Implementation of evidence on management of pleural diseases: insights from a territory-wide survey of clinicians in Hong Kong.

BACKGROUND: Major advances in management of common pleural diseases have taken place in the past decade. However, pleural diseases are often managed by physicians of diverse training background and research on implementation of new knowledge is scanty. We aim to evaluate the practice pattern in pleural medicine among physicians in Hong Kong, for identification of possible gaps for clinical service improvement. METHODS: The Hong Kong Thoracic Society undertook a cross-sectional questionnaire survey in 2019, targeting clinicians of various subspecialties in internal medicine and levels of experience (basic and higher trainees, specialists) from twelve regional hospitals of diverse service scopes throughout Hong Kong. Respondents were selected by non-probability quota sampling. The questionnaire tool consisted of 46 questions covering diagnostic and therapeutic aspects of common pleural diseases. The responses were anonymous, and analysed independently using SPSS statistics software. RESULTS: The survey collected 129 responses, 47(36%) were from clinicians specialized in respiratory medicine. Majority of the respondents (98%) managed pleural diseases, including performing pleural procedures in their practice. Fifty-five percent of all the respondents had not received any formal training in transthoracic ultrasonography. A significant proportion of clinicians were unaware of pleuroscopy for investigation of exudative pleural effusion, indwelling pleural catheter for recurrent malignant pleural effusion, and combined intra-pleural Alteplase plus DNase for treatment of pleural infection (30%, 15% and 70% of non-respiratory clinicians respectively). Significant heterogeneity was found in the management of pleural infection, malignant pleural effusion and pneumothorax among respiratory versus non-respiratory clinicians. Contributing factors to the observed heterogeneity included lack of awareness or training, limited accessibility of drugs, devices, or dedicated service support. CONCLUSION: Significant heterogeneity in management of pleural diseases was observed among medical clinicians in Hong Kong. Continuous medical education and training provision for both specialists and non-specialists has to be strengthened to enhance the implementation of advances, improve quality and equity of healthcare provision in pleural medicine.

Perinatal exposure to environmental chemicals that disrupt thyroid function can perturb testis development.

Thyroid hormones (THs) are essential for normal growth and development. Their role in skeletal and brain development is well established, with congenital hypothyroidism causing stunted growth and severe intellectual disability. THs are also important for the development of other tissues and organs, including the testis. Developmental hypothyroidism can manifest as smaller testes in early postnatal life that later develop into macroorchidism in adulthood due to increased proliferation of Sertoli cells. Effects of hypothyroidism on the testes can be modelled in rodents by exposing developing animals to TH-suppressing pharmaceuticals such as propylthiouracil (PTU) and methimazole (MMI). These drugs act by inhibiting the thyroperoxidase (TPO) enzyme in the thyroid gland, inhibiting the synthesis of THs. It is possible that environmental chemicals that inhibit TPO activity can also cause TH-mediated effects on the developing testis, but the extent to which this occurs is not known. Herein, we characterized the effects of perinatal exposure to the herbicide amitrole together with the antithyroid drug MMI. Pregnant Sprague-Dawley rats were exposed by oral gavage to two doses of amitrole (25 or 50 mg/kg body weight/day) or MMI (8 or 16 mg/kg body weight/day) from gestational day 7 until birth. After birth, pup exposure was continued by dosing lactating dams from day of delivery until pup day 16. Both chemicals caused a significant reduction in TH levels on day 16. This perinatal hypothyroidism disrupted both germ and Sertoli cell development, resulting in smaller testes and reduced seminiferous tubule diameter in 16-day old pups. Notably, fetal male blood progesterone levels were increased after exposure to both amitrole and MMI, whereas the amitrole-exposed animals also displayed increased estradiol levels. Our study raises concerns that exposure to environmental chemicals that happen to disrupt TH production may disrupt TH-dependent testis development, with adverse consequences to human reproductive health.

The hospital telemedicine TELEMED database: Providing information on evidence-based telemedicine services to hospital managers and healthcare professionals.

BACKGROUND: Increased use of telemedicine in the healthcare system is a political goal in Denmark. Although the number of hospital patients using interventions such as the video consultation has increased in recent years only a small proportion of the outpatient and inpatient visits involve telemedicine. The TELEMED database (https://telemedicine.cimt.dk/) has been launched at the Center for Innovative Medical Technology in Denmark to ensure that hospital managers and healthcare professionals have access to information about telemedicine services and their effectiveness. This article describes the development and the content of the TELEMED database. METHODS: A structured literature search was made in the PubMed Database for randomised controlled trials or observational studies with a control group that investigated the effect of telemedicine interventions for hospital patients. Data were extracted from each article on the clinical effectiveness, patient perceptions, economic effects and implementation challenges. As the database should only provide inspiration to healthcare professionals regarding possibilities for use of telemedicine, the risk of bias in the studies was not assessed. RESULTS: The literature search resulted in 2825 hits. Based on full text assessment, 331 articles were included for data extraction and assessment. These articles present telemedicine services used in 22 different medical specialities. Forty-eight percent of the studies found a positive, statistically significant clinical effect, while 47% showed no statistically significant difference. In 48% of the studies, patients' experiences were examined and of these 68% found positive patient experiences. Fifty-four percent of the articles included information on the economic effects and, of these, 51% found reduction in healthcare utilization. In the majority of studies between two and four types of implementation challenges were found.Conclusions and recommendations: The TELEMED database provides an easily accessible overview of existing evidence-based telemedicine services for use by hospital managers and health professionals, who whish to to implement telemedicine. The database is freely available and expected to be continuously improved and broadened over time.

Employment Status and Health Literacy in Denmark: A Population-Based Study.

Objectives: Examining whether specific population groups who are not working and those who have an employment have the same health literacy level. Methods: Data were retrieved from a nationally representative cross-sectional study of the Danish population conducted with the health literacy questionnaire (HLS-EU-Q16) in 2016 and 2017. Socio-demographic characteristics were drawn from national registers. Odds ratio for the association between employment status and health literacy was estimated from logistic regression models, adjusted for socio-demographic characteristics. Probability weights were used to adjust for differences in responses. Results: Logistic regression analyses showed that receiving unemployment benefits, social assistance, employment and support allowance, retirement pension and sickness benefit were significantly associated with having inadequate health literacy compared to being employed in any industry. The highest odds ratio for inadequate health literacy was present for receiving unemployment benefit OR = 1.78 (95% CI: 1.23-2.56). Conclusion: Population groups not working and receiving economic public support have higher odds of inadequate health literacy competencies compared to those active in the labor force, considering age and socioeconomic factors. The result contributes to understanding health disparities in connection to occupational situation.

Cefoxitin treatment of MRSA leads to a shift in the IL-12/IL-23 production pattern in dendritic cells by a mechanism involving changes in the MAPK signaling.

Methicillin resistant Staphylococcus aureus (MRSA) constitute a serious health care problem worldwide. This study addresses the effect of ß-lactam treatment on the ability of clinically relevant MRSA strains to induce IL-12 and IL-23. MRSA strains induced a dose-dependent IL-12 response in murine bone-marrow-derived dendritic cells that was dependent on endocytosis and acidic degradation. Facilitated induction of IL-12 (but not of IL-23) called for activation of the MAP kinase JNK, and was suppressed by p38. Compromised peptidoglycan structure in cefoxitin-treated bacteria - as denoted by increased sensitivity to mutanolysin -caused a shift from IL-12 towards IL-23. Moreover, cefoxitin treatment of MRSA led to a p38 MAPK-dependent early up-regulation of Dual Specificity Phosphatase (DUSP)-1. Compared to common MRSA, characteristics associated with a persister phenotype increased intracellular survival and upon cefoxitin treatment, the peptidoglycan was not equally compromised and the cytokine induction still required phagosomal acidification. Together, these data demonstrate that ß-lactam treatment changes the MRSA-induced IL-12/IL-23 pattern determined by the activation of JNK and p38. We suggest that accelerated endosomal degradation of the peptidoglycan in cefoxitin-treated MRSA leads to an early expression of DUSP-1 and accordingly, a reduction in the IL-12/IL-23 ratio in dendritic cells. This may influence the clearance of S. aureus.

Reduced granulation tissue and wound strength in the absence of α11ß1 integrin.

Previous wound healing studies have failed to define a role for either α1ß1 or α2ß1 integrin in fibroblast-mediated wound contraction, suggesting the involvement of another collagen receptor in this process. Our previous work demonstrated that the integrin subunit α11 is highly induced during wound healing both at the mRNA and protein level, prompting us to investigate and dissect the role of the integrin α11ß1 during this process. Therefore, we used mice with a global ablation of either α2 or α11 or both integrin subunits and investigated the repair of excisional wounds. Analyses of wounds demonstrated that α11ß1 deficiency results in reduced granulation tissue formation and impaired wound contraction, independently of the presence of α2ß1. Our combined in vivo and in vitro data further demonstrate that dermal fibroblasts lacking α11ß1 are unable to efficiently convert to myofibroblasts, resulting in scar tissue with compromised tensile strength. Moreover, we suggest that the reduced stability of the scar is a consequence of poor collagen remodeling in α11(-/-) wounds associated with defective transforming growth factor-ß-dependent JNK signaling.

Hypoglycemia and embryonic heart development.

Abnormal embryonic development is a complication of the diabetic pregnancy, and heart defects are among the most common and detrimental congenital malformations of the diabetic embryopathy. Hypoglycemia is a common side effect of diabetes therapy and is a potential teratogen. An association between hypoglycemia and congenital defects has been difficult to demonstrate in humans, but in vivo and in vitro animal studies have illustrated the importance of glucose as a substrate for normal development. Hypoglycemia alters embryonic heart morphology, producing abnormal looping and chamber expansion, decreased myocardial thickness, disorganized layers, and decreased overall size. Hypoglycemia decreases embryonic heart rate and vascularity, and it alters embryonic heart metabolism by increasing glucose uptake and glycolysis. Hypoglycemia also affects protein expression in the embryonic heart, increasing the expression of glucose regulated proteins, hexokinase, and glucose transport protein. Thus, hypoglycemia interferes with normal cardiogenesis and alters morphology, function, metabolism, and expression of certain proteins in the developing heart. It is likely that these factors contribute to heart defects observed in the diabetic embryopathy, but the definitive link has yet to be made. Future studies are expected to further elucidate mechanisms mediating hypoglycemia-induced cardiac dysmorphogenesis.

[An in vitro study on the mechanism of CA125 production of endometrial cells--comparison of eutopic and heterotopic endometrium].

Human eutopic and heterotopic endometrium were cultured and epithelial cells were isolated from stromal cells by the modified method of Satyaswaroop et al. in order to investigate the cause of elevated serum CA125 levels in patients with adenomyosis. Flow cytometry (FCM) was used to analyze the relationship between cell cycle and CA125 production. 1. Microscopically, epithelial cells showed a tadpole-like appearance, while stromal cells were spindle-shaped. However, morphologically, no difference could be found between eutopic and heterotopic endometrial cells. 2. Immunocytochemical techniques (indirect enzyme immunoassay and fluorescence method) have demonstrated the presence of CA125 both on the cell membrane and in the cytoplasm of eutopic and heterotopic epithelial cells. Stromal cells were weakly stained by the fluorescence method, but not by enzyme immunoassay. 3. Double staining of CA125 and DNA was performed and analysed with FCM. Heterotopic epithelial cells produced a significantly higher amount (16 times higher) of CA125 than the eutopic epithelial cells. Stromal cells produced a small amount of CA125. These findings suggest that the elevation of serum CA125 levels in patients with adenomyosis may be due to greatly increased production of CA125 by heterotopic epithelial cells, in addition to the production of CA125 by eutopic ones.

Tolbutamide alters glucose transport and metabolism in the embryonic mouse heart.

BACKGROUND: Tolbutamide is a sulfonylurea oral hypoglycemic agent widely used for the treatment of non insulin-dependent diabetes mellitus. Tolbutamide produces dysmorphogenesis in rodent embryos and becomes concentrated in the embryonic heart after maternal oral dosing. Tolbutamide increases glucose metabolism in extra-pancreatic adult tissues, but this has not previously been examined in embryonic heart. METHODS: CD-1 mouse embryos were exposed on GD 9.5 to tolbutamide (0, 100, 250, or 500 microg/ml) for 6, 12, or 24 hr in whole-embryo culture. Isolated hearts were evaluated for (3)H-2DG uptake and conversion of (14)C-glucose to (14)C-lactate. Glut-1, HKI, and GRP78 protein levels were determined by Western analysis, and Glut-1 mRNA was measured by RT-PCR. RESULTS: Cardiac (3)H-2DG uptake increased after exposure to 500 microg/ml tolbutamide for 6 hr, and 100, 250, or 500 microg/ml tolbutamide for 24 hr, compared to controls. Glycolysis increased after exposure to 500 microg/ml tolbutamide for 6 or 24 hr compared to controls. Glut-1 protein levels increased in hearts exposed to 500 microg/ml tolbutamide for 12 or 24 hr, and Glut-1 mRNA increased in hearts exposed to 500 microg/ml tolbutamide for 24 hr compared to controls. HKI protein levels increased in hearts exposed to 500 microg/ml tolbutamide for 6 hr, but not 12 or 24 hr. There was no effect on GRP78 protein levels in hearts exposed to tolbutamide for 6, 12, or 24 hr. CONCLUSIONS: Tolbutamide stimulates glucose uptake and metabolism in the embryonic heart, as occurs in adult extra-pancreatic tissues. Glut-1 and HKI, but not GRP78, are likely involved in tolbutamide-induced cardiac dysmorphogenesis.

[Qualitative assessment and characterization of CA125 antigen produced from human endometrial epithelial cells].

We have established an in vitro system in which epithelial cells (EC) and stromal cells (SC) from the human endometrium are placed in culture to examine the production of CA125. There was a much greater amount of CA125 in heterotopic EC after culture cells reached confluence than during the logarithmic growth phase. Heterotopic EC in culture secreted nine times as much CA125 constitutively after reaching confluence as eutopic EC. Flow cytometry (FCM) analysis indicated that the changes in CA125 expression correlated with the cell cycle. The CA125 expression was mainly observed in the G0/G1-phase in the cell cycle. There was no amplification of the CA125 expression in heterotopic EC membranes. The results of SDS-PAGE and Western blot indicated that the 110 KDa molecule of CA125 might be specific for adenomyosis. The biochemical and physical nature of CA125 was examined to characterize the antigenic determinant of this antigen. These results strongly suggested that the CA125 antigenic determinant from EC was composed of conformationally dependent peptides. We conclude that significantly increased secretion of CA125 from heterotopic EC could be attributed to the increase in serum CA125 in patients with adenomyosis.

Molecular characteristics of the CA 125 antigen produced by human endometrial epithelial cells: comparison between eutopic and heterotopic epithelial cells.

OBJECTIVE: To characterize the CA 125 antigen purified from the conditioned media using an in vitro system that we have established for the culture of epithelial cells from human uterine endometrium. STUDY DESIGN: CA 125 was purified separately from the conditioned media of eutopic and heterotopic epithelial cells by gel chromatography and OC 125 immunoaffinity column chromatography. RESULTS: Western blot analysis of conditioned media from eutopic epithelial cells revealed a single polydisperse band of 200 kd, whereas two major CA 125 isoforms of 200 and 110 kd, as well as two minor forms of 100 and 70 kd, were observed in heterotopic epithelial cells. The 110 kd CA 125 was more prominent than the 200 kd antigen in heterotopic epithelial cells. CONCLUSION: These results strongly suggest that CA 125 antigens purified by immunoaffinity chromatography have different molecular mass in eutopic and heterotopic epithelial cells even though the OC 125 binding site may remain intact.

Quantitative and qualitative assessment of CA-125 production by human endometrial epithelial cells: comparison of eutopic and heterotopic epithelial cells.

We have established an in vitro system for the culture of epithelial cells (ECs) from human uterine endometrium to examine the production of CA 125 and to characterize the CA-125 antigen purified from the conditioned media. CA-125 secretion was higher in heterotopic ECs than in eutopic ECs and it was more significant after heterotopic ECs reached confluence than during the logarithmic growth phase. CA-125 expression was observed mainly in the G0/G1-phase. CA-125 expression on cell membranes did not correlate with the volume of CA 125 released per cell, and there was no amplification of CA-125 expression in heterotopic EC membranes. Treatment of the purified CA-125 antigen with 6 M urea yielded a much lower molecular-mass peak (200 kDa). The results of Western blot indicated the presence of a single polydisperse band of 200 kDa in the conditioned media from eutopic ECs, whereas 2 major CA-125 isoforms of 200 kDa and 110 kDa, as well as 2 minor forms of 100 kDa and 70 kDa, were observed in the conditioned media of the heterotopic ECs. We conclude that, in heterotopic ECs, the 110-kDa CA-125 is more prominent than the 200-kDa antigen, and that the elevation of CA-125 levels in the conditioned media could be attributed to significantly increased release of 110-kDa CA-125 from heterotopic ECs.

THE EFFECTS OF 5-AZA-2'-DEOXYCYTIDINE (D-AZA) ON SONIC HEDGEHOG EXPRESSION IN MOUSE EMBRYONIC LIMB BUDS.

5-Aza-2'-deoxycytidine (d-AZA) causes temporally-related defects in the mouse. At 1.0 mg/kg on gestational day (GD) 10, d-AZA causes hindlimb phocomelia. Sonic hedgehog (Shh) plays a significant role in the normal development of limbs in rodent species. Sonic hedgehog peptides, found in the posterior mesenchyme of limb buds, are involved in patterning functions and in the regulation of both anterior-posterior polarity and proximal-distal outgrowth of the limb. The objective of the present study was to analyze alterations in Shh expression subsequent to d-AZA exposure. Pregnant mice were treated with d-AZA via intraperitonlal injection on GD 10. Controls were untreated. The reverse transcription-polymerase chain reaction (RT-PCR), whole mount in situ hybridization (ISH), and whole mount immunohistochemistry (WMI) were used to analyze expression patterns of Shh . For RT-PCR, embryonic hindlimb buds (buds) were taken 0, 4, 8, 12, or 24 hr after exposure. Cyclophilin was used as the baseline monitor. RNA was transcribed to cDNA and used as template with Shh specific primers for amplification. Whole embryos were collected 12 and 24 hr posttreatment for ISH. An antisense primer specific for Shh was used in an oligo-based ISH protocol. Whole embryos were collected 36 and 48 hr posttreatment for WMI. The antibody corresponding to the amino terminal subunit of the Shh peptide was used. There was a treatment related up-regulation of Shh transcripts by 12 and 24 hr posttreatment. The protein response of up-regulation was detectable by 36 and 48 hr posttreatment. Our data suggest that 5-aza-2'-deoxycytidine-induced hindlimb defects may be associated with alterations in the level of Shh expression. This may be part of a cascade of signaling events involved in d-AZA-induced hindlimb defects. Work is ongoing to determine the relationship of other gene species that may cooperate with Shh in the induction of the hindlimb defects.

In vivo hyperglycemia and its effect on Glut-1 expression in the embryonic heart.

BACKGROUND: Maternal diabetes exposes embryos to periods of hyperglycemia. Glucose is important for normal cardiogenesis, and Glut-1 is the predominant glucose transporter in the embryo. METHODS: Pregnant mice were exposed to 6 or 12 hr hyperglycemia during organogenesis using intraperitoneal (IP) injections of D-glucose on gestational day (GD) 9.5 (plug = GD 0.5). Embryos were examined for morphology and total cardiac protein, and embryonic hearts were evaluated for Glut-1 protein and mRNA expression immediately after treatment (GD 9.75, GD 10.0), as well as on GD 10.5 and GD 12.5. RESULTS: IP glucose injections were effective in producing sustained maternal hyperglycemia. Maternal hyperglycemia for 6 or 12 hr on GD 9.5, followed by normoglycemia, produced a decrease in overall size and total cardiac protein in embryos evaluated on GD 10.5 but no difference on GD 12.5. Cardiac Glut-1 expression was immediately upregulated in embryos exposed to 6 or 12 hr maternal hyperglycemia. On GD 10.5, cardiac Glut-1 expression was not different in embryos exposed to maternal hyperglycemia for 6 hr but was downregulated in embryos exposed for 12 hr. On GD 12.5, cardiac Glut-1 expression in embryos exposed to maternal hyperglycemia on GD 9.5 for 6 or 12 hr, followed by normoglycemia, was not different from controls. The temporal pattern was the same for Glut-1 protein and mRNA expression. CONCLUSIONS: Hyperglycemia-induced alterations in Glut-1 expression likely interfere with balance of glucose available to the embryonic heart that may affect cardiac morphogenesis.

[Heterogeneity of CA 125 antigens released from human endometrial heterotopic epithelium and ovarian cancer].

We purified CA125 antigen from the conditioned media (CM) of eutopic and heterotopic endometrial epithelial cells (EC) as well as ovarian cancer cell lines, SHIN-3 and HOC-I, to determine what molecular weight forms of CA125 antigen were identifiable. Treatment of the high-molecular-weight CA125 antigen with 6M urea yielded a much lower molecular mass peak. After purification by OC125 affinity column chromatography, samples were applied to 3 to 7% polyacrylamide gradient gel and analyzed by Western blot. A single band with a molecular weight (MW) of 200KDa was identified in eutopic EC materials. The CA125 polypeptide of the 110KDa molecule could be detected in all of the CM obtained from heterotopic EC, irrespective of the length of time in the cell culture. A MW of approximately 200 KDa was also observed in some heterotopic EC samples. On the other hand, although the multiple bands with a MW equal to orless than 200KDa were observed in the CM of two ovarian cancer cells, the CA125 polypeptide of 110KDa molecules could not be detected. This preliminary finding offers promise that the 110KDa molecule detection method may be a useful adjunct in the differential diagnosis of heterotopic EC and ovarian cancer.

13C-NMR study of hypoglycemia-induced glycolytic changes in embryonic mouse heart.

BACKGROUND: Glucose metabolites can be detected in embryonic mouse tissues using 13C-NMR spectroscopy. The advantage of this method is in its chemical specificity and the ability to follow metabolic changes. METHODS: In this study, CD-1 mice were mated and embryos excised on gestational day (GD) 10.5 (plug = GD 0.5). Hearts were isolated and cultured in 150 mg/dl glucose (normoglycemic medium) or 40 mg/dl glucose (hypoglycemic medium) for 6 hr. 13C-labeled glucose comprised 62%-64% of total glucose in the culture medium. Pre- and postculture media were treated with deuterated water (D2O), and 13C spectra were obtained using a Bruker Avance 500 MHz spectrometer operating at 11.744 tesla (125.7 MHz for 13C). NMR spectra demonstrated resonances for 13C-glucose in preculture normoglycemic and hypoglycemic media. Postculture spectra for normoglycemic and hypoglycemic media demonstrated 13C-glucose signals as well as a signal for 13C-lactate. Area under the curve (AUC) was measured for the [1-(13)C-glucose] resonance from preculture media and the [3-(13)C-lactate] resonance from postculture media. The ratios of AUC for postculture [3-(13)C-lactate] to preculture [1-(13)C-glucose] were calculated and found to be higher in hypoglycemic than in normoglycemic media. RESULTS: Our results confirm earlier findings using radiolabeled substrates and suggest that 13C-NMR spectroscopy can be used to study glucose metabolism in isolated embryonic hearts exposed to hypoglycemia. CONCLUSIONS: NMR effectively measures glucose and its metabolite, lactate, in the same spectrum and thus determines metabolic flux in the isolated embryonic heart after exposure to hypoglycemia and normoglycemia. This method could evaluate glucose metabolism in embryonic tissues following other teratogenic exposures.