Richard A. Carchman

Light and intermittent cigarette smokers: a review (1989–2009)

RationaleGrowing proportions of smokers in the USA do not smoke everyday and can be referred to as light and intermittent smokers (LITS). Despite a current prevalence of LITS in the USA estimated at 25–33% of all smokers, a systematic review of the literature on this group of smokers has yet to be written.ObjectivesThe aim of this paper is to review and evaluate research on LITS and to identify, describe and discuss commonalities and differences between LITS and daily smokers.MethodsThe primary databases used to search for publications were Pub Med (National Library of Medicine) and SCOPUS (Elsevier).ResultsLITS inhale smoke and have post-smoking blood nicotine concentrations that are broadly equivalent to those found in daily smokers. However, LITS differ from daily smokers with regard to cigarette consumption and frequency of cigarette use, sociodemographic and socioeconomic characteristics, motives, personality traits, dependence, withdrawal and craving, response to smoking-related cues, quitting perception, past-smoking status, and initiation.ConclusionsIn contrast to daily smokers, LITS show few or no signs of dependence as currently defined by DSM-IV criteria, appear to exercise more self-control, seem to be less impulsive, and their smoking experience is primarily associated with positive rather than negative reinforcement. Conclusions drawn from the reviewed literature highlight the multivariate factors that must be taken into account when defining LITS and emphasize the importance of further research on this increasing fraction of smokers. The potential implications of increased LITS prevalence on smoking-related disease risks remain to be thoroughly investigated.

Prostacyclin: A potent stimulator of adrenal steroidogenesis

The relative potencies of various prostaglandins were investigated in trypsin-dispersed cat adrenocortical cells. Prostacyclin proved to be the most potent steroidogenic prostaglandin, being 100-1000 times more potent than PGE2. This stimulant effect of prostacyclin was only partially dependent upon the presence of extracellular calcium and was associated with increased levels of cyclic AMP. These data suggest a possible role for prostacyclin in corticosteroidogenesis.

Humoral and cell-mediated immune status in mice exposed to trichloroethylene in the drinking water☆

Abstract A 14-day study using male CD-1 mice exposed to trichloroethylene (TCE) by daily po gavage suggested inhibition of cell-mediated immunity. Therefore, an evaluation of the immune status was undertaken after exposure of male and female mice to TCE in the drinking water for either 4 or 6 months. The immunological parameters assessed were humoral immunity, cell-mediated immunity, lymphocyte responsiveness, bone marrow function, and macrophage function. Females were more affected than males by TCE, particularly after a 4-month exposure. In the female, humoral immunity was inhibited only at the highest concentrations of TCE (2.5 and 5 mg/ml), whereas cell-mediated immunity and bone marrow stem cell colonization were inhibited at all four concentrations of TCE (0.1, 1.0, 2,5, and 5 mg/ml). The males were relatively unaffected after both 4 and 6 months compared to effects observed in the 14-day study.

Application of Response Surface Methods for Evaluating the Interactions of Soman, Atropine, and Pralidioxime Chloride

Response surface methods were employed to model survival data obtained in guinea pigs following subcutaneous exposure to soman (GD; 30-84.6 micrograms/kg) with various treatment regimens (i.e., atropine/pralidioxime chloride [ATR/2-PAM] combinations, given im, 1 min post-GD). The analysis of the proportions of surviving animals in the various groups revealed that the use of individual treatment agents (i.e., ATR or 2-PAM) was effective in increasing survival. The level of GD exposure altered the nature of the ATR/2-PAM interaction. Exploration of the response surface indicates that the optimal treatment combinations (greater than 94% survival) of ATR/2-PAM change as a function of GD exposure in the following manner: GD 30 micrograms/kg-ATR/2-PAM, 217 mg/kg/0 mg/kg; GD 42.4 micrograms/kg-179/29 mg/kg; mg/kg; GD 60 micrograms/kg-148/83 mg/kg; GD 84.6 micrograms/kg-168/150 mg/kg. At higher exposures of GD (greater than 42.4 micrograms/kg), therapeutic synergy was observed with the use of the treatment combinations, as compared to optimal single agent treatments. Evaluation of the apparent toxicities of treatment combinations can also be determined in this procedure. RSM is not geometrically restricted by the number of variables under consideration. A variety of experimental designs, when used in conjunction with RSM, permit the modeling of multiple responses and provide estimates of optimal therapeutic modalities subject to constraints (e.g., behavioral toxicity).

Human T lymphocyte mitogenesis in response to the B oligomer of pertussis toxin is associated with an early elevation in cytosolic calcium concentrations

Pertussis toxin was found to serve as a mitogen in the human T lymphocyte, an effect which could be mimicked by its resolved binding component, the B oligomer. The mechanism of action of this component appeared to involve a rapid and sustained elevation of cytosolic calcium levels, as monitored by fura‐2 fluorescence. The source of mobilized calcium was predominantly extracellular, suggesting that the binding of the B oligomer to the T cell plasma membrane in some way elicited calcium channel activation. Notably, the influx of calcium was not observed with cholera toxin, an AB toxin lacking mitogenic effects on the human T lymphocyte.

Chronic nose-only inhalation study in rats, comparing room-aged sidestream cigarette smoke and diesel engine exhaust.

Nose-only exposure of male and female Wistar rats to a surrogate for environmental tobacco smoke, termed room-aged sidestream smoke (RASS), to diesel engine exhaust (DEE), or to filtered, fresh air (sham) was performed 6 hours/day, 7 days/week for 2 years, followed by a 6-month post-exposure period. The particulate concentrations were 3 and 10 mg/m3. Markers of inflammation in bronchoalveolar lavage showed that DEE (but not RASS) produced a dose-related and persistent inflammatory response. Lung weights were increased markedly in the DEE (but not RASS) groups and did not decrease during the 6-month post-exposure period. Bulky lung DNA adducts increased in the RASS groups, but not in the DEE groups. Cell proliferation in the lungs was unaffected by either experimental treatment. Histopathological responses in the RASS groups were minimal and almost completely reversible; lung tumors were similar in number to those seen in the sham-exposed groups. Rats exposed to DEE showed a panoply of dose-related histopathological responses: largely irreversible and in some cases progressive. Malignant and multiple tumors were seen only in the DEE groups; after 30 months, the tumor incidence (predominantly bronchiolo-alveolar adenomas) was 2% in the sham-exposed groups, 5%in the high RASS groups, and 46% in the high DEE groups (sexes combined). Our results suggest that in rats exposed to DEE, but not to RASS, the following series of events occurs: particle deposition in lungs → lung “overload” → pulmonary inflammation → tumorigenesis, without a significant modifying role of cell proliferation or DNA adduct formation.

Kepone: cellular sites of action.

Kepone produced a dose-dependent inhibition of cellular proliferation, stimulation of respiration, and a bimodal alteration (enhancement preceding depression) of phagocytic activity in the P388D1 “macrophage-like” cell in tissue culture. Dinitrophenol, an uncoupler of oxidative phosphorylation, similarly inhibited cellular proliferation and stimulated respiration. Kepone (IC50 = 3.5 × 10−6 M) was 77 times more potent than dinitrophenol (IC50 = 2.7 × 10−4 M) by the method of Litchfield and Wilcoxon. The dose-response curves did not deviate significantly from parallelism, suggesting that the mechanisms of toxicity may be similar. The binding of 14C-Kepone to the cells in culture was determined. After 60 min of preincubation, 1% of the Kepone was bound to the cells. Since it has been postulated that the clinical syndrome of Kepone toxicity in humans may be due to an alteration in calcium metabolism, the effect of Kepone on the kinetics of free radiocalcium distribution was determined. Kepone decreased the size of the mitochondrial exchangeable calcium pool while increasing the efflux rate constant of that organelle. The effects of Kepone on energy metabolism and cellular calcium distribution may be cellular events related to the observed in vivo toxicity.

Inhibition of rat brain mitochondrial calcium transport by chlordecone

Abstract Assessment of 45 Ca 2+ transport in rat brain mitochondria following in vitro and in vivo exposures to the neurotoxic insecticide chlordecone revealed a locus for chlordecones mitochondrial impairment in the coupling reactions of oxidative phosphorylation. Mitochondrial 45 Ca 2+ transport supported by either 2 m m succinate (free energy supplied via electron transport) or 800 μ m ATP (free energy supplied via the Mg 2+ ATPase reaction) was inhibited by low concentrations of chlordecone (10 −8 –10 −5 m ). Administration of a tremorigenic dose (40 mg/kg, po) of chlordecone to rats similarly inhibited both succinate- and ATP-supported 45 Ca 2+ uptake in brain mitochondria in vitro . Studies on the subcellular distribution of [ 14 C]chlordecone in rat brain following in vivo administrations were compared to those on the mitochondrial uptake of [ 14 C]chlordecone in vitro . Administration of the 40-mg/kg tremorigenic dose of chlordecone produced mitochondrial chlordecone concentrations which were comparable to the tissue concentrations achieved by exposing mitochondria to a 2 × 10 −6 m concentration of chlordecone in vitro . These data lend further support for mitochondrial inhibition as a mechanism for chlordecone toxicity.

Angiofollicular lymph node hyperplasia (Castleman's disease) in an adolescent female. Clinical and immunologic findings

Angiofollicular lymph node hyperplasia is a heterogeneous disorder of unclear etiology and has a wide spectrum of systemic symptoms. This report describes a case of this disorder in a 15‐year‐old girl and examines the response of the primary mass, systemic symptoms, and alterations of selected immune parameters at diagnosis, as a result of steroid therapy and radiation therapy (RT). The patient had a 1‐year history of growth failure, delayed puberty, and refractory iron deficiency anemia. Computed tomography scan showed a posterior mediastinal mass. Biopsy revealed angiofollicular lymph node hyperplasia of mixed hyaline‐vascular and plasma cell type histologic type. Immunoperoxidase studies showed polyclonal B‐cells, predominance of T‐helper cells (CD4) over cytotoxic/suppressor T‐cells (CD8), and the presence of natural killer (NK) cells. Southern blot analysis demonstrated germ line gene configuration for the T‐cell antigen receptor and Ig heavy chain. The patient clinically improved with RT after failing to respond to steroids. Immunophenotyping of peripheral blood lymphocytes before therapy revealed a CD4:CD8 ratio of 0.8 with decreased numbers of circulating T‐cells; this increased to 1.4 after steroid therapy. The patients T‐lymphocytes had no proliferative response to phytohemagglutinin (PHA) or concanavalin A (Con A) before RT. After RT, a small but significant mitogenic response to these reagents was noticed. The proliferative response to recombinant interleukin‐2 (rIL‐2) remained similar to that of control lymphocytes. Induction of second messenger signals by activation of protein kinase C (PKC) and elevation of free cytosolic calcium through the use of the phorbol ester, phorbol 12, 13‐dibutyrate (PDBu), and ionomycin (Io) resulted in a strong proliferative response at diagnosis and after RT. In vitro cytotoxicity assays revealed diminished NK activity before and after therapy. Lymphokine‐activated killer (LAK) activity remained comparable with that of control cells and was not affected by therapy. Before RT patient lymphocytes maintained cytotoxic capabilities after coincubation with rIL‐2 and PDBu plus Io, whereas coincubation with these reagents abrogated cytotoxic function of normal cells. This case demonstrates a clinical response to RT as well as improvement in immune parameters. Intact signal transduction mechanisms through PKC activation and elevation of cytosolic calcium were also demonstrated in the circulating lymphocytes.

Biochemical characteristics of phagocytosis in the p388 d1 cell.

Adherence and phagocytosis of 51chromium labeled sheep red blood cells ([51Cr]-sRBC) by P388 D1 cells in tissue culture were studied under various conditions and were found to possess certain requirements including opsonization, temperature, microfilaments and cyclic nucleotide levels. Exogenous administration of 10−2 M N6, O2-dibutyryl adenosine 3′–5′ cyclic monophosphoric acid (db-cAMP) or adenosine 3′–5′ cyclic monophosphoric acid (cAMP) inhibited phagocytosis of opsonized [51Cr]-sRBC by 36 and 42%, respectively. Aminophylline potentiated the inhibitory response to both cAMP and db-cAMP. The measurement of endogenous cyclic nucleotide levels during phagocytosis of opsonized sRBC showed a rise in guanosine 3′–5′ cyclic monophosphate (cGMP) during the first 5 min with a gradual decline to control levels at 45 min and a rise in cAMP levels reaching a peak at 30 min which remained above control values for the duration of the experiment. As the rate of phagocytosis decreased the ratio of cAMPcGMP increased. These observations emphasize the importance of metabolic functions and cyclic nucleotides during phagocytosis by the P388 D1 cells and strengthen the usefulness of the P388 D1 cells as a model in evaluating various macrophage activities.