Secondary sulphonylurea failure: what pathogenesis is responsible?

Sulphonylurea (SU) stimulates insulin secretion by pancreatic beta-cells and is generally used as a first-line treatment for type 2 diabetes. However, after long-term SU treatment (six months or over), some patients begin to show an increase in blood glucose once again (secondary SU failure). Two theories have been put forward to explain this failure--dysfunction of the proinsulin conversion machinery or insulin resistance. However, the primary pathogenesis behind secondary SU failure still needs to be investigated. Using a reliable technique that specifically identifies intact proinsulin (IPI), total proinsulin (TPI) and specific insulin (SI), this study aims to discover if a defect in the proinsulin converting mechanism plays a role in SU failure. Three groups were recruited for this study: healthy controls (n=8), SU responders (n=38) and secondary SU failures (n= 46). Serum concentrations of insulin-related molecules released in response to a standard glucose challenge test were compared between the groups. It was found that total SI was lower in the patient groups (P<0.05 compared to the control group), while TPI and IPI showed no distinct difference between the three groups (P>0.05). TPI:SI ratio and IPI:SI ratio showed marked increases in the patient groups (P<0.05 compared to control group), with no obvious quantitative difference between SU responders and secondary SU failures (P>0.05). Similar results for the Homa Insulin Resistant Index were found between the two patient groups. Interestingly, blood glucose at 180 mins after glucose challenge was significantly higher in the secondary SU failure group (P<0.05), with no correlation to SI, while the SU responder group showed good correlation between the parameters (P<0.05). We conclude that type 2 diabetes is associated with obvious dysfunction in the proinsulin-converting process and shows severe SI deficiency in responding to glucose challenge. Dysfunction of the proinsulin conversion mechanism was not an extra cause responsible for SU failure.     

Induction of human airway smooth muscle apoptosis by neutrophils and neutrophil elastase

Neutrophils are an important component of airway inflammation and may interact with human airway smooth muscle cells (HASMC). We investigated the effect of neutrophils and of neutrophil-derived proteases on HASMC survival. When co-incubated with neutrophils (0.1-1 x 10(6) cells/ml), attachment of human ASMC was reduced to 12.3 +/- 4.3% compared with untreated controls after 72 h. HASMC showed nuclear condensation and fragmentation (41.6 +/- 8.1% compared with baseline of 3.1 +/- 0.4%), and the biochemical markers of apoptosis, annexin V binding (9.7 +/- 0.7%; baseline 1.1 +/- 0.3%) and cleaved caspase-3 expression, were observed. The proteolytic activity released by neutrophils was essential for the proapoptotic effect because inhibition of elastase activity by alpha(1)-antitrypsin and MeOSuc-Ala-Ala-Pro-Ala-CMK (MSACK) reduced HASMC apoptosis. Human neutrophil elastase (0.1-3 microg/ml) induced apoptosis of HASMC, as well as other neutrophil serine proteases, cathepsin G, and proteinase 3. Fibronectin degradation products were present in HASMC supernatants exposed to neutrophil-conditioned media and to neutrophil elastase. The local release of proteases from neutrophils present in airway smooth muscle cells may lead to HASMC apoptosis as a result of matrix degradation and loss of cell attachment. This may limit pathologic changes such as ASMC hyperplasia and extracellular matrix deposition seen in airway remodeling.     

Use of bomb pulse carbon-14 to age senile plaques and neurofibrillary tangles in Alzheimer's disease.

The time course of formation of neurofibrillary tangles (NFT) and senile plaques (SP) in Alzheimer's disease (AD) brain is unknown. Above ground nuclear weapons testing in the late 1950s and early 1960s led to significantly increased levels of 14C in the atmosphere and carbon cycle. Because the amyloid beta peptide of SP and paired helical filaments of NFT, once formed, are relatively resistant to degradation, 14C levels observed in SP and NFT should reflect their year of formation. The purpose of this study was to develop a method to determine whether 14C levels could be used to define NFT and SP ages. Using accelerator mass spectrometry to measure bomb-pulse 14C levels, we determined the average age of formation of isolated SP and NFT fractions in bulk brain samples of 6 AD subjects. Although preliminary, the results demonstrate that it is possible to use bomb pulse 14C to determine the average year of formation of NFT and SP in the brain in AD. In addition, the data show that these structures, once formed, have a much slower carbon turnover rate than normal brain and are not in a formation/enzymatic degradation equilibrium.     

Plasmids encoding foot-and-mouth disease virus VP1 epitopes elicited immune responses in mice and swine and protected swine against viral infection

VP1 is a capsid protein of foot-and-mouth disease virus (FMDV) and contains epitopes of the virus. Plasmids encoding two VP1 epitopes (amino acid residues 141-160 and 200-213) and a host-self immunoglobulin molecule were constructed to produce a new type of FMD DNA vaccine. Two plasmids, namely, pCEIM and pCEIS, containing mouse immunoglobulin (IgG) or swine IgG were subjected to immunogenicity testing in mice and swine, respectively. In mice administrated pCEIM in the abdomen using a genegun, both FMDV-specific T-cell proliferation and neutralizing antibodies were detected. In swine immunized with pCEIS at the back of the ear, immune responses were achieved after the second administration. Swine showed a T-cell proliferative response with a stimulation index (SI) of up to 8.1 and a neutralizing antibody response that was able to protect suckling mice from 10(2) LD(50) (lethal dose 50) FMDV challenge. To compare the immunogenicity of the DNA-based vaccine candidate, versus the protein-based vaccine candidates, a second group of swine was immunized with the protein F1-scIgG, which was encoded by the plasmid pCEIS. Injection with F1-scIgG elicited a T-cell proliferative response of SI < 1.7 and a neutralizing antibody response that protected suckling mice from up to 10(5) LD(50) FMDV challenge. In the challenge test, three of three swine immunized with pCEIS were fully protected from FMDV challenge.     

Discrete choice experiment with duration versus time trade-off: a comparison of test–retest reliability of health utility elicitation approaches in SF-6Dv2 valuation

Quality of Life Research - To evaluate and compare the test–retest reliability of discrete choice experiments with duration (DCETTO) and time trade-off (TTO) in the Chinese SF-6Dv2 valuation...     

结节病患者肺功能变化研究

目的：肺结节病患者肺功能测试的研究。方法：40例肺结节病患者不同时期肺功能测试结果和应用激素的回顾分析。结果：显示此类患者有限性通气功能障碍并伴有弥散功能下降和小气道功能受限,PaO2明显下降,pH升高,PaCO2也有下降的趋势。激素治疗结果显示,患者的MMF有明显的提高。其它肺功能指标如VC,RV,RV/TLC,MVV,FEV1,DLCO等都有升高的趋势。结论：VC,RV,MMF,DLCO,DLCO/VA等对诊断结节病的病情发展有直接参考价值,而MMF在糖皮质激素治疗后有显著的变化,提高MMF对结节病的治疗和预后具有动态参考价值。     

Clinical significance and assessment of cytokines in various stages of ulcerative colitis

Summary In order to study the clinical significance and change of interleukin (IL)-1β and IL-10 concentration in intestinal mucosal tissues in various stage of ulcerative colitis (UC), IL-1β and IL10 levels were measured by enzyme linked immunosorbent assays (ELISA). Our results showed that IL-β level caused by spontaneous secretion in the intestinal mucous tissues in active stage of ulcerative colitis was significantly higher than that in normal controls and in remission stage of ulcerative colitis (P <0. 01,P<0. 001). IL-10 level in various stage of UC was relatively lower in controls, but there was no significantly difference between the two groups. Our study suggested that higher IL-1β level in active might play an important role in pathogenesis of UC, and IL-10, as an anti-inflammatory cytokine, was low in active UC, suggesting that it may be a important factor contributing to the development of higher IL-1β level. This project was supported by the grant of the Scientific Research Fund of the Ministry of Health (No. 98-2-387).     

Efficacy of non-ablative fractional 1440-nm laser therapy for treatment of facial acne scars in patients with rosacea: a prospective,interventional study

Lasers in Medical Science - Acne scarring is one of the most common facial skin disorders. The appropriate treatments for acne scars in patients with rosacea have not been studied. This study was...