Program evaluation of postgraduate obstetrics and gynecology training in Lao people's democratic republic - using the CIPP model.

BACKGROUND: The obstetrics and gynaecology (OB-GYN) residency training program in Lao People's Democratic Republic (PDR) began in 2003 based on the Millennium Development Goals (MDGs) and 'Reproductive, maternal, newborn, and child health interventions (RMNCH) strategies and action plan'. However, the training program had not been properly evaluated previously. The purpose of this study is to evaluate the current postgraduate OB-GYN residency training program in Lao PDR by using CIPP model to identify the current problems (the strengths and weaknesses) and suggest a future plan to promote continuous improvement. METHOD: The context, input, process, and product classification (CIPP) model was used to develop criteria and indicators. A mixed-methods approach was used for this study. To capture instructional material for quantitative analysis, a Google survey with 38 items and a t-test were used to determine a significant difference in responses between residents and lecturers (N = 120). Based on qualitative analysis, an in-depth interview was done (four questions based on study outcomes, including satisfaction, strengths and weaknesses, and future opportunities), and six interviews provided different viewpoints on the course. The SPSS software program was used to measure validity, with p-values = 0.05. RESULTS: The overall average response rate was 97.5%. Two significant differences in program perspectives were revealed between lecturers and residents, difficulties in maintaining the course (professors 3.66 ± 1.03 and residents 3.27 ± 0.98, p = 0.04) and learning outcomes achieved (professors 3.57 ± 0.85 and residents 3.14 ± 0.95, p = 0.01 The overall average for the context part of the questionnaire was under 3.00, with the lowest scores for overlapped learning outcomes and difficulties in maintaining the course. The input part, lack of the classroom, skills lab and staff; the process part, lecturer to collect student opinions and the product part on learning outcomes. CONCLUSION: Curriculum improvement based on the program evaluation results, including regular evaluation and feedback, will advance the residency training program based on the RMNCH strategy and contribute to the promotion of maternal health in the Lao PDR.

Combined therapeutic potential of nuclear receptors with receptor tyrosine kinase inhibitors in lung cancer.

Cancer heterogeneity is a big hurdle in achieving complete cancer treatment, which has led to the emergence of combinational therapy. In this study, we investigated the potential use of nuclear receptor (NR) ligands for combinational therapy with other anti-cancer drugs. We first profiled all 48 NRs and 48 biological anti-cancer targets in four pairs of lung cell lines, where each pair was obtained from the same patient. Two sets of cell lines were normal and the corresponding tumor cell lines while the other two sets consisted of primary versus metastatic tumor cell lines. Analysis of the expression profile revealed 11 NRs and 15 cancer targets from the two pairs of normal versus tumor cell lines, and 9 NRs and 9 cancer targets from the primary versus metastatic tumor cell lines had distinct expression patterns in each category. Finally, the evaluation of nuclear receptor ligand T0901317 for liver X receptor (LXR) demonstrated its combined therapeutic potential with tyrosine kinase inhibitors. The combined treatment of cMET inhibitor PHA665752 or EGFR inhibitor gefitinib with T0901317 showed additive growth inhibition in both H2073 and H1993 cells. Mechanistically, the combined treatment suppressed cell cycle progression by inhibiting cyclinD1 and cyclinB expression. Taken together, this study provides insight into the potential use of NR ligands in combined therapeutics with other biological anti-cancer drugs.

Education of History of Medicine for 80 Years: History and Current Status in Republic of Korea.

Medical history education enables the medical students to understand the humanistic aspects of medicine and also help to promote the professionalism of doctors. It makes them understand the disappearing or emerging diseases by recognizing the historical changes and trends to respond appropriately. Therefore, it is helpful to study and understand modern medicine. As of March 2023, 22 (55.0%) out of 40 medical schools in Republic of Korea have medical history course as an independent subject and two schools have integrated courses with medical ethics. Compared to 53.1% in 1995 and 56.2% in 2010, similar percentage of medical schools maintained the subject independently. However, the average credits of 18 schools in 2023(2.0) are higher than those of 1995(1.4) and 2010(1.2). The number of full-time professor who specialized in the history of medicine was 2 in 1995, 6 in 2010, and 11 in 2023. Generally, a full-time professor majoring medical history tend to have other duties besides the education and research of medical history, depending on the role of the department to which he or she belongs since they are assigned to the humanities education other than medical history education. Currently, the curriculums that have been recommended by Korea Association of Medical Colleges(KAMC), Korean Institute of Medical Education and Evaluation(KIMEE), and The Korean Society of Medical Education(KSMED), emphasize medical humanities but do not necessarily include the medical history. As a result, medical history courses have increased slightly, but the other humanities classes have increased significantly since 2000. The knowledge of medical history will help students become a doctor, and a doctor with professionalism adapting to the rapidly changing medical environment. Students will also be able to establish the ideas they must pursue in the present era when they come into contact with numerous historical situations. And if they share a sense of history, they will inspire a sense of unity as a profession and will be more active in solving social problems such as health equity. It is hoped that The Korean Society for the History of Medicine will step forward to set the purpose and goal of the medical history education, and organize the contents of the education. Classes should be prepared so that students are interested in them, and education should be focused on how the contents of education will be able to be used in medicine. To this end, it is necessary to establish the basic learning outcomes of history of medicine, and prepare learning materials based on these learning outcomes. It is also necessary to increase the competencies of educators for the history of medicine, such as performing workshops. With the dedication of the pioneers who devoted their energy to the education of medical history, it is expected that medical history will find out what to do in medical education to foster better doctors and provide better education.

Needs assessment for faculty development in dental education, at the University of Health Sciences, Lao PDR.

Due to the short history of dental education in Laos, the educational system is still incomplete, with only a few faculty development (FD) programs. This study aims to identify the needs assessment for FD, in Lao dental education. A survey was conducted, with dentists from the Faculty of Dentistry, in 2022. Data on demographics, perceived importance, and ability, on the 13 roles and competencies of teachers, as well as the 26 FD items' needs assessment were collected. Data were compared between the two groups (lecturers and assistant teachers), and analyzed to identify different needs. Sixty-seven responses were included, after excluding inappropriate ones. Lecturers and assistant teachers expressed their needs for developing a syllabus, and teaching using simulation. Lecturers revealed the need to improve their roles as resource developers, followed by learning facilitators and lecturer in a classroom setting. Assistant teachers reported their prioritized needs for improving their role as on-the-job role models, followed by lecturer in a classroom setting, and mentor, personal adviser, or tutor. Assistant teachers showed higher educational needs scores than lecturers, in most questionnaire items. Although the needs assessment of FD indicates different needs, based on the differing roles and responsibilities, assistant teachers' needs scores are generally higher. An FD program could prioritize the most common needs of both groups at an early stage, but the topics most needed by each group should also be considered. This study can inform a future FD program, to improve Lao dental education.

Predictive factors for interferon and ribavirin combination therapy in patients with chronic hepatitis C.

AIM: To confirm the predictive factors for interferon (IFN)-alpha and ribavirin combination therapy for chronic hepatitis patients with hepatitis C virus (HCV) genotype 1b. METHODS: HCV RNA from 50 patients infected with HCV genotype 1b was studied by cloning and sequencing of interferon sensitivity determining region (ISDR), PKR-eIF2alpha phosphorylation homology domain (PePHD). Patients were treated with IFN-alpha and ribavirin for 6 mo and grouped by effectiveness of the therapy. A variety of factors were analyzed. RESULTS: Our data showed that age, HCV RNA titer, and ISDR type could be used as the predictive factors for combined IFN-alpha and ribavirin efficacy. Characteristically, mutations in PePHD appeared only when the combination therapy was effective. Other factors, such as sex and alanine aminotransferase (ALT) level, were not related to its efficacy. Adjusting for age and HCV RNA titer indicated that the ISDR type was the most potent predictive factor. CONCLUSION: HCV RNA ISDR type is an important factor for predicting efficacy of IFN-alpha and ribavirin combination therapy in Korean patients.

Human zinc fingers as building blocks in the construction of artificial transcription factors.

We describe methods for generating artificial transcription factors capable of up- or downregulating the expression of genes whose promoter regions contain the target DNA sequences. To accomplish this, we screened zinc fingers derived from sequences in the human genome and isolated 56 zinc fingers with diverse DNA-binding specificities. We used these zinc fingers as modular building blocks in the construction of novel, sequence-specific DNA-binding proteins. Fusion of these zinc-finger proteins with either a transcriptional activation or repression domain yielded potent transcriptional activators or repressors, respectively. These results show that the human genome encodes zinc fingers with diverse DNA-binding specificities and that these domains can be used to design sequence-specific DNA-binding proteins and artificial transcription factors.

Characteristic of aromatic amino acid substitution at alpha 96 of hemoglobin.

Replacement of valine by tryptophan or tyrosine at position alpha96 of the alpha chain (alpha96Val), located in the alpha(1)beta(2) subunit interface of hemoglobin leads to low oxygen affinity hemoglobin, and has been suggested to be due to the extra stability introduced by an aromatic amino acid at the alpha96 position. The characteristic of aromatic amino acid substitution at the alpha96 of hemoglobin has been further investigated by producing double mutant r Hb (alpha42Tyr --> Phe, alpha96Val --> Trp). r Hb (alpha42Tyr --> Phe) is known to exhibit almost no cooperativity in binding oxygen, and possesses high oxygen affinity due to the disruption of the hydrogen bond between alpha42Tyr and beta99Asp in thealpha(1)beta(2) subunit interface of deoxy Hb A. The second mutation, alpha96Val -->Trp, may compensate the functional defects of r Hb (alpha42Tyr --> Phe), if the stability due to the introduction of trypophan at the alpha 96 position is strong enough to overcome the defect of r Hb (alpha42Tyr --> Phe). Double mutant r Hb (alpha42Tyr --> Phe, alpha96Val --> Trp) exhibited almost no cooperativity in binding oxygen and possessed high oxygen affinity, similarly to that of r Hb (alpha42Tyr --> Phe). (1)H NMR spectroscopic data of r Hb (alpha42Tyr --> Phe, alpha96Val --> Trp) also showed a very unstable deoxy-quaternary structure. The present investigation has demonstrated that the presence of the crucible hydrogen bond between alpha 42Tyr and beta 99Asp is essential for the novel oxygen binding properties of deoxy Hb (alpha96Val --> Trp) .

Nuclear Receptor Expression and Function in Human Lung Cancer Pathogenesis.

Lung cancer is caused by combinations of diverse genetic mutations. Here, to understand the relevance of nuclear receptors (NRs) in the oncogene-associated lung cancer pathogenesis, we investigated the expression profile of the entire 48 NR members by using QPCR analysis in a panel of human bronchial epithelial cells (HBECs) that included precancerous and tumorigenic HBECs harboring oncogenic K-rasV12 and/or p53 alterations. The analysis of the profile revealed that oncogenic alterations accompanied transcriptional changes in the expression of 19 NRs in precancerous HBECs and 15 NRs according to the malignant progression of HBECs. Amongst these, peroxisome proliferator-activated receptor gamma (PPARγ), a NR chosen as a proof-of-principle study, showed increased expression in precancerous HBECs, which was surprisingly reversed when these HBECs acquired full in vivo tumorigenicity. Notably, PPARγ activation by thiazolidinedione (TZD) treatment reversed the increased expression of pro-inflammatory cyclooxygenase 2 (COX2) in precancerous HBECs. In fully tumorigenic HBECs with inducible expression of PPARγ, TZD treatments inhibited tumor cell growth, clonogenecity, and cell migration in a PPARγ-sumoylation dependent manner. Mechanistically, the sumoylation of liganded-PPARγ decreased COX2 expression and increased 15-hydroxyprostaglandin dehydrogenase expression. This suggests that ligand-mediated sumoylation of PPARγ plays an important role in lung cancer pathogenesis by modulating prostaglandin metabolism.

Iontophoresis and sonophoresis stimulate epidermal cytokine expression at energies that do not provoke a barrier abnormality: lamellar body secretion and cytokine expression are linked to altered epidermal calcium levels.

We performed this study to identify whether the expression of epidermal cytokines is altered by changes in epidermal calcium content, independent of skin barrier disruption. Iontophoresis and sonophoresis with the energies that do not disrupt the skin barrier, but induce changes in the epidermal calcium gradient, were applied to the skin of hairless mice. Immediately after iontophoresis and sonophoresis, immersion in a solution containing calcium was carried out, and iontophoresis in either high- or low-calcium solutions was performed. The biopsy specimens were taken for real-time quantitative RT-PCR to detect changes in mRNA level of interleukin-1alpha (IL-1alpha), tumor necrosis factor-alpha (TNF-alpha), and transforming growth factor-beta in the epidermis and for immunohistochemical stain with primary antibodies to IL-1alpha and TNF-alpha. The expression of each cytokine mRNA increased in the epidermis treated with iontophoresis and sonophoresis compared to a nontreated control as well as in tape-stripped skin used as a positive control and was lower after immersion in a high-calcium solution than in low-calcium solution. IL-1alpha and TNF-alpha immunohistochemical protein staining increased with iontophoresis at low calcium. These studies suggest that changes in epidermal calcium can directly signal expression of epidermal cytokines in vivo, independent of changes in barrier function.

Analysis of polymorphism of the GLUT2 promoter in NIDDM patients and its functional consequence to the promoter activity.

Glucose transporter type 2 (GLUT2), along with glucokinase, has been implicated to participate in glucose-induced insulin secretion in pancreatic beta-cells. Recently, several sequence variations in the promoter of GLUT2 have been identified in patients with non-insulin dependent diabetes mellitus (NIDDM), but the functional effects of these polymorphisms on promoter activity have not previously been studied. We compared the incidence of sequence variations in the GLUT2 promoter in 100 normal subjects and 100 NIDDM patients. Sequencing of the promoter region (-294 to +301) revealed that an A --> G variant at position -44 was found in 45 of 100 NIDDM patients, but only in 23 of 100 normal subjects. In addition, -269 A --> C and + 103 A --> G mutations were identified in a single diabetic patient. Electrophoretic mobility shift assays using double-stranded oligonucleotide containing -44A as a probe showed a clearly shifted band of DNA-protein. To examine whether the sequence variation at position -44 affects the promoter activity, we carried out in vitro transfection experiments. Site-specific mutagenesis at position -44 region from A to C, T, or G resulted in reductions of CAT activity by 52.3%, 63.8%, and 63.6%, respectively. The -269 A --> C and + 103 A --> G mutations also decreased the promoter activity. These results suggest that polymorphisms at positions -269, -44, or + 103 may affect GLUT2 gene transcription, possibly associated with reduced expression of the GLUT2 gene in NIDDM patients.

The Advent of Lifestyle Medicine.

The fact that lifestyle is closely associated with the pathogenesis of chronic diseases has been known for more than three decades. Smoking may cause lung cancer, and a lifestyle of fast food consumption and little exercise can cause metabolic diseases. The importance of lifestyle changes in terms of a new medical paradigm to solve chronic diseases is becoming popular in modern times. Lifestyle medicine is a medicine based on personal lifestyle. To apply it to patients and ordinary people, physicians have to cooperate with experts in many fields such as nutrition, exercise, psychology, etc. In addition, patients must be partners in the treatment rather than passive recipients. The advent of lifestyle medicine has been caused by changes in disease patterns. In the past, acute diseases like infectious disease were prevalent; however, in the late 20(th) century, chronic diseases such as metabolic diseases, cancers, neurological disease, etc. increased in occurrence. As lifestyle is closely related with these diseases, the attitudes toward medicine need to be changed. Recently, the concept of "Lifestyle Medicine" was proposed, and we predict it will be an important field in future medicine.

Application of 'writing for healing' in premedical humanities education.

There has been a recent tendency to attach special importance to writing education. Books on 'writing to heal' are being written in or translated into Korean. According to these texts, writing is a valuable tool for internal healing, depending on the mode of application. Writing can have positive effects and give hope to an individual or group, but it can also be a source of frustration and despair. Based on the distinct effects of writing, we cannot overemphasize the significance of writing education. Writing is generally taught during a premedical course that targets students who will eventually practice medicine. Many reports have examined immorality in medical students and health care providers, which is a reason that writing education is important for medical systems. 'Writing for Healing' is open to freshmen at Yonsei University Wonju College of Medicine. The aim of this subject is to help students identify and acknowledge internal diseases to lead a healthier life and eventually become positive and responsible health care providers. However, in addition to the vague definition of what 'healing' is, the concept of 'writing for healing' has not been defined. This paper attempts to define the concept of 'writing for healing' and considers what influences it can have on a humanities curriculum in medical colleges.

Src family kinase potentiates the activity of nicotinic acetylcholine receptor in rat autonomic ganglion innervating urinary bladder.

Src family kinases (SFKs), one of the tyrosine kinase groups, are primary regulators of signal transductions that control cellular functions such as cell proliferation, differentiation, survival, metabolism, and other important roles of the cell. One of the crucial functions of SFKs is to regulate the activities of various neuronal channels. In this study, we investigated the modulatory action of SFK on nicotinic acetylcholine receptors (nAChRs) expressed in rat major pelvic ganglion (MPG) neurons innervating the urinary bladder. PP1 and PP2 (5 µM), selective Src-kinase inhibitors, attenuated ACh-induced ionic currents and [Ca²+](i) transients in MPG neurons, whereas PP3, an inactive analogue, had no effect. Blocking the tyrosine kinase activity of Src kinase by pp60 c-src inhibitory peptide also reduced the ACh-induced currents. Conversely, sodium orthovanadate (200 µM), a tyrosine phosphatase inhibitor, significantly augmented the ACh-induced currents. In the kinase assay, the activities of SFKs in MPG neurons were also inhibited by PP2, but not by PP3. These data suggests that SFKs may have a facilitative role on the synaptic transmission in rat pelvic autonomic ganglion.

Functional Expression of P2Y Receptors in WERI-Rb1 Retinoblastoma Cells.

P2Y receptors are metabotropic G-protein-coupled receptors, which are involved in many important biologic functions in the central nervous system including retina. Subtypes of P2Y receptors in retinal tissue vary according to the species and the cell types. We examined the molecular and pharmacologic profiles of P2Y purinoceptors in retinoblastoma cell, which has not been identified yet. To achieve this goal, we used Ca(2+) imaging technique and western blot analysis in WERI-Rb-1 cell, a human retinoblastoma cell line. ATP (10 µM) elicited strong but transient [Ca(2+)](i) increase in a concentration-dependent manner from more than 80% of the WERI-Rb-1 cells (n=46). Orders of potency of P2Y agonists in evoking [Ca(2+)](i) transients were 2MeS-ATP>ATP>>UTP=αß-MeATP, which was compatible with the subclass of P2Y(1) receptor. The [Ca(2+)](i) transients evoked by applications of 2MeS-ATP and/or ATP were also profoundly suppressed in the presence of P2Y(1) selective blocker (MRS 2179; 30 µM). P2Y(1) receptor expression in WERI-Rb-1 cells was also identified by using western blot. Taken together, P2Y(1) receptor is mainly expressed in a retinoblastoma cell, which elicits Ca(2+) release from internal Ca(2+) storage sites via the phospholipase C-mediated pathway. P2Y(1) receptor activation in retinoblastoma cell could be a useful model to investigate the role of purinergic [Ca(2+)](i) signaling in neural tissue as well as to find a novel therapeutic target to this lethal cancer.

Serum levels of angiopoietin-related growth factor are increased in metabolic syndrome.

Angiopoietin-related growth factor (AGF), a novel hepatokine, showed therapeutic implications in diabetic and obese animal models. Although the physiologic functions of human AGF have not yet been identified, serum levels of AGF displayed up-regulation in groups with diseases including preeclampsia and diabetes; and there was little association between genetic variability of AGF and metabolic syndrome-related phenotypes. We analyzed serum levels of AGF and other biochemical and anthropometric markers in 216 Korean persons--the numbers of healthy controls and those with metabolic syndrome were 138 and 78, respectively--to confirm research data from animal models. Women had higher AGF than men (265.01 vs 311.84 ng/mL, P = .003). This study showed that serum AGF levels were significantly higher in subjects with metabolic syndrome (325.89 ng/mL) than those in the healthy group (272.44 ng/mL) (P = .003). Among the components of metabolic syndrome, subjects with high waist circumference or decreased high-density lipoprotein cholesterol had significantly increased serum AGF (271.92 vs 313.68 ng/mL, P = .013; 271.01 vs 310.58 ng/mL, P = .023, respectively). According to multivariate regression analysis, metabolic syndrome itself and waist circumference could be used, in addition to sex and age, as predictors of serum AGF level. In conclusion, serum AGF levels were paradoxically increased in metabolic syndrome, in comparison with data from animal experiments and data on sex, age, and waist circumference. Metabolic syndrome can be a predictor of serum AGF level. Further studies are needed to explore the possibilities of compensatory up-regulation, or AGF resistance, to explain the physiologic roles of AGF in metabolic syndrome.

Repression of human telomerase reverse transcriptase using artificial zinc finger transcription factors.

Telomerase activation is a key step in the development of human cancers. Expression of the catalytic subunit, human telomerase reverse transcriptase (hTERT), represents the limiting factor for telomerase activity. In this study, we have used artificial zinc finger protein (ZFP) transcription factors (TF) to repress the expression of hTERT in human cancer cell lines at the transcriptional level. We have constructed four-fingered ZFPs derived from the human genome which binds 12-bp recognition sequences within the promoter of the hTERT gene and fused them with a KRAB repressor domain to create a potent transcriptional repressor. Luciferase activity was decreased by >80% in all of the transcriptional repressors with luciferase reporter assay. When they were transfected into the telomerase-positive HEK293 cell line, a decrease of mRNA level and telomerase activity together with shortening of telomere length was observed. Actual growth of HEK293 cells was also inhibited by transfection of artificial ZFP-TFs. The repression was maintained for 100 days of culture. The repression of telomerase expression by artificial ZFP-TFs targeting the promoter region of the hTERT presents a new promising strategy for inhibiting the growth of human cancer cells.

Calcium mobilization by activation of M(3)/M(5) muscarinic receptors in the human retinoblastoma.

Activation of muscarinic acetylcholine receptors (mAChR) is one of the most important signal transduction pathways in the human body. In this study, we investigated the role of mAChR activation in relation to its subtypes in human retinoblastoma cell-lines (WERI-Rb-1) using Ca(2+) measurement, real-time PCR, and Western Blot techniques. Acetylcholine (ACh) produced prominent [Ca(2+)](i) transients in a repeated manner in WERI-Rb-1 cells. The maximal amplitude of the [Ca(2+)](i) transient was almost completely suppressed by 97.3 +/- 0.8% after atropine (1 microM) pretreatment. Similar suppressions were noted after pretreatments with thapsigargin (1 microM), an ER Ca(2+)-ATPase (SERCA) inhibitor, whereas the ACh-induced [Ca(2+)](i) transient was not affected even in the absence of extracellular calcium. U-73122 (1 microM), a PLC inhibitor, and xestospongin C (2 microM), an IP(3)-receptor antagonist, elicited 11.5 +/- 2.9% and 17.8 +/- 1.9% suppressions, respectively. The 50% inhibitory concentration of (IC(50)) values for blockade of a 100 microM ACh response by pirenzepine and 4-DAMP were 315.8 and 9.1 nM, respectively. Moreover, both M(3) and M(5) mAChRs were prominent in quantitative real-time-PCR. Taken together, the M(3)/M(5) subtypes appear to be the major contributor, leading to intracellular calcium mobilization from the internal store via an IP(3)-dependent pathway in the undifferentiated retinoblastoma cells.

On the role of pore helix in regulation of TRPV5 by extracellular protons.

The transient receptor potential channel TRPV5 is localized to the apical membrane of the distal renal tubule and plays an important role in the regulation of transepithelial Ca(2+) reabsorption in kidney. We have previously reported that extracellular protons inhibit TRPV5 by binding to glutamate-522 (E522) in the extracellular domain of the channel. We suggested that E522 is an extracellular "pH sensor" and its titration by extracellular protons inhibits TRPV5 via conformational change(s) of the pore helix. We now report that mutation of a pore helix residue glutamate-535 to glutamine (E535Q) enhances the sensitivity of the channel to inhibition by extracellular protons (i.e., shifting the apparent pKa for inhibition by extracellular protons to the more alkaline extracellular pH). The enhancement of extracellular proton-mediated inhibition of E535Q mutant is also dependent on E522. We have also reported that intracellular acidification enhances the sensitivity of TRPV5 to inhibition by extracellular protons. We now find that modulation of the extracellular proton-mediated inhibition by intracellular acidification is preserved in the E535Q mutant. These results provide further support for the idea that pore helix is involved in the regulation of TRPV5 by extracellular protons. Inhibition of TRPV5 by extracellular protons may contribute to hypercalciuria in diseases associated with high acid load.