Crocus sativus is a triploid sterile plant characterized by its red stigmas, which produce significant quantities of carotenoid derivatives formed from the oxidative cleavage of β-carotene and zeaxanthin. The accumulation of three major carotenoid derivatives- crocin, picrocrocin, and safranal- is responsible for the color, bitter taste, and aroma of saffron, which is obtained from the dried stigma of Crocus. Maximum apocarotenoid accumulation occurs during fully developed scarlet stage of stigma development. Zeaxanthin is the precursor for biosynthesis of apocarotenoids. Crocus zeaxanthin 7, 8 (7, 8)-cleavage dioxygenase gene (CsZCD) encodes a chromoplast enzyme that initiates the biogenesis of these apocarotenoids by cleaving zeaxanthin. The Reverse Transcription-PCR analysis revealed that CsZCD gene expression followed different patterns during stigma development. Highest levels of CsZCD gene expression was observed in fully developed scarlet stage of stigma. Real Time PCR analysis showed that there is a sharp increase in gene expression from yellow to orange and orange to scarlet stages of stigma development. Increase in CsZCD gene expression parallels with the apocarotenoid content during the development of stigma, suggesting its regulatory role for apocarotenoid biosynthesis and stigma development in saffron.
Electronic supplementary material
The online version of this article (doi:10.1007/s12298-012-0131-9) contains supplementary material, which is available to authorized users.
Saffron; CsZCD; Real time PCR; Gene expression; Apocarotenoid
Hallermann-Streiff syndrome (HSS) is a rare disorder characterized by dyscephalia, with facial and dental abnormalities. We report a 12-year-old female child who presented with abnormal facial features, dental abnormalities and sparse scalp hair.
Abnormal facial features; dental anomalies; Hallermann-Streiff syndrome
The stable lineage commitment of naïve T helper cells to a hybrid Th1/2 phenotype reveals the cell-intrinsic reconciliation of two opposing T cell differentiation programs and provides a self-limiting mechanism to dampen immunopathology.
Differentiated T helper (Th) cell lineages are thought to emerge from alternative cell fate decisions. However, recent studies indicated that differentiated Th cells can adopt mixed phenotypes during secondary immunological challenges. Here we show that natural primary immune responses against parasites generate bifunctional Th1 and Th2 hybrid cells that co-express the lineage-specifying transcription factors T-bet and GATA-3 and co-produce Th1 and Th2 cytokines. The integration of Th1-promoting interferon (IFN)-γ and interleukin (IL)-12 signals together with Th2-favoring IL-4 signals commits naive Th cells directly and homogeneously to the hybrid Th1/2 phenotype. Specifically, IFN-γ signals are essential for T-bet+GATA-3+ cells to develop in vitro and in vivo by breaking the dominance of IL-4 over IL-12 signals. The hybrid Th1/2 phenotype is stably maintained in memory cells in vivo for months. It resists reprogramming into classic Th1 or Th2 cells by Th1- or Th2-promoting stimuli, which rather induce quantitative modulations of the combined Th1 and Th2 programs without abolishing either. The hybrid phenotype is associated with intermediate manifestations of both Th1 and Th2 cell properties. Consistently, hybrid Th1/2 cells support inflammatory type-1 and type-2 immune responses but cause less immunopathology than Th1 and Th2 cells, respectively. Thus, we propose the self-limitation of effector T cells based on the stable cell-intrinsic balance of two opposing differentiation programs as a novel concept of how the immune system can prevent excessive inflammation.
T helper (Th) cells, a subgroup of white blood cells important in the immune system, can differentiate into diverse lineages, for example Th1 and Th2, whose effector mechanisms target different types of pathogens but cause problems if not properly regulated. Lineage commitment is driven by cytokine signals that control the expression of distinct lineage-specifying “master regulator” transcription factor molecules. Lineage commitment is thought to reflect alternative cell-fate decisions because the initiated differentiation programs have self-amplifying and mutually repressive features. Here we show that the Th1 and Th2 differentiation programs are more compatible with each other than previously thought. Individual naive T cells can simultaneously integrate Th1- and Th2-polarizing signals and develop into hybrid Th1/2 cells that stably co-express both the Th1 master regulator T-bet and the Th2 master regulator GATA-3. We find that hybrid Th1/2 cells arise naturally during parasite infections and that the two opposing differentiation programs can stably co-exist in resting memory Th1/2 cells for periods of months. Th1- or Th2-polarizing stimuli induced quantitative modulations in the hybrid state but did not extinguish either program. The cell-intrinsic antagonism gives the hybrid Th1/2 cells properties that are quantitatively intermediate between those of Th1 and Th2 cells. Thus, in typical Th1 and Th2 immune responses, hybrid Th1/2 cells cause less immunopathology than their classic Th1 or Th2 counterparts, demonstrating a cell-intrinsic self-limiting mechanism that can prevent excessive inflammation.
The authors describe two patients who underwent transfemoral endovascular procedures followed by the use of the Angio-seal arterial percutaneous closure device. In the first patient, distal migration of the device occurred with consequent occlusion of the ipsilateral popliteal artery 2 days post procedure. In the second patient, thrombotic occlusion of the femoral artery occurred and the patient presented with acute leg ischaemia 3 weeks post procedure. Surgical removal of the closure device with consequent revascularisation of the affected leg was achieved in both patients. This report aims to alert clinicians to the possibility of device-induced arterial occlusion, dislodgment and their sequelae.
Granulosis rubra nasi is a rare disorder of the eccrine glands, inherited as an autosomal dominant trait. It is clinically characterized by hyperhidrosis of the central part of the face, most conspicuous on the tip of the nose, followed by appearance of diffuse erythema over the nose, cheeks, chin, and upper lip. It is commonly seen in childhood, but can also occur in adults. This is a case report of a 27-year-old male patient who presented with excessive sweating over the nose. Physical examination of the nose revealed erythema and multiple telangiectatic vesicles. Biopsy findings supported the diagnosis of granulosis rubra nasi. This case is being reported for its rarity since to the best of our knowledge, it has not been reported in Indian subjects so far.
Disorder of eccrine glands; granulosis rubra nasi; telengiectasia
Socioeconomic development is the best contraceptive. Himachal Pradesh has made developments in all the fields, especially reducing the size of the family via family planning program.
The objectives of this analysis are to describe the various methods of family planning used from 2003 to 2010 and their impact in averting the births in the state and in stabilizing the population.
Materials and Methods:
We collected secondary data of the family planning program and the various methods employed from the total population (Census 2011) covered under family planning program (FPP) of the state. We analyzed and compared the results with India. We measured the impact of the program due to FP methods adopted. We employed the standardized program indicators- total fertility rate, birth rate, death rate, growth rate and census trend towards population growth; fertility rate (in %), birth rate and death rate (per thousand of the population per year) from 3.8, 31.5 and 11.1 in 1981 to 1.9, 17.2 and 7.2 in 2009. We entered dataset by double data entry technique and analyzed descriptively using Epi info version 3.3.2 and stat calc software.
The state has the population of 6,856,509, sex ratio in age 0-6 years is 906/1000 males. The unmet need for family planning services is 15%. The impact of family planning program has resulted in averting of 3,387,744 of pregnancies from 2003 to 2010. The total fertility rate (TFR) has come down to 1.9 in 2008 from 3.8 children per woman in 1981. The death rate has declined from 11.1 per 1000 live births in 1981 to 7.2 per 1000 live births in 2009. The trend in decadal growth rate of the state is observable as 23.0% in 1971 while in 2011, it is 12.8%; more towards young population and for geriatric one as well but not exploding like India.
Total population is on the increase with reference to the population of reproductive age bracket (15-49 years) and also geriatric population above 60 steadily despite good social and health indicators. Bulging reproductive age group with mild upward shift of the geriatric population is the root cause for increasing population in hills of Himachal Pradesh.
Geriatric population; Hills population; Himachal Pradesh; Reproductive age group
This study was designed to assess the utility of the scarf osteotomy in the management of symptomatic adolescent hallux valgus.
Materials and methods
This is a case series of 29 patients (39 feet) with a mean follow up of 38.6 months (range 6–60 months). The mean age at the time of surgery was 14.1 years (range 10–17 years). American Orthopaedic Foot and Ankle Society (AOFAS) scores were collected at final follow up, along with a rating of the overall satisfaction. Any complications were recorded. Pre- and post-surgical radiographic angles were measured and analysed using the Student’s t-test. The angles measured were the hallux valgus angle (HVA), the inter-metatarsal angle (IMA) and the distal metatarsal articular angle (DMAA). A second surgeon independently reviewed the angles in order to assess the inter-rater reliability using the Pearson product moment correlation.
The mean AOFAS score at final follow up was 94.2 (range 54–100). Of all patients, 93 % were either satisfied or very satisfied with their final outcome. One patient has been listed for revision surgery after symptomatic recurrence at 3 years follow up. The pre-operative HVA, IMA and DMAA were 34.8°, 15.9° and 16.0°, respectively. The post-operative values were 16.3°, 8.8° and 9.2°, respectively (p < 0.001 for each). Pearson’s r coefficient values demonstrated good inter-rater reliability of measurement.
We have presented the results of the largest case series of scarf osteotomies for adolescent hallux valgus reported in the literature up to now, as far as we are aware. AOFAS scores at final follow up are comparable to the smaller studies previously reported and provide evidence that good outcomes and high levels of patient satisfaction can be achieved. Early follow up demonstrates a low level of symptomatic recurrence, but longer term data are still required.
Adolescent; Hallux; Valgus; Scarf; Osteotomy; Bunions
The prevalence and negative health effects of chronic diseases are disproportionately high among Hispanics, the largest minority group in the United States. Self-management of chronic conditions by older adults is a public health priority. The objective of this study was to examine 6-week differences in self-efficacy, time spent performing physical activity, and perceived social and role activities limitations for participants in a chronic disease self-management program for Spanish-speaking older adults, Tomando Control de su Salud (TCDS).
Through the Healthy Aging Regional Collaborative, 8 area agencies delivered 82 workshops in 62 locations throughout South Florida. Spanish-speaking participants who attended workshops from October 1, 2008, through December 31, 2010, were aged 55 years or older, had at least 1 chronic condition, and completed baseline and post-test surveys were included in analysis (N = 682). Workshops consisted of six, 2.5-hour sessions offered once per week for 6 weeks. A self-report survey was administered at baseline and again at the end of program instruction. To assess differences in outcomes, a repeated measures general linear model was used, controlling for agency and baseline general health.
All outcomes showed improvement at 6 weeks. Outcomes that improved significantly were self-efficacy to manage disease, perceived social and role activities limitations, time spent walking, and time spent performing other aerobic activities.
Implementation of TCDS significantly improved 4 of 8 health promotion skills and behaviors of Spanish-speaking older adults in South Florida. A community-based implementation of TCDS has the potential to improve health outcomes for a diverse, Spanish-speaking, older adult population.
Metastatic carcinomas involving the lung are a common specimen encountered in surgical pathology. These metastases may have different morphologic, and architectural patterns and may mimic primary pulmonary adenocarcinoma, especially the intra-alveolar (lepidic) pattern of spread which may simulate a primary pulmonary bronchioloalveolar carcinoma (adenocarcinoma in situ). We present the case of a metastatic pancreatic adenocarcinoma that morphologically mimicked bronchioloalveolar carcinoma of the lung in that the tumor had an exclusive intra-alveolar pattern of spread and had an immunophenotype that was noninformative as to the site of origin (cytokeratin 7+, cytokeratin 20−, TTF-1−). In this case, we used KRAS gene mutation analysis to support that the lung carcinoma represented a metastatic pancreatic carcinoma as they both possessed identical codon 12 KRAS mutations. We show that this method may be a useful way to prove site of origin of metastatic carcinoma—particularly if standard morphologic or immunohistochemical analysis is not definitive.
Hyper-IgG4 disease is a rare systemic disorder that usually affects middle age males. It is characterized by elevated serum IgG4 levels and infiltration of organs by IgG4 positive plasma cells associated with fibrosis. Patients usually present with mass or masses in the involved organ that mimic neoplasia. While initially described in the pancreas, IgG4-related inflammatory tumors have been now described in many organs. We describe an unusual case of an IgG4-related pseudotumor of the kidney.
Lymphocytic choriomeningitis virus (LCMV) exhibits natural tropism for dendritic cells and represents the prototypic infection that elicits protective CD8+ T cell (cytotoxic T lymphocyte (CTL)) immunity. Here we have harnessed the immunobiology of this arenavirus for vaccine delivery. By using producer cells constitutively synthesizing the viral glycoprotein (GP), it was possible to replace the gene encoding LCMV GP with vaccine antigens to create replication-defective vaccine vectors. These rLCMV vaccines elicited CTL responses that were equivalent to or greater than those elicited by recombinant adenovirus 5 or recombinant vaccinia virus in their magnitude and cytokine profiles, and they exhibited more effective protection in several models. In contrast to recombinant adenovirus 5, rLCMV failed to elicit vector-specific antibody immunity, which facilitated re-administration of the same vector for booster vaccination. In addition, rLCMV elicited T helper type 1 CD4+ T cell responses and protective neutralizing antibodies to vaccine antigens. These features, together with low seroprevalence in humans, suggest that rLCMV may show utility as a vaccine platform against infectious diseases and cancer.
The aim of this study was to compare the usefulness of 99Tcm-methoxy-isobutyl-isonitrile (MIBI) scintimammography and ultrasonography, alone and in combination, for the detection of chest wall recurrence in the post-mastectomy breast. A total of 41 consecutive post-mastectomy patients (mean age 46.6 years; median age 45 years) with clinical suspicion of breast cancer recurrence were evaluated. For scintimammography all patients received a 740–900 MBq iv injection of 99Tcm-MIBI; planar images were taken 5–10 min post-injection followed by supine single photon emission CT. Breast ultrasonography was performed in each patient using a 7.5 MHz transducer. Both MIBI uptake and ultrasound findings were documented using standard protocols. All patients had fine needle aspiration cytology biopsy (FNAC), core biopsy or excision biopsy for final tissue diagnosis. Of the 41 patients, 24 had true positive signs of local breast cancer recurrence upon ultrasonography, 10 were diagnosed as true negatives, a sensitivity of 86%, specificity 77%, positive predictive value (PPV) 89%, negative predictive value (NPV) 71% and accuracy 83% (p = 0.001). By comparison, scintimammography findings were found to be true positive in 25 patients and true negative in 12 patients — sensitivity 89%, specificity 92%, PPV 96%, NPV 80% and accuracy 90% (p = 0.001). Using a combination of these two modalities, the combined sensitivity was 100%, specificity 77%, PPV 90%, NPV 100% and accuracy 93%. The high NPV of the two studies in combination implies a potential use of this approach to exclude recurrent disease in patients with a low initial index of suspicion and/or when histology is indeterminate.
For patients with relapsed Hodgkin Lymphoma, high dose chemotherapy with stem cell rescue may improve survival over chemotherapy alone. We assessed outcomes of HDCT-SCT in 37 consecutive adolescent and young adult patients with relapsed HL whose malignancy was categorized based on sensitivity to chemotherapy. We determined whether current outcomes supported the use of HDCT-SCT in all of our patients or just those patients with lower risk characteristics such as chemosensitivity. With a median follow up of 6.5 years, the 2 year overall survival was 89% (95% CI: 62%–97%) for the chemo-sensitive patients (n=21). Whereas for patients with resistant disease (n=16) OS was 53% (95%CI: 25%–74%). Both autologous and allogeneic transplants were well tolerated, with 100 day treatment related mortality under 10%. Our data show encouraging outcomes for patients with chemosensitive relapsed HL who receives HSCT and supports the value of the procedure even when the disease is chemoresistant.
Hodgkin’s Lymphoma; Stem Cell Transplant; Salvage Therapy
Quercetin (QE), one of natural flavanoid group, was widely distributed as a secondary metabolite in plant kingdom. It has been believed that oxidative stress plays a role in the pathogenesis of diabetes mellitus (DM). The aim of the present study was the evaluation of possible effects of QE on blood glucose and antioxidant enzymes in experimental streptozotocin (STZ)-induced diabetes in rats. STZ was injected intraperitoneally with single dose of 50 mg/kg for diabetes induction. QE (15 mg/kg bw day, intraperitoneal (i.p.) injection) was injected for 3 days prior to STZ administration; these injections were continued to the end of the study (for 25 days). Glucose tolerance test and random plasma glucose were done for all animals. Cellular antioxidant enzymes such as glutathione peroxidase (GSHPx), superoxide dismutase (SOD) and catalase (CAT) activities were measured in pancreatic homogenates. Quercetin had no effect on plasma glucose level of normal animals but its pre- treatment was able to prevent diabetes induced by single intraperitoneal injection of streptozocintreated rats. Antioxidant enzyme activity significantly decreased in STZ induced diabetic group. QE treatment significantly increased the antioxidant enzyme activities. It could be concluded that quercetin, a flavonoid with antioxidant properties, exerting its beneficial antidiabetic effects.
Quercetin; Flavonoid; Antioxidant; Antidiabetic
Tracheobronchial obstruction along with compression of pulmonary vessels is a rare complication after stenting of aortic aneurysm. We present this rare situation in a young patient who underwent stenting of traumatic thoracic aortic aneurysm and developed this near fatal complication and also the conservative management plan which we adopted to manage this case.
Bronchial obstruction; pulmonary vessel compression; thoracic aortic aneurysm
Needle length plays an important role for the success of ophthalmic block. The standard practice is to use 25 mm needles length; however, unnecessarily long needles may increase the risk of complications especially in the presence of staphyloma or previous scleral buckle.
This work was designed to compare the efficacy of using 15 and 25 mm needle in performing extraconal block for patients undergoing vitreoretinal surgery.
Settings and Design:
Prospective randomized double blinded study.
Materials and Methods:
A total of 120 patients were enrolled in this study and were divided in two groups. In group (1) extraconal block was performed using 25 mm needle, while in group (2) 15 mm needle was used. After primary injection, assessment of the block was done by an anesthesiologist who was unaware of the needle used. If satisfactory akinesia was not achieved a supplementation was provided. At the end of the procedures, patients and surgeons were asked to assess their pain and satisfaction with the anesthetic technique.
Statistical Analysis used:
The sample size calculation using N-Quary version 4. Numerical and categorical data were analyzed using an independent sample, a two-tailed t-test, and chi-square test, respectively.
The volume of primary injectable was significantly higher in group 2. The two groups were comparable as regards total volume of local anesthetic, supplementation rate, akinesia, pain score, and surgeon satisfaction.
Using 15 mm needle length to perform extraconal blockade for posterior segment procedures is equally effective to 25 mm needle.
Peribulbar blockade; retinal surgery; scleral buckle; short needle
Interleukin-8 (IL-8/CXCL-8) is a prototype of the ELR+CXC chemokines that play an important role in the promotion and progression of many human cancers including breast cancer. We have recently showed the implication of polymorphism (-251) T/A of IL-8 gene in the susceptibility and prognosis of breast carcinoma. IL-8 acts through its CXCR1 and CXCR2 receptors. CXCR2, expressed on the endothelial cells, is the receptor involved in mediating the angiogenic effects of ELR+CXC chemokines and in particular IL-8.
In the current study, we investigated the susceptibility and prognostic implications of the genetic variation in CXCR2 in breast carcinoma. We also confirmed the implication of IL-8 (-251) T/A polymorphism in a larger cohort. Finally, we combined the IL-8 and CXCR2 variant alleles and analyzed their effects in breast cancer risk and prognosis.
We used the allele-specific polymerase chain reaction to characterize the variation of IL-8 and CXCR2 for 409 unrelated Tunisian patients with breast carcinoma and 301 healthy control subjects. To estimate the relative risks, Odds ratios and 95% confidence intervals were calculated using unconditional logistic regression after adjusting for the known risk factors for breast cancer. Associations of the genetic marker with the rates of breast carcinoma-specific overall survival and disease-free survival were assessed using univariate and multivariate analyses.
A highly significant association was found between the homozygous CXCR2 (+ 1208) TT genotype (adjusted OR = 2.89; P = 0.008) and breast carcinoma. A significantly increased risk of breast carcinoma was associated with IL-8 (-251) A allele (adjusted OR = 1.86; P = 0.001). The presence of two higher risk genotypes (the TA and TT in IL-8, and the TT in CXCR2) significantly increased the risk of developing breast carcinoma (adjusted OR = 4.15; P = 0.0004).
The CXCR2 (+ 1208) T allele manifested a significant association with an aggressive phenotype of breast carcinoma as defined by a large tumor size, a high histological grade, and auxiliary's lymph node metastasis. A significant association between the IL-8 (-251) A allele and the aggressive form of breast carcinoma was also found.
Moreover, the presence of the IL-8 (-251) A and/or the CXCR2 (+ 1208) T allele showed a significant association with a decreased overall survival and disease-free survival in breast carcinoma patients.
Our results indicated that the polymorphisms in IL-8 and CXCR2 genes are associated with increased breast cancer risk, as well as disease progress, supporting our hypothesis for IL-8 and ELR+CXC chemokine receptor (CXCR2) involvement in breast cancer pathogenesis.
Epidermal growth factor receptor (EGFR) is overexpressed in ovarian carcinomas, with direct or indirect activation of EGFR able to trigger tumour growth. We demonstrate significant activation of both signal transducer and activator of transcription (STAT)3 and its upstream activator Janus kinase (JAK)2, in high-grade ovarian carcinomas compared with normal ovaries and benign tumours. The association between STAT3 activation and migratory phenotype of ovarian cancer cells was investigated by EGF-induced epithelial–mesenchymal transition (EMT) in OVCA 433 and SKOV3 ovarian cancer cell lines. Ligand activation of EGFR induced a fibroblast-like morphology and migratory phenotype, consistent with the upregulation of mesenchyme-associated N-cadherin, vimentin and nuclear translocation of β-catenin. This occurred concomitantly with activation of the downstream JAK2/STAT3 pathway. Both cell lines expressed interleukin-6 receptor (IL-6R), and treatment with EGF within 1 h resulted in a several-fold enhancement of mRNA expression of IL-6. Consistent with that, EGF treatment of both OVCA 433 and SKOV3 cell lines resulted in enhanced IL-6 production in the serum-free medium. Exogenous addition of IL-6 to OVCA 433 cells stimulated STAT3 activation and enhanced migration. Blocking antibodies against IL-6R inhibited IL-6 production and EGF- and IL-6-induced migration. Specific inhibition of STAT3 activation by JAK2-specific inhibitor AG490 blocked STAT3 phosphorylation, cell motility, induction of N-cadherin and vimentin expression and IL6 production. These data suggest that the activated status of STAT3 in high-grade ovarian carcinomas may occur directly through activation of EGFR or IL-6R or indirectly through induction of IL-6R signalling. Such activation of STAT3 suggests a rationale for a combination of anti-STAT3 and EGFR/IL-6R therapy to suppress the peritoneal spread of ovarian cancer.
ovarian carcinoma; epithelial–mesenchymal transition; migration; Janus kinase 2; signal transducer and activator of transcription 3
Metal cutting processes are important due to increased consumer demands for quality metal cutting related products (more precise tolerances and better product surface roughness) that has driven the metal cutting industry to continuously improve quality control of metal cutting processes. This paper presents optimum surface roughness by using milling mould aluminium alloys (AA6061-T6) with Response Ant Colony Optimization (RACO). The approach is based on Response Surface Method (RSM) and Ant Colony Optimization (ACO). The main objectives to find the optimized parameters and the most dominant variables (cutting speed, feedrate, axial depth and radial depth). The first order model indicates that the feedrate is the most significant factor affecting surface roughness.
response surface method; ant colony; aluminium alloys; surface roughness
platelet polymorphisms; glycoprotein Ibα; Kozak; PFA‐100
Peroxisome proliferator-activated receptor β (PPARβ) is a member of the nuclear hormone receptor family and is a ligand-activated transcription factor with few known molecular targets including 3-phosphoinositide-dependent protein kinase 1(PDK1). In view of the association of PPARβ and PDK1 with cancer, we have examined the expression of PPARβ and PDK1 in normal ovaries and different histological grades of ovarian tumours. Normal ovaries, benign, borderline, grades 1, 2 and 3 ovarian tumours of serous, muciuous, endometrioid, clear cell and mixed subtypes were analysed by immunohistochemistry for PPARβ and PDK1 expression. All normal ovarian tissues, benign, borderline and grade 1 tumours showed PPARβ staining localised in the epithelium and stroma. Staining was predominantly nuclear, but some degree of cytoplasmic staining was also evident. Approximately 20% of grades 2 and 3 tumours lacked PPARβ staining, whereas the rest displayed some degree of nuclear and cytoplasmic staining of the scattered epithelium and stroma. The extent of epithelial and stromal PPARβ staining was significantly different among the normal and the histological grades of tumours (χ2=59.25, d.f.=25, P<0.001; χ2=64.48, d.f.=25, P<0.001). Significantly different staining of PPARβ was observed in the epithelium and stroma of benign and borderline tumours compared with grades 1, 2 and 3 tumours (χ2=11.28, d.f.=4, P<0.05; χ2=16.15, d.f.=4, P<0.005). In contrast, PDK1 immunostaining was absent in 9 out of 10 normal ovaries. Weak staining for PDK1 was observed in one normal ovary and 40% of benign ovarian tumours. All borderline and malignant ovarian tumours showed positive cytoplasmic and membrane PDK1 staining. Staining of PDK1 was confined to the epithelium and the blood vessels, and no apparent staining of the stroma was evident. Significantly different PDK1 staining was observed between the benign/borderline and malignant ovarian tumours (χ2=22.45, d.f.=5, P<0.001). In some borderline and high-grade tumours, staining of the reactive stroma was also evident. Our results suggest that unlike the colon, the endometrial, head and neck carcinomas, overexpression of PPARβ does not occur in ovarian tumours. However, overexpression of PDK1 was evident in borderline and low- to high-grade ovarian tumours and is consistent with its known role in tumorigenesis.
ovarian carcinoma; peroxisome proliferating-activated receptor; phosphoinositide-dependent protein kinase 1; metastasis; differentiation
CD8 T cells are recognized key players in control of persistent virus infections, but increasing evidence suggests that assistance from other immune mediators is also needed. Here, we investigated whether specific antibody responses contribute to control of lymphocytic choriomeningitis virus (LCMV), a prototypic mouse model of systemic persistent infection. Mice expressing transgenic B cell receptors of LCMV-unrelated specificity, and mice unable to produce soluble immunoglobulin M (IgM) exhibited protracted viremia or failed to resolve LCMV. Virus control depended on immunoglobulin class switch, but neither on complement cascades nor on Fc receptor γ chain or Fc γ receptor IIB. Cessation of viremia concurred with the emergence of viral envelope-specific antibodies, rather than with neutralizing serum activity, and even early nonneutralizing IgM impeded viral persistence. This important role for virus-specific antibodies may be similarly underappreciated in other primarily T cell–controlled infections such as HIV and hepatitis C virus, and we suggest this contribution of antibodies be given consideration in future strategies for vaccination and immunotherapy.
Persistent viruses such as hepatitis C virus (HCV) or HIV can defeat the body's defense system and cause devastating epidemics worldwide. Recent attempts at vaccinating against HIV have relied on the induction of specific antiviral killer T lymphocytes but have failed to confer protection on the host. Better knowledge about how a successful defense should operate is therefore essential for developing and refining new vaccines. Here, we have used a prototypic mouse model to investigate basic defense mechanisms required to eliminate persisting viruses. Experiments in several genetically engineered mouse models show that contrary to common belief, not only antiviral killer T cells, but also antibodies (produced by B cells), are needed to prevent a virus from persisting in its host. These findings suggest that induction of antibodies, along with antiviral killer T lymphocytes, should be envisaged when devising new strategies for vaccinating against HIV or HCV.
Andreas Bergthaler and colleagues reveal that T cell control of systemic persistent viral infections requires support by antibodies produced by B cells, which may have important implications for future vaccination strategies against HIV and hepatitis C.
The basic helix-loop-helix transcriptional repressor twist1, as an antagonist of nuclear factor κB (NF-κB)–dependent cytokine expression, is involved in the regulation of inflammation-induced immunopathology. We show that twist1 is expressed by activated T helper (Th) 1 effector memory (EM) cells. Induction of twist1 in Th cells depended on NF-κB, nuclear factor of activated T cells (NFAT), and interleukin (IL)-12 signaling via signal transducer and activator of transcription (STAT) 4. Expression of twist1 was transient after T cell receptor engagement, and increased upon repeated stimulation of Th1 cells. Imprinting for enhanced twist1 expression was characteristic of repeatedly restimulated EM Th cells, and thus of the pathogenic memory Th cells characteristic of chronic inflammation. Th lymphocytes from the inflamed joint or gut tissue of patients with rheumatic diseases, Crohn's disease or ulcerative colitis expressed high levels of twist1. Expression of twist1 in Th1 lymphocytes limited the expression of the cytokines interferon-γ, IL-2, and tumor necrosis factor-α, and ameliorated Th1-mediated immunopathology in delayed-type hypersensitivity and antigen-induced arthritis.