Neutralizing antibodies are recognized to be one of the essential elements of the adaptive immune response that must be induced by an effective vaccine against HIV. However, only a limited number of antibodies have been identified to neutralize a broad range of primary isolates of HIV-1 and attempts to induce such antibodies by immunization were unsuccessful. The difficulties to generate such antibodies are mainly due to intrinsic properties of HIV-1 envelope spikes, such as high sequence diversity, heavy glycosylation, and inducible and transient nature of certain epitopes. In vitro neutralizing antibodies are identified using "conventional" neutralization assay which uses phytohemagglutinin (PHA)-stimulated human PBMCs as target cells. Thus, in essence the assay evaluates HIV-1 replication in CD4+ T cells. Recently, several laboratories including us demonstrated that some monoclonal antibodies and HIV-1-specific polyclonal IgG purified from patient sera, although they do not have neutralizing activity when tested by the "conventional" neutralization assay, do exhibit potent and broad neutralizing activity in "unconventional" ways. The neutralizing activity of these antibodies and IgG fractions is acquired through post-translational modifications, through opsonization of virus particles into macrophages and immature dendritic cells (iDCs), or through expression of antibodies on the surface of HIV-1-susceptible cells. This review will focus on recent findings of this area and point out their potential applications in the development of preventive strategies against HIV.

OBJECTIVEUnderstand the public's current attitudes and knowledge about suicide and, thus, provide essential information to the development of targeted public education programs-important components of the suicide prevention effort.

METHODSSeventeen mental health professionals who were extensively trained in the methods of conducting focus groups used a pre-tested focus group outline on attitudes and knowledge about suicide to conduct 101 focus groups and 18 individual in-depth interviews with a total of 842 community respondents from 6 regions in northern China. The focus groups and in-depth interviews were audio-taped, transcribed and analyzed using the QSR Nvivo text analysis software.

RESULTSMost respondents believed that suicide was a greater problem in rural areas and among women and identified physical illnesses, economic problems and interpersonal conflicts (particularly family conflicts) as the main causes of suicide. Rural residents and women were believed to exhibit impulsive suicidal behavior because of their personal limitations and over-sensitiveness. Most thought that suicide was understandable and a small proportion felt that it was acceptable behavior in certain circumstances. Almost all felt that suicide resulted in the stigmatization and a loss of 'face' for the family. Most believed that one should show concern for persons who have suicidal behavior and their family members and expressed a willingness to have superficial social relationships with them but were unwilling to establish close personal relations with them. The vast majority believed that suicide was either very difficult or impossible to prevent.

CONCLUSIONSIn China the community is tolerant, sympathetic and, in some cases, accepting of suicide but there remains a substantial underlying stigmatization of suicide. Community members have some misunderstandings about suicide; the most obvious misunderstanding is the underestimation of the importance of mental illness as a cause of suicide. The content of public health messages used in suicide prevention programs should be developed by combining findings from both qualitative and quantitative research.

China ; Health Knowledge, Attitudes, Practice ; Humans ; Social Support ; Suicide ; prevention & control ; psychology ; Surveys and Questionnaires

Purpose: The aim of this study was to retrospectively evaluate contrast-enhanced ultrasound (CEUS) findings in patients with peliosis hepatis (PH). Methods: A retrospective analysis was conducted of CEUS features in 24 patients with histopathologically confirmed PH (11 men and 13 women; mean age, 32.4±7.1 years; range, 28 to 41 years). All lesions were histologically proven, either by core needle biopsy (n=10) or by hepatic surgery (n=14). Results: The mean size was 36.8±12.4 mm (range, 10 to 80 mm). On B-mode ultrasonography (BMUS), all PH lesions were heterogeneously hypoechoic, with well-defined margins but irregular shapes. No mass effect was observed. During the arterial phase of CEUS, all lesions displayed mild heterogeneous hyperenhancement (83.3%, 20/24) or isoenhancement (16.7%, 4/24). Furthermore, 87.5% of the PH lesions showed mild washout after 1 minute in the portal venous phase (30-120 seconds) and mild washout in the late phase (>120 seconds). Conclusion The lack of a mass effect on BMUS, mild heterogeneous arterial hyperenhancement, and washout in the very late portal venous phase (after 1 minute) on CEUS are characteristic of PH. Although it is a histological diagnosis, PH should be considered in the differential diagnosis when the clinical context does not favor a malignancy or infection.

Adult ; Arteriovenous Malformations ; therapy ; Embolization, Therapeutic ; methods ; Enbucrilate ; therapeutic use ; Female ; Humans ; Kidney ; blood supply ; Male ; Middle Aged

BACKGROUND AND OBJECTIVEResearch has shown that 5-bromotetrandrine (BrTet) can effectively reverse multidrug resistance (MDR). Imatinib plays an important role in cell proliferation. This study explored the efficacy of the combination of imatinib and BrTet on reversing MDR of tumor cells and its mechanism.

METHODSCytoxicity was assessed by MTT assay. Apoptosis of K562/A02 cells was analyzed by flow cytometry. The expressions of mdr1 mRNA and P-glycoprotein (P-gp) were detected using reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis.

RESULTSAfter 48 h of treatment with 0.0625 micromol/L imatinib, 0.5 micromol/L BrTet, or both, the 50% inhibition concentration (IC50) of daunorubicin (DNR) for the K562/A02 cells were 5.69 mg/L, 5.41 mg/L, and 2.19 mg/L, respectively. The gray-scale values of mdr1 mRNA expression in the K562/A02 cells were 0.65+/-0.02, 0.64+/-0.01, and 0.25+/-0.03, respectively. The expression levels of P-gp were 0.74+/-0.02, 0.52+/-0.02, and 0.29+/-0.02, respectively. All decreased significantly in the K562/A02 cells treated with both imatinib and BrTet compared to cells treated with imatinib and BrTet alone (P<0.05). The apoptosis rates of the K562/A02 cells increased without a significant difference after treatment with DNR, imatinib, or BrTet (P>0.05), while increased significantly after treatment with DNR combined with imatinib, BrTet, or both (P<0.05).

CONCLUSIONSThe MDR of K562/A02 cells may be partially reversed by imatinib or BrTet, and the mechanism may be related to the downregulation of mdr1 mRNA and P-gp expression and the upregulation of the rate of apoptosis in K562/A02 cells. Imatinib combined with BrTet showed a synergistic effect on K562/A02 cells.

ATP Binding Cassette Transporter, Sub-Family B ; ATP-Binding Cassette, Sub-Family B, Member 1 ; genetics ; metabolism ; Antibiotics, Antineoplastic ; pharmacokinetics ; pharmacology ; Antineoplastic Agents ; pharmacology ; Apoptosis ; drug effects ; Benzamides ; Benzylisoquinolines ; pharmacology ; Cell Proliferation ; drug effects ; Daunorubicin ; pharmacokinetics ; pharmacology ; Down-Regulation ; Drug Resistance, Multiple ; drug effects ; Drug Resistance, Neoplasm ; drug effects ; Drug Synergism ; Gene Expression Regulation, Leukemic ; Humans ; Imatinib Mesylate ; K562 Cells ; drug effects ; Piperazines ; pharmacology ; Pyrimidines ; pharmacology ; RNA, Messenger ; metabolism

BACKGROUNDTo construct a DC-Ad-Ki-ras(V12) vaccine and investigate the anti-tumor activities of lung cancer dendritic cell vaccine modified by mutant Ki-ras gene in vitro.

METHODSKi-ras(V12) cDNA was transfected into cultured bone marrow-derived DC with the recombinant adenovirus [(Ad-Ki-ras(V12)] containing human mutant Ki-ras gene. Anti-tumor activity of the vaccine was studied in vitro by flow cytometry, PCR, MLR and cytotoxicity assay.

RESULTS(1) The DC vaccine was confirmed not only to express Ki-ras(V12) gene, but also to remarkably stimulate lymphocyte proliferation and improve CTL activity. (2) The DC vaccine modified by mutant Ki-ras gene could induce specifical CTL activity of immunized mice against Lewis lung carcinoma that could express Ki-ras(V12) gene, but not to B16.

CONCLUSIONSThe DC vaccine modified by mutant Ki-ras gene can induce obvious anti-tumor activities against Lewis lung carcinoma that can express Ki-ras(V12) gene.

OBJECTIVETo investigate the reversible effect of nilotinib, BrTet (5-bromotetrandrine) and their combination on multidrug resistance cell line K562/A02 and its mechanism.

METHODSCell proliferation inhibition was assessed by MTT method and cell apoptosis by flow cytometry (FCM). The expression of mdr1 mRNA was determined by RT-PCR, and the expression of P-gp was assessed by Western blot.

RESULTSAfter 48 h 5 nmol/L nilotinib or 0.5 µmol/L BrTet treatment, IC(50) of daunorubicin (DNR) to K562/A02 was 4.52 mg/L or 5.41 mg/L respectively; While on combinative treatment, its IC(50) decreased to 2.98 mg/L. Nilotinib or BrTet alone was not able to increase the DNR induced apoptosis rate of K562/A02 cell (P > 0.05), while on combination treatment the apoptosis rate increased remarkably. After 48 h 5 nmol/L nilotinib or 0.5 µmol/L BrTet treatment alone, gray-scale value of mdr1 mRNA was 0.48 ± 0.04 or 0.64 ± 0.01, respectively; while on combinative treatment the value decreased to 0.35 ± 0.04. The P-gp expression level in K562/A02 cells was 0.61 ± 0.05, or 0.52 ± 0.02 when treated with 5 nmol/L nilotinib or 0.5 µmol/L BrTet alone for 48 h, but on combination treatment, the level decreased to 0.44 ± 0.03.

CONCLUSIONNilotinib or BrTet alone can partially reverse drug resistance of K562/A02 cells. The mechanism may be associated with the decrease of mdr1 mRNA and P-gp expression and increase of the apoptosis rate. And there is a synergistic action with these two agants in combination.

ATP-Binding Cassette, Sub-Family B, Member 1 ; metabolism ; Daunorubicin ; pharmacology ; Drug Resistance, Multiple ; drug effects ; Drug Resistance, Neoplasm ; drug effects ; Humans ; K562 Cells

Aneurysm, Dissecting/surgery* ; Aorta, Thoracic/surgery* ; Aortic Aneurysm, Thoracic/surgery* ; Blood Vessel Prosthesis Implantation ; Humans ; Treatment Outcome ; Vascular Surgical Procedures

Background: The initiation of sodium-glucose cotransporter-2 inhibitors (SGLT2i) typically leads to a reversible initial dip in estimated glomerular filtration rate (eGFR). The implications of this phenomenon on clinical outcomes are not well-defined. Methods: We searched MEDLINE, Embase, and Cochrane Library from inception to March 23, 2023 to identify randomized controlled trials and cohort studies comparing kidney and cardiovascular outcomes in patients with and without initial eGFR dip after initiating SGLT2i. Pooled estimates were calculated using random-effect meta-analysis. Results: We included seven studies in our analysis, which revealed that an initial eGFR dip following the initiation of SGLT2i was associated with less annual eGFR decline (mean difference, 0.64; 95% confidence interval [CI], 0.437 to 0.843) regardless of baseline eGFR. The risk of major adverse kidney events was similar between the non-dipping and dipping groups but reduced in patients with a ≤10% eGFR dip (hazard ratio [HR], 0.915; 95% CI, 0.865 to 0.967). No significant differences were observed in the composite of hospitalized heart failure and cardiovascular death (HR, 0.824; 95% CI, 0.633 to 1.074), hospitalized heart failure (HR, 1.059; 95% CI, 0.574 to 1.952), or all-cause mortality (HR, 0.83; 95% CI, 0.589 to 1.170). The risk of serious adverse events (AEs), discontinuation of SGLT2i due to AEs, kidney-related AEs, and volume depletion were similar between the two groups. Patients with >10% eGFR dip had increased risk of hyperkalemia compared to the non-dipping group. Conclusion Initial eGFR dip after initiating SGLT2i might be associated with less annual eGFR decline. There were no significant disparities in the risks of adverse cardiovascular outcomes between the dipping and non-dipping groups.

INTRODUCTION: Despite adhering to criteria for extubation, up to 20% of intensive care patients require re-intubation, even with use of post-extubation high-flow nasal cannula (HFNC). This study aims to identify independent predictors and outcomes of extubation failure in patients who failed post-extubation HFNC. METHODS: We conducted a multicentre observational study involving 9 adult intensive care units (ICUs) across 5 public hospitals in Singapore. We included patients extubated to HFNC following spontaneous breathing trials. We compared patients who were successfully weaned off HFNC with those who failed HFNC (defined as re-intubation ≤7 days following extubation). Generalised additive logistic regression analysis was used to identify independent risk factors for failed HFNC. RESULTS: Among 244 patients (mean age: 63.92±15.51 years, 65.2% male, median APACHE II score 23.55±7.35), 41 (16.8%) failed HFNC; hypoxia, hypercapnia and excessive secretions were primary reasons. Stroke was an independent predictor of HFNC failure (odds ratio 2.48, 95% confidence interval 1.83-3.37). Failed HFNC, as compared to successful HFNC, was associated with increased median ICU length of stay (14 versus 7 days, CONCLUSION Post-extubation HFNC failure, especially in patients with stroke as a comorbidity, remains a clinical challenge and predicts poorer clinical outcomes. Our observational study highlights the need for future prospective trials to better identify patients at high risk of post-extubation HFNC failure.
Adult ; Airway Extubation ; Cannula ; Critical Care ; Female ; Humans ; Intensive Care Units ; Male ; Middle Aged ; Respiratory Insufficiency/therapy* ; Singapore/epidemiology*