High myopia at high altitudes.

Background: Optic nerve sheath diameter (ONSD) increases significantly at high altitudes, and is associated with the presence and severity of acute mountain sickness (AMS). Exposure to hypobaria, hypoxia, and coldness when hiking also impacts intraocular pressure (IOP). To date, little is known about ocular physiological responses in trekkers with myopia at high altitudes. This study aimed to determine changes in the ONSD and IOP between participants with and without high myopia (HM) during hiking and to test whether these changes could predict symptoms of AMS. Methods: Nine participants with HM and 18 without HM participated in a 3-day trek of Xue Mountain. The ONSD, IOP, and questionnaires were examined before and during the trek of Xue Mountain. Results: The ONSD values increased significantly in both HM (p = 0.005) and non-HM trekkers (p = 0.018) at an altitude of 1,700 m. In the HM group, IOP levels were greater than those in the non-HM group (p = 0.034) on the first day of trekking (altitude: 3,150 m). No statistically significant difference was observed between the two groups for the values of ONSD. Fractional changes in ONSD at an altitude of 1,700 m were related to the development of AMS (r pb = 0.448, p = 0.019) and the presence of headache symptoms (r pb = 0.542, p = 0.004). The area under the ROC curve for the diagnostic performance of ONSD fractional changes at an altitude of 1,700 m was 0.859 for predicting the development of AMS and 0.803 for predicting the presence of headache symptoms. Conclusion: Analysis of changes in ONSD at moderate altitude could predict AMS symptoms before an ascent to high altitude. Myopia may impact physiological accommodation at high altitudes, and HM trekkers potentially demonstrate suboptimal regulation of aqueous humor in such environments.

Post-radiation primary hypothyroidism in patients with head and neck cancer: External validation of thyroid gland dose-volume constraints with long-term endocrine outcomes.

BACKGROUND: Post-radiation primary hypothyroidism is a common late complication in head and neck cancer (HNC) survivors. No radiation dose-volume constraint of the thyroid gland has been externally validated for predicting long-term thyroid function outcomes. MATERIALS AND METHODS: This external validation study evaluated the diagnostic properties of 22 radiation dose-volume constraints of the thyroid gland proposed in the literature. Radiation dosimetric data from 488 HNC patients who underwent neck irradiation from January 2013 to December 2015 at two tertiary oncology centers were reviewed. The diagnostic metrics of candidate constraints were computed by inverse probability of censoring weighting and compared using time-dependent receiver operating characteristic (ROC) curves with death designated as a competing event. Multivariable regression analyses were performed using the Fine-Gray sub-distribution hazard model. RESULTS: Over a median follow-up period of 6.8 years, 205 (42.0 %) patients developed post-radiation primary hypothyroidism. The thyroid volume spared from 60 Gy (VS60) had the largest area under ROC curve of 0.698 at 5 years after radiotherapy. Of all evaluated constraints, VS60 at a cutoff value of 10 cc had the highest F-score of 0.53. The 5-year hypothyroidism risks of patients with thyroid VS60 ≥ 10 cc and < 10 cc were 14.7 % and 38.2 %, respectively (p < 0.001). The adjusted sub-hazard ratio for post-radiation primary hypothyroidism for VS60 < 10 cc was 1.87 (95 % confidence interval, 1.22-2.87; p < 0.001). CONCLUSION: Thyroid VS60 is the best radiation dose-volume parameter to predict the long-term risk of primary hypothyroidism in patients with HNC who underwent neck irradiation. VS60 ≥ 10 cc is a robust constraint that limits the 5-year primary hypothyroidism risk to less than 15 % and should be routinely employed during radiotherapy optimization.

Adjunctive probiotics after periodontal debridement versus placebo: a systematic review and meta-analysis.

OBJECTIVE: To comprehensively investigate the efficacy of adjunctive probiotics compared to placebo, using conventional and novel treatment outcomes. MATERIALS AND METHODS: Three databases (MEDLINE, EMBASE, and CENTRAL) were searched. Outcomes included percent change in the total number of deep sites before and after therapy, change in mean probing pocket depth (mm), percentage patients requiring additional therapy, risk for disease progression, and microbiological and immunological results. Meta-analysis was conducted to evaluate treatment effects wherever appropriate. RESULTS: Ten studies were selected from 818 records. Meta-analysis showed that adjunctive probiotics had no additional benefit for percentage change of the total number of deeper sites (≥5 mm, ≥6 mm, ≥7 mm) before and after therapy. No significant difference was observed for mean probing pocket depth reduction at 3 and 6 months. Statistically significant beneficial odds ratios for need for additional therapy (OR = 0.19, 95% CI [0.07-0.56]) and risk of disease progression (OR = 0.32, 95% CI [0.14-0.73]) were observed with probiotic administration. Immunological rather than microbiological outcomes correlated more consistently with clinical findings. No adverse events were reported. CONCLUSIONS: Adjunctive probiotics are safe in systemically healthy individuals and could offer additional patient-level benefits compared to placebo, hence its use can sometimes be justified.

EGFR mutation-guided use of afatinib, erlotinib and gefitinib for advanced non-small-cell lung cancer in Hong Kong - A cost-effectiveness analysis.

INTRODUCTION: Tyrosine kinase inhibitors (TKIs) therapy targets at epidermal growth factor receptor (EGFR) gene mutations in non-small-cell lung cancer (NSCLC). We aimed to compare the EGFR mutation-guided target therapy versus empirical chemotherapy for first-line treatment of advanced NSCLC in the public healthcare setting of Hong Kong. METHODS: A Markov model was designed to simulate outcomes of a hypothetical cohort of advanced (stage IIIB/IV) NSCLC adult patients with un-tested EGFR-sensitizing mutation status. Four treatment strategies were evaluated: Empirical first-line chemotherapy with cisplatin-pemetrexed (empirical chemotherapy group), and EGFR mutation-guided use of a TKI (afatinib, erlotinib, and gefitinib). Model outcome measures were direct medical cost, progression-free survival, overall survival, and quality-adjusted life-years (QALYs). Incremental cost per QALY gained (ICER) was estimated. Sensitivity analyses were performed to examine robustness of model results. RESULTS: Empirical chemotherapy and EGFR mutation-guided gefitinib gained lower QALYs at higher costs than the erlotinib group. Comparing with EGFR mutation-guided erlotinib, the afatinib strategy gained additional QALYs with ICER (540,633 USD/QALY). In 10,000 Monte Carlo simulations for probabilistic sensitivity analysis, EGFR mutation-guided afatinib, erlotinib, gefitinib and empirical chemotherapy were preferred strategy in 0%, 98%, 0% and 2% of time at willingness-to-pay (WTP) 47,812 USD/QALY (1x gross domestic product (GDP) per capita), and in 30%, 68%, 2% and 0% of time at WTP 143,436 USD/QALY (3x GDP per capita), respectively. CONCLUSIONS: EGFR mutation-guided erlotinib appears to be the cost-effective strategy from the perspective of Hong Kong public healthcare provider over a broad range of WTP.

Nasopharyngeal carcinoma MHC region deep sequencing identifies HLA and novel non-HLA TRIM31 and TRIM39 loci.

Despite pronounced associations of major histocompatibility complex (MHC) regions with nasopharyngeal carcinoma (NPC), causal variants underlying NPC pathogenesis remain elusive. Our large-scale comprehensive MHC region deep sequencing study of 5689 Hong Kong Chinese identifies eight independent NPC-associated signals and provides mechanistic insight for disrupted transcription factor binding, altering target gene transcription. Two novel protective variants, rs2517664 (Trs2517664 = 4.6%, P = 6.38 × 10-21) and rs117495548 (Grs117495548 = 3.0%, P = 4.53 × 10-13), map near TRIM31 and TRIM39/TRIM39-RPP21; multiple independent protective signals map near HLA-B including a previously unreported variant, rs2523589 (P = 1.77 × 10-36). The rare HLA-B*07:05 allele (OR < 0.015, P = 5.83 × 10-21) is absent in NPC, but present in controls. The most prevalent haplotype lacks seven independent protective alleles (OR = 1.56) and the one with additional Asian-specific susceptibility rs9391681 allele (OR = 2.66) significantly increased NPC risk. Importantly, this study provides new evidence implicating two non-human leukocyte antigen (HLA) genes, E3 ubiquitin ligases, TRIM31 and TRIM39, impacting innate immune responses, with NPC risk reduction, independent of classical HLA class I/II alleles.

Clinical utility of serial analysis of circulating tumour cells for detection of minimal residual disease of metastatic nasopharyngeal carcinoma.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is an important cancer in Hong Kong. We aim to utilise liquid biopsies for serial monitoring of disseminated NPC in patients to compare with PET-CT imaging in detection of minimal residual disease. METHOD: Prospective serial monitoring of liquid biopsies was performed for 21 metastatic patients. Circulating tumour cell (CTC) enrichment and characterisation was performed using a sized-based microfluidics CTC chip, enumerating by immunofluorescence staining, and using target-capture sequencing to determine blood mutation load. PET-CT scans were used to monitor NPC patients throughout their treatment according to EORTC guidelines. RESULTS: The longitudinal molecular analysis of CTCs by enumeration or NGS mutational profiling findings provide supplementary information to the plasma EBV assay for disease progression for good responders. Strikingly, post-treatment CTC findings detected positive findings in 75% (6/8) of metastatic NPC patients showing complete response by imaging, thereby demonstrating more sensitive CTC detection of minimal residual disease. Positive baseline, post-treatment CTC, and longitudinal change of CTCs significantly associated with poorer progression-free survival by the Kaplan-Meier analysis. CONCLUSIONS: We show the potential usefulness of application of serial analysis in metastatic NPC of liquid biopsy CTCs, as a novel more sensitive biomarker for minimal residual disease, when compared with imaging.

Recombinant human thyrotropin versus thyroid hormone withdrawal in an Asian population.

CONTEXT: To prepare for radioactive iodine therapy in post total thyroidectomy patients with well-differentiated thyroid cancer (WDTC), either thyroid hormone withdrawal (THW) or administration of recombinant human thyrotropin (rhTSH) can be performed. OBJECTIVE: Our objective is to compare quality of life (QoL) parameters using the SF-36v2 questionnaire (Short Form health survey) and a self-evaluated item, and the hypothyroid status using modified Billewicz scores in an Asian population undergoing either THW or rhTSH for remnant ablation or adjuvant treatment following total thyroidectomy for WDTC. We will also assess the proportion of patients achieving TSH level of >30 mU/L after 4 weeks of thyroid hormone withdrawal. RESULTS: Patients in the rhTSH group were better in the QoL domains of physical functioning, role functioning/physical and bodily pain, while patients in THW group were better in mental health. This was however, not statistically significant. Modified Billewicz scores were higher in patients in THW group as compared with rhTSH group and statistically significant. A total of 96.3% of patients achieved TSH level >30 mU/L after 4 weeks of THW. CONCLUSION: Clinical symptoms and signs of hypothyroidism as assessed with modified Billewicz scores were statistically significantly higher in the THW group. However, there was no statistically significant difference in QoL in the rhTSH group.

Whole-exome sequencing identifies multiple loss-of-function mutations of NF-κB pathway regulators in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is an epithelial malignancy with a unique geographical distribution. The genomic abnormalities leading to NPC pathogenesis remain unclear. In total, 135 NPC tumors were examined to characterize the mutational landscape using whole-exome sequencing and targeted resequencing. An APOBEC cytidine deaminase mutagenesis signature was revealed in the somatic mutations. Noticeably, multiple loss-of-function mutations were identified in several NF-κB signaling negative regulators NFKBIA, CYLD, and TNFAIP3 Functional studies confirmed that inhibition of NFKBIA had a significant impact on NF-κB activity and NPC cell growth. The identified loss-of-function mutations in NFKBIA leading to protein truncation contributed to the altered NF-κB activity, which is critical for NPC tumorigenesis. In addition, somatic mutations were found in several cancer-relevant pathways, including cell cycle-phase transition, cell death, EBV infection, and viral carcinogenesis. These data provide an enhanced road map for understanding the molecular basis underlying NPC.

Predictive value of plasma neutrophil gelatinase-associated lipocalin for acute renal failure in patients with severe sepsis.

BACKGROUND: Predicting acute renal failure in patients with severe sepsis is important, because patients may need renal replacement therapy (RRT). Neutrophil gelatinase-associated lipocalin (NGAL) has been evaluated for its ability to detect and predict acute kidney injury (AKI) in critically ill patients. This study aimed to assess the predictive value of plasma NGAL for acute renal failure in adult severely septic patients. METHODS: Thirty healthy adults and 85 adult patients admitted to the medical intensive care unit (ICU) were enrolled. Serum creatinine, plasma NGAL, and interleukin (IL)-6, IL-10, and IL-17 levels were evaluated. AKI was classified as Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease (RIFLE). RESULTS: RIFLE-Failure (RIFLE-F) developed in 30 of 76 (39.5%) patients with severe sepsis without chronic kidney disease within 7 days after ICU admission. Serum creatinine, plasma NGAL, IL-6, and IL-10 could predict RIFLE-F within 7 days after ICU admission. The discriminatory power of plasma NGAL was not significant for predicting hospital mortality. The area under the receiver operating characteristic curve of plasma NGAL was not higher than that of serum creatinine in predicting RIFLE-F within 7 days. CONCLUSION: Plasma NGAL is a useful tool for predicting acute renal failure in adult patients with severe sepsis. Serum creatinine has a similar ability to detect RIFLE-F occurrence.

Associations of T helper 1, 2, 17 and regulatory T lymphocytes with mortality in severe sepsis.

OBJECTIVE AND DESIGN: T helper 17 (Th17) and regulatory T (Treg) lymphocytes might play important roles in patients with severe sepsis. The association of Th17 or Treg lymphocytes with survival is also unclear. METHODS: Eighty-seven patients with severe sepsis were enrolled from our intensive care units between August 2008 and July 2010. Leukocyte antigens and clinical data were determined on day 1 in all patients and on day 7 in first-year patients. RESULTS: The percentages in peripheral blood mononuclear cells (PBMCs) and circulatory counts of CD4⁺ and CD8⁺ lymphocytes in survivors were higher than those in non-survivors. Th1/CD4⁺ ratios and circulatory Th1 lymphocyte counts in survivors were higher than in non-survivors. Absolute counts of Th17 and Treg lymphocytes in survivors were higher than in non-survivors. The percentages of CD4⁺ and CD8⁺ in survivors' PBMCs were increased after 6 days. Th17/CD4⁺ ratios and circulatory Th17 lymphocyte counts in survivors were increased after 6 days. CONCLUSIONS: Higher Th1 differentiation and total CD4⁺ T lymphocyte counts were associated with higher survival. The association of circulatory Th17 and Treg lymphocytes with mortality in severe sepsis may be due to the change in total CD4⁺ T lymphocytes. In survivors, Th17 differentiation and counts were restored.

Neurological manifestations of phaeochromocytomas and secretory paragangliomas: a reappraisal.

OBJECTIVE: To determine the frequency and range of neurological manifestations of phaeochromocytomas and secretory paragangliomas. METHODS: A retrospective review of case notes of patients admitted to Auckland Hospital from 1985 to 2011 with a discharge diagnosis of phaeochromocytoma or secretory paraganglioma. RESULTS: Ninety-three patients were admitted with a phaeochromocytoma or secretory paraganglioma. Sixty-eight patients (73%) had neurological symptoms, but only 15 patients (16%) received a neurological consultation. Neurological manifestations occurred in three main clinical contexts. First, paroxysmal symptoms occurred in 66 of 93 patients (71%). Neurological symptoms were common features of these attacks and included headache (47 patients), anxiety (24 patients), tremulousness (15 patients) and dizziness (12 patients). The headaches typically had an explosive onset. Delay in diagnosis was common. Second, 28 patients (30%) had an acute crisis, which was associated with neurological symptoms in 11 (39%) of the episodes: headache (10 patients); seizures (five patients); strokes (three patients); delirium (three patients) and subarachnoid haemorrhage (one patient). Third, five of six patients with a head and neck secretory paraganglioma had neurological symptoms related to infiltration of the middle ear or compression of cranial nerves. Reversible cerebral vasoconstriction syndrome (RCVS) was documented in three patients. CONCLUSIONS: Neurological manifestations of phaeochromocytomas and secretory paragangliomas were common, and these tumours can present with various neurological manifestations. The paroxysmal symptoms can be incorrectly attributed to other headache syndromes, panic attacks or cerebral vasculitis. RCVS may play a role in the pathogenesis of the neurological symptoms associated with acute crises and paroxysmal attacks.

A randomized trial of tenecteplase versus alteplase for acute ischemic stroke.

BACKGROUND: Intravenous alteplase is the only approved treatment for acute ischemic stroke. Tenecteplase, a genetically engineered mutant tissue plasminogen activator, is an alternative thrombolytic agent. METHODS: In this phase 2B trial, we randomly assigned 75 patients to receive alteplase (0.9 mg per kilogram of body weight) or tenecteplase (0.1 mg per kilogram or 0.25 mg per kilogram) less than 6 hours after the onset of ischemic stroke. To favor the selection of patients most likely to benefit from thrombolytic therapy, the eligibility criteria were a perfusion lesion at least 20% greater than the infarct core on computed tomographic (CT) perfusion imaging at baseline and an associated vessel occlusion on CT angiography. The coprimary end points were the proportion of the perfusion lesion that was reperfused at 24 hours on perfusion-weighted magnetic resonance imaging and the extent of clinical improvement at 24 hours as assessed on the National Institutes of Health Stroke Scale (NIHSS, a 42-point scale on which higher scores indicate more severe neurologic deficits). RESULTS: The three treatment groups each comprised 25 patients. The mean (±SD) NIHSS score at baseline for all patients was 14.4±2.6, and the time to treatment was 2.9±0.8 hours. Together, the two tenecteplase groups had greater reperfusion (P=0.004) and clinical improvement (P<0.001) at 24 hours than the alteplase group. There were no significant between-group differences in intracranial bleeding or other serious adverse events. The higher dose of tenecteplase (0.25 mg per kilogram) was superior to the lower dose and to alteplase for all efficacy outcomes, including absence of serious disability at 90 days (in 72% of patients, vs. 40% with alteplase; P=0.02). CONCLUSIONS: Tenecteplase was associated with significantly better reperfusion and clinical outcomes than alteplase in patients with stroke who were selected on the basis of CT perfusion imaging. (Funded by the Australian National Health and Medical Research Council; Australia New Zealand Clinical Trials Registry number, ACTRN12608000466347.).

Oral ginseng formulae for stable chronic obstructive pulmonary disease: a systematic review.

Ginseng alone or combined with other herbs has been increasingly used for chronic obstructive pulmonary disease (COPD). This review aims to evaluate the effectiveness and safety of oral Ginseng formulae for stable COPD. Four English databases and three Chinese databases were searched to identify randomized controlled trials. Methodological quality was assessed by Cochrane risk of bias and Jadad's scale. Data were analyzed using Review Manager 5.0. Twelve studies overall of low quality, involving 1560 participants were included. Results of three studies showed a mean difference (MD) of 0.30 (95%CI 0.02 to 0.58) for forced expiratory volume in 1 s (FEV(1)) improvement of Ginseng formulae versus placebo control. Findings of three studies revealed an MD of 9.43 (95%CI 3.64 to 15.21) of FEV(1) % predicted between Ginseng formulae and placebo control. Quality of life (Qol) measured by St. George's Respiratory Questionnaire was improved (MD -10.32, 95%CI -14.99 to -5.65) with Ginseng formulae plus pharmacotherapy versus pharmacotherapy alone in one study. There were no severe adverse events reported. Ginseng formulae for stable COPD patients show promising evidence of lung functions and Qol improvement. However, the degree of benefit is uncertain due to potential risk of bias of the included studies.

Cerebral amyloid angiopathy related inflammation: three case reports and a review.

Cerebral amyloid angiopathy related inflammation (CAA-I), previously described under various names, is a treatable encephalopathy usually occurring in older adults. Here, three patients are described with histopathologically confirmed CAA-I, and summarised data from the published literature are presented. CAA-I has a characteristic combination of clinical and radiological features. Definite diagnosis requires brain and leptomeningeal biopsy. A favourable response to immunosuppressive therapy is common and treatment without brain biopsy may be considered in selected patients. Diagnostic criteria for CAA-I are proposed.

Serial cytokine levels in patients with severe sepsis.

OBJECTIVE AND DESIGN: The serial or dynamic changes of cytokine levels in severely septic patients, between shock and no shock, survivors and non-survivors are still unclear. METHODS: Seventy-six patients with severe sepsis were enrolled to our study. Plasma levels of interferon-gamma, interleukin (IL)-6, IL-10, IL-12 and transforming growth factor-beta1 from day 1 to day 7 were determined. RESULTS: IL-6 level in non-survivors was higher than that in survivors on day 1. IL-10 level in non-survivors was higher than that in survivors on day 1, 2, and 3. IL-6 level in shock patients was higher than that in non-shock patients on day 1, 2, 6 and 7. IL-10 level in shock patients was higher than that in non-shock patients from day 1 to day 7. Plasma time-course curves of IL-6 and IL-10 were different between survivors and non-survivors. Plasma time-course curve of IL-6 was different between patients with shock and without shock. Regression analysis found that IL-6 was correlated with IL-10 and shock. IL-10 was correlated with IL-6 and mortality. CONCLUSION: IL-6 and IL-10 were the key cytokines in the pathogenesis of severe sepsis. IL-6 was comparatively more associated with septic shock and IL-10 was comparatively more associated with mortality.

Plasma transforming growth factor-beta1 level in patients with severe community-acquired pneumonia and association with disease severity.

BACKGROUND/PURPOSE: Pro- and anti-inflammatory cytokines, such as interferon (IFN)-gamma, interleukin (IL)-6, IL-10, IL-12 and transforming growth factor (TGF)-beta1, have been shown to be mediators associated with severe community-acquired pneumonia (CAP). It is unknown whether plasma TGF-beta1 level can help physicians to judge disease severity. In this study, we investigated the value of predicting mortality in patients with severe CAP by the plasma levels of IFN-gamma, IL-6, IL-10, IL-12 and TGF-beta1 on admission day. METHODS: Patients who were admitted to the emergency department and soon transferred to the ICU because of severe CAP were enrolled in this study. Plasma levels of IFN-gamma, IL-6, IL-10, IL-12 and TGF-beta1 on the day of admission were determined in 49 survivors and 14 non-survivors within 28 days by ELISA. Clinical characteristics were also recorded. RESULTS: Plasma IL-6, IL-10 and TGF-beta1 levels on admission were significantly different between survivors and non-survivors. Conversely, there was no significant difference in plasma IFN-gamma and IL-12 levels between the survivors and non-survivors. Furthermore, the plasma TGF-beta1 level was the only independent factor associated with mortality. The value of predicting mortality in patients with severe CAP was similar for IL-6, IL-10 and TGF-beta1. Plasma IL-6 level was not related to the Acute Physiology and Chronic Health Evaluation (APACHE) II score. However, plasma IL-10 and TGF-beta1 levels were correlated with APACHE II score. CONCLUSION: A severity scoring system, including TGF-beta1 level on admission, may be considered as a useful parameter to predict outcomes of patients with severe CAP.

Inhibition of release of inflammatory mediators in rat peritoneal mast cells and murine macrophages by a Chinese herbal medicine formula (RCM-102).

RCM-102 is a Chinese herbal medicine formulation derived from a formula which was shown to be effective in treating seasonal allergic rhinitis (SAR) in a randomized placebo-controlled trial. The aim of this study was to investigate the in vitro effect of RCM-102 on the formation of inflammatory mediators, histamine, prostaglandin and nitric oxide, which are known to be involved in the pathophysiology of SAR. The effect of RCM-102 on histamine release was tested in compound 48/80-stimulated rat peritoneal mast cells. The effects of RCM-102 on the release of NO and prostaglandins (PGE(2)) and the expression of inducible NO synthase (iNOS) and COX-2 were studied in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. In rat peritoneal mast cells, RCM-102 significantly reduced the compound 48/80-induced histamine release. It also significantly reduced NO and PGE(2) production as well as the expression of COX-2 and iNOS in RAW 264.7 cells. These findings indicate that RCM-102 inhibits the formation of several allergic/inflammatory mediators and thus may be used for treating related conditions such as SAR. The actions of RCM-102 are likely to be contributed by the synergistic actions of individual herbal ingredients.

The interleukin-4 expression in patients with severe sepsis.

PURPOSE: Sepsis is a complicated syndrome in which proinflammatory and anti-inflammatory cytokines are expressed simultaneously. However, it remains unclear for the expression of interleukin (IL)-4 and IL-4delta2 in patients with severe sepsis. MATERIALS AND METHODS: By nested reverse transcriptase-polymerase chain reaction and the expression of glyceraldehydes-3-phosphate dehydrogenase as the internal reference, the expression levels of IL-4 and IL-4delta2 were determined in peripheral blood mononuclear cells (PBMCs) of 76 patients with severe sepsis and were immediately admitted to an intensive care unit. Plasma IL-4 level was measured by enzyme-linked immunosorbent assay. Clinical characteristics were monitored and recorded prospectively. RESULTS: The IL-4 messenger RNA (mRNA) expression in PBMCs of patients who had survived was significantly higher than that of those who had died. The IL-4delta2/IL-4 ratio in PBMCs of patients who had survived was significantly lower than that of those who had died. The IL-4delta2 expression did not differ between survivors and nonsurvivors. After regression analysis, the IL-4delta2/IL-4 ratio still was an independent factor for death in patients with severe sepsis. The expression of IL-4delta2 mRNA was positively correlated with that of IL-4 mRNA in patients with severe sepsis. The plasma IL-4 levels in septic patients on admission day did not differ between survivors and nonsurvivors. CONCLUSIONS: The IL-4 mRNA expression might be associated with survival in patients with severe sepsis. The IL-4delta2/IL-4 ratio might be served as the net immunity of IL-4 activity.

Inhibition of inducible nitric oxide production and iNOS protein expression in lipopolysaccharide-stimulated rat aorta and Raw 264.7 macrophages by ethanol extract of a Chinese herbal medicine formula (RCM-101) for allergic rhinitis.

AIM OF THE STUDY: A Chinese herbal formula (RCM-101) has shown to be effective in reducing symptoms of seasonal allergic rhinitis (SAR) in a randomised, placebo-controlled clinical trial. The aim of this study is to investigate the effects of RCM-101 on the actions and synthesis of nitric oxide (NO). l-Arginine-induced endothelium-independent relaxations were studied in rat isolated aorta which was pre-treated with lipopolysaccharide (LPS). MATERIALS AND METHODS: NO production and inducible nitric oxide synthase (iNOS) protein expression were studied in LPS and interferon gamma-stimulated murine macrophages (Raw 264.7), measured by NO sensors and Western blotting. RESULTS: In rat aortic preparations, RCM-101 significantly inhibited endothelium-independent relaxations to l-arginine, but not affected those to sodium nitroprusside (SNP). In Raw 264.7 cells, RCM-101 and some of its individual ingredients (e.g., Radix glycyrrhizae, Radix bupleuri, Radix saposhnikoviae and Atractylodis rhizome macrocephalae) significantly inhibited the NO production and iNOS protein expression. CONCLUSIONS: The findings indicate that RCM-101 may inhibit inducible NO production by suppressing iNOS. In addition, its inhibitory action of iNOS is likely to be mediated by several key herbal ingredients.