Culture on a native bone marrow-derived extracellular matrix restores the pancreatic islet basement membrane, preserves islet function, and attenuates islet immunogenicity.

Islet transplantation in man is limited by multiple factors including islet availability, islet cell damage caused by collagenase during isolation, maintenance of islet function between isolation and transplantation, and allograft rejection. In this study, we describe a new approach for preparing islets that enhances islet function in vitro and reduces immunogenicity. The approach involves culture on native decellularized 3D bone marrow-derived extracellular matrix (3D-ECM), which contains many of the matrix components present in pancreas, prior to islet transplantation. Compared to islets cultured on tissue culture plastic (TCP), islets cultured on 3D-ECM exhibited greater attachment, higher survival rate, increased insulin content, and enhanced glucose-stimulated insulin secretion. In addition, culture of islets on 3D-ECM promoted recovery of vascular endothelial cells within the islets and restored basement membrane-related proteins (eg, fibronectin and collagen type VI). More interestingly, culture on 3D-ECM also selectively decontaminated islets of "passenger" cells (co-isolated with the islets) and restored basement membrane-associated type VI collagen, which were associated with an attenuation in islet immunogenicity. These results demonstrate that this novel approach has promise for overcoming two major issues in human islet transplantation: (a) poor yield of islets from donated pancreas tissue and (b) the need for life-long immunosuppression.

Series of Noncontrast Time-of-Flight Magnetic Resonance Angiographies to Identify Problems with Arteriovenous Fistula Maturation.

BACKGROUND: Successful maturation of arteriovenous fistulas (AVFs) remains a challenge for those managing patients with end-stage renal disease. Time-of-flight magnetic resonance angiography (TOF-MR) can be used to evaluate AVFs without the risk of radiation exposure, intravenous contrast, or reliance on the operator-dependent modality of color Doppler ultrasonography (CDUS). The objective of our study was to assess the utility of TOF-MR in the evaluation of nonmaturing AVFs and to identify the best clinical situations to use this technology. METHODS: Consecutive patients with abnormal findings on CDUS or physical examination after AVF creation underwent 3-dimensional (3D) TOF-MR. Imaging was performed at 3 T with a scan acquisition time of approximately 15 min. The technique was similar to head and neck magnetic resonance angiography (MRA), except presaturation bands were not used, thereby allowing simultaneous visualization of both arterial and venous flow. A total of 19 TOF-MR studies were performed. RESULTS: Nineteen patients underwent imaging and were the focus of this study. Seventeen of 19 TOF-MR studies were of diagnostic quality and yielded findings which enabled the vascular surgeon to take corrective measures. Findings included inflow stenosis, anastomotic narrowing, venous outflow stenosis, and hemodynamically significant venous tributaries. Twelve of 17 patients required conventional digital subtraction angiography (DSA). The congruence rate between TOF-MR and DSA was 83.3%. Four patients (21%) avoided DSA and went directly to definitive surgical treatment including branch ligation (3) or new access (1). CONCLUSIONS: This is the first report in the literature of successful implementation of 3D TOF-MR to assist in identifying AVF maturation problems. This unique noninvasive imaging modality provides actionable images without contrast or radiation exposure and can obviate the need for invasive diagnostic procedures or provide an anatomic map for planning corrective intervention.

Matrix-bound Cyr61/CCN1 is required to retain the properties of the bone marrow mesenchymal stem cell niche but is depleted with aging.

Previously, we showed that extracellular matrices (ECMs), produced ex vivo by various types of stromal cells, direct bone marrow mesenchymal stem cells (BM-MSCs) in a tissue-specific manner and recapitulate physiologic changes characteristic of the aging microenvironment. In particular, BM-MSCs obtained from elderly donors and cultured on ECM produced by young BM stromal cells showed improved quantity, quality and osteogenic differentiation. In the present study, we searched for matrix components that are required for a functional BM-MSC niche by comparing ECMs produced by BM stromal cells from "young" (≤25 y/o) versus "elderly" (≥60 y/o) donors. With increasing donor age, ECM fibrillar organization and mechanical integrity deteriorated, along with the ability to promote BM-MSC proliferation and responsiveness to growth factors. Proteomic analyses revealed that the matricellular protein, Cyr61/CCN1, was present in young, but undetectable in elderly, BM-ECM. To assess the role of Cyr61 in the BM-MSC niche, we used genetic methods to down-regulate the incorporation of Cyr61 during production of young ECM and up-regulate its incorporation in elderly ECM. The results showed that Cyr61-depleted young ECM lost the ability to promote BM-MSC proliferation and growth factor responsiveness. However, up-regulating the incorporation of Cyr61 during synthesis of elderly ECM restored its ability to support BM-MSC responsiveness to osteogenic factors such as BMP-2 and IGF-1. We next examined aging bone and compared bone mineral density and Cyr61 content of L4-L5 vertebral bodies in "young" (9-11 m/o) and "elderly" (21-33 m/o) mice. Our analyses showed that low bone mineral density was associated with decreased amounts of Cyr61 in osseous tissue of elderly versus young mice. Our results strongly demonstrate a novel role for ECM-bound Cyr61 in the BM-MSC niche, where it is responsible for retention of BM-MSC proliferation and growth factor responsiveness, while depletion of Cyr61 from the BM niche contributes to an aging-related dysregulation of BM-MSCs. Our results also suggest new potential therapeutic targets for treating age-related bone loss by restoring specific ECM components to the stem cell niche.

Organ-specific extracellular matrix directs trans-differentiation of mesenchymal stem cells and formation of salivary gland-like organoids in vivo.

BACKGROUND: Current treatments for salivary gland (SG) hypofunction are palliative and do not address the underlying cause or progression of the disease. SG-derived stem cells have the potential to treat SG hypofunction, but their isolation is challenging, especially when the tissue has been damaged by disease or irradiation for head and neck cancer. In the current study, we test the hypothesis that multipotent bone marrow-derived mesenchymal stem cells (BM-MSCs) in a rat model are capable of trans-differentiating to the SG epithelial cell lineage when induced by a native SG-specific extracellular matrix (SG-ECM) and thus may be a viable substitute for repairing damaged SGs. METHODS: Rat BM-MSCs were treated with homogenates of decellularized rat SG-ECM for one hour in cell suspension and then cultured in tissue culture plates for 7 days in growth media. By day 7, the cultures contained cell aggregates and a cell monolayer. The cell aggregates were hand-selected under a dissecting microscope, transferred to a new tissue culture dish, and cultured for an additional 7 days in epithelial cell differentiation media. Cell aggregates and cells isolated from the monolayer were evaluated for expression of SG progenitor and epithelial cell specific markers, cell morphology and ultrastructure, and ability to form SG-like organoids in vivo. RESULTS: The results showed that this approach was very effective and guided the trans-differentiation of a subpopulation of CD133-positive BM-MSCs to the SG epithelial cell lineage. These cells expressed amylase, tight junction proteins (Cldn 3 and 10), and markers for SG acinar (Aqp5 and Mist 1) and ductal (Krt 14) cells at both the transcript and protein levels, produced intracellular secretory granules which were morphologically identical to those found in submandibular gland, and formed SG-like organoids when implanted in the renal capsule in vivo. CONCLUSIONS: The results of this study suggest the feasibility of using autologous BM-MSCs as an abundant source of stem cells for treating SG hypofunction and restoring the production of saliva in these patients.

Construct Validity of the Routine Assessment of Patient Index Data 3 (RAPID3) in the Evaluation of Axial Spondyloarthritis.

OBJECTIVE: Although there are different tools to evaluate axial spondyloarthritis (axSpA), they are hardly used in routine clinical practice due to time constraints. The Routine Assessment of Patient Index Data 3 (RAPID3) is a composite measure feasible for use as a sole metric in busy clinics. We aimed to test its measurement properties in patients with axial SpA in a real-world clinical setting. METHODS: This cross-sectional study included 131 consecutive patients with axial SpA. The convergent (Spearman ρ) and discriminant (receiver-operating characteristic [ROC] curve analysis) validity of RAPID3 were tested against several axSpA-specific measures (Bath Ankylosing Spondylitis Disease Activity Index [BASDAI], Ankylosing Spondylitis Disease Activity Score [ASDAS], Bath Ankylosing Spondylitis Functional Index [BASFI], and modified Stoke Ankylosing Spondylitis Spinal Score [mSASSS]). A multivariate model was built to detect disease factors associated with RAPID3 remission (values ≤ 3). RESULTS: The study included 82 men and 49 women, with a median age of 55 (IQR 46-61) years, and a median disease duration of 11 (IQR 6-24) years. Mean RAPID3 was 9.45 ± 6.7. The BASDAI showed moderate correlation with ASDAS (ρ 0.66, P < 0.0001), but higher correlations with BASFI (ρ 0.78, P < 0.0001) and RAPID3 (ρ 0.75, P < 0.0001). The ASDAS had moderate correlations with BASFI, BASDAI, and RAPID3 (ranges 0.66-0.68, P < 0.0001). Higher correlations were found between BASFI and BASDAI (ρ 0.78, P < 0.0001), and BASFI and RAPID3 (ρ 0.73, P < 0.0001). The mSASSS did not show any correlation with any of the above composite measures. κ agreement between RAPID3 remission and other SpA remission criteria was moderate (κ 0.46-0.56). The RAPID3 thresholds to define remission ranged from values ≤ 2 to ≤ 6 with areas under the ROC curve between 0.86-0.91. Female sex (OR 0.34, 95% CI 0.12-0.90, P = 0.03) and nonsteroidal antiinflammatory drug intake (OR 0.26, 95% CI 0.10-0.66, P = 0.005) were independently associated with lower odds of achieving RAPID3 remission. CONCLUSION: RAPID3 demonstrated construct validity in this cross-sectional study. This index can be useful for a more comprehensive assessment of axSpA in busy clinical settings.

Children Change Their Answers in Response to Neutral Follow-Up Questions by a Knowledgeable Asker.

Burgeoning evidence suggests that when children observe data, they use knowledge of the demonstrator's intent to augment learning. We propose that the effects of social learning may go beyond cases where children observe data, to cases where they receive no new information at all. We present a model of how simply asking a question a second time may lead to belief revision, when the questioner is expected to know the correct answer. We provide an analysis of the CHILDES corpus to show that these neutral follow-up questions are used in parent-child conversations. We then present three experiments investigating 4- and 5-year-old children's reactions to neutral follow-up questions posed by ignorant or knowledgeable questioners. Children were more likely to change their answers in response to a neutral follow-up question from a knowledgeable questioner than an ignorant one. We discuss the implications of these results in the context of common practices in legal, educational, and experimental psychological settings.

Native extracellular matrix, synthesized ex vivo by bone marrow or adipose stromal cells, faithfully directs mesenchymal stem cell differentiation.

Mesenchymal stem cells (MSCs) are highly responsive to cues in the microenvironment (niche) that must be recapitulated ex vivo to study their authentic behavior. In this study, we hypothesized that native bone marrow (BM)- and adipose (AD)-derived extracellular matrices (ECM) were unique in their ability to control MSC behavior. To test this, we compared proliferation and differentiation of bone marrow (BM)-derived MSCs when maintained on native decellularized ECM produced by BM versus AD stromal cells (i.e. BM- versus AD-ECM). We found that both ECMs contained similar types of collagens but differed in the relative abundance of each. Type VI collagen was the most abundant (≈60% of the total collagen present), while type I was the next most abundant at ≈30%. These two types of collagen were found in nearly equal proportions in both ECMs. In contrast, type XII collagen was almost exclusively found in AD-ECM, while types IV and V were only found in BM-ECM. Physically and mechanically, BM-ECM was rougher and stiffer, but less adhesive, than AD-ECM. During 14 days in culture, both ECMs supported BM-MSC proliferation better than tissue culture plastic (TCP), although MSC-related surface marker expression remained relatively high on all three culture surfaces. BM-MSCs cultured in osteogenic (OS) differentiation media on BM-ECM displayed a significant increase in calcium deposition in the matrix, indicative of osteogenesis, while BM-MSCs cultured on AD-ECM in the presence of adipogenic (AP) differentiation media showed a significant increase in Oil Red O staining, indicative of adipogenesis. Further, culture on BM-ECM significantly increased BM-MSC-responsiveness to rhBMP-2 (an osteogenic inducer), while culture on AD-ECM enhanced responsiveness to rosiglitazone (an adipogenic inducer). These findings support our hypothesis and indicate that BM- and AD-ECMs retain unique elements, characteristic of their tissue-specific microenvironment (niche), which promote retention of MSC differentiation state (i.e. "stemness") during expansion and direct cell response to lineage-specific inducers. This study provides a new paradigm for precisely controlling MSC fate to a desired cell lineage for tissue-specific cell-based therapies.

Brachytherapy versus radical hysterectomy after external beam chemoradiation: a non-randomized matched comparison in IB2-IIB cervical cancer patients.

BACKGROUND: A current paradigm in the treatment of cervical cancer with radiation therapy is that intracavitary brachytherapy is an essential component of radical treatment. This is a matched retrospective comparison of the results of treatment in patients treated with external beam chemoradiation (EBRT-CT) and radical hysterectomy versus those treated with identical chemoradiation followed by brachytherapy. METHODS: In this non-randomized comparison EBRT-CT protocol was the same in both groups of 40 patients. In the standard treated patients, EBRT-CT was followed by one or two intracavitary Cesium (low-dose rate) applications within 2 weeks of finishing external radiation to reach a point A dose of at least 85 Gy. In the surgically treated patients, radical hysterectomy with bilateral pelvic lymph node dissection and para-aortic lymph node sampling were performed within 7 weeks after EBRT-CT. Response, toxicity and survival were evaluated. RESULTS: A total of 80 patients were analyzed. The patients receiving EBRT-CT and surgery were matched with the standard treated cases. There were no differences in the clinicopathological characteristics between groups or in the delivery of EBRT-CT. The pattern of acute and late toxicity differed. Standard treated patients had more chronic proctitis while the surgically treated had acute complications of surgery and hydronephrosis. At a maximum follow-up of 60 months, median follow-up 26 (2-31) and 22 (3-27) months for the surgery and standard therapy respectively, eight patients per group have recurred and died. The progression free and overall survival are the same in both groups. CONCLUSION: The results of this study suggest that radical hysterectomy can be used after EBRT-CT without compromising survival in FIGO stage IB2-IIB cervical cancer patients in settings were brachytherapy is not available. A randomized study is needed to uncover the value of surgery after EBRT-CT.

The effect of amniotomy on urine protein creatinine ratio test accuracy.

Introduction: While the gold standard for evaluation of maternal urinary protein is a 24-hr urine collection, spot urine protein/creatinine ratio has been instituted as an alternative for quantification proteinuria. Though it seems intuitive to obtain a catheterized urine sample on patients with ruptured amniotic membranes, it is a common practice to forgo this step under the argument that there is no data to show its necessity. Data on the effect of amniotomy, spontaneous or artificial, on the accuracy of the protein/creatinine ratio are scant. The present study was designed to address this issue and objectively compare protein/creatinine ratio values on samples obtained from the same patient before and after amniotomy. Methods: We conducted a prospective non-interventional study. Women presenting in active labor or for labor induction with intact amnion were enrolled. Separate random catch urines for the protein/creatinine ratio were obtained prior to and immediately after spontaneous or assisted amniotomy. The urine samples were analyzed in the hospital chemistry department, and the results were compared. Results: Of the 137 patients consented, 63 had pre- and post-amniotomy protein/creatinine ratios collected. The mean age was 28.5±5.6 y, Gravidity 2.7±1.6, Gestational age 39.2±1.8 wks, and BMI 31.6±6.4 kg/m2. Comorbidities included gestational diabetes (5/63, 7.9%), chronic hypertension (3/63, 4.7%), and pre-eclampsia (5/63, 7.9%). Post-amniotomy protein/creatinine ratio was significantly higher than pre-amniotomy ratio (1.3±2.5 vs 0.34±0.83, p<0.001). In addition, the number of patients with protein/creatinine ratio greater than 0.3 was higher post-amniotomy than pre-amniotomy (41/63 vs 14/63, p<0.001). Conclusion: Amniotomy results in a false elevation of the protein/creatinine ratio in term patients. Urine samples should be obtained by catheterization in the setting of ruptured membranes to reduce falsely elevated results. Although the same can be assumed for other gestational ages, further studies including this population need to be conducted.

A Randomized Controlled Trial Comparing Laparoscopic Lens Defogging Techniques through Simulation Model.

CONTEXT: Current literature demonstrates a lack of comparative studies regarding effective techniques for reducing laparoscopic lens fogging. AIM: Our primary objective is to determine the efficacy of various laparoscopic defogging techniques (LDT) through a randomized controlled trial that employs a novel simulation model of the abdominopelvic cavity. SETTINGS AND DESIGN: This study was conducted at academic community hospital. This study design was a randomized controlled trial through simulation. SUBJECTS AND METHODS: A chamber was constructed that simulated the abdominopelvic cavity. We used 5 and 10 mm 0° laparoscopes. A 10 cm visual analog scale was developed to assign visual clarity (VC) scores. The 10 cm mark indicated perfect VC. We employed the following LDTs: (1) glove warming (GLOVE), (2) surfactant solution (Fog Reduction and Elimination Device [FRED]), (3) chlorhexidine solution (SOAP), (4) warm saline (SALINE), and (5) control. Three observers were blinded to the LDT used. Primary outcomes included VC scores at designated time intervals (5, 30, and 60 s) for each LDT. A minimum of 10 observations per time interval were required to achieve adequate power based on a 2.5 cm difference in VC scores. RESULTS: For the 10 mm laparoscope, FRED, SOAP, and SALINE had a VC score at 60 s (VC60) higher than control (4.8 ± 2.2, 7.8 ± 0.8, 7.9 ± 0.7 vs. 2.4 ± 0.72, P < 0.05). Both SOAP and SALINE VC60 scores were higher than FRED (7.8 ± 0.8, 7.9 ± 0.7 vs. 4.8 ± 2.2, P < 0.05). No differences were noted in VC60 scores between control and GLOVE (2.4 ± 0.72 vs. 3.1 ± 2.2, P > 0.05) and between SOAP and SALINE (7.8 ± 0.8 vs. 7.9 ± 0.7, P > 0.05). Similar results were noted with the 5 mm laparoscope. CONCLUSIONS: Common LDTs such as SALINE and SOAP were more effective than FRED, while GLOVE was no different than control. These results demonstrate that the use of effective LDTs can potentially translate into improved patient care and operative outcomes during surgery.

Structure-activity relationship and pharmacokinetic studies of 3-O-substitutedflavonols as anti-prostate cancer agents.

Thirty-eight 3-O-substituted-3',4'-dimethoxyflavonols and twenty-five 3-O-substituted-3',4',7-trimethoxyflavonols have been synthesized for systematic investigation on the structure-activity relationships of 3-O-substituted-3',4'-dimethoxyflavonols in three human prostate cancer cell models. Our findings indicate that incorporation of an appropriate amino group to 3-OH of 3',4'-dimethoxyflavonol and 3',4',7-trimethoxyflavonol through a 3- to 5-carbon linker can substantially improve the in vitro antiproliferative potency in three human prostate cancer cell models, but not in two non-neoplastic human epithelial cell models (MCF 10A and PWR-1E). 1-Methylpiperazine, pyrrolidine, and dibutylamine are optimal terminal amine groups that, in combination with a 3- to 5-carbon linker, are notably beneficial to the anti-proliferative potency of 3-O-substituted-3',4'-dimethoxyflavonols. It is worth noting that 3-O-(4-methylpiperazin-1-yl)propyl-3',4',7-trimethoxyflavonol (76) induces PC-3 cell death in a completely different way from 3-O-pyrrolidinopentyl-3',4',7-trimethoxyflavonol (81) even though they belong to 3-O-substituted-3',4',7-trimethoxyflavonols and exhibit similar potency in inhibiting PC-3 cell proliferation, suggesting that the mechanism of action for each specific 3-O-substitutedflavonol varies with different amino moiety. 3-O-(N,N-Dibutylamino)propyl-3',4'-dimethoxyflavonol (42) emerged as the most promising derivative due to its substantially improved potency in cell models, superior bioavailability in rats, and good selectivity of inhibiting prostate cancer cell proliferation over non-neoplastic human epithelial cell proliferation.

Expression of KATP channels in human cervical cancer: Potential tools for diagnosis and therapy.

Various ion channels, including ATP-sensitive potassium (KATP) channels, are expressed in cancer and have been suggested as potential tumor markers and therapeutic targets. KATP channels are composed of at least two types of subunit, an inwardly rectifying K+ channel (Kir6.x) and a sulfonylurea receptor (SUR). However, the association between KATP channels and cervical cancer remains elusive. The present study determined that the Kir6.2, SUR1 and SUR2 subunits are expressed in cervical cancer cell lines and/or human biopsies. The potential association of subunit expression with tumor differentiation and invasion was analyzed. The effect of the KATP channel blocker glibenclamide on the proliferation of cervical cancer cell lines was also studied. Five cervical cancer cell lines, two primary cultures of cervical cancer cells, one normal keratinocyte cell line and 74 human biopsies were used in the experiments. The mRNA and protein levels of the Kir6.2 subunit were assessed by reverse transcription-polymerase chain reaction and immunochemistry, respectively. Cell proliferation was evaluated by MTT assay. Kir6.2 subunit overexpression compared with control, was observed in some cervical cancer cell lines and cervical tumor tissues. Additionally, increased KATP channel expression was observed in high-grade, poorly differentiated and invasive human cervical cancer biopsies. Kir6.2 subunit expression was not observed in the majority of the non-cancerous cervical tissues. The effect of the KATP channel blocker glibenclamide on the proliferation of five different cervical cancer cell lines was studied, revealing that as Kir6.2 mRNA expression increased, the inhibitory effect of glibenclamide also increased. The results of the present study suggest, for the first time to the best of our knowledge, that the KATP channel subunits, Kir6.2 and SUR2, could potentially represent tools for diagnosing and treating cervical cancer.

Restoring the quantity and quality of elderly human mesenchymal stem cells for autologous cell-based therapies.

BACKGROUND: Degenerative diseases are a major public health concern for the aging population and mesenchymal stem cells (MSCs) have great potential for treating many of these diseases. However, the quantity and quality of MSCs declines with aging, limiting the potential efficacy of autologous MSCs for treating the elderly population. METHODS: Human bone marrow (BM)-derived MSCs from young and elderly donors were obtained and characterized using standard cell surface marker criteria (CD73, CD90, CD105) as recommended by the International Society for Cellular Therapy (ISCT). The elderly MSC population was isolated into four subpopulations based on size and stage-specific embryonic antigen-4 (SSEA-4) expression using fluorescence-activated cell sorting (FACS), and subpopulations were compared to the unfractionated young and elderly MSCs using assays that evaluate MSC proliferation, quality, morphology, intracellular reactive oxygen species, ß-galactosidase expression, and adenosine triphosphate (ATP) content. RESULTS: The ISCT-recommended cell surface markers failed to detect any differences between young and elderly MSCs. Here, we report that elderly MSCs were larger in size and displayed substantially higher concentrations of intracellular reactive oxygen species and ß-galactosidase expression and lower amounts of ATP and SSEA-4 expression. Based on these findings, cell size and SSEA-4 expression were used to separate the elderly MSCs into four subpopulations by FACS. The original populations (young and elderly MSCs), as well as the four subpopulations, were then characterized before and after culture on tissue culture plastic and BM-derived extracellular matrix (BM-ECM). The small SSEA-4-positive subpopulation representing ~ 8% of the original elderly MSC population exhibited a "youthful" phenotype that was similar to that of young MSCs. The biological activity of this elderly subpopulation was inhibited by senescence-associated factors produced by the unfractionated parent population. After these "youthful" cells were isolated and expanded (three passages) on a "young microenvironment" (i.e., BM-ECM produced by BM cells from young donors), the number of cells increased ≈ 17,000-fold to 3 × 109 cells and retained their "youthful" phenotype. CONCLUSIONS: These results suggest that it is feasible to obtain large numbers of high-quality autologous MSCs from the elderly population and establish personal stem cell banks that will allow serial infusions of "rejuvenated" MSCs for treating age-related diseases.

Pre-exenterative chemotherapy, a novel therapeutic approach for patients with persistent or recurrent cervical cancer.

BACKGROUND: Most cervical cancer patients with pelvic recurrent or persistent disease are not candidates for exenteration, therefore, they only receive palliative chemotherapy. Here we report the results of a novel treatment modality for these patients pre-exenterative chemotherapy- under the rational that the shrinking of the pelvic tumor would allow its resection. METHODS: Patients with recurrent or persistent disease and no evidence of systemic disease, considered not be candidates for pelvic exenteration because of the extent of pelvic tumor, received 3-courses of platinum-based chemotherapy. Response was evaluated by CT scan and bimanual pelvic examination; however the decision to perform exenteration relied on the physical findings. Toxicity to chemotherapy was evaluated with standard criteria. Survival was analyzed with the Kaplan-Meier method. RESULTS: Seventeen patients were studied. The median number of chemotherapy courses was 4. There were 9 patients who responded to chemotherapy, evaluated by bimanual examination and underwent pelvic exenteration. Four of them had pathological complete response. Eight patients did not respond and were not subjected to surgery. One patient died due to exenteration complications. At a median follow-up of 11 months, the median survival for the whole group was 11 months, 3 months in the non-operated and 32 months in those subjected to exenteration. CONCLUSION: Pre-exenterative chemotherapy is an alternative for cervical cancer patients that are no candidates for exenteration because of the extent of the pelvic disease. Its place in the management of recurrent disease needs to be investigated in randomized studies, however, its value for offering long-term survival in some of these patients with no other option than palliative care must be stressed.

Low glycemic index lunch on satiety in overweight and obese people with type 2 diabetes.

Several studies have shown that isocaloric diets have different effects on satiety. The aim of the present study was to compare the effect of lunches with different glycemic indexes (GI) in type 2 diabetics. Ten men and women with type 2 diabetes participated in the study. Subjects were given two experimental lunches with glycemic indexes of 43 and 88. Visual analogue rating scales were completed before and after each experimental meal periodically to record subjective feelings of satiety. Satiety Area Under the Curve was 1024 +/- 160 mm after the low GI diet and 711 +/- 190 mm after the high GI diet. Eating a lunch with a low GI index resulted in higher satiety perception. These results suggest the need to promote culturally based combined foods with high fiber and low GI. This approach might contribute to the prevention of obesity by increasing the perception of satiety while also improving metabolic control of diabetics. In addition, this is a low cost approach for people with limited financial resources.

Induction chemotherapy with gemcitabine and oxaliplatin for locally advanced cervical carcinoma.

Induction chemotherapy followed by surgery, particularly with newer agents or combinations, remains to be explored in locally advanced cervical cancer. Gemcitabine cisplatin is a very active combination for this tumor, therefore we explored the activity of gemcitabine in combination with oxaliplatin. Ten untreated patients with histologic diagnosis of cervical carcinoma and staged as IB2 to IIIB were treated with 3 21-day courses of oxaliplatin 130 mg/m day 1 and gemcitabine 1,250 mg/m days 1 and 8 followed by locoregional treatment with either surgery or concomitant chemoradiation. Response and toxicity were evaluated at the end of chemotherapy. All patients were evaluable. The overall clinical response rate was 80%, being complete in 3 patients (30%) and partial in 5 (50%). Seven (70%) patients underwent surgery, and three (30%) had chemoradiation as definitive treatment. Hematologic toxicity was moderate, with leukopenia grades III-IV in 17 and 0%; granulocytopenia grades III-IV in 23 and 3%, respectively. Eight patients had grade I oropharyngeal toxicity. At a median follow-up of 11 months (range: 10-12), all patients are disease free. Gemcitabine oxaliplatin is a very active and well-tolerated combination for locally advanced cervical cancer.

Vólvulo primario de íleon: una rara forma de obstrucción intestinal en el adulto: reporte de caso y revisión de la literatura / Primary volvulus of ileum: A rare form of intestinal obstruction in the adult: case report and literature review

Resumen Antecedentes El vólvulo de intestino delgado se produce por el giro anormal del intestino delgado alrededor del eje de su propio mesenterio, lo cual puede generar obstrucción intestinal, isquemia, infarto o perforación. Caso clínico Paciente masculino de 71 años que cursó con abdomen agudo. Sospechando cuadro de oclusión intestinal, se realizó exploración quirúrgica en la que se encontró como hallazgos vólvulo de intestino delgado en la válvula ileocecal, con isquemia y necrosis de 280 cm de intestino delgado, por lo cual se realizó resección intestinal e ileostomía terminal, preservando 320 cm de intestino delgado viable desde ángulo duodeno-yeyunal. Cursó con una evolución satisfactoria. Discusión El vólvulo de intestino delgado es una entidad infrecuente y una urgencia quirúrgica que amenaza la vida. Se debe sospechar en todos los pacientes que presenten dolor abdominal abrupto y signos de obstrucción intestinal, sin cirugía abdominal previa ni otras causas obvias. El diagnóstico precoz y la intervención quirúrgica inmediata son factores clave asociados con un mejor pronóstico para este grupo de pacientes.

Background The small bowel volvulus is caused by the abnormal rotation of the small intestine around the axis of its own mesentery. This can lead to intestinal obstruction, ischemia, infarction or perforation. Clinical case A 71-year-old male patient with an acute abdominal pain, suspicious for a bowel occlusion, performed a surgical exploration, finding small bowel volvulus at the ileocecal valve level, with necrosis and ischemia of 280 cm of the small intestine, resulting in intestinal resection and terminal ileostomy. Still preserving 320 cm of viable small intestine from the duodenojejunal angle, with a satisfactory evolution. Discussion Small bowel volvulus is an uncommon entity, and a life-threatening surgical emergency, that should be suspected in all patients with abrupt abdominal pain and signs of bowel obstruction, without previous abdominal surgery or other obvious causes. Early diagnosis and immediate surgical intervention are key factors associated with a better prognosis for this group of patients.

Selective silencing of angiotensin receptor subtype 1a (AT1aR) by RNA interference.

Angiotensin II exerts its physiological effects by activating multiple subtypes of its receptor such as AT1a-, AT1b-, and AT2-receptors. Because of a high degree of similarity among these G-protein-coupled receptors, it has been difficult to assign diverse physiological actions of angiotensin II through these receptor subtypes. We have developed small interfering RNAs to selectively inhibit the expression of the AT1a receptor (AT1aR) subtype. A dsRNA, AT1 47, was found to be highly selective and efficient in reducing the levels of AT1aR subtype. Transfection of AT1aR-expressing CHO cells with dsRNA AT1 47 resulted in an 80% decrease in the AT1aR expression. In contrast, dsRNA AT1 47 showed no significant effects on both AT1bR and AT2R subtypes. Thus, AT1 47 provides us with a powerful tool to selectively silence this subtype of receptor to investigate its role in cardiovascular physiology.