results, other studies found that the CO2 and control group results are similar. It also is impossible to draw a firm conclusion in regards to the bacterial clearance studies presently. Similarly, the data regarding NK cell counts and function conflict also to the point that a definite conclusion cannot be made. Serum cortisol levels are similar after both types of surgery. The clear majority of the data suggests that open surgery is associated with significantly higher levels of IL-6 and CRP. Minimally invasive methods are less stressful, as judged by these parameters. It seems that one way to avoid or minimize immunosuppression after surgery is to use minimally invasive methods. In theory, based on the animal evidence reviewed in the previous text, laparoscopic cancer resection methods may be associated with improved long-term oncologic outcome. There is no human evidence to support this hypothesis. Middle range results from nonrandomized human cancer colectomy studies, thus far, have yielded outcomes similar to those following open surgery. The incidence of incisional tumor recurrences is similar after both open and closed approaches. The results of the randomized prospective colectomy trials are anxiously awaited. If, as is the case with closed methods, merely preserving the majority of an animal's immune function after surgery lowers the chances of tumor cells establishing metastases, then purposefully stimulating the immune system perioperatively may be a way to avoid the detrimental effects of laparotomy. Such up-regulation of immune function also might improve further the oncologic results after minimally invasive cancer surgery. The early postoperative period may be an ideal window for immune-based anticancer therapies because the tumor burden is at its absolute lowest immediately following resection of the primary. There is strong evidence in the animal setting that a whole host of agents that broadly stimulate the immune system are effective in reducing significantly the incidence of tumor metastases and the growth of tumors after surgery. There also is preliminary evidence that suggests that preoperative tumor vaccines may be an effective means of establishing specific immune responses against the tumor before resection. In theory, the combination of nonspecific perioperative immune up-regulation and preoperative tumor vaccines would provide the patient with the ability to kill tumor cells immediately following surgery period through specific and innate (i.e., nonspecific) immune responses. The arrival of advanced laparoscopic methods for the resection of cancers has led to research that has made it clear that surgery has important detrimental immune consequences. This work also has suggested novel means to avoid postoperative immunosuppression. Minimally invasive methods may be associated with oncologic advantages that go well beyond less pain, a quicker recovery, and a shorter length of stay. More basic science and human studies are needed to shed more light on this intriguing area.

Animals↗

Is there a best transplant conditioning regimen for acute myeloid leukemia?

The outcome of marrow transplantation is largely determined by the effectiveness of the transplant preparative regimen. Nonetheless, there have been startlingly few randomized trials attempting to identify optimal regimens for specific conditions and, at present, no single approach has emerged as superior for the treatment of acute myeloid leukemia (AML) in the few trials that have been performed. Newer approaches that appear encouraging in phase II studies include substituting etoposide for cyclophosphamide, adding thiotepa to the traditional cyclophosphamide plus total body irradiation combination in the setting of T cell depletion, and using antibody-based targeted radiotherapy as part of the transplant regimen. The ability to obtain allogeneic engraftment with nonablative regimens may open the door to additional innovative approaches, combining very specific antileukemia therapy with relatively nontoxic measures to ensure engraftment.

Acute Disease↗

A predictive model for regulatory sequences directing liver-specific transcription.

The identification and interpretation of the regulatory signals within the human genome remain among the greatest goals and most difficult challenges in genome analysis. The ability to predict the temporal and spatial control of transcription is likely to require a combination of methods to address the contribution of sequence-specific signals, protein-protein interactions and chromatin structure. We present here a new procedure to identify clusters of transcription factor binding sites characteristic of sequence modules experimentally verified to direct transcription selectively to liver cells. This algorithm is sufficiently specific to identify known regulatory sequences in genes selectively expressed in liver, promising acceleration of experimental promoter analysis. In combination with phylogenetic footprinting, this improvement in the specificity of predictions is sufficient to motivate a scan of the human genome. Potential regulatory modules were identified in orthologous human and rodent genomic sequences containing both known and uncharacterized genes.

Animals↗

Immunocytochemical analysis of estrogen receptors in human breast carcinomas. Evaluation of 130 cases and review of the literature regarding concordance with biochemical assay and clinical relevance.

An estrogen receptor-immunocytochemical assay (ER-ICA) was performed on frozen sections of 130 samples of human breast carcinoma. A standard dextran-coated charcoal assay (DCCA) was performed on the same samples. Concordance of results between the tests was 91%. The sensitivity and specificity of the ER-ICA, compared with the DCCA, were 92% and 89%, respectively. We describe the ER-ICA technique and review the literature regarding the use of the ER-ICA in evaluating breast cancer with respect to the agreement of results with the DCCA, the nature of discordant results, the ability to predict the clinical response to hormone therapy, and the ability to predict disease-free survival. The combined experience of many studies has shown that the ER-ICA is a highly specific and sensitive method for measuring the level of ERs in breast tumors with a high level of agreement with the DCCA. Early experience has suggested that the ER-ICA can predict the response to hormone therapy and disease-free survival, as well as or better than the DCCA. The evaluation of receptor heterogeneity, made possible by the ER-ICA, may enhance our ability to discriminate ER-positive tumors with a relatively high risk of recurrence.

Breast Neoplasms↗

In silico data filtering to identify new angiogenesis targets from a large in vitro gene profiling data set.

The objective of this study was to use gene expression data from well-defined cell culture models, in combination with expression data from diagnostic samples of human diseased tissues, to identify potential therapeutic targets and markers of disease. Using Affymetrix oligonucleotide array technology, we identified a common profile of genes upregulated during endothelial morphogenesis into tubelike structures in three in vitro models of angiogenesis. Rigorous data selection criteria were used to identify a list of over 1,000 genes whose expression was increased more than twofold over baseline at either 4, 8, 24, 40 or 50 h. To further refine and prioritize this list, we used standard bioinformatic algorithms to identify potential transmembrane and secreted proteins. We then overlapped this gene set with genes upregulated in colon tumors vs. normal colon, resulting in a subset of 128 genes in common with our endothelial list. We removed from this list those genes expressed in 6 different colon tumor lines, resulting in a list of 24 putative, vascular-specific angiogenesis-associated genes. Three genes, gp34, stanniocalcin-1 (STC-1), and GA733-1, were expressed at levels 10-fold or more in colon tumors compared with normal mucosa. We validated the vascular-specific expression of one of these genes, STC-1, by in situ hybridization. The ability to combine in vitro and in vivo data sets should permit one to identify putative angiogenesis target genes in various tumors, chronic inflammation, and other disorders where therapeutic manipulation of angiogenesis is a desirable treatment modality.

Animals↗

The 13C isotope and nuclear magnetic resonance: unique tools for the study of brain metabolism.

As studies of brain metabolism grow in complexity, investigators turn increasingly to nuclear magnetic resonance spectroscopy combined with 13C isotopic labeling. The unique ability to detect labeling non-destructively in specific carbon positions of individual compounds has opened the way to investigate brain metabolism in systems ranging from cellular preparations to the human brain in vivo. This review is written for investigators whose backgrounds do not include detailed knowledge of principles of nuclear magnetic resonance. Its purpose is to show the wide array of NMR techniques for 13C detection that are available for application in different systems to study aspects of brain metabolism, such as metabolic compartmentation and measurements of the tricarboxylic acid cycle rate in vivo. Basic NMR concepts are explained, and, because each detection method possesses specific advantages to address the requirements of different experimental goals, basic explanations and examples are given for each technique. The review should provide readers with a basic understanding of the methods of 13C detection by NMR and assess which of the methods are most applicable to the particular issues they may face in their own research.

Brain↗

Identification and characterization of polypeptide growth factors secreted by murine embryonal carcinoma cells.

Undifferentiated P19 and PC13 murine embryonal carcinoma (EC) cells have been analyzed for their ability to secrete polypeptide growth factors. This has been carried out by a combination of specific bioassays and the use of biochemical and immunological detection methods. Both P19 and PC13 EC cells secrete a platelet-derived growth factor (PDGF)-like growth factor, a type beta transforming growth factor, and insulin-like growth factors. In addition, PC13 EC cells secrete a heparin-binding growth factor functionally related to fibroblast growth factor, while P19 EC cells secrete transforming growth factor-alpha. This is the first demonstration for secretion of transforming growth factor-alpha by an equivalent of early embryonic cells. The possible paracrine growth stimulating effects of these growth factors have been tested on differentiated derivatives of P19 EC cells, corresponding to all three germ layers. The differences in growth factor production by various embryonal carcinoma cells are discussed in relation to the developmental origin of these cell lines.

Animals↗

Pilot study of allele-specific multi-InDel markers for the detection of extremely unbalanced DNA mixtures.

Mixtures are common in forensic casework, and they represent one of the most challenging types of biological evidence. Traditional short tandem repeat analyses are often associated with limitations when dealing with extremely unbalanced mixtures because alleles from minor contributors can easily be masked by those of major contributors. Consequently, researchers have developed new technologies and methods for improving the analysis of mixtures, spanning upstream DNA extraction and downstream software analysis. Among these, strategies combining allele-specific amplification with compound markers have drawn particular interest because of their ability to selectively detect minor contributors in complex mixtures. In this study, we screened multi-InDels across the entire genome, designed allele-specific primers compatible with the capillary electrophoresis platform, and further explored their potential in unbalanced DNA mixtures and cell-free fetal DNA (cffDNA). Ultimately, a set comprising 10 multi-InDels was developed, and this included two groups of primers that separately amplified the long alleles (L primer set) and short alleles (S primer set). The results demonstrated that each primer pair could detect the minor component at a 1:1000 mixture ratio, whereas the L and S primer sets successfully detected the minor contributors at mixture ratios of 1:200 and 1:500, respectively. Furthermore, in the cffDNA analysis, 60 of 78 informative markers were successfully detected, with the complete detection of all informative markers achieved in 18 mother-child reference pairs. Overall, allele-specific amplification-based multi-InDel markers enabled the sensitive detection of minor contributors, providing a potential strategy for the analysis of unbalanced two-person mixtures.

Allelic-specific amplification↗

Murein synthesis and beta-lactam antibiotic susceptibility during rod-to-sphere transition in a pbpA(Ts) mutant of Escherichia coli.

The conditional morphology mutant of Escherichia coli SP45 grows as a rod at 30 degrees C and assumes a spherical shape after 90 min of incubation at 42 degrees C. The rod-to-sphere morphological transition has been found to be associated with the disappearance of penicillin-binding protein 2 (PBP-2), the progressive reduction (as much as 50%) of murein synthesis, as measured both in intact cells and ether-permeabilized bacteria, and alterations in the structure of the cell envelope, including detachment of the outer membrane from the underlying structures. The detachment was initially localized at the poles of the cells and then spread over the entire surface. Shape transition was also linked to increased susceptibility to beta-lactam antibiotics which preferentially bound to PBP-1A (cephalothin, cephaloridine) or to PBP-3 (furazlocillin, piperacillin). Treatment with beta-lactams possessing a high affinity for PBP-1A, although inducing a low degree of peptidoglycan synthesis inhibition (5 to 10%), was associated with a marked loss of cell viability and massive lysis. On the other hand, the simultaneous absence of PBP-2 and inhibition of PBP-3 causes a significant reduction of peptidoglycan synthesis, yet only slightly affected cell viability. Whereas PBP-1A inhibition during shape transition had no effect on morphology, addition of antibiotics binding to PBP-3 30 min after the temperature shift-up caused formation of elongated cells with a centrally located bulge, not observed in similarly treated cells grown at 30 degrees C. Inhibition of PBP-3 in round cells 90 min after temperature shift caused formation of giant cells, indicating complete loss of elongation ability. The different effects of the simultaneous inhibition of two PBPs, combining mutational loss with specific binding in vivo of another PBP by beta-lactams, provide new insight into the role of these proteins and the killing mechanisms of this class of antibiotics.

Bacterial Proteins↗

Screening and early detection of prostate cancer will decrease morbidity and mortality from prostate cancer: the argument against.

The ability of prostate specific antigen, digital rectal examination and transurethral ultrasound, either individually or in combination, to detect unsuspected prostate cancer is beyond doubt. Early detection programmes have revealed prostate cancer in 6% of men over 50 years of age. Most are stage T1c, or confined to the prostate but, protagonists claim that, on the basis of size, they are 'clinically significant'. Mortality from this disease should be reduced by their treatment. Available statistics suggest that the lifetime incidence of 'screen-detected' cancers will far exceed the likelihood of dying from prostate cancer. Given the current operative mortality of total prostatectomy and the physical and psychological morbidity of screening, biopsy and treatment, it is far from certain that mortality or morbidity from prostate cancer will be decreased. Long-term outcome data for T1c prostate cancer do not exist. Is the likelihood of prostate cancer death the same for prostate-specific antigen thresholds of 2, 3 or 4 ng/ml, or from tumours found in 1 of 6, or 1 of 12 needle biopsies? None of this is known. European men deserve the benefit of scientifically based information before being exposed to another North American fashion. Prospective randomised trials investigating mortality, quality of life and cost benefit are the only solution.

Aged↗

Antiemetics.

The development of specific receptor antagonists, especially dopamine and serotonin, has broadened and strengthened the options available for the treatment of nausea and vomiting. In addition to the availability of these specific receptor antagonists, the use of combination regimens has become a major improvement in the ability to reduce side effects of many treatment protocols.

Antiemetics↗