Recent Insights into the Measurement of Carbon Dioxide Concentrations for Clinical Practice in Respiratory Medicine.

In the field of respiratory clinical practice, the importance of measuring carbon dioxide (CO2) concentrations cannot be overemphasized. Within the body, assessment of the arterial partial pressure of CO2 (PaCO2) has been the gold standard for many decades. Non-invasive assessments are usually predicated on the measurement of CO2 concentrations in the air, usually using an infrared analyzer, and these data are clearly important regarding climate changes as well as regulations of air quality in buildings to ascertain adequate ventilation. Measurements of CO2 production with oxygen consumption yield important indices such as the respiratory quotient and estimates of energy expenditure, which may be used for further investigation in the various fields of metabolism, obesity, sleep disorders, and lifestyle-related issues. Measures of PaCO2 are nowadays performed using the Severinghaus electrode in arterial blood or in arterialized capillary blood, while the same electrode system has been modified to enable relatively accurate non-invasive monitoring of the transcutaneous partial pressure of CO2 (PtcCO2). PtcCO2 monitoring during sleep can be helpful for evaluating sleep apnea syndrome, particularly in children. End-tidal PCO2 is inferior to PtcCO2 as far as accuracy, but it provides breath-by-breath estimates of respiratory gas exchange, while PtcCO2 reflects temporal trends in alveolar ventilation. The frequency of monitoring end-tidal PCO2 has markedly increased in light of its multiple applications (e.g., verify endotracheal intubation, anesthesia or mechanical ventilation, exercise testing, respiratory patterning during sleep, etc.).

Evaluation of time courses of agreement between minutely obtained transcutaneous blood gas data and the gold standard arterial data from spontaneously breathing Asian adults, and various subgroup analyses.

BACKGROUND: Usual clinical practice for arterial blood gas analysis (BGA) in conscious patients involves a one-time arterial puncture to be performed after a resting period of 20-30 min. The aim of this study was to evaluate the use of transcutaneous BGA for estimating this gold standard arterial BGA. METHODS: Spontaneously breathing Asian adults (healthy volunteers and respiratory patients) were enrolled (n = 295). Transcutaneous PO2 (PtcO2) and PCO2 (PtcCO2) were monitored using a transcutaneous monitor (TCM4, Radiometer Medical AsP, Denmark) with sensors placed on the chest, forearm, earlobe or forehead. Transcutaneous BGA at 1-min intervals was compared with arterial BGA at 30 min. Reasonable steps to find severe hypercapnia with PaCO2 > 50 mmHg were evaluated. RESULTS: Sensors on the chest and forearm were equally preferred and used because of small biases (n = 272). The average PCO2 bias was close to 0 mmHg at 4 min, and was almost constant (4-5 mmHg) with PtcCO2 being higher than PaCO2 at ≥8 min. The limit of agreement for PCO2 narrowed over time: ± 13.6 mmHg at 4 min, ± 7.5 mmHg at 12-13 min, and ± 6.3 mmHg at 30 min. The limit of agreement for PO2 also narrowed over time (± 23.1 mmHg at 30 min). Subgroup analyses showed that the PaCO2 and PaO2 levels, gender, and younger age significantly affected the biases. All hypercapnia subjects with PaCO2 > 50 mmHg (n = 13) showed PtcCO2 ≥ 50 mmHg for until 12 min. CONCLUSIONS: Although PtcCO2 is useful, it cannot completely replace PaCO2 because PCO2 occasionally showed large bias. On the other hand, the prediction of PaO2 using PtcO2 was unrealistic in Asian adults. PtcCO2 ≥ 50 mmHg for until 12 min can be used as a screening tool for severe hypercapnia with PaCO2 > 50 mmHg.

Characteristics of severe asthma with fungal sensitization.

BACKGROUND: Some patients with severe asthma also have fungal sensitization and are considered to have severe asthma with fungal sensitization. However, there is limited information on the clinical features of SAFS. OBJECTIVE: To investigate the clinical characteristics of severe asthma with fungal sensitization. METHODS: The present study enrolled 124 patients with severe asthma. We evaluated clinical aspects, such as various serum cytokines, fractional exhaled nitric oxide, pulmonary function, and serum immunoglobulin E (IgE). Fungal sensitization was assessed by determining serum levels of IgE specific to fungal allergens (Aspergillus, Alternaria, Candida, Cladosporium, Penicillium, and Trichophyton species and Schizophyllum commune). The protocol was registered at a clinical trial registry (www.umin.ac.jp/ctr/index-j.htm; UMIN 000002980). RESULTS: Thirty-six patients (29%) showed sensitization to at least 1 fungal allergen. The most common species were Candida (16%), Aspergillus (11%), and Trichophyton (11%). The rate of early-onset asthma (<16 years of age) was higher in patients with fungal sensitization than in those without fungal sensitization (45% vs 25%; P = .02). Interleukin-33 levels were higher in patients with fungal sensitization than in those without fungal sensitization. Of patients with atopic asthma, Asthma Control Test scores were worse in patients with multiple fungal sensitizations than in patients with a single fungal sensitization or those without fungal sensitization. CONCLUSION: Severe asthma with fungal sensitization is characterized by early onset of disease and high serum levels of interleukin-33. Multiple fungal sensitizations are associated with poor asthma control. TRIAL REGISTRATION: UMIN Clinical Trials Registry (UMIN-CTR; www.umin.ac.jp/ctr/index-j.htm): UMIN 000002980.

Phenotype of asthma related with high serum periostin levels.

BACKGROUND: Asthma is a heterogeneous disease composed of various phenotypes. Periostin, a molecule inducible with interleukin (IL)-4 or IL-13 in bronchial epithelial cells, is a biomarker of "TH2-high" asthma. The objective of this study is to examine whether the serum periostin concentrations are correlated with the severity, specific phenotype(s), or comorbidity of asthma. METHODS: Serum concentrations of periostin were measured in 190 Japanese asthmatic patients and 11 healthy controls. The protocol was registered under UMIN 000002980 in the clinical trial registry. RESULTS: The serum concentrations of periostin were significantly higher (P = 0.014) in asthmatics [70.0 (54.0-93.5) ng/ml] than in healthy subjects [57.0 (39.0-63.0) ng/ml], though we found no correlation between serum periostin concentrations and treatment steps required to control asthma. To characterize "high-periostin" phenotype(s), the patients with asthma were divided among tertiles based on the serum concentrations of periostin. The high-periostin group was older at onset of asthma (P = 0.04), had a higher prevalence of aspirin intolerance (P = 0.04) or concomitant nasal disorders (P = 0.03-0.001), higher peripheral eosinophil counts (P < 0.001), and lower pulmonary function (P = 0.02-0.07). The serum concentrations of periostin were particularly high in asthmatic patients complicated by chronic rhinosinusitis with nasal polyps and olfactory dysfunction. In contrast, neither atopic status, control status of asthma, nor quality of life were related with the "high-periostin" phenotype. CONCLUSION: Elevated periostin concentrations in serum were correlated with a specific phenotype of eosinophilic asthma, late-onset and often complicated by obstructive pulmonary dysfunction and nasal disorders.

Upper Respiratory Symptoms as Long COVID: Insight from a Multicenter Cohort Study.

Objective: This study aimed to investigate the clinical features of long COVID cases presenting with upper respiratory symptoms, a topic not yet fully elucidated. Study Design: Prospective cohort study. Setting: A multicenter study involving 26 medical facilities in Japan. Methods: Inclusion criteria were patients aged ≥18 years old with a confirmed COVID-19 diagnosis via severe acute respiratory syndrome coronavirus 2 polymerase chain reaction or antigen testing, who were hospitalized at the participating medical facilities. Analyzing clinical information and patient-reported outcomes from 1009 patients were analyzed. The outcome measured the degree of initial symptoms for taste or olfactory disorders and assessed the likelihood of these symptoms persisting as long COVID, as well as the impact on quality of life if the upper respiratory symptoms persisted as long COVID. Results: Patients with high albumin, low C-reactive protein, and low lactate dehydrogenase in laboratory tests tended to experience taste or olfactory disorders as part of long COVID. Those with severe initial symptoms had a higher risk of experiencing residual symptoms at 3 months, with an odds ratio of 2.933 (95% confidence interval [CI], 1.282-6.526) for taste disorders and 3.534 (95% CI, 1.382-9.009) for olfactory disorders. Presence of upper respiratory symptoms consistently resulted in lower quality of life scores. Conclusion: The findings from this cohort study suggest that severe taste or olfactory disorders as early COVID-19 symptoms correlate with an increased likelihood of persistent symptoms in those disorders as long COVID.

Real-world effects of once-daily inhaled steroid (fluticasone furoate) combined with long-acting beta-2 agonist (vilanterol) and long-acting muscarinic antagonist (umeclidinium) on lung function tests of asthma patients in Japan.

Background: The Japanese drug use system allowed the once-daily use of inhaled corticosteroid fluticasone furoate (FF) combined with a long-acting beta-2 agonist vilanterol (VI) and a long-acting muscarinic antagonist umeclidinium (UMEC) against asthma on 18 February 2021. We investigated the real-world effects of these drugs (FF/UMEC/VI) mainly on lung function tests. Methods: This was an open-label, uncontrolled, within-group time-series (before-after) study. Prior asthma treatment (inhaled corticosteroid with/without a long-acting beta-2 agonist with/without a long-acting muscarinic antagonist) was switched to FF/UMEC/VI 200/62.5/25 µg. Subjects were evaluated by lung function tests prior to, and 1-2 months after, initiation of FF/UMEC/VI 200/62.5/25 µg. Patients were asked questions regarding the asthma control test and preference for drugs. Results: Overall, 114 asthma outpatients (97% Japanese) were enrolled from February 2021 to April 2022: 104 subjects completed the study. Forced expiratory volume in 1 s, peak flow, and asthma control test score of FF/UMEC/VI 200/62.5/25 µg-treated subjects were significantly increased (p < 0.001, p < 0.001, and p < 0.01, respectively). In contrast with FF/VI 200/25 µg, instantaneous flow at 25% of the forced vital capacity and expiratory reserve volume were significantly increased by FF/UMEC/VI 200/62.5/25 µg (p < 0.01, p < 0.05, respectively). Sixty-six percent of subjects declared they wanted to continue FF/UMEC/VI 200/62.5/25 µg in the future. Adverse effects, mainly local, were seen in 30% of patients, but no serious adverse effects were seen. Conclusion: Once-daily FF/UMEC/VI 200/62.5/25 µg was effective against asthma without serious adverse events. This is the first report that demonstrated FF/UMEC/VI dilated peripheral airways using lung function tests. This evidence on drug effects may improve our understanding of pulmonary physiology and the pathophysiology of asthma.

Clinical features of Japanese patients with gastrointestinal long-COVID symptoms.

Gastrointestinal (GI) long-COVID symptoms, including diarrhea and abdominal pain, have been reported in patients with long-COVID. However, the clinical features of patients with GI long-COVID symptoms remain unclear. We conducted a large-scale prospective cohort study focusing on the clinical characteristics of patients with GI long-COVID symptoms in Japan. Among 943 COVID-19 patients, 58 patients (6.2%) had GI long-COVID symptoms. The health-related quality of life (QOL) parameters (the Short Form-8 [SF-8] and Euro Quality of Life 5 Dimensions 5 level [EQ-5D-5L]) at 12 months after diagnosis in patients with GI long-COVID symptoms were significantly lower than in those without GI long-COVID symptoms (P < 0.0001). Moreover, patients with GI long-COVID symptoms had more varied long-COVID symptoms compared to patients without GI long-COVID symptoms.

Effects of smoking cessation using varenicline on the serum concentrations of oxidized high-density lipoprotein: Comparison with high-density lipoprotein cholesterol.

BACKGROUND: The oxidized high-density lipoprotein (oxHDL) is a possible marker for cardiovascular diseases. This study investigated the effects of smoking cessation with varenicline (a partial agonist of nicotinic acetylcholine receptors) on the levels of oxHDL in the serum of subjects compared with those of high-density lipoprotein cholesterol (HDL-C). METHODS: Data of 99 nicotine-dependent adult subjects who visited the smoking cessation outpatient services at International University of Health and Welfare Shioya Hospital were reviewed. Each subject was treated with varenicline titrated up to 1.0 mg twice daily for 12 weeks. Serum levels of oxHDL and HDL-C were repeatedly measured by enzyme-linked immunosorbent assay and enzymatic method, respectively. RESULTS: The serum levels of oxHDL were significantly decreased from 163.2 ± 96.6 to 148.3 ± 80.7 U/mL (p = 0.034, n = 99). This effect was more prominent when the data of subjects in whom the treatment was objectively unsuccessful (exhaled carbon monoxide at 3 months ≥ 10 ppm) were omitted (from 166.6 ± 98.4 to 147.4 ± 80.6 U/mL; p = 0.0063, n = 93). In contrast, the serum levels of HDL-C were significantly increased (p = 0.0044, n = 99). There was a close relationship between the baseline levels of oxHDL and HDL-C (R = 0.45, p < 0.0001, n = 99). Changes in the levels of oxHDL were closely associated with changes in the levels of exhaled carbon monoxide in subjects in whom smoking cessation with varenicline was very effective (decrease in exhaled carbon monoxide by ≥ 15 ppm after treatment with varenicline; R = 0.42, p = 0.0052, n = 43). CONCLUSIONS: Although there was a close relationship between the baseline serum concentrations of oxHDL and HDL-C, smoking cessation decreased oxHDL and increased HDL-C. This effect on oxHDL may be associated with the effectiveness of smoking cessation.

Dual orexin receptor blocker suvorexant attenuates hypercapnic ventilatory augmentation in mice.

Suvorexant (Belsomra(R)), a dual orexin receptor antagonist widely used in the treatment of insomnia, inhibits the arousal system in the brain. However, the drug's ventilatory effects have not been fully explored. This study aims to investigate the expression of orexin receptors in respiratory neurons and the effects of suvorexant on ventilation. Immunohistology of brainstem orexin receptor OX2R expression was performed in adult mice (n = 4) in (1) rostral ventral respiratory group (rVRG) neurons projecting to the phrenic nucleus (PhN) retrogradely labeled by Fluoro-Gold (FG) tracer, (2) neurons immunoreactive for paired like homeobox 2b (Phox2b) in the parafacial respiratory group/retrotrapezoid nucleus (pFRG/RTN), and (3) neurons immunoreactive for neurokinin 1 receptor (NK1R) and somatostatin (SST) in the preBötzinger complex (preBötC). Additionally, we measured in vivo ventilatory responses to hyperoxic hypercapnia (5% CO2) and hypoxia (10% O2) before and after suvorexant pretreatment (10 and cumulative 100 mg/kg) in unrestrained mice (n = 10) in a body plethysmograph. We found the OX2R immunoreactive materials in pFRG/RTN Phox2b and preBötC NK1R/SST immunoreactive neurons but not in FG-labeled rVRG neurons, which suggests the involvement of orexin in respiratory control. Further, suvorexant expressly suppressed the hypercapnic ventilatory augmentation, otherwise unaffecting ventilation. Central orexin is involved in shaping the hypercapnic ventilatory chemosensitivity. Suppression of hypercapnic ventilatory augmentation by the orexin receptor antagonist suvorexant calls for caution in its use in pathologies that may progress to hypercapnic respiratory failure, or sleep-disordered breathing. Clinical trials are required to explore the role of targeted pharmacological inhibition of orexin in ventilatory pathologies.

Effects of Normoxic Recovery on Intima-Media Thickness of Aorta and Pulmonary Artery Following Intermittent Hypoxia in Mice.

Obstructive sleep apnea (OSA) patients are at risk for increased blood pressure and carotid intima-media thickness (IMT), with pulmonary hypertension and right-sided heart failure potentially developing as well. Chronic intermittent hypoxia (IH) has been used as an OSA model in animals, but its effects on vascular beds have not been evaluated using objective unbiased tools. Previously published and current experimental data in mice exposed to IH were evaluated for IMT in aorta and pulmonary artery (PA) after IH with or without normoxic recovery using software for meta-analysis, Review Manager 5. Because IMT data reports on PA were extremely scarce, atherosclerotic area percentage from lumen data was also evaluated. IH significantly increased IMT parameters in both aorta and PA as illustrated by Forest plots (P < 0.01), which also confirmed that IMT values after normoxic recovery were within the normal range in both vascular beds. One-sided scarce lower areas in Funnel Plots were seen for both aorta and PA indicating the likelihood of significant publication bias. Forest and Funnel plots, which provide unbiased assessments of published and current data, suggest that IH exposures may induce IMT thickening that may be reversed by normoxic recovery in both aorta and PA. In light of the potential likelihood of publication bias, future studies are needed to confirm or refute the findings. In conclusion, OSA may induce IMT thickening (e.g., aorta and/or PA), but the treatment (e.g., nasal continuous positive airway pressure) will likely lead to improvements in such findings.

Intermittent hypoxia, energy expenditure, and visceral adipocyte recovery.

BACKGROUND AND OBJECTIVE: Body weight of patients with obstructive sleep apnea after initiation of nasal continuous positive airway pressure appears to increase. We hypothesized that intermittent hypoxia (IH) will decrease energy expenditure (EE), and that normoxic recovery will lead to body weight gains. METHODS: C57BL/6 J male mice were exposed to either 12 h/day of mild IH (alternating FIO2-10-11% and 21%; 640 s cycle), or severe IH (FIO2-6-7%-21%; 180 s cycle) or sham IH daily for 4 or 8 weeks. After exposures, EE was evaluated while mice were kept under normoxia for 5 weeks and organ histology was evaluated. RESULTS: EE was not decreased by IH. However, visceral white adipocyte size after normoxic recovery was significantly increased in severe IH in an intensity-dependent manner. CONCLUSION: Our hypothesis that IH would decrease EE was not corroborated. However, IH and normoxic recovery seem to promote severity-dependent enlargement of visceral adipocytes, likely reflecting altered energy preservation mechanisms induced by IH.

Hyperventilation and finger exercise increase venous-arterial Pco2 and pH differences.

INTRODUCTION: Since the invention of the pulse oximeter, physicians often or even routinely perform venous blood gas analysis (VBGA). However, it has not been generally agreed that the application of VBGA is practically meaningful in routine clinical situations such as in an ED. METHODS: We measured venous-arterial Pco(2) difference ((v-a)Pco(2)) and arterial-venous pH difference ((a-v)pH), and analyzed the physiological factors that affect these differences in healthy volunteers and hyperventilation patients. RESULTS: In healthy volunteers, both (v-a)Pco(2) and (a-v)pH increased during finger exercise or hyperventilation in an intensity-dependent manner. Doppler echography indicated that increases in (v-a)Pco(2) and (a-v)pH during hyperventilation are induced by reduction of peripheral blood flow. Approximately 40% of patients with untreated respiratory alkalosis were found to be incorrectly diagnosed if based only on VBGA. CONCLUSIONS: It must be noted that VBGA may lead to overestimation of acidosis and to underestimation of respiratory alkalosis when extremities muscles are active or patients are hyperventilating. Physicians should keep these limitations in mind when conducting VBGA.

Possible involvement of monoamine neurons in the emotional abnormality in Kir6.2-deficient mice.

ATP-sensitive potassium (KATP) channels consist of two structurally different subunits: a pore-forming subunit of the Kir6.0-family (Kir6.1 or Kir6.2) and a regulatory sulfonylurea receptor subunit (SUR1, SUR2A or SUR2B). Although Kir6.2 is widely distributed in the brain, the mechanisms that underlie the impact of Kir6.2 on emotional behavior are not yet fully understood. To clarify the role of Kir6.2 in emotional behavior, in the present study, we investigated the behavioral characteristics of Kir6.2-knockout (Kir6.2-/-) mice. Kir6.2-/- mice showed impaired general behavior in a locomotor activity test and open field test. In addition, anxiety-like behavior was observed in the open field test, elevated plus-maze test and light-dark test. In particular, excessive anxiety-like behavior was observed in female Kir6.2-/- mice. Moreover, we investigated whether Kir6.2 is expressed on monoamine neurons in the brain. Immunohistochemical studies showed that Kir6.2 was co-localized with tryptophan hydroxylase (TPH), a marker of serotonergic neurons, in dorsal raphe nuclei. Kir6.2 was also co-localized with tyrosine hydroxylase (TH), a marker of dopaminergic/noradrenergic neurons, in the ventral tegmental area and locus coeruleus. Next, we checked the protein levels of TH and TPH in the midbrain. Interestingly, TPH expression was significantly elevated in female Kir6.2-/- mice. These results suggest that Kir6.2 in monoamine neurons, especially serotonergic neurons, could play a key role in emotional behavior.

A low-cost digital filing system for echocardiography data with MPEG4 compression and its application to remote diagnosis.

The high cost of digital echocardiographs and the large size of data files hinder the adoption of remote diagnosis of digitized echocardiography data. We have developed a low-cost digital filing system for echocardiography data. In this system, data from a conventional analog echocardiograph are captured using a personal computer (PC) equipped with an analog-to-digital converter board. Motion picture data are promptly compressed using a moving pictures expert group (MPEG) 4 codec. The digitized data with preliminary reports obtained in a rural hospital are then sent to cardiologists at distant urban general hospitals via the internet. The cardiologists can evaluate the data using widely available movie-viewing software (Windows Media Player). The diagnostic accuracy of this double-check system was confirmed by comparison with ordinary super-VHS videotapes. We have demonstrated that digitization of echocardiography data from a conventional analog echocardiograph and MPEG 4 compression can be performed using an ordinary PC-based system, and that this system enables highly efficient digital storage and remote diagnosis at low cost.

Analysis of recent cases of intestinal tuberculosis in Japan.

In Japan, which ranks first among developed countries in the incidence of tuberculosis, intestinal tuberculosis should be regarded as an important disease. However, few studies of this condition have recently been reported. We analyzed nine patients treated at our hospital during and after 2000. Our results differ from those of previous studies in that many of the patients were healthy, not elderly, had primary intestinal tuberculosis and presented with non-gastrointestinal symptoms. All seven patients tested were found to be whole blood interferon gamma release assay (IGRA)-positive. These results suggest that IGRA is useful as an adjunct method for diagnosing intestinal tuberculosis.

Marked improvement of Churg-Strauss syndrome neuropathy by intravenous immunoglobulin and cyclophosphamide.

A 42-year-old Japanese man developed Churg-Strauss syndrome 7 years after being diagnosed with chronic eosinophilic pneumonia. Prominent eosinophilia, subcutaneous nodules, and neuropathy in the left leg were seen. A pathological diagnosis of necrotizing vasculitis was determined by a biopsy of a subcutaneous nodule. The leg pain was severe and there was prominent atrophy of the thigh and calf, but the muscle weakness was mild. Serum anti-myeloperoxidase anti-neutrophil cytoplasmic antibody was positive. Because the initial treatment with an intravenous methylprednisolone pulse at 1 g/day for 3 days was not sufficient, a onetime treatment with intravenous cyclophosphamide at 15 mg/kg and intravenous immunoglobulin therapy (IVIG) at 400 mg/kg/day for 5 days were administered. Peripheral eosinophilia improved and the leg pain significantly improved. IVIG was repeated 1 month later and symptoms gradually improved further. The early diagnosis of Churg-Strauss syndrome and the early initiation of IVIG with cyclophosphamide were thought to be important.

Varenicline-assisted smoking cessation decreases oxidative stress and restores endothelial function.

Smoking cessation decreases oxidative stress and restores vascular endothelial function. However, a recent meta-analysis suggests that the use of varenicline, a α4ß2 nicotinic acetylcholine receptor partial agonist, increases the risk of cardiovascular events. This study was designed to determine the effect of varenicline-assisted smoking cessation on vascular endothelial function. Study subjects were 11 healthy Japanese males (mean age, 54.4 years) without evidence of cardiovascular disease who were eager to quit smoking. Each subject was treated with varenicline titrated up to 1.0 mg twice daily. We evaluated serum derivatives of reactive oxygen metabolites (d-ROMs) as a marker of oxidative stress, and flow-mediated dilation (FMD) of the brachial artery as a marker of vascular endothelial function. Both measurements were performed before and 3 months after completing smoking cessation. All subjects gained weight (average, 1.7 kg) after smoking cessation. However, there were no significant differences in the following parameters before and after smoking cessation: systolic blood pressure, diastolic blood pressure, heart rate, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, glucose and hemoglobin A1c. Serum d-ROM levels significantly decreased from 340.7±70.4 to 300.0±43.2 U.CARR (P=0.012), and FMD significantly increased from 3.36±1.26 to 5.25±1.33% (P=0.00067) after smoking cessation. There was an inverse correlation between FMD and serum d-ROM levels (R=-0.377; P=0.043). Our observations suggest that varenicline-assisted smoking cessation restores vascular endothelial function, and this is associated with decreased oxidative stress, despite an increase in body weight. As varenicline-assisted smoking cessation possibly has beneficial effects on vascular endothelial function, it might also reduce cardiovascular risk.

Bleeding Brunner's Gland Hyperplasia of the Duodenum: A Case Report With a Review of the Japanese Literature.

A man taking antithrombotic agents was admitted because of melena. Upper gastrointestinal endoscopy revealed a large, pedunculated polyp bleeding from erosions on its top. The polyp was endoscopically resected, and histopathologically diagnosed as Brunner's gland hyperplasia. It is commonly encountered as a small, raised lesion, but may enlarge or bleed. We report this case, with a review of the Japanese literature and discussion of the mechanism of bleeding.

A Case of Refractory Gastric Cardia Ulcer in Which Marked Elevation of the Surrounding Mucosa was Observed During the Clinical Course.

A 55-year-old man visited our department because of epigastric pain. Upper gastrointestinal endoscopy revealed a small, undermined ulcer in the gastric cardia. He had no history of taking NSAIDs, and was positive for Helicobacter pylori (Hp) infection. After Hp eradication therapy followed by 8 weeks of proton pump inhibitor (PPI) administration, re-endoscopy showed that the ulcer had slightly shrunk without scarring, and the surrounding mucosa was markedly elevated, like in a submucosal tumor. Endoscopic ultrasonography, performed at the same time, showed thickening of the submucosal and muscular layers around the ulcer. After continuous PPI administration, the mucosal elevation disappeared, and the ulcer shrunk and later scarred. However, when the dose of PPI was reduced with the aim of discontinuing it after the confirmation of successful Hp eradication, the ulcer recurred. We report this case of gastric ulcer because of its peculiar clinical presentation.

Does smoking cessation with varenicline worsen vascular endothelial function?

OBJECTIVES: A meta-analysis suggested that the use of varenicline, which is a partial agonist of nicotinic acetylcholine receptors and is effective in smoking cessation, increases the risk of cardiovascular events within 52 weeks of starting treatment. Defining these events as occurring during drug treatment (usually for 12 weeks) or within 30 days of discontinuation, another meta-analysis showed that the risk was statistically insignificant. In the present study, we aimed to clarify the effect of varenicline-assisted smoking cessation on vascular endothelial function assessed by flow-mediated vasodilation (FMD). DESIGN: Before-after and time-series. SETTING: Tochigi Prefecture, Japan. PARTICIPANTS: Data of 85 participants who visited nicotine-dependent outpatient services were reviewed. FMD was repeatedly measured in 33 of the 85 participants. INCLUSION CRITERIA: 20 years and older, Brinkman index ≥200, Tobacco Dependence Screener ≥5 and stated motivation to quit smoking. INTERVENTIONS: Each participant was treated with varenicline titrated up to 1.0 mg twice daily (for 12 weeks in total). PRIMARY AND SECONDARY OUTCOME MEASURES: Participants were evaluated by FMD prior to, and 3 months after, complete smoking cessation. Follow-up FMD measurements were carried out every 3 months if possible. Changes in FMD during varenicline use were also evaluated. RESULTS: FMD was significantly increased from 4.0±1.8% to 5.5±2.2% (p<0.01, n=22) 3 months after complete cessation. Although the timecourse of FMD in most of the cases showed an increase with fluctuations, there was an exceptional case where FMD decreased over the 9 months following complete cessation. Although statistically insignificant, FMD also increased during varenicline use (from 3.7±2.7% to 4.3±2.8%, n=11). CONCLUSIONS: Our observations suggest that in ceasing smokers, varenicline and smoking cessation do not lead to a worsening of the vascular endothelial function. TRIAL REGISTRATION: FK-79 (International University of Health and Welfare).