T cell costimulatory blockade: new therapies for transplant rejection.

Optimal T cell responses occur when T cells receive both antigen-specific signals through the T cell receptor and non-antigen-specific costimulatory signals through accessory cell surface molecules. The best understood costimulatory receptor is CD28. Signals through the T cell receptor and CD28 cooperatively induce cytokine gene expression and promote T cell proliferation and survival. Negative signals delivered through a related cell surface receptor, cytotoxic T lymphocyte antigen (CTLA-4), act to terminate immune responses and are required for normal immune homeostasis. This article reviews T cell costimulation, including the CD28/CTLA-4 system and other potential costimulatory pathways (such as CD40/CD154), the role of these pathways in normal immune responses, and the potential for the inhibition of these pathways to induce transplantation tolerance.     

Mixed micropapillary–ductal carcinomas of the breast: a genomic and immunohistochemical analysis of morphologically distinct components

Micropapillary carcinomas (MPCs) can present as a rare histological special type of breast cancer; however, this histological type is more frequently found admixed with invasive ductal carcinomas of no special type (IDC‐NSTs). We have previously demonstrated that pure MPCs constitute a distinct entity at the morphological and genetic levels. Here, we sought to determine whether mixed MPCs have genomic aberrations similar to those found in pure MPCs, and to investigate whether the distinct morphological components of MPCs harbour different genetic aberrations. Using high‐resolution microarray comparative genomic hybridization (aCGH), we profiled a series of 10 MPCs of mixed histology and 20 IDC‐NSTs matched for grade and oestrogen receptor (ER) status. In addition, we generated tissue microarrays containing a series of 24 pure and 40 mixed MPCs and performed immunohistochemical analysis with ER, progesterone receptor (PR), Ki‐67, HER2, cytokeratin (CK) 5/6, CK14, CK17, EGFR, topoisomerase‐IIα, cyclin D1, caveolin‐1 and E‐cadherin antibodies. In situ hybridization was employed to evaluate the prevalence of HER2, TOP2A, EGFR, CCND1, MYC and FGFR1 gene amplification. Our results demonstrate that mixed MPCs harbour similar patterns of genomic aberrations and phenotype (82.5% luminal and 17.5% HER2) compared to pure MPCs. A comparison between the distinct morphological components of mixed MPCs in a pairwise fashion revealed that both components harbour strikingly similar genomic profiles. When compared to grade‐ and ER‐matched IDC‐NSTs, mixed MPCs significantly more frequently harboured amplification of multiple regions on 8q (adjusted Fisher's p value < 0.05). Furthermore, mixed MPCs displayed higher proliferative rates than grade‐ and ER‐matched IDC‐NSTs. Our results suggest that micropapillary differentiation in breast cancer may identify a subgroup of more aggressive ER‐positive breast carcinomas, even in those featuring a mixed histology, and that mixed MPCs are more closely related to pure MPCs than to IDC‐NSTs. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Association analysis of ADPRT1, AKR1B1, RAGE,GFPT2 and PAI-1 gene polymorphisms with chronic renal insufficiency among Asian Indians with type-2 diabetes

Background  

To determine association of nine single nucleotide polymorphisms (SNPs) in ADP ribosyltransferase-1 (ADPRT1), aldo-keto reductase family 1 member B1 (AKR1B1), receptor for advanced glycation end-products (RAGE), glutamine:fructose-6-phosphate amidotransferase-2 (GFPT2), and plasminogen activator inhibitor-1 (PAI-1) genes with chronic renal insufficiency (CRI) among Asian Indians with type 2 diabetes; and to identify epistatic interactionss between genes from the present study and those from renin-angiotensin-aldosterone system (RAAS), and chemokine-cytokine, dopaminergic and oxidative stress pathways (previously investigated using the same sample set).     

Cholera in India: an analysis of reports, 1997�C2006

Objective

To more accurately define the annual incidence of cholera in India, believed to be higher than reported to the World Health Organization (WHO).

Methods

We searched the biomedical literature to extract data on the cases of cholera reported in India from 1997 to 2006 and compared the numbers found to those reported annually to WHO over the same period. The latter were obtained from WHO’s annual summaries of reported cholera cases and National health profile 2006, published by India’s Central Bureau of Health Intelligence.

Findings

Of India’s 35 states or union territories, 21 reported cholera cases during at least one year between 1997 and 2006. The state of West Bengal reported cases during all 10 years, while the state of Maharashtra and the union territory of Delhi reported cases during nine, and Orissa during seven. There were 68 outbreaks in 18 states, and 222 038 cases were detected overall. This figure is about six times higher than the number reported to WHO (37 783) over the same period. The states of Orissa, West Bengal, Andaman and Nicobar Islands, Assam and Chhattisgarh accounted for 91% of all outbreak-related cases.

Conclusion

The reporting of cholera cases in India is incomplete and the methods used to keep statistics on cholera incidence are inadequate. Although the data are sparse and heterogeneous, cholera notification in India is highly deficient.     

肾移植后多瘤病毒相关性肾病

背景：多瘤病毒感染是导致多瘤病毒相关性肾病和移植肾失功的重要原因之一。 目的：观察分析多瘤病毒相关性肾病的临床特征及其病理学特点。 方法：121例患者移植肾活检行多瘤病毒大T抗原染色,发现9例阳性诊断为多瘤病毒相关性肾病,利用SV-40 大 T 抗原免疫组织化学染色,对确认为多瘤病毒相关性肾病患者进行临床、病理、免疫荧光、免疫组织化学观察。 结果与结论：多瘤病毒相关性肾病组肾活检时检测霉酚酸-AUC 0-12和他克莫司血药浓度均明显高于同期非多瘤病毒相关性肾病组(P < 0.05)。9例活检组织经SV-40 大T抗原染色,肾皮质和髓质均可见散在的肾小管多瘤病毒阳性。免疫荧光IgG,IgM,IgA,C3,C4,C1q和C4d全阴性,所有肾组织病理均可见肾间质大量聚集的CD3,CD4,CD8,CD68阳性细胞,1例合并排斥反应者,人白细胞DR抗原和白细胞介素2受体高表达;不合并排斥者人白细胞DR抗原和白细胞介素2受体表达多小于5%。9例多瘤病毒相关性肾病患者随访均超过半年,移植肾失功1例,3例好转,2例稳定,3例恶化。结果表明,多瘤病毒相关性肾病的诊断主要依赖于移植肾活检组织病理;利用SV-40 大T 抗原免疫组织化学染色可提高多瘤病毒相关性肾病的诊断率;移植肾组织C4d、白细胞介素2受体和人白细胞DR抗原检测对多瘤病毒感染相关性肾病的鉴别诊断具有极其重要的临床价值。     

What factors are associated with the maintenance of PTSD after a motor vehicle accident? The role of sex differences in a help-seeking population

To investigate potential sex differences in factors that are associated with chronic PTSD, data from 223 participants were examined using logistic regression analyses. Each participant had been involved in a serious motor vehicle accident (MVA), which had occurred at least 6 months earlier (range 6mos-37 years). Although men and women did not differ in the rate of diagnosed PTSD, four variables were found to interact significantly with sex in the prediction of chronic PTSD: peritraumatic experiences of helplessness, danger, and the certainty that one would die during the MVA and lack of employment. Follow up analyses indicated that although the peritraumatic experience variables were statistically significant, no notable differences emerged in the odds ratios of men and of women. In contrast, men who were unemployed were 9.94 times more likely to be diagnosed with PTSD, relative to men who were employed, while unemployed women were 2.85 times more likely to be diagnosed with PTSD, relative to women who were employed. Results are discussed in light of the role of functional limitations and their impact on the maintenance of PTSD in men and women.     

Abstracts from other journals

The aim of the present study was to clinically evaluate fissure sealants on the occlusal fissures and buccal pits of permanent first and second molars after 20 and 15 years, respectively. The population consisted of 72 children, each of whom had had their four first molars sealed between 1977 and 1980. At the annual examinations, all caries-free, newly erupted second molars were sealed. When sealant was applied to the second molars, the first molars were checked and sealant was reapplied to those that had deficient sealants. At the follow-up, when the subjects were 26–27 years of age, 27 in the original group had moved from the community. Thus, the present result is based on 45 subjects. One hundred and fifty-three sealed first molars and 161 sealed second molars were available for inspection. At the follow-up examination of the first molars 20 years after sealant had been applied, 65% showed complete retention, 22% partial retention without caries, and 1306 caries or restoration in the occlusal fissures or buccal pits. At the 15-year follow-up of the second molars, the corresponding figures were 65%, 30% and 5%, respectively. Of the restored or carious molars, significantly more were found in the mandible than in the maxilla ( P  < 0.001). This longitudinal study showed that pit and fissure sealants, applied during childhood, have a long-lasting, caries-preventive effect.     

Critical role of factors II and X during coumarin anticoagulation and their combined measurement with a new Fiix-prothrombin time

Vitamin K antagonists (VKA) are monitored with prothrombin time (PT) based assays that are equally sensitive to reductions in factors II, VII or X. We compared the effect of vitamin K dependent (VKD) coagulation factors on PT and also on rotational thromboelastometric (ROTEM) parameters. The PT was equally sensitive to reductions in factors II, VII or X but ROTEM parameters correlated poorly with the PT in anticoagulated patients´ plasmas. ROTEM parameters were more affected by mild and moderate reductions in FII or FX than by FVII or FIX which had little influence except at very low coagulant activity. We developed a modified PT that was sensitive only to reductions in factors II and X. The Fiix-PT (Fiix-INR) correlated well with PT (INR) but the Fiix-INR fluctuated less than the INR in an anticoagulated patient reflecting its insensitivity to FVII. The ROTEM results suggest that mild to moderate reductions in factors II or X are more important during clot formation than factors VII or IX. Reductions in FII and X may better reflect anticoagulation with VKA than FVII or IX. The new Fiix-PT may more accurately reflect the degree of therapeutic anticoagulation in patients treated with VKA than the current PT which is subject to a confounding variation caused by FVII.     

Age dependence of otoacoustic emissions: the loss of amplitude is primarily caused by age-related hearing loss and not by aging alone

The amplitude of otoacoustic emissions (OAE) is known to decrease with increasing age, but it is still unclear whether this is due to aging alone or to age-related hearing loss. This study describes the exploration of a large database (5,142 patients from 0.4 to 89.8 years) collected in a routine clinical testing. Reliable pure tone audiograms, transitory evoked otoacoustic emissions (TEOAE) and distortion product otoacoustic emissions (DPOAE) recordings were available from 5,424 ears without conductive loss, acute sudden deafness or retrocochlear disorder. From this database, group 1 with behavioral thresholds of 10 dB HL or better at all frequencies from 1 to 4 kHz and group 2 with age-accordant thresholds after ISO 7029 were formed. In both groups, the OAE amplitude decreased with increasing age, but in group 1, the effect was significant only for DPOAE recorded at 3 and 4 kHz. In group 2, the loss of amplitude was steeper and highly significant for TEOAE as well as DPOAE at all frequencies, but most pronounced at high frequencies. These findings support the hypothesis that the reduction of OAE amplitude with increasing age is primarily caused by age-linked hearing loss and not by aging alone.     

Intranasal administration of midazolam in a cyclodextrin based formulation: bioavailability and clinical evaluation in humans.

Intranasal administration of midazolam has been of particular interest because of the rapid and reliable onset of action, predictable effects, and avoidance of injections. The available intravenous formulation (Dormicum i.v. solution from Hoffmann-La Roche) is however less than optimal for intranasal administration due to low midazolam concentration and acidity of the formulation (pH 3.0-3.3). In this study midazolam was formulated in aqueous sulfobutylether-beta-cyclodextrin buffer solution. The nasal spray was tested in 12 healthy volunteers and compared to intravenous midazolam in an open crossover trial. Clinical sedation effects, irritation, and serum drug levels were monitored. The absolute bioavailability of midazolam in the nasal formulation was determined to be 64 +/- 19% (mean +/- standard deviation). The peak serum concentration from nasal application, 42 +/- 11 ng ml-1, was reached within 10-15 min following administration and clinical sedative effects were observed within 5 to 10 min and lasted for about 40 min. Intravenous administration gave clinical sedative effects within 3 to 4 min, which lasted for about 35 minutes. Mild to moderate, transient irritation of nasal and pharyngeal mucosa was reported. The nasal formulation approaches the intravenous form in speed of absorption, serum concentration and clinical sedation effect. No serious side effects were observed.