CXCR2 expression during melanoma tumorigenesis controls transcriptional programs that facilitate tumor growth.

BACKGROUND: Though the CXCR2 chemokine receptor is known to play a key role in cancer growth and response to therapy, a direct link between expression of CXCR2 in tumor progenitor cells during induction of tumorigenesis has not been established. METHODS: To characterize the role of CXCR2 during melanoma tumorigenesis, we generated tamoxifen-inducible tyrosinase-promoter driven BrafV600E/Pten-/-/Cxcr2-/- and NRasQ61R/INK4a-/-/Cxcr2-/- melanoma models. In addition, the effects of a CXCR1/CXCR2 antagonist, SX-682, on melanoma tumorigenesis were evaluated in BrafV600E/Pten-/- and NRasQ61R/INK4a-/- mice and in melanoma cell lines. Potential mechanisms by which Cxcr2 affects melanoma tumorigenesis in these murine models were explored using RNAseq, mMCP-counter, ChIPseq, and qRT-PCR; flow cytometry, and reverse phosphoprotein analysis (RPPA). RESULTS: Genetic loss of Cxcr2 or pharmacological inhibition of CXCR1/CXCR2 during melanoma tumor induction resulted in key changes in gene expression that reduced tumor incidence/growth and increased anti-tumor immunity. Interestingly, after Cxcr2 ablation, Tfcp2l1, a key tumor suppressive transcription factor, was the only gene significantly induced with a log2 fold-change greater than 2 in these three different melanoma models. CONCLUSIONS: Here, we provide novel mechanistic insight revealing how loss of Cxcr2 expression/activity in melanoma tumor progenitor cells results in reduced tumor burden and creation of an anti-tumor immune microenvironment. This mechanism entails an increase in expression of the tumor suppressive transcription factor, Tfcp2l1, along with alteration in the expression of genes involved in growth regulation, tumor suppression, stemness, differentiation, and immune modulation. These gene expression changes are coincident with reduction in the activation of key growth regulatory pathways, including AKT and mTOR.

Characteristic findings of cervical Papanicolaou tests from transgender patients on androgen therapy: Challenges in detecting dysplasia.

INTRODUCTION: The characteristic features of Papanicolaou (Pap) tests collected from female-to-male (FTM) transgender patients on androgen therapy have not been well defined in the literature. FTM transgender patients require cervical cancer screening with the same recommended frequency as cis-gender females. Dysplasia remains challenging to differentiate from atrophy. Without pertinent history, the atrophic findings in younger transgender patients can be misinterpreted as high-grade dysplasia. METHODS: A review of all cervical Pap tests of transgender patients receiving androgen therapy (2010-2017) was performed. Bethesda diagnosis, cytomorphological features, HPV testing and cervical biopsy results were reviewed. RESULTS: Eleven transgender patients receiving androgen therapy were identified with 23 cervical Pap tests, 11 HPV tests and five cervical biopsies performed. A review of the Pap tests demonstrated: 57% negative for intraepithelial lesion; 13% unsatisfactory; 13% atypical squamous cells of undetermined significance; 13% atypical squamous cells - cannot exclude high-grade squamous intraepithelial lesion; and 4% high-grade squamous intraepithelial lesion. The rates of abnormal tests were higher than our age-matched cis-gender atrophic cohort rates of unsatisfactory (0.5%), atypical squamous cells of undetermined significance (7%), atypical squamous cells-cannot exclude high-grade squamous intraepithelial lesion (0%) and high-grade squamous intraepithelial lesion (0.5%). The cytological findings from liquid-based preparations included dispersed and clustered parabasal-type cells, scattered degenerated cells, smooth evenly dispersed chromatin, and occasional mild nuclear enlargement and irregularity. Dysplastic cells had larger nuclei, hyperchromatic clumped chromatin, and more irregular nuclear contours. CONCLUSIONS: The evaluation of dysplasia can be challenging on Pap tests from transgender patients on androgen therapy. The cohort evaluated had higher rates of unsatisfactory and abnormal Pap tests. Pathologists should be familiar with the distinctive cytomorphological changes in the Pap tests from patients on androgen therapy to evaluate them appropriately.

Age cut-off for reporting endometrial cells on a Papanicolaou test: 50 years may be more appropriate than 45 years.

OBJECTIVE: The 2001 Bethesda System for Reporting Cervical Cytology includes documenting 'endometrial cells in women ≥40 years of age' (E40) to help identify endometrial carcinoma (EC) on a Papanicolaou (Pap) test. The 2014 Bethesda System for Reporting Cervical Cytology raises the threshold to ≥45 years of age (E45). As many of these women are menstruating, routine biopsy after E40, or even E45, may lead to unnecessary procedures for benign endometrial cells. Establishing a different age threshold in combination with other clinical findings may help to guide management. METHODS: A retrospective chart review was performed on consecutive EC specimens and E40 Pap tests. Clinical, pathological data such as age, biopsy diagnosis, FIGO grade and the time of the last Pap test, Pap test diagnosis and resection diagnosis, depth of invasion, stage and metastases were recorded. RESULTS: Sixty-three EC cases had prior Pap smears, with the following diagnoses: negative for an intraepithelial lesion or malignancy (n = 27), atypical glandular cells, not otherwise specified (AGC, NOS) (n = 14), adenocarcinoma (n = 10) and E40 (n = 1; 51 years). Six hundred and forty-two E40 cases had 138 (21.5%) biopsies and/or hysterectomies. Out of the 138 cases, two (1.4%) had EC (both 51 years; postmenopausal), one had complex hyperplasia with atypia (52 years; abnormal uterine bleeding), and eight had hyperplasia without atypia. CONCLUSIONS: In asymptomatic women less than 50 years, E40 correlated with benign, non-hyperplastic endometrium. However, post-menopausal women with E40 had a risk of EC. Perhaps endometrial cells should only be reported in post-menopausal women or women greater than or equal to 50 years of age.

Disposition of midazolam in asphyxiated neonates receiving therapeutic hypothermia--a pilot study.

Moderate hypothermia has become an established therapy for asphyxiated neonates. Midazolam is a frequently used sedative for this indication, although it has never been investigated how therapeutic hypothermia and asphyxia influence midazolam metabolism in neonates.9 asphyxiated newborns were treated with whole body hypothermia of 32-34°C for 72 h and all of them received continuous midazolam infusion for sedation. Serum concentrations of midazolam and its metabolites 1-hydroxy-midazolam and 4-hydroxy-midazolam were measured during hypothermia and the rewarming period. Renal and hepatic parameters were assessed to take into account the influence of asphyxia related renal or hepatic impairment.We found a high interindividual variability of serum midazolam concentrations in asphyxiated neonates with therapeutic hypothermia; median midazolam concentration was 369.3 ng/ml (minimum 36.6; maximum 3 218.6 ng/ml). The population pharmacokinetic model revealed a midazolam clearance of 2.57 ml/kg/min, comparable to midazolam clearances observed in normothermic critically ill neonates. However, midazolam clearance was significantly decreased in patients with asphyxia related renal and hepatic impairment.It seems that isolated hypothermia does not significantly influence midazolam metabolism. However, neonates with asphyxia related hepatic and renal impairment are at risk of generating unexpectedly high serum midazolam concentrations. In addition pronounced interindividual variability of midazolam metabolism may contribute to dangerously high midazolam concentrations.

[Randomly discovered enlargement in the region of sella turcica]. / Náhodne zjistené expanze v selární oblasti.

Computer tomography (CT) and magnetic resonance imaging (MRI) quite often detect unexpected cases of enlargement in the hypothalamus-hypophysial region, without the above methods being indicated for clinical manifested symptomatology provoked by the tumour. This is not surprising if we consider that autopsies show the presence of hypophysial adenomas of 10-15% of population on an average. X ray, CT or MRI are indicated in the case of head traumas, lateral nasal cavity inflammations, headaches, strokes, neurological diseases and other disorders. A number of tumours of diverse etiology occur in the hypothalamus-hypophysial region, but hypophysial adenomas are by far the most frequent among all (above 90 %). Among other primary enlargements, the most frequent are craniopharyngeomas and meningeomas, while other enlargements are by fare less common. Such randomly detected tumours are mostly asymptomatic, but targeted anamnesis may show some of the symptoms quite clearly. The symptomatology can be linked with possible slight hormonal overproduction of hypophysial adenomas, a deficit of hypophysial hormones or local manifestations of expansion. Exact assessment of MRI results, of hormonal activity of the enlargement, of the relation to surrounding structures, especially the optic nerves, and the assessment of hypophysial functions are important for the therapeutic decision. Depending on the type and extension of the tumour the options considered are pharmacotherapy (the treatment of choice in the case of prolactinomas), surgery, radiotherapy (today prevailingly using the gamma knife), and if no intervention is necessary, follow up with regular MRI examinations. Tumorous growth is more often observed in "macroadenomas" than in "microadenomas" (up to 10 mm).

Combination antimicrobial therapy in patients with Staphylococcus aureus bacteraemia-a post hoc analysis in 964 prospectively evaluated patients.

OBJECTIVES: The evidence for using combination antimicrobial therapy (CoRx) in Staphylococcus aureus bacteraemia (SAB) is limited. We aimed to investigate whether CoRx is associated with higher survival or lower SAB-related late complications. METHODS: We performed a post hoc analysis of a prospective SAB cohort study. CoRx was defined as a cell wall-active antistaphylococcal agent plus either rifampicin, a fluoroquinolone, fosfomycin or an aminoglycoside. To adjust for survivor bias multivariable Cox models that included CoRx as a time-dependent covariable were calculated. RESULTS: Of 964 evaluable patients, 512 (53%) received CoRx, most of them (301/512, 59%) rifampicin-containing CoRx. All-cause mortality after 30 and 90 days was similar for the two groups, although the patients in the CoRx group had more often endocarditis, deep-seated or disseminated infections and severe sepsis/septic shock. For the entire cohort, only age, comorbidity and severe sepsis/septic shock were associated with a higher mortality and infectious disease consultation, but not CoRx with a lower mortality. However, in the subgroup of patients with implanted foreign bodies or devices CoRx was independently associated with a lower mortality at 30 days (hazard ratio 0.6, 95% confidence interval 0.3-1.1) and at 90 days (hazard ratio 0.6, 95% confidence interval 0.4-0.9). SAB-related late complications in this subgroup occurred in 15 (10.6%) of 142 patients in the monotherapy group vs. nine (4.5%) of 202 patients in the CoRx group (p 0.03). CONCLUSIONS: In a setting of optimized management of adult patients with SAB secured by infectious disease consultations, this observational study could not prove CoRx to be independently associated with improved survival or reduced late complications in the entire cohort. However, administration of CoRx may be associated with lower mortality and fewer SAB-related late complications in the subgroup of patients with implanted foreign bodies or devices. Prospective randomized trials should be performed to prove this benefit.

Plasma levels of total and active ghrelin in acromegaly and growth hormone deficiency.

Ghrelin is an endogenous growth hormone (GH) secretagogue recently isolated from the stomach. Although it possesses a strong GH releasing activity in vitro and in vivo, its physiological significance in endogenous GH secretion remains unclear. The aim of this study was to characterize plasma ghrelin levels in acromegaly and growth hormone deficiency (GHD). We investigated plasma total and active ghrelin in 21 patients with acromegaly, 9 patients with GHD and 24 age-, sex- and BMI-matched controls. In all subjects, we further assessed the concentrations of leptin, soluble leptin receptor, insulin, IGF-I, free IGF-I and IGFBP-1, 2, 3 and 6. Patients with acromegaly and GHD as well as control subjects showed similar levels of total ghrelin (controls 2.004+/-0.18 ng/ml, acromegalics 1.755+/-0.16 ng/ml, p=0.31, GHD patients 1.704+/-0.17 ng/ml, p=0.35) and active ghrelin (controls 0.057+/-0.01 ng/ml, acromegalics 0.047+/-0.01 ng/ml, p=0.29, GHD patients 0.062+/-0.01 ng/ml, p=0.73). In acromegalic patients plasma total ghrelin values correlated negatively with IGF-I (p<0.05), in GHD patients active ghrelin correlated with IGF-I positively (p<0.05). In the control group, total ghrelin correlated positively with IGFBP-2 (p<0.05) and negatively with active ghrelin (p=0.05), BMI (p<0.05), WHR (p<0.05), insulin (p=0.01) and IGF-I (p=0.05). Plasma active ghrelin correlated positively with IGFBP-3 (p=0.005) but negatively with total ghrelin and free IGF-I (p=0.01). In conclusion, all groups of the tested subjects showed similar plasma levels of total and active ghrelin. In acromegaly and growth hormone deficiency plasma ghrelin does not seem to be significantly affected by changes in GH secretion.

[The use of benzodiazepines and Z-drugs for patients with sleeping problems - A survey among hospital doctors and nurses]. / Benzodiazepine und Z-Substanzen als Schlaf- und Beruhigungsmittel in einem Krankenhaus.

Aim | Benzodiazepines and Z-drugs are frequently prescribed sleep medications in spite of their poor risk-benefit ratio when used over a longer period of time. The aim of the study was to find out how the medical and nursing staff in a general hospital estimated the frequency of use for these drugs, and the risk-benefit ratio for elderly patients as well as the factors which positively influence the perceived use of these drugs. Methods | All members of the medical and nursing staff of a hospital received a questionnaire about their use of, and attitudes towards, benzodiazepines and Z-drugs. Absolute and relative frequencies were calculated to estimate the perceived frequency of use and the risk-benefit ratio. Multiple logistic regressions were used to analyze which factors are associated with a perceived high use of benzodiazepines or Z-drugs for insomnia. Results | More nurses than hospital doctors believed that they dispensed benzodiazepines often or always (57 % vs. 29 %) to patients with insomnia; this was also the case for Z-drugs (66 % vs. 29 %). Nearly half of the hospital doctors and 29 % of the nurses perceived more harms than benefits for benzodiazepines in the elderly. The following factors were associated with a high perceived usage of Z-drugs: working as a nurse (OR: 13,95; 95%-CI: 3,87-50,28), working in a non-surgical department (5,41; 2,00-14,61), having < 5 years of professional experience (4,90; 1,43-16,81) and feeling that the benefits of Z-drugs outweigh the risks for elderly patients (5,07; 1,48-17,35). For benzodiazepines, only the perceived positive risk-benefit ratio had an influence on the perceived use (3,35; 1,28-8.79). Conclusion | The medical and nursing staff perceived the frequency of prescription of benzodiazepines and Z-drugs and the risk-benefit ratio in different ways. Other aspects, such as working in a non-surgical department or having a smaller amount of working experience may also influence the decision to use Z-drugs.

Signalling pathways in two-component phosphorelay systems.

Two-component systems are characterized by phosphotransfer reactions involving histidine and aspartate residues in highly conserved signalling domains. Although the basic principles of signal transduction by these systems have been elucidated, several important aspects, such as their integration into more complex cellular regulatory networks and the molecular basis of the specificity of signal transduction, remain unknown.

Dimerization of signalling modules of the EvgAS and BvgAS phosphorelay systems.

Biophysical and biochemical properties of signalling proteins or domains derived from the unorthodox EvgAS and BvgAS two-component phosphorelay systems of Escherichia coli and Bordetella pertussis were investigated. Oligomerization of the effector proteins EvgA and BvgA and of truncated EvgS and BvgS derived signalling proteins containing the receiver and histidine containing phosphotransfer (HPt) domains or comprising only the HPt domains were characterized by native gel electrophoresis, gel permeation experiments and analytical ultracentrifugation. The results obtained by the different methods are consistent with non-phosphorylated EvgA and BvgA proteins being dimers in solution with a dissociation constant significantly below 1 microM. In contrast, all sensor derived domains of EvgS and BvgS were observed to be monomers in vitro. No indications for a phosphorylation induced stimulation of oligomerization of the C-terminal histidine kinase domains could be detected. In agreement with these data, surface plasmon resonance studies revealed a 2:1 stoichiometry in the interaction of EvgA with the immobilized EvgS HPt domain and an affinity constant of 1. 24x10(6) M(-1).

Functional model of subcomponent C1 of human complement.

The domain organization of the zymogen subunits of the first component of human complement C1s, C1r2 and the complex C1s-C1r2-C1s was studied by electron microscopy. In the absence of Ca2+, monomeric C1s was visualized as a dumb-bell-shaped molecule consisting of two globular domains (center-to-center distance 11 nm) connected by a rod. One of the globular domains is assigned to the light chain (B-chain) of the activated molecule, which is homologous to trypsin and other serine proteases. The second globular domain and the rod are assigned to the heavy chain (A-chain) of CIs. The subunit C1r is a stable dimer in the presence or absence of Ca2+. This dimer C1r2 was visualized as composed of two dumb-bells of dimensions similar to those observed for C1s. These are connected near the junctions between the rod and one of the globular domains. This leads to the structure of an asymmetrical X with two inner closely spaced globules (center-to-center distance 7 nm) and two outer globules at a larger distance (14 nm). By comparison with fragment C1rII2, in which part of the A-chain is removed, the inner globular domains were assigned to the catalytic B-chains. This characteristic structure of C1r2 is readily recognized in the central portion of the thread-like 54 nm long C1s-C1r2-C1s complex formed in the presence of Ca2+. By affinity-labeling of C1s with biotin and visualization of avidin-ferritin conjugates in the reconstituted complex, it was demonstrated that C1s forms the outer portion of the complex. A detailed model of C1s-C1r2-C1s is proposed, according to which two C1s monomers bind to the outer globes of C1r2 by contacts between their heavy chains and those of C1r. According to this model the catalytic domains of C1r are located in the center and those of C1s at the very tips of the C1s-C1r2-C1s complex. On the basis of the structure of C1s-C1r2-C1s, we derived a detailed model of the C1 complex (composed of C1q and the tetrameric complex) and we discuss this model with a view to finding a possible activation mechanism of C1.(ABSTRACT TRUNCATED AT 400 WORDS)

Rational design and molecular characterization of a chimaeric response regulator protein.

BvgA and EvgA are closely related response regulators from Bordetella pertussis and Escherichia coli. To analyze the domain borders and linker sequences of these proteins, we used limited proteolysis and matrix-assisted laser desorption/ionization-mass spectrometry analysis of the in-gel-digested proteolytic fragments. The thermolysin-sensitive linker regions were found to extend from Leu130 to Thr144 for BvgA and from Leu127 to Ser133 for EvgA. These data provided the rationale for the construction of the chimaeric protein HA. HA carries the EvgA receiver and BvgA output domains, fused in the central part of the linker sequences of the parent proteins. Thermolysin-sensitive sites of HA were found at positions identical with those in the EvgA and BvgA linker sequences, indicating intact folding of its receiver and output domains. Consistent with this, the chimaera showed virtually unchanged phosphorylation and dimerization properties. However, BvgA and HA differed in the effect of phosphorylation on their DNA-binding activities. In the case of BvgA, phosphorylation resulted in an increased affinity and specificity in DNA binding, whereas the DNA-binding properties of HA were not affected by phosphorylation. The chimaera HA was unable to activate transcription of the BvgA-dependent fha promoter, either in vivo or in vitro. These results indicate that the phosphorylation-induced activation of BvgA requires specific interactions between the receiver and output domains that are disturbed in the chimaera.

Direct effects of minoxidil on epidermal cells in culture.

Minoxidil, a potent antihypertensive agent, induces generalized hypertrichosis when administered systemically, or localized hair regrowth when applied topically to sites of severe alopecia areata. The pharmacologic mechanisms by which minoxidil stimulates hair growth are unknown. This study was designed to examine whether minoxidil has direct effects on neonatal murine epidermal cells in culture. In the presence of minoxidil, cultures showed a marked dose-dependent second peak of DNA synthesis 8-10 days after culture initiation. In addition, two morphologically distinct cell types appeared. Indirect immunofluorescence staining with keratin-specific antibody revealed cytoplasmic keratin fibers, suggesting the epidermal origin of these cells. Our experiments demonstrate that minoxidil can affect epidermal cells in culture by altering their growth pattern and phenotypic appearance.

Immunopathology of psoriasis: a comparison with other parakeratotic lesions.

Characteristic in vivo binding of IgG and C3 to the stratum corneum of psoriatic lesions has been implicated as a significant event in the pathogenesis of the disease. Immunofluorescent findings of psoriatic lesions are compared with other parakeratotic and nonparakeratotic lesions. Parakeratotic lesions studied include verrucae vulgares in patients with psoriasis, verrucae vulgares in patients without psoriasis, actinic keratoses and lichen simplex chronicus. Psoriatic lesions and other parakeratotic lesions demonstrate similar immunopathological phenomena within the involved stratum corneum: (1) A high percentage of the lesions stain positively with one or more of the immunoglobulins (IgG, IgM and IgA). (2) No predominance of any immunoglobulin class is found. (3) The predominant sites of immunoglobulin deposition are within the regions of parakeratosis. (4) C3 deposition is found in a high percentage of the lesions and is present at the sites of immunoglobulin binding. By contrast only a small percentage of nonparakeratotic lesions display stratum corneum fluorescence. These data are consistent with macromolecular leakage through the lesional microvasculature and high affinity binding of immunoglobulins by parakeratotic stratum corneum. Similar immunofluorescent findings in psoriatic lesions and nonpsoriatic parakeratotic lesions suggest that immunoglobulin binding in psoriatic lesional stratum corneum is not a significant event in the pathogenesis of psoriatic lesions.

Quantification of scalp hair--a computer-aided methodology.

A method for obtaining a quantitative assessment of hair density is described. First, a photographic image of the scalp is digitized onto a high-resolution computer graphics screen. Second, the frequency of each of 256 gray levels (one for each of 500 vertical X 500 horizontal = 250,000 locations on the screen) is obtained and the frequency histogram of gray levels is displayed. Third, a statistical procedure, gaussian mixture analysis, is used to resolve the frequency distribution into two normally distributed component distributions. The first component distribution describes the range of gray levels that are typically associated with hair. The second component distribution describes shades of gray that are typically associated with scalp. The statistical model provides a precise measure of the proportion of the head that exhibits gray levels in each of the two component distributions (hair or scalp). The proportion of the first component distribution is a scale-independent measure of hair density. The difference in this quantity before and after treatment provides an accurate quantitative determination of the change in hair density and hence of the efficacy of treatment.

Titration of nicotine intake with full-length and half-length cigarettes.

Titration, the self-regulation of nicotine intake, was studied in 12 smokers by gas chromatograph assays of urinary nicotine levels. Results demonstrated that excretion of urinary nicotine in the proximal condition (half cigarette close to the filter) did not differ significantly from the whole cigarette condition; however, less nicotine was excreted in the distal condition (half cigarette farther from the filter) because of a rod filtration effect. Subjects extracted proportionately more nicotine from the half than from the whole cigarettes; titration was approximately the same in both half-cigarette conditions. On scales of strength and satisfaction, full-length cigarettes were given the highest rating, followed by proximal and then distal cigarettes.

Plasma nicotine and cotinine concentrations in habitual smokeless tobacco users.

Plasma nicotine and cotinine levels were measured in habitual users of smokeless tobacco. The subjects were 12 male college students who regularly used smokeless tobacco (11 dipped snuff and one chewed tobacco) and did not smoke cigarettes. Subjects abstained from tobacco use overnight and blood was drawn at 8 A.M. and again after a single day of ad libitum consumption of their own tobacco product. Subjects recorded the times at which tobacco was used and the remainder product was weighed. Plasma samples were analyzed by both gas-liquid chromatography (GLC) and radioimmunoassay (RIA) techniques. Subjects consumed about one third of a can of moist ground snuff (10.8 gm) in eight dips spaced throughout the day. Nicotine absorption was observed and an increase in mean plasma concentration fro 2.9 ng/ml after overnight abstinence to 21.6 ng/ml after 6 to 8 hr ad libitum consumption was recorded. Plasma cotinine concentrations rose from a morning mean of 137.3 ng/ml to an afternoon mean of 197.2 ng/ml, concentrations that are typical of those reached in regular cigarette smokers. Subjects fell into two subgroups by post hoc analysis: two-thirds absorbed substantial amounts of nicotine and one-third appeared to have almost no absorption. Subjective effects of tobacco use were not marked; there was little perception of physiologic changes, stimulation, or feelings of relaxation/satisfaction. Results are discussed in terms of pharmacologic effects, comparison of results from GLC and RIA methodologies, and implications for health behaviors.

Craniofacial abnormalities and their relevance for sleep apnoea syndrome aetiopathogenesis in acromegaly.

OBJECTIVE: To explain the effect of craniofacial relations on the development of the sleep apnoea syndrome (SAS) in acromegaly, and to elucidate how the activity of acromegaly affects the severity of SAS. DESIGN: Prospective observational study. METHODS: Cephalometry and sleep ventilation measurements were performed in 26 acromegalic men and in 96 men with SAS. RESULTS: SAS was found in 20 acromegalic men. Compared with non-acromegalic men with SAS, patients with acromegaly and SAS were found to have: enlargement of almost all linear dimensions; increased angle indicating mandibular protrusion; increased difference between maxillary and mandibular protrusion; articular angle decrease; soft palate lengthening; and pharyngeal airway space (PAS) enlargement in the palatal and uvular-tip planes. A comparison of acromegalic men with and without SAS revealed no significant difference in the craniofacial skeleton, although there was a narrowing of the minimal PAS (MinPAS) and of PAS in the uvular-tip plane in patients with SAS. SAS was more frequent in the patients with active acromegaly. MinPAS in the patients with active acromegaly was narrower than in those without disease activity. CONCLUSION: Skeletal abnormalities in acromegalic men with SAS were different from those in SAS patients without acromegaly. Upper airway narrowing due to changes in pharyngeal soft tissues takes a more relevant share in the development of SAS in acromegalic men than skeletal anomalies.

Can cigarette size and nicotine content influence smoking and puffing rates?

The stimuli controlling the rate at which people smoke cigarettes have not been clearly defined. On the hypothesis that smoking is basically nicotine-seeking behavior, nicotine available to the subject was experimentally manipulated through controlling cigarette size and nicotine content. In Experiment I, subjects given their won cigarettes in whole, half, quarter, and eighth lengths, increased the number of cigarettes smoked and number of puffs to compensate for reductions in size. Satisfaction was directly related to cigarette length. In Experiment II, subjects given special cigarettes delivering 0.2 or 2.0 mg nicotine/cigarette smoked significantly more of the low than of the high nicotine cigarettes and took significantly more puffs. As in Experiment I, significantly more quarter length than full length cigarettes were smoked, but total number of puffs did not differ. These results support the hypothesis that nicotine controls smoking behavior.