Unusual hard metal lung disease: bronchiolocentric interstitial pneumonia.

A 38-year-old woman experienced a persistent dry cough and progressively worsening dyspnoea for 2 years. Spirometry testing revealed a moderate-to-severe restrictive abnormality. High-resolution chest computed tomography showed diffuse reticulonodular opacities. A lung biopsy disclosed alveolar parenchymal inflammation and fibrosis with bronchiolocentric features, prompting consideration of interstitial pneumonia. Following a thorough investigation of her occupational history and an on-site inspection, it was discovered that the patient had been grinding drill bits designed for printed circuit boards for 8 years, exposing her to hard metals. Mineralogical analyses confirmed excessive tungsten in urine, serum and hair, leading to a diagnosis of hard metal lung disease due to tungsten carbide-cobalt exposure. After discontinuing exposure and commencing corticosteroid therapy, her symptoms, pulmonary function and imaging showed modest improvement. This case highlights the significance of assessing occupational history in patients with interstitial pneumonia and understanding industrial hazards for accurate diagnosis and care.

Phase III randomized study of taselisib or placebo with fulvestrant in estrogen receptor-positive, PIK3CA-mutant, HER2-negative, advanced breast cancer: the SANDPIPER trial.

BACKGROUND: The phase III SANDPIPER study assessed taselisib (GDC-0032), a potent, selective PI3K inhibitor, plus fulvestrant in estrogen receptor-positive, HER2-negative, PIK3CA-mutant locally advanced or metastatic breast cancer. PATIENTS AND METHODS: Postmenopausal women with disease recurrence/progression during/after an aromatase inhibitor were randomized 2 : 1 to receive taselisib (4 mg; taselisib arm) or placebo (placebo arm) plus fulvestrant (500 mg). Stratification factors were visceral disease, endocrine sensitivity, and geographic region. Patients with PIK3CA-mutant tumors (central cobas® PIK3CA Mutation Test) were randomized separately from those without detectable mutations. The primary endpoint was investigator-assessed progression-free survival (INV-PFS) in patients with PIK3CA-mutant tumors. Secondary endpoints included objective response rate, overall survival, clinical benefit rate, duration of objective response, PFS by blinded independent central review (BICR-PFS), safety, and time to deterioration in health-related quality of life. RESULTS: The PIK3CA-mutant intention-to-treat population comprised 516 patients (placebo arm: n = 176; taselisib arm: n = 340). INV-PFS was significantly improved in the taselisib {7.4 months [95% confidence interval (CI), 7.26-9.07]} versus placebo arm (5.4 months [95% CI, 3.68-7.29]) (stratified hazard ratio [HR] 0.70; 95% CI, 0.56-0.89; P = 0.0037) and confirmed by BICR-PFS (HR 0.66). Secondary endpoints, including objective response rate, clinical benefit rate, and duration of objective response, showed consistent improvements in the taselisib arm. Safety was assessed in all randomized patients who received at least one dose of taselisib/placebo or fulvestrant regardless of PIK3CA-mutation status (n = 629). Serious adverse events were lower in the placebo versus taselisib arm (8.9% versus 32.0%). There were more discontinuations (placebo arm: 2.3%; taselisib arm: 16.8%) and dose reductions (placebo arm: 2.3%; taselisib arm: 36.5%) in the taselisib arm. CONCLUSION: SANDPIPER met its primary endpoint; however, the combination of taselisib plus fulvestrant has no clinical utility given its safety profile and modest clinical benefit.

Patients' beliefs and behaviors related to treatment adherence in patients with asthma requiring maintenance treatment in Asia.

OBJECTIVES: To identify patients' beliefs or behaviors related to treatment adherence and to assess association between asthma control and adherence in Asian patients with asthma. METHODS: We conducted a cross-sectional observational study of adult patients with asthma from specialist clinics in six Asian countries. Patients who were deemed by their treating physicians to require a maintenance treatment with an inhaler for at least 1 year were recruited. Patients completed a 12-item questionnaire related to health beliefs and behaviors, the 8-item Morisky Medication Adherence Scale (MMAS-8), the Asthma Control Test (ACT™), and the Standardized Asthma Quality of Life Questionnaire (AQLQ-S). RESULTS: Of the 1054 patients recruited, 99% were current users of inhaled corticosteroids. The mean ACT score was 20.0 ± 4.5 and 64% had well-controlled asthma. The mean MMAS-8 score was 5.5 ± 2.0 and 53% were adherent. Adherence was significantly associated with patients' understanding of the disease and inhaler techniques, and with patients' acceptance of inhaler medicines in terms of benefits, safety, convenience, and cost (p < 0.01 for all). In multivariate analysis, three questions related to patients' acceptance of inhaler medicines remained significantly associated with poor adherence, after adjusting for potential confounders: "I am not sure inhaler type medicines work well" (p = 0.001), "Taking medicines more than once a day is inconvenient" (p = 0.002), and "Sometimes I skip my inhaler to use it over a longer period" (p < 0.001). CONCLUSIONS: Our study showed that patients' acceptance of the benefits, convenience and cost of inhaler medications have a significant impact on treatment adherence in the participating Asian countries.

Optimal computed tomography-based biomarkers for prediction of incisional hernia formation.

PURPOSE: Unstructured data are an untapped source for surgical prediction. Modern image analysis and machine learning (ML) can harness unstructured data in medical imaging. Incisional hernia (IH) is a pervasive surgical disease, well-suited for prediction using image analysis. Our objective was to identify optimal biomarkers (OBMs) from preoperative abdominopelvic computed tomography (CT) imaging which are most predictive of IH development. METHODS: Two hundred and twelve rigorously matched colorectal surgery patients at our institution were included. Preoperative abdominopelvic CT scans were segmented to derive linear, volumetric, intensity-based, and textural features. These features were analyzed to find a small subset of OBMs, which are maximally predictive of IH. Three ML classifiers (Ensemble Boosting, Random Forest, SVM) trained on these OBMs were used for prediction of IH. RESULTS: Altogether, 279 features were extracted from each CT scan. The most predictive OBMs found were: (1) abdominopelvic visceral adipose tissue (VAT) volume, normalized for height; (2) abdominopelvic skeletal muscle tissue volume, normalized for height; and (3) pelvic VAT volume to pelvic outer aspect of body wall skeletal musculature (OAM) volume ratio. Among ML prediction models, Ensemble Boosting produced the best performance with an AUC of 0.85, accuracy of 0.83, sensitivity of 0.86, and specificity of 0.81. CONCLUSION: These OBMs suggest increased intra-abdominopelvic volume/pressure as the salient pathophysiologic driver and likely mechanism for IH formation. ML models using these OBMs are highly predictive for IH development. The next generation of surgical prediction will maximize the utility of unstructured data using advanced image analysis and ML.

Pediatric asthma control in Asia: phase 2 of the Asthma Insights and Reality in Asia-Pacific (AIRIAP 2) survey.

BACKGROUND: We conducted Phase 2 of the Asthma Insights and Reality in the Asia-Pacific (AIRIAP 2) survey in 2006 to determine the level of asthma control in this region and the validity of the Asthma Control Test (ACT) and childhood ACT (C-ACT) in relation to asthma control. METHODS: Pediatric participants (0 to <16 years; N = 988) with diagnosed asthma and current asthma symptoms or taking anti-asthma medications were recruited from 12 geographic areas in Asia. The survey consisted of the AIRIAP 2 questionnaire (asthma symptoms, use of urgent healthcare services and anti-asthma medication) and the ACT or C-ACT (English or Chinese translations only), both administered in the participant's preferred language. A symptom control index based on the Global Initiative for Asthma criteria (except lung function) was used to classify asthma control status. RESULTS: Most participants had inadequately controlled asthma ('uncontrolled' = 53.4%, 528/988; 'partly controlled' = 44.0%, 435/988). Only 2.5% (25/988) had 'controlled' asthma. Demand for urgent healthcare services (51.7%, 511/988) and use of short-acting beta-agonists (55.2%, 545/988) was high. The optimal ACT and C-ACT cutoff score for detecting uncontrolled asthma (compared with controlled or partly controlled asthma) was determined to be ≤19 (receiver operating characteristic analysis) with good agreement between the ACT and C-ACT and the symptom control index. CONCLUSIONS: Findings from this survey show that asthma control is suboptimal in many children in the Asia-Pacific region. Practical tools, such as the ACT or C-ACT, may help clinicians assess asthma control and facilitate adjustment of asthma medication.

National epidemiologic trends (2008-2018) in the United States for the incidence and expenditures associated with incisional hernia in relation to abdominal surgery.

PURPOSE: It is unknown whether the trend of rising incisional hernia (IH) repair (IHR) incidence and costs until 2011 currently persists. We aimed to evaluate how the IHR procedure incidence, cost and patient risk-profile have changed over the last decade relative to all abdominal surgeries (AS). METHODS: Repeated cross-sectional analysis of 38,512,737 patients undergoing inpatient 4AS including IHR within the 2008-2018 National Inpatient Sample. Yearly incidence (procedures/1,000,000 people [PMP]), hospital costs, surgical and patient characteristics were compared between IHR and AS using generalized linear and multinomial regression. RESULTS: Between 2008-2018, 3.1% of AS were IHR (1,200,568/38,512,737). There was a steeper decrease in the incidence of AS (356.5 PMP/year) compared to IHR procedures (12.0 PMP/year) which resulted in the IHR burden relative to AS (2008-2018: 12,576.3 to 9,113.4 PMP; trend difference P < 0.01). National costs averaged $47.9 and 1.7 billion/year for AS and IHR, respectively. From 2008-2018, procedure costs increased significantly for AS (68.2%) and IHR (74.6%; trends P < 0.01). Open IHR downtrended (42.2%), whereas laparoscopic (511.1%) and robotic (19,301%) uptrended significantly (trends P < 0.01). For both AS and IHR, the proportion of older (65-85y), Black and Hispanic, publicly-insured, and low-income patients, with higher comorbidity burden, undergoing elective procedures at small- and medium-sized hospitals uptrended significantly (all P < 0.01). CONCLUSION: IH persists as a healthcare burden as demonstrated by the increased proportion of IHR relative to all AS, disproportionate presence of high-risk patients that undergo these procedures, and increased costs. Targeted efforts for IH prevention have the potential of decreasing $17 M/year in costs for every 1% reduction.

The incisional hernia epidemic: evaluation of outcomes, recurrence, and expenses using the healthcare cost and utilization project (HCUP) datasets.

BACKGROUND: Incisional hernias (IH) following abdominal surgery persist as morbid, costly, and multi-disciplinary surgical challenges. Using longitudinal, multi-state, administrative claims data (HCUP State Inpatient Databases (SID)); (HCUP State Ambulatory Surgery and Services Databases (SASD)), we aimed to characterize the epidemiology, outcomes, recurrence, and costs of IH. STUDY DESIGN: 529,108 patients undergoing abdominal surgery in 2010 across six specialties (colorectal, general/bariatric, hepatobiliary, obstetrics/gynecology, urology, and vascular) were identified within inpatient and ambulatory databases for Florida (FL), Iowa (IA), Nebraska (NE), New York (NY), and Utah (UT). IH repairs, complications, and expenditures were assessed through 2014. Predictive regression modeling was validated using a training set of 1000 bootstrapped repetitions. RESULTS: 16,169 (3.1%) patients developed hernias requiring repair (4.3-year mean follow-up), 3176 (20%) underwent recurrent repair, and 731 (23%) underwent re-recurrent repair. Patients with IH had increased readmissions (6.6 vs. 2.4), morbidity (39 vs. 8% surgical and 22 vs. 7% medical), and costs ($46,000 vs. $25,000) when compared to patients without IH (p < 0.001). IH expenditures totaled $875 million: initial ($687 million), recurrent ($155 million), and re-recurrent hernias ($33 million). IH predominated in colorectal (10%), hepatobiliary (8%), and vascular (5%) procedures. Of 31 significant independent IH risk factors (p < 0.001), obesity, age, smoking, open surgery, and prior surgery were pervasive across surgical specialties. CONCLUSION: IH represents an unremitting surgical epidemic associated with considerable morbidity, costs, and features consistent with a chronic disease state. We define critical pervasive risk factors (obesity, age, smoking open surgery, and prior surgery) independently associated with IH across surgical disciplines. With failed repairs, subsequent success becomes less likely, increasing morbidity and costs-underscoring the critical importance of optimal treatment and prevention.

Shared and persistent asymptomatic cutaneous human papillomavirus infections in healthy skin.

Cutaneous human papillomavirus (HPV) types are commonly found in normal skin, and some of them have been suspected to play a role in the development of non-melanoma skin cancer. This present study is divided into three sections, the aims of this study were to examine if certain HPV-types persist over time and if HPV-types are shared within families. From the first part of the study, swab samples from foreheads were collected for three longitudinal studies from one family with a newborn baby. Five specific HPV-types were isolated from the family with a newborn, with HPV-5 and FA67 being found at various time points and prevalence rates in all four members of the family. Part 2 consisted of a followed up study from two families with a 6 years interval. Six of the family members were found to have at least one of the HPV-types identified in the family 6 years earlier. Many of the HPV-types identified were shared within the families studied. Part 3 of this study involved weekly samples from four healthy females for 4 months. Among the four healthy individuals, 11%, 65%, and 56% of the weekly samples were HPV-DNA positive with one individual HPV-negative. All specimens were tested for HPV-DNA by PCR using the broad range HPV-type primer pair FAP59/64. The positive samples were HPV-type determined by cloning and sequencing. Specific cutaneous HPV-types persist over long periods of time in healthy skin in most individuals investigated and certain HPVs are shared between family members.

The lore of the RINGs: substrate recognition and catalysis by ubiquitin ligases.

Recently, many new examples of E3 ubiquitin ligases or E3 enzymes have been found to regulate a host of cellular processes. These E3 enzymes direct the formation of multiubiquitin chains on specific protein substrates, and - typically - the subsequent destruction of those proteins. We discuss how the modular architecture of E3 enzymes connects one of two distinct classes of catalytic domains to a wide range of substrate-binding domains. In one catalytic class, a HECT domain transfers ubiquitin directly to substrate bound to a non-catalytic domain. Members of the other catalytic class, found in the SCF, VBC and APC complexes, use a RING finger domain to facilitate ubiquitylation. The separable substrate-recognition domains of E3 enzymes provides a flexible means of linking a conserved ubiquitylation function to potentially thousands of ubiquitylated substrates in eukaryotic cells.

Type 2 diabetes mellitus severity correlates with risk of hip fracture in patients with osteoporosis.

BACKGROUND: Osteoporosis is a major public health problem because of its associated fractures and the resulting complications. The objective of this study was to identify the association between the severity of type 2 diabetes mellitus (T2DM) and the risk of hip fracture in osteoporotic patients. METHODS: The patients who received a diagnosis of osteoporosis between 2006 and 2010, with an adequate follow-up between 2006 and 2015, were enrolled in this study. Among patients with T2DM, the severity of the disease was evaluated using the Diabetes Complication Severity Index (DCSI). Logistic regression models were used to calculate the odds ratios and to predict the risk of hip fracture in diabetic osteoporotic patients. RESULTS: A total of 1188 patients were enrolled in the final study, 87 patients had hip fractures in the follow-up period between 2006 and 2015. Among the diabetic patients, each level of the continuous DCSI was associated with a 1.56-fold greater risk of hip fracture. In further stratification, patients with a DCSI > 3 had a significantly higher risk of hip fracture in comparison with those with a DCSI ≤ 1. The categorical DCSI (DCSI > 3), HbA1c level on the diagnosis of T2DM and duration of diabetes, facilitate predicting the risk of hip fracture. CONCLUSION: The severity of T2DM reflects the risk of hip fracture in osteoporotic patients. Physicians should pay attention to osteoporotic patients presenting with a high HbA1c level on diagnosis of T2DM and a higher DCSI because of their vulnerability to hip fracture.

ET-1 expression and growth inhibition of prostate cancer cells: a retinoid target with novel specificity.

Endothelin-1 (ET-1) is not only a potent vasoconstrictor but also serves as an important growth stimulator in various cancers, including breast, cervical, pancreatic, and prostate cancer. This suggests that blockage of ET-1 production may suppress tumor growth and possibly metastasis. We observed that certain synthetic retinoids, and all-trans-retinoic acid can repress LNCaP prostate cancer cell growth in vitro. In addition, these retinoid compounds counteracted exogenous ET-1-induced growth stimulation. Retinoid-dependent growth retardation of LNCaP cells coincided with suppression of ET-1 gene expression to a level undetectable by reverse transcription-PCR. Contrarily, the androgen-insensitive DU145 cells were refractory to retinoid treatment. To investigate the underlying mechanisms of the cell-specific response to retinoids, we transfected ET-1 promoter constructs containing wild-type or mutated AP-1 or GATA-2 site into prostate cancer cells. Distinct regulations of ET-1 promoter activity were found; in LNCaP cells, both binding sites are essential for optimal promoter activation, whereas in DU145 cells, additional promoter sequences and/or transcriptional factors seem to be involved. Furthermore, several anti-AP-1 selective retinoids failed to repress ET-1 promoter activity and to exhibit a cell growth-inhibitory effect on LNCaP cells, suggesting that different retinoid structural configurations are required for the inhibition of an AP-1 complex versus an AP-1/GATA-2 complex.

Reduced 1alpha-hydroxylase activity in human prostate cancer cells correlates with decreased susceptibility to 25-hydroxyvitamin D3-induced growth inhibition.

Evidence from epidemiological, molecular, and genetic studies suggests a role for vitamin D in the development and/or progression of prostate cancer. In experimental models and clinical trials, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] was shown to exert antiproliferative, prodifferentiating, and antimetastatic/invasive effects on prostatic epithelial cells. Because the direct clinical application of 1,25(OH)2D3 is limited by the major side effect of hypercalcemia, we investigated the potential therapeutic utility of its less calcemic precursor, 25-hydroxyvitamin D3 [25(OH)D3], which is converted locally within the prostate to 1,25(OH)2D3 by 1alpha-hydroxylase. Quantification of 1alpha-hydroxylase activity in human prostatic epithelial cells by enzyme-substrate reaction analyses revealed a significantly decreased activity in cells derived from adenocarcinomas compared with cells derived from normal tissues or benign prostatic hyperplasia (BPH). In growth assays, we found that 25(OH)D3 inhibited growth of normal or BPH cells similarly to 1,25(OH)2D3. In contrast, in primary cultures of cancer cells and established cell lines, the antiproliferative action of 25(OH)D3 was significantly less pronounced than that of 1,25(OH)2D3. Our results indicate that growth inhibition by 25(OH)D3 depends on endogenous 1alpha-hydroxylase activity, and that this activity is deficient in prostate cancer cells. This finding has ramifications for both the prevention and therapy of prostate cancer with vitamin D compounds.

Expression and cellular localization of ribonucleotide reductase small subunit M2 protein in hydroxyurea-resistant Leishmania mexicana amazonensis.

We raised a specific antiserum against the recombinant M2 subunit protein of ribonucleotide reductase of Leishmania mexicana amazonensis in rabbit. This antiserum was used to study the expression and cellular location of the M2 protein in wildtype as well as hydroxyurea-resistant variants (HuR) of the parasite. The protein increased with increasing dose of the drug used for selection of resistance. The increase in protein level was accompanied by an increase in the copy numbers of mRNA of the M2 gene in the variants. In contrast to mammalian cells, the M2 protein of Leishmania is located in the nucleus rather than in the cytoplasm. The number of cells expressing M2 protein is also different in mammalian cells versus Leishmania. In mammalian cells, expression of M2 protein is a strictly S-phase-correlated event and in exponentially growing cells only approximately 50% of the cells are in S-phase and only these cells synthesize M2 protein. In L. m. amazonensis, however, almost all exponentially growing cells are positive for M2 protein. This makes it unlikely that M2 protein expression in Leishmania is S-phase dependent. In view of these findings, a fresh look in the future into the regulatory mechanisms of synthesis and the site of action of RNR in L. m. amazonensis is warranted.

Gastroduodenal motility in neonates: response to human milk compared with cow's milk formula.

It is known that breast milk empties more quickly from the stomach than does infant formula. We studied the difference in gastroduodenal motility between neonates fed with human milk and those fed with infant formula. Twenty-four five- to 36-day-old neonates were fed with mother's breast milk or with a cow's milk-based formula. Postprandial gastroduodenal contractions were recorded manometrically for three hours. Repetitive, high-amplitude nonmigrating contractions were the dominant wave form during the postprandial period. The number of episodes, duration, amplitude, and frequency of nonmigrating contractions were not different following the different feedings. The migrating myoelectric complex, which signals a return to the interdigestive (fasting) state, appeared in 75% of breast milk-fed infants but only 17% of formula-fed infants (P less than .05) within the three-hour recording period. Because contractions were similar following the two meals, but a fasting state recurred more rapidly in breast-fed infants, we conclude that factors other than phasic, nonpropagated antroduodenal contractions were responsible for the differences in gastric emptying between breast milk and formula.

Preliminary result of phase II study of paclitaxel and cisplatin chemotherapy for advanced non-small-cell lung cancer in Chinese patients.

This phase II study was designed to assess the response rate and toxicity of paclitaxel and cisplatin chemotherapy in Chinese patients with untreated advanced non-small-cell lung cancer (NSCLC). Eligibility requirements included histologically confirmed stage IIIb-IV NSCLC, Eastern Cooperative Oncology Group performance status less than 2, no previous chemotherapy, and adequate bone marrow, renal, and hepatic function. From April 1996 through March 1997, 32 patients were treated. The dose of paclitaxel was 135 mg/m2 as a 3-hour infusion on day 1 and cisplatin 75 mg/m2 on day 2. The regimen was repeated every 3 to 4 weeks for up to 6 to 8 cycles unless there was evidence of tumor progression. The median age was 57 years (range, 31-77 years). Sixty-five percent were men. Sixty-nine percent had adenocarcinoma, and 75% had stage IV disease. One hundred seventy-two cycles were administrated; 18 patients (56%) completed all six cycles. Peripheral neuropathy and myelosuppression were the principle toxicities. Neurotoxicity appeared to be dose limiting and manifested primarily as paresthesia. Grade 2 neurotoxicity was observed in 5% of courses, which was slowly reversible. However, the severity of myelosuppression was generally mild to moderate. No episode of neutropenic fever was noted. Thrombocytopenia remained infrequent throughout the study. Other nonhematologic toxicities were also generally mild. The objective response rate was 50%. In conclusion, this combination of paclitaxel and cisplatin is active in Chinese patients with advanced NSCLC. It merits further investigation in phase III trials.

Color Doppler ultrasound pulsatile flow signals of thoracic lesions: comparison of lung cancers and benign lesions.

Color Doppler ultrasound (US) was performed in 153 patients (including 102 with lung cancer and 51 with benign lesions) to assess pulsatile flow signals in thoracic lesions. The values of resistive index (RI) and pulsatility index (PI) of color Doppler US pulsatile flow signals in lung cancers and benign lesions were measured, analyzed, and compared. In the enrolled 153 patients with thoracic lesions, 61 lung cancers and 34 benign lesions had detectable color Doppler US pulsatile flow signals, and lung cancers had lower RI and PI values than benign lesions (RI: 0.70+/-0.03 vs. 0.79+/-0.04, p < 0.05; PI: 1.61+/-0.15 vs. 2.44+/-0.25, p < 0.005). However, overlapping RI and PI values in lung cancers and benign lesions somewhat limited color Doppler US pulsatile flow signals to differentiate lung cancers from benign lesions. Further analysis of RI and PI values in subgroups of lung cancers [squamous cell carcinoma (SCC, n = 34), adenocarcinoma (AC, n = 18), and small-cell lung cancer (SCLC, n = 6)] and benign lesions [cavitary benign lesions (CBL, n = 8), and noncavitary benign lesions (NCBL, n = 26)] revealed that all different cell types of lung cancers (SCC, AC, and SCLC), indeed, had lower RI and PI values than NCBL (for RI, all p < 0.01; for PI, all p< or =0.001). Moreover, the mean RI and PI values showed a significant incremental decrease from NCBL (mean RI, PI = 0.88, 2.94) toward SCC and AC (for SCC, mean RI, PI = 0.71, 1.68; for AC, mean RI, PI = 0.68, 1.67) and, finally, to SCLC (mean RI, PI = 0.62, 1.05). In contrast, CBL had relatively lower RI and PI values than AC and SCLC (for CBL, mean RI, PI = 0.53, 0.80; both p > 0.05 for RI and PI), and even a significant difference from SCC (p < 0.05 for RI and PI). We conclude that color Doppler US pulsatile flow signal is somewhat limited to differentiate lung cancers from benign lesions, but provides a noninvasive in vivo model to assess the neovascularity intensity of lung cancers.

Heparin/endothelial cell growth supplement regulates matrix gene expression and prolongs life span of vascular smooth muscle cells through modulation of interleukin-1.

Vascular smooth muscle cells produce and respond to interleukin-1, a cytokine which modifies inflammation-associated vascular activities including the synthesis of extracellular matrix proteins. We have established vascular smooth muscle cells culture conditions in which heparin, in the presence of endothelial cell growth supplement, promotes cell proliferation and inhibits interleukin-1 and matrix protein expression. To test whether interleukin-1 mediates growth and matrix modulation by heparin/endothelial cell growth supplement, vascular smooth muscle cells were transfected with an Epstein-Barr virus-derived expression vector designed to express interleukin-1 antisense transcripts. RNase protection and ELISA assays demonstrated a complete block of interleukin-1 transcription and protein synthesis. Northern blot analysis also showed that interleukin-1 antisense decreased the expression of matrix genes such as type I collagen, fibronectin, and decorin similar to downregulation after heparin/endothelial cell growth supplement treatment. In contrast, the expression of versican was not affected, indicating a selective suppression of matrix proteins. In addition, interleukin-1 antisense significantly prolonged the life span of vascular smooth muscle cells in culture. Our data suggest that heparin/endothelial cell growth supplement induces matrix remodeling and controls growth and senescence of vascular smooth muscle cells through down-regulation of interleukin-1.

Importance of sputum differential cell counting in the diagnosis of airway diseases.

We examined the sputum of 114 subjects by noninvasive methods (voluntary coughing or induced cough with hypertonic saline) to determine whether sputum examination could be used to separate patients with episodic wheezing, dyspnea or cough of unknown origin into different diagnostic categories. An increased percentage of sputum eosinophils was seen in 92% (48/52) of asthmatics, 36% (9/25) of patients with chronic obstructive pulmonary disease (COPD) and 28% (7/25) of chronic coughers, but not in any of the 12 patients with congestive heart failure (CHF). Eight patients with combined symptoms of COPD and asthma (mixed COPD subgroup) showed above average diurnal peak expiratory flow variation (10.3 +/- 2.1% vs 2.5 +/- 1.4%, p < 0.05) and an above average percentage of sputum eosinophils (19.8 +/- 9.1 vs 2.1 +/- 3.2, p < 0.01) than those in the pure COPD group. After therapeutic corticosteroid trial, all of the mixed COPD patients and six of the 17 pure COPD patients were steroid responders. Seven of the 25 chronic coughers had sputum eosinophilia, but no asthmatic symptoms. The cough symptoms subsided in five of these seven patients after steroid treatment but not in the other 18 chronic coughers. Further study is indicated to determine if simple eosinophilic bronchitis is an early stage of asthma. In conclusion, sputum differential cell counting is a useful noninvasive diagnostic tool in differentiating diseases with episodic wheezing or chronic cough.

[Intraoperative pleural lavage in lung cancer patients].

In lung cancer patients, pleural effusion may or may not be present even if cancer cells have invaded the pleura. Using the traditional staging methods, not all pleural metastasis can be detected before the presence of pleural effusion. We performed intraoperative pleural lavage on 38 patients who underwent a thoracotomy due to tumors of the lungs. The first lavage (lavage 1) was performed just after the pleural cavity was open; the second lavage (lavage 2) was performed after all surgical procedures were completed (including lung resection and mediastinal lymph node dissection). Totally 12 of the 32 primary lung cancer patients were found to have positive lavage 1 cytology; 13 had positive lavage 2 cytology. In 13 patients whose visceral pleura was invaded by tumor, 11 had a positive lavage 1, 10 had a positive lavage 2. For prediction of positive lavage 1 cytology from visceral pleural involvement, the accuracy was 90.6%, the sensitivity was 84.6%, the specificity was 94.7%, the positive predictive rate was 91.7%, the negative predictive rate was 90.0%. For lavage 2, the accuracy was 81.2%, the sensitivity was 76.9%, the specificity was 84.2%, the positive predictive rate was 76.9%, the negative predictive rate was 84.2%. Stage of disease and cell type seemed to have no relationship to the incidence of positive lavage fluid cytology. Further investigation is recommended to evaluate the prognosis of patients with positive lavage fluid cytology.