Accuracy of combinations of visual inspection using acetic acid or lugol iodine to detect cervical precancer: a meta-analysis.

BACKGROUND: Visual inspection of the cervix with acetic acid (VIA) or with Lugol's iodine (VILI) have been evaluated for cervical cancer screening in developing countries. OBJECTIVES: To assess the diagnostic accuracy and clinical utility of visual methods to detect cervical intraepithelial neoplasia grade 2+ (CIN2+) using: (1) VIA alone; (2) VILI alone; (3) co-testing; and (4) VILI as a triage test of a positive VIA result. SEARCH STRATEGY: PubMed, EMBASE, and the Cochrane Library were searched up to May 2016. SELECTION CRITERIA: All reports on the accuracy of VIA and VILI, or combinations of VIA/VILI, to detect CIN2+ were identified. Histology and colposcopy when no biopsy was taken were used as the reference standard. DATA COLLECTION AND ANALYSIS: Selected studies were scored on methodological quality, and sensitivity and specificity were computed. Clinical utility was assessed from the positive predictive value (PPV) and the complement of the negative predictive value (cNPV). MAIN RESULTS: We included 23 studies comprising 101 273 women. The pooled sensitivity and specificity of VILI was 88 and 86%, respectively. VILI was more sensitive, but not less specific, compared with VIA (relative sensitivity = 1.11; 95% confidence interval, 95% CI, 1.06-1.16; relative specificity = 0.98; 95% CI 0.95-1.01). Co-testing was hardly more sensitive, but significantly less specific, than VILI alone. VILI to triage VIA-POSITIVE women was not less sensitive, but more specific, compared with VIA alone (relative sensitivity = 0.98, 95% CI 0.96-1.01; relative specificity = 1.04, 95% CI 1.02-1.05). The average PPVs were low (range 11-16%), whereas the cNPV varied between 0.3% (VILI, co-testing) and 0.6% (triage). CONCLUSIONS: Although imperfect, VILI alone appeared to be the most useful visual screening strategy. TWEETABLE ABSTRACT: VILI alone seems to be the most useful visual screening test for cervical cancer screening.

Mid-trimester maternal serum hCG levels in predicting adverse pregnancy outcome.

OBJECTIVE: In this prospective study, we investigated the association between mid-trimester maternal serum human chorionic gonadotropin (ms-hCG) levels and adverse pregnancy outcome in a South-Western Greek population. MATERIALS AND METHODS: 130 healthy Greek women with spontaneous pregnancies were investigated for ms-hCG levels between the 13th and 24th weeks of gestation and followed for adverse pregnancy outcome, hCG levels > 2.0 multiples of the median value for gestation were considered abnormal. Statistical analysis was performed by Pearson's chi-square test. RESULTS: Gestational complications developed in a total of 12 of the 130 women studied (9.23%). Elevated ms-hCG levels were detected in a total of 14 of the 130 women studied (10.77%). CONCLUSION: Multiparameter testing of placental function in the mid-trimester (uterine artery Doppler, placental morphology and ms-hCG screening) may allow us to identify women with increased risk of developing severe placental insufficiency and pregnancy complications.

Evaluation of nasal mucociliary clearance after medical or surgical treatment of chronic rhinosinusitis.

An evaluation of mucociliary clearance, with the use of rhinoscintigraphy and other objectives and subjectives measures, in medically and surgically treated patients with chronic rhinosinusitis, as well in patients with or without nasal polyposis, can add to the understanding of ciliary function and its role in the pathogenesis of chronic rhinosinusitis. Thirty-four patients medically treated and 21 surgically treated (FESS) patients evaluated with rhinoscintigraphy, CT-scans, and SNOT-20. Nine of the surgically treated patients had nasal polyps and studied as a separate group. Although the various groups differ on Lund-Mackay scores (H = 11.659, P = 0.003) and SNOT-20 results (F = 26.904, P < 0.001), a statistically significant difference between mucociliary transport velocity (MTV) values could not be found. Moreover, multiple linear regression could not prove a statistically significant correlation between MTV and other variables. The various groups of chronic rhinosinusitis patients cannot be differentiated on the basis of possible nasal mucociliary clearance alternations.

Mid-trimester maternal serum markers in predicting adverse pregnancy outcome.

OBJECTIVE: In a prospective study, we investigated the association between mid-trimester maternal serum AFP (ms-AFP), maternal serum hCG (ms-hCG) levels and adverse pregnancy outcome in a South-Western Greek population. MATERIALS AND METHODS: 126 healthy Greek women with spontaneous pregnancies were investigated for ms-AFP and ms-hCG levels between the 13th and 24th weeks of gestation and followed for adverse pregnancy outcome. Abnormal outcomes were considered as ms-AFP levels or ms-hCG levels > 2.0 multiples of the median value for gestation (MoM). Statistical analysis was performed by Pearson's chi-square test. RESULTS: Elevated ms-AFP levels were detected in a total of 25 out of the 126 women studied (19.84%). Elevated ms-hCG levels were detected in a total of ten of the 126 women studied (7.93%). Elevated ms-AFP and ms-hCG levels were detected in a total of four of the 126 women studied (3.17%). CONCLUSION: Multiparameter testing of placental function in the mid-trimester (uterine artery Doppler, placental morphology, ms-AFP and ms-hCG screening) may allow us to identify women with increased risk of developing severe placental insufficiency and pregnancy complications.

A double-blind study on a patient with tardive dyskinesia treated with pallidal deep brain stimulation.

BACKGROUND: Tardive dyskinesia (TD) is a neurological disorder typically induced by long-term exposure to neuroleptics. Deep brain stimulation (DBS) of the globus pallidus internus (GPi) may represent a therapeutic alternative for TD, which is often resistant to conservative treatment. AIMS OF THE STUDY: This report's objective is to present a case of TD successfully treated with DBS, as well as to indicate a putative role of brain perfusion scintigraphy as a helpful tool correlating functional imaging findings with clinical responsiveness to DBS. METHODS/RESULTS: A 42-year-old male patient suffering from refractory TD underwent bilateral GPi DBS surgery. Post-operative Burke-Fahn-Mardsen Dystonia Rating Scale (BFMDRS) and Abnormal Involuntary Movement Scale (AIMS) total scores have been reduced by 90.7% and 76.7% respectively on the 6-month follow-up assessment. Brain perfusion scintigraphy, performed post-operatively in the two stimulation states, revealed a decrease in cerebral blood flow, during the 'on-DBS', compared with the 'off-DBS' state. CONCLUSIONS: Clinical improvement of this patient, correspondent to previous studies, suggests that continuous bilateral GPi DBS may provide a promising treatment option for TD. Furthermore, this report could imply, as no previous such comparison study exists, a possible correlation between brain functional imaging findings and the movement disorder's response to DBS.

Mid-trimester maternal serum AFP levels in predicting adverse pregnancy outcome.

OBJECTIVE: In this prospective study, we investigated the association between mid-trimester maternal serum alpha-fetoprotein AFP (MSAFP) levels and adverse pregnancy outcome in a South-Western Greek population. MATERIALS AND METHODS: 110 healthy Greek women with spontaneous pregnancies, investigated for MSAFP levels between the 13th and 24th week of gestation and followed for adverse pregnancy outcome. AFP levels > 2.0 multiples of the median value for gestation were considered abnormal. Statistical analysis was performed by Pearson's chi-square test. RESULTS: Elevated MSAFP levels were detected in a total of 27 of the 110 women studied (24.5%). Among them, only four women (14.8%) developed pregnancy complications. CONCLUSION: Multiparameter testing of placental function in the mid-trimester (uterine artery Doppler, placental morphology and MSAFP screening) may allow us to identify women with increased risk of developing severe placental insufficiency and pregnancy complications.

[Diagnosis of septic loosening of hip prosthesis with LeukoScan. SPECT scan with 99mTc-labeled monoclonal antibodies]. / Diagnose septischer Hüftprothesenlockerung via LeukoScan. SPECT-Scan mit 99mTc-markierten monoklonalen Antikörpern.

Diagnosis of septic loosening of hip endoprosthesis with antigranulocyte scintigraphy (AGS) was analysed. Twenty-one hip prostheses were studied using laboratory tests and, in cases of elevated values, three-phase bone scan (BS) and AGS. Elective SPECT/CT scans were performed. Histologic and microbiologic exams verified the diagnosis. The AGS analysis revealed sensitivity, specificity and accuracy of value 1, while positive and negative predictive values were also 1. BS showed sensitivity of 1 and specificity of 0.33. In three cases, SPECT/CT scans corroborated the AGS interpretation. This diagnostic algorithm proved effective in the detection of septic loosening of hip prostheses. AGS can be avoided without risk of infection being overlooked.

Pre-eclampsia and peripartum cardiomyopathy in molar pregnancy: clinical implication for maternally imprinted genes.

Molar pregnancies are associated with increased maternal complications, notably pre-eclampsia, but peripartum cardiomyopathy has been rarely observed. Here we report on a 34-year-old woman, gravida 2 para 1, who presented to our obstetric clinic for routine screening at 16 weeks of gestation. Elevated maternal serum alpha-fetoprotein and free beta-human chorionic gonadotropin were observed. Amniocentesis revealed a triploid constitution (69,XXX) and ultrasound examination showed growth restriction, fetal anomalies, placentomegaly and a total placenta previa. On admission at 18 weeks' gestation, the patient developed vaginal bleeding and pre-eclampsia. She underwent a Cesarean delivery and 6 h later developed congestive heart failure requiring intensive care support. Molecular analysis of the conceptus and parental DNA demonstrated an excess of paternal genomic contribution. The over-representation of the paternal chromosome complement may support the role of genomic imprinting in the clinical course of this case.

Euthyroid sick syndrome in acute ischemic syndromes.

The purposes of this study were to assess the occurrence of euthyroid sick syndrome in patients with acute myocardial infarction (AMI) or unstable angina (UA), and the relationship with beta-blocker or thrombolytic therapy. Plasma triiodothyronine (T3), reverse T3 (rT3), free T3 (FT3), thyroxine (T4), free T4 (FT4), thyroid-stimulating hormone (TSH), thyroxine-binding globulin (TBG), and albumin (ALB) levels were determined in 95 patients (59 males, 36 females, aged 58.4+/-9) with AMI and 19 patients (13 males, 6 females aged 54.7+/-12.3) with UA for 5 consecutive days from the onset of the acute syndrome and 1 month later. Patients were divided according to beta-blocker therapy and thrombolytic therapy. There was a significant T3 decrease and rT3 increase in all patients during the first 5 days following admission (p < 0.05). FT3 and FT4 remained unchanged during the study. In patients with complicated infarctions, the rT3 increase and the T3 decrease were significantly greater compared to those with uncomplicated infarctions (p<0.03). TSH, T4, TBG, and ALB were significantly (p<0.05) decreased only in complicated infarctions. No differences were observed between patients with or without thrombolysis or patients with or without beta-blocker treatment. The apparent decrease in T3, the increase in rT3 levels and the decreased TSH and T4 levels, show clearly that the euthyroid sick syndrome (low T3) occurs not only in AMI but also in UA. In addition, these hormonal changes are not affected by beta-blocker therapy and thrombolysis does not influence the occurrence of the syndrome. The degree of T3 decrease is proportional to the severity of cardiac damage and may have a possible prognostic value.

Primary screening for cervical cancer precursors by the combined use of liquid-based cytology, computer-assisted cytology and HPV DNA testing.

Primary screening for cervical cancer precursors has considerably evolved with the introduction of new technology to improve the early detection of disease. The objective of this study was to elaborate a diagnostic pathway integrating liquid-based and computer-assisted cytology and human papillomavirus DNA testing to focus screening on women at risk which may be more cost-effective for the healthcare system. A single laboratory analysis was conducted during a 5-month period using liquid-based cytology followed by human papillomavirus DNA testing for women with an abnormal result or with previous abnormal cytology. Human papillomavirus prevalence was estimated by testing 909 consecutive unselected samples. All slides were then rescreened using automated cytologic testing and triaged into a high- or low-score group according to computer results. Of the 8676 slides scanned, 352 had a test result of atypical squamous cells of undetermined significance or worse. Two hundred and ninety-seven (84.3%) samples with an atypical squamous cells of undetermined significance or worse result and 100% of those with detection of high-grade squamous intraepithelial lesions and carcinomas (HSIL+) were triaged into the high-score group. The combination of instrument scores and human papillomavirus results indicated that 51.0% of high score/human papillomavirus-positive cases should be considered as ASCUS+, while 99.6% of low-score/human papillomavirus negative cases remained negative in the final cytologic diagnosis, representing 49.0% of all cases. Of the screened women 89.5% should test negative for human papillomavirus and be reported as such in the final cytologic diagnosis. In conclusion, preliminary results suggest that this diagnostic pathway has the potential to improve primary cervical cancer screening and cost-effectiveness. By using a combination of testing methods to focus screening and clinical attention to cases at risk, it would be possible to lengthen screening intervals for 90% of women and to archive without further review all low-score/human papillomavirus-negative slides, representing 50% of the screening workload.

High- and intermediate-risk human papillomavirus infection in sexually active adolescent females.

STUDY OBJECTIVE: To determine the prevalence of high- and intermediate-risk type human papillomavirus (HPV) infection and cervical dysplasia in an urban Swiss adolescent population attending the local Adolescent Clinic, using a liquid-based Pap test combined with risk type HPV DNA testing. To determine the prevalence of Chlamydia trachomatis in the same study population. DESIGN: Observational study. SETTING: The Adolescent Clinic of the Department of Obstetrics and Gynaecology at the University Clinic, Geneva, Switzerland. PARTICIPANTS: 134 women between 14 and 20 years of age were enrolled in the study. MAIN OUTCOME MEASURES: A standardized patient file on demographic and sexual history information was compiled and completed by physical examination, including a Pap test with adjunct high- and intermediate-risk type HPV DNA detection. RESULTS: Of the 134 specimens analyzed for HPV, 115 patients were negative and 19 (14.2%) were positive for HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, or 68. A significant association between HPV infection and having had more than one lifetime sexual partner was found (P <.05). Six (31.6%) of the HPV-positive and three (2.6%) of the HPV-negative specimens had a low-grade squamous intraepithelial lesion (SIL) by cytology. Abnormal Pap test was related to HPV infection (odds ratio, 46.2; 95% confidence interval, 7.4 to 287.4) and, inversely, to age at first sexual intercourse (odds ratio, 0.98; 95% confidence interval,.97 to 1.0). CONCLUSION: High- and intermediate-risk type HPV infection is a frequent finding in our study group and is linked to having had more than one lifetime sexual partner. No association was found between HPV infection and other potential risk factors such as patient's age, age at first intercourse, frequency of intercourse during the three months prior to the investigation, smoking habits, or alcohol consumption.

Combined screening for Chlamydia trachomatis and squamous intra-epithelial lesions using a single liquid-based cervical sample.

BACKGROUND: Cervicitis is believed to alter cytological interpretation and could compromise a combined screening for Chlamydia trachomatis (CT) cervicitis and squamous intra-epithelial lesions (SIL). Liquid-based cytological methods have been shown to limit obscuring factors and permit the detection of infectious agents by DNA amplification techniques. The aim of this study was to evaluate a combined screening for SIL and CT cervicitis with a single liquid-based cervical sample. METHODS: Two cervical samples were obtained from each of 590 women considered at high risk for CT. The modified Ligase chain reaction (LCR) procedure for CT detection using specimens collected in the AutoCyte's preservative fluid was compared with the conventional Abbott LCx method using cervical swabs. We have also compared the percentage of inflammatory specimens and adequacy of cellular material in the populations of CT+ and CT- women. RESULTS: The results show total agreement for 588 of 590 cervical samples using the two LCR protocols (Kappa = 0.96; 95% confidence interval: 0.91-1.00). The quality of cervical cytology was not compromised by CT cervicitis. CONCLUSIONS: We demonstrated the feasibility of combined screening for CT and SIL with a single liquid-based cervical sample.

Novel application of IGF-I and IGFBP-3 generation tests in the diagnosis of growth hormone axis disturbances in children with beta-thalassaemia.

OBJECTIVE: Children with beta-thalassaemia major (beta-thal) frequently have growth retardation in the presence of low serum IGF-I and a normal GH response to pharmacological stimulation suggesting that they have GH insensitivity (GHIS). This study was carried out to study the cause of their growth retardation. DESIGN: We studied IGF-I and IGFBP-3 generation after exogenous GH administration for four days, in 15 prepubertal controls (C) and 41 prepubertal beta-thal patients divided into three groups according to their growth status: (Group 1) 15 with normal growth (N-thal) (Group 2) 16 with decelerated growth (D-thal) and (Group 3) 10 with short stature (S-thal), in order to determine whether GHIS is the cause of their growth retardation. MEASUREMENTS: IGF-I and IGFBP-3 were measured daily, before and for 4 days after daily administration of 0.1 IU/kg hGH, in 3 groups of prepubertal beta-thal patients and normal controls. RESULTS: N-thal and C had similar basal serum IGF-I (142 +/- 52 and 196 +/- 56 ng/ml, respectively) and IGFBP-3 concentrations (2.07 +/- 0.49 and 2.66 +/- 0.41 mg/l, respectively) as well as a similar percent increase of IGF-I (101 +/- 23% and 104 +/- 37%, respectively) and IGFBP-3 (52 +/- 36%, and 38 +/- 14%, respectively) during the generation tests. S-thal and D-thal had significantly lower basal IGF-I and IGFBP-3 concentrations (85 +/- 42 and 101 +/- 36 ng/ml; and 1.60 +/- 0.49 and 1.79 +/- 0.52 mg/l, respectively) as compared to N-thal and C (P < 0.001 and P < 0.005, respectively), and a significantly higher percent increase of IGF-I and IGFBP-3 during the generation tests (249 +/- 43 and 161 +/- 76%; and 121 +/- 99 and 73 +/- 35%, respectively) as compared to N-thal and C (P < 0.0001 and P < 0.01, respectively). Twenty-five percent of the growth retarded patients had classic GH deficiency (GHD) and percent increases of IGF-I and IGFBP-3 in the generation tests (164 +/- 86% and 80 +/- 49%, respectively) which were similar to those of the remaining growth-retarded children. CONCLUSION: The greater percent increases of IGF-I and IGFBP-3 in the generation tests of the growth retarded beta-thal patients, both with and without GHD, strongly suggest impaired GH secretion rather than GHIS as the cause of their growth retardation. We conclude that the IGF-I and IGFBP-3 generation tests are useful tools for the study not only of GHIS but also of GH secretory disorders in patients with beta-thal and short stature that can easily be performed in an outpatient setting as an initial test to identify the patients that may benefit from GH therapy.

Biopsy-based comparison of liquid-based, thin-layer preparations to conventional Pap smears.

OBJECTIVE: To evaluate and compare histologic diagnosis of squamous intraepithelial neoplasia and cancer of the cervix with cytologic diagnosis using the conventional Pap smear versus the AutoCyte PREP liquid-based, thin-layer preparation. STUDY DESIGN: Two randomly selected, large patient groups from the same population were studied using two different cervical cytology preparation techniques. Cytologic results were compared to histologic diagnosis to estimate the relative sensitivities and specificities of the preparations. RESULTS: AutoCyte's liquid-based, thin-layer preparation method demonstrated improved agreement with histologic diagnosis as compared to the conventional Pap smear. This result supported the previously reported finding that use of this thin-layer method reduced atypical squamous cells of undetermined significance cases and substantially increased the detection of squamous intraepithelial lesions (SILs). CONCLUSION: Our cytohistologic correlation for conventional Pap smears and the AutoCyte PREP liquid-based preparations demonstrate that the increased rate of both low and high grade SILs on AutoCyte PREP reflects real detection as opposed to overdiagnosis.

Preliminary results of the use of Re-186-HEDP for palliation of pain in patients with metastatic bone disease.

We evaluated the effectiveness of Re-186-HEDP in 25 patients with painful metastatic bone disease. Twenty-five patients with known prostatic (n = 19), non-small-cell lung cancer (n = 1) and breast cancer (n = 5) and multiple confirmed skeletal metastases were studied. All were taking analgesics daily (nonsteroidal antiinflammatory drugs/opiates). Re-186-HEDP (mean 35.2 mCi) was administered and patients were monitored for at least 50 days. In five patients, a repeat dose was administered 9 to 10 weeks later. The evaluation of the analgesic effect was based on a "pain diary" and by recording the use of analgesics. In 80% (20 of 25) of the patients, the effect was significant palliation, moderate in 3 patients (12%), and insignificant in 2 (8%). No significant myelotoxicity was observed. Transient pain flare was recorded in 8 of 25 patients. These results indicate that Re-186-HEDP can offer pain palliation in patients with painful bone metastases without being complicated by significant myelotoxicity.

Scintigraphic imaging of sarcomatous tumors with [(111)In-DTPA-phe-1]-octreotide.

The objective of the present study was to investigate the efficacy of (111)In-DTPA-octreotide (OC) for in vivo scintigraphic imaging of these relatively uncommon tumors. Thirteen patients (9 males, 4 females, mean age 59 years) with known sarcomatous lesions were studied. All patients had known lesions as demonstrated by previous investigation with other modalities, e.g. CAT, MRI. Following intravenous injection of 10 microg of OC labeled with 2.8-4.2 mCi (111)In, planar imaging was done at 6 +/- 1 and 22 +/- 2 h, respectively. Histologic verification was obtained in all cases, either from fine needle aspiration or from surgically removed tissue. Positive imaging was observed in 12/13 cases (92.3%). One scan was false-negative (7.7%). Occult lesions were demonstrated in two patients. The histologic typing and the scintigraphy results were: fibrosarcoma (1+/1), embryonic rhabdomyosarcoma (1+/1), leiomyosarcomas (3+/3), liposarcomas (2+/2), uterine sarcomas (2+/2), HIV (-) Kaposi sarcoma (1+/1), osteosarcoma (1+/1), chondrosarcoma (1-/1) and neurogenous sarcoma (1+/1). OC appears to have properties that lead to a new indication for its use. Other possible applications relate to the therapeutic use of octreotide either unlabeled or labeled with a beta-emitting radionuclide, as well as its use in radioimmunoguided surgery. Regarding the latter, our preliminary results are encouraging.

Radioimmunoscintigraphy in patients with ovarian cancer.

The targeting potential of three different monoclonal antibodies (MAbs) was assessed in patients with ovarian cancer. HMFG1, OC-125 and H17E2 labelled with 111In or 123I were evaluated prospectively for their ability to localize ovarian tumour. Forty two patients with ovarian cancer, aged 40-78 years (median = 58 years) were studied using OC-125 (n = 9), HMFG1 (n = 11) and H17E2 (n = 22). Imaging data were compared with the CT and the surgical findings. Presence of tumour was confirmed in 35/42 (83%) patients (8/9 OC-125, 10/11 HMFG1 and 17/22 H17E2) and correlated well with the conventional radiology diagnostic methods. One patient with a negative H17E2 scan and a large abdominal mass detected at laparotomy revealed a PLAP-negative tumour on immunohistochemistry. Scintigraphy revealed the presence of active disease, confirmed by laparotomy/laparoscopy in 6/8 patients considered to be in clinical remission. The sensitivity of the method was high enough and the diagnostic contribution of this approach should be further evaluated.

Cord blood alpha-fetoprotein concentrations in term newborns of smoking mothers.

UNLABELLED: To investigate the toxic effect of tobacco smoke on the fetus, we measured in cord blood the concentrations of alpha-fetoprotein (AFP), the principal serum protein in early ontogenic development, and erythropoietin (EPO), as an index of chronic fetal hypoxia. A total of 103 consecutively enrolled term newborns of smoking mothers and 103 term infants of nonsmoking parents were studied. The mean +/- SD AFP concentrations in the newborns of the mothers who smoked 1-50, 5-50, and 10-50 cigarettes/day were 86.4 +/- 88.9, 96.3 +/- 91.9 and 118.7 +/- 103.7 ng/ml, respectively. The difference of all three groups from the control neonates (57.7 +/- 37.2) was significant. The EPO concentrations in the newborns of the mothers who smoked 1-50 (53.9 +/- 64.6 mU/ml) and 5-50 (56.3 +/- 68.5) cigarettes/day were significantly greater than in the control neonates (29.5 +/- 16.1). In the newborns of the smoking mothers there was a significant positive correlation between AFP concentrations and number of cigarettes smoked per day, and a negative correlation between AFP and birth weight or length. There was no correlation between AFP and EPO concentrations, as well as between EPO and birth weight, length or number of cigarettes smoked per day. CONCLUSION: The absence of a correlation between erythropoietin and birth weight or length and the negative correlations between alpha-fetoprotein and these anthropometric parameters suggest that the intra-uterine growth retardation caused by maternal smoking is not due to tissue hypoxia, but that both growth retardation and elevated alpha-fetoprotein result from the direct or indirect toxic effect of a factor(s) present in tobacco smoke.