SV40 associated miRNAs are not detectable in mesotheliomas.

BACKGROUND: Simian virus-40 (SV40) is a DNA tumour virus that was introduced into the human population with contaminated poliovirus vaccine, and its role in mesothelioma is widely debated. PCR based testing has been called into question, as false positives can be because of cross-reactivity with related viruses, or to laboratory contamination. The Institute of Medicine has recommended the development of more sensitive and specific tests to resolve this controversy. METHODS: We have characterized highly sensitive RT-PCR based assays that are specific for SV40-encoded microRNAs (miRNAs), as an alternative to current testing methods. RESULTS: Using this sensitive and specific detection method, we were unable to identify SV40 miRNA expression in human malignant pleural mesothelioma (MM) samples. CONCLUSION: Our work indicates that SV40 miRNAs are not likely to contribute to mesothelioma tumourogenesis, but highlights the value of this approach when compared with the relatively unspecific current testing methods.

Intestinal necrosis due to sodium polystyrene sulfonate (Kayexalate) in sorbitol.

BACKGROUND: Sodium polystyrene sulfonate (SPS, Kayexalate) has been implicated in the development of intestinal necrosis. Sorbitol, added as a cathartic agent, may be primarily responsible. Previous studies have documented bowel necrosis primarily in postoperative, dialysis, and transplant patients. We sought to identify additional clinical characteristics among patients with probable SPS-induced intestinal necrosis. METHODS: Rhode Island Hospital surgical pathology records were reviewed to identify all gastrointestinal specimens reported as containing SPS crystals from December 1998 to June 2007. Patient demographics, medical comorbidities, and hospital courses of histologically verified cases of intestinal necrosis were extracted from the medical records. RESULTS: Twenty-nine patients with reports of SPS crystals were identified. Nine cases were excluded as incidental findings with normal mucosa. Nine patients were excluded as their symptoms began before SPS administration or because an alternate etiology for bowel ischemia was identified. Eleven patients had confirmed intestinal necrosis and a temporal relationship with SPS administration suggestive of SPS-induced necrosis. Only 2 patients were postoperative, and only 4 had end-stage renal disease (ESRD). All patients had documented hyperkalemia, received oral SPS, and developed symptoms of intestinal injury between 3 hours and 11 days after SPS administration. Four patients died. CONCLUSION: Intestinal ischemia is a recognized risk of SPS in sorbitol. Our series highlights that patients may be susceptible even in the absence of ESRD, surgical intervention, or significant comorbidity.

A proteomic analysis reveals the loss of expression of the cell death regulatory gene GRIM-19 in human renal cell carcinomas.

Gene associated with retinoid interferon-induced mortality (GRIM)-19, an inhibitor of transcription factor STAT3, was originally identified as a critical regulatory protein in a genetic screen that was designed to identify the gene products necessary for Interferon (IFN)-beta- and retinoic acid-induced cell death. Over expression of GRIM-19 activates cell death. Conversely, inactivation of its expression promotes cell growth. STAT3 is a transcription factor that regulates gene expression in response to multiple extra cellular growth factors. In contrast to its normal feedback inhibition, a constitutive activation of STAT3 has been documented in several tumors. Although many STAT3-inhibitors are described, their relevance to human cancer is unclear. In an attempt to define the molecular alterations associated with human renal cell carcinoma (RCC) using mass spectrometry, we have discovered that expression of GRIM-19 is lost or severely depressed in a number of primary RCC and in some urinogenital tumors. Using an RCC cell line, we show that down regulation of GRIM-19 promotes tumor growth via an augmentation of STAT3-dependent gene expression. These studies for the first time show a tumor-suppressor like activity of GRIM-19.

Human eosinophils can express the cytokines tumor necrosis factor-alpha and macrophage inflammatory protein-1 alpha.

By in situ hybridization, 44-100% of the blood eosinophils from five patients with hypereosinophilia and four normal subjects exhibited intense hybridization signals for TNF-alpha mRNA. TNF-alpha protein was detectable by immunohistochemistry in blood eosinophils of hypereosinophilic subjects, and purified blood eosinophils from three atopic donors exhibited cycloheximide-inhibitable spontaneous release of TNF-alpha in vitro. Many blood eosinophils (39-91%) from hypereosinophilic donors exhibited intense labeling for macrophage inflammatory protein-1 alpha (MIP-1 alpha) mRNA, whereas eosinophils of normal donors demonstrated only weak or undetectable hybridization signals for MIP-1 alpha mRNA. Most tissue eosinophils infiltrating nasal polyps were strongly positive for both TNF-alpha and MIP-1 alpha mRNA. By Northern blot analysis, highly enriched blood eosinophils from a patient with the idiopathic hypereosinophilic syndrome exhibited differential expression of TNF-alpha and MIP-1 alpha mRNA. These findings indicate that human eosinophils represent a potential source of TNF-alpha and MIP-1 alpha, that levels of expression of mRNA for both cytokines are high in the blood eosinophils of hypereosinophilic donors and in eosinophils infiltrating nasal polyps, that the eosinophils of normal subjects express higher levels of TNF-alpha than MIP-1 alpha mRNA, and that eosinophils purified from the blood of atopic donors can release TNF-alpha in vitro.

Microscopic analysis and significance of vascular architectural complexity in renal cell carcinoma.

The objective of this study was to evaluate the utility of measuring microvessel fractal dimension (MFD) as a parameter of architectural microvascular complexity in localized renal cell carcinoma (RCC). Forty-nine patients with low-stage clear cell RCC were assessed in a 9-year follow-up retrospective study. Tumor vessels were visualized with the endothelial marker CD34. Tumor microvessel density (MVD) was measured by computerized morphometry. Fractal analysis of the RCC microvascular network was performed and the MFD was computed in each case. Correlation between tumor vascular parameters, histological grade, extent of tumor necrosis and patient survival were tested by uni- and multivariate analyses. A significant correlation was found between tumor grade and decreased survival (P = 0.04). The extent of macroscopic tumor necrosis also significantly correlated with poor prognosis (P = 0.0001). Survival analysis revealed a significantly higher MVD in patients who survived longer than 5 years as compared with those who died before the end of the 5-year follow-up period (MVD = 10.8 +/- 4.7% versus 6.4 +/- 3.7%; P = 0.03). MVD was also inversely associated with the extent of tumor necrosis (P = 0.03). Microvessel fractal dimension was significantly higher in low- as compared with high-grade tumors (1.55 +/- 0.11 versus 1.45 +/- 0.15; P = 0.03). Survival analysis revealed a significantly higher MFD in those who lived >5 years as compared with those who died earlier (1.56 +/- 0.11 versus 1.46 +/- 0.15; P = 0.02). The MFD was inversely associated with the extent of tumor necrosis (P = 0.01). Multivariate analysis revealed that the MFD was the only significant factor to correlate with tumor necrosis, and that tumor necrosis was the only independent predictor of patient survival. These results indicate that the analysis of MFD as a marker of tumor microvascular complexity may provide important prognostic information as well as novel insight into the biology of tumor angiogenesis.

Similar and divergent patterns in the regulation of matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of MMP-1 gene expression in benign and malignant human thyroid cells.

An imbalance between the activity of matrix metalloproteinases (MMPs) (proteolytic enzymes that degrade protein components of the extracellular matrix) and their inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), may be one of the mechanisms responsible for tumor cell invasion. We have investigated the regulation of MMP-1 and TIMP-1 gene expression in benign and malignant (follicular, anaplastic, and papillary) human thyroid cells. As expected of cells with invasive potential, detectable MMP-1 messenger RNA (mRNA) levels were observed in malignant cells under basal conditions, in contrast to undetectable levels in benign cells. Exposure of these cells, for 1 h, to the active phorbol ester, phorbol 12-myristate 13-acetate (TPA, 100 nmol/L), acting via protein kinase C (PKC), elicited an increase in MMP-1 mRNA, with a peak stimulation after a 3- to 4-h culture period. Epidermal growth factor (EGF, 25 ng/mL), however, acting via protein tyrosine kinase (PTK), stimulated such gene expression in malignant cells but failed to do so in benign cells. TIMP-1 mRNA was not significantly altered by the TPA-PKC, EGF-PTK, or TSH-protein kinase A (PKA) pathways in malignant cells. In benign cells, however, TPA induced a small, though significant, increase in TIMP-1. The MMP-1 stimulation by EGF and lack of TPA-induced rise in TIMP-1 in malignant cells, in sharp contrast to the effects obtained in benign thyrocytes, seems to indicate that the MMP: TIMP balance favors a more extensive extracellular matrix protein breakdown by malignant thyrocytes, as expected of cells exhibiting invasive capacity. TSH (10-500 microU/mL) failed to significantly influence basal MMP-1 or TIMP-1 mRNA levels, but it caused a dose-dependent inhibition in TPA- and EGF-induced MMP-1 mRNA in malignant cells, and TPA-stimulated MMP-1 and TIMP-1 in benign cells. The repressive action of TSH on MMP-1 mRNA was mimicked by forskolin and 8-bromo-cAMP and was abrogated by the PKA inhibitor, H-89, suggesting that the TSH inhibitory action is PKA-mediated. In conclusion, the present study provides novel data on MMP-1 and TIMP-1 gene expression and their modulation by the major signal transduction pathways operating in human thyroid cells. Similar and divergent patterns have emerged in the regulation of such gene expression in benign and malignant human thyrocytes, in many instances in accord with the concept of MMP playing the role of stimulating, and TIMP inhibiting, cell invasion. Although MMP-1 may be just one of the many factors responsible for tumor cell invasion, the present findings demonstrating the possibility, at least in vitro, of repressing MMP gene expression may have important clinical ramifications.

Adaptive hypoxic tolerance in the subterranean mole rat Spalax ehrenbergi: the role of vascular endothelial growth factor.

Spalax ehrenbergi has evolved adaptations that allow it to survive and carry out normal activities in a highly hypoxic environment. A key component of this adaptation is a higher capillary density in some Spalax tissues resulting in a shorter diffusion distance for oxygen. Vascular endothelial growth factor (VEGF) is an angiogenic factor that is critical for angiogenesis during development and in response to tissue ischemia. We demonstrate here that VEGF expression is markedly increased in those Spalax tissues with a higher capillary density relative to the normal laboratory rat Rattus norvegicus. Upregulation of VEGF thus appears to be an additional mechanism by which Spalax has adapted to its hypoxic environment.

Hepatic adenoma in the pediatric age group. Clinicopathological observations and assessment of cell proliferative activity.

The clinicopathological findings of eight children with hepatic adenoma in the absence of cirrhosis are presented. The lesions ranged in diameter from 0.1 to 14.5 cm. Associated disorders were Fanconi's anemia, type I glycogen storage disease. Hurler's disease, and severe combined immunodeficiency with ADA deficiency. The remaining three children had adenoma without known associated disorders. In the children with glycogenosis and Hurler's disease the adenomas were multiple. Significant dysplasia occurred in the two children with Fanconi's anemia; however, the lesions behaved in a benign fashion--one with regression of the tumor after cessation of androgen therapy and the other with nonrecurrence after complete resection. Proliferating cell nuclear antigen (PCNA) labeling index (LI) of the adenoma arising in patients with Fanconi's anemia was significantly greater than the PCNA-LI of adenoma in the other children (mean 4.1% versus 0.9% of nuclei), approaching the lower end of the spectrum for reported hepatocellular carcinoma cases. We emphasize that the worrisome pathology that may occur in hepatic adenoma in children, particularly with Fanconi's anemia, does not necessarily predict malignant behavior. The association of hepatic adenoma with Hurler's disease or severe combined immunodeficiency has not been reported previously.

Developmental intervention for low birth weight infants: improved early development outcome.

This prospective longitudinal study was designed to evaluate the effects of a multidisciplinary infant development program (IDP) on the mental and physical development of low birth weight infants (less than 1,800 g). Infants in the neonatal intensive care were randomly assigned to the IDP or to traditional care (control group). IDP infants received developmental interventions in the hospital and at home through the first 2 years of life. Counseling and parenting education were provided to their parents during this same period. The control group received all the postnatal care and referrals customarily given in traditional care. Both IDP and control infants were enrolled in an independent follow-up program, which used the Bayley Scales of Infant Development in a blind evaluation design. The IDP group had a significantly lower incidence of developmental delay (P less than .05) and scored significantly higher than the control group (P less than .05) on mean mental and physical indices at 12 and 24 months of adjusted age.

Prospective pricing system for tertiary neonatal intensive care.

This study assessed the potential impact of the federal neonatal diagnosis-related group (DRG) pricing system upon reimbursement to a state neonatal intensive care program. Data for length of intensive care unit stay, procedures, hospital charges, and audited cost reports from the state of Florida's ten regional neonatal intensive care centers were analyzed for 8,492 neonates whose charges totaled $118 million. Mean lengths of stay in these tertiary care centers were substantially longer than those reported for the federal DRGs, which were based on community hospital data. If federal DRG-based reimbursement to hospitals were implemented in Florida's perinatal intensive care program, compensation would range from 9% to 56% of actual hospital care charges. Federal DRG price rates were not predictive of hospital charges. Only 16% of the total variation in hospital charges was explained by differences among federal DRG rates (R2 = .16). Analysis of data by major determinants of resource consumption provided groups more homogeneous with respect to hospital charges and, hence, cost. Therefore, we developed a prospective pricing system that used modifications of federal newborn DRG system. These modifications resulted in a threefold increase in R2 (.52). Our proposed system permits prediction of cost and reimbursement for infants by three criteria: birth weight, need for mechanical ventilation and/or major surgery, and survival status and length of survival for those who die.

Prospective pricing model for neonatologists and obstetricians in tertiary care centers.

According to the new federal diagnosis-related group (DRG) system, hospitals are reimbursed fixed sums based on discharge diagnoses, rather than variable sums that depend on specific goods and services consumed and number of days hospitalized. The government is now exploring DRGs as a potential mechanism for reimbursing physicians. In Florida, two DRG-type reimbursement systems were developed for neonatal and obstetrical hospitalizations in tertiary care settings, as departures from the federal DRG system. Called neonatal care groups (NCGs) and obstetrical care groups (OBCGs), both classification systems predicted hospital charges in these settings more accurately than did federal DRGs. The feasibility of a prospective pricing system for neonatologists and obstetricians based on NCGs and OBCGs was investigated. The data showed that neonatologists' charges had a high correlation with hospital charges (r = .90) and that increasing levels of intensity of care as defined by the NCGs were reflected by consistent increases in reimbursement to neonatologists. If the NCG system were to be applied, neonatologists would receive compensation equivalent to that which they currently earn according to the fee-for-service system. In contrast, obstetricians' charges bore almost no relationship to hospital charges. However, modest differences in obstetrician's charges did emerge as a reflection of number of complications, which are incorporated into the OBCG categories; this suggests that a reimbursement system based on hospital OBCG categories might be applied to obstetricians.

Educational disabilities of neonatal intensive care graduates.

OBJECTIVE: To determine the relationship between perinatal and sociodemographic factors in low birth weight and sick infants hospitalized at regional neonatal intensive care units (NICUs) and subsequent educational disabilities. METHOD: NICU graduates born between 1980 and 1987 at nine statewide regionalized level III centers were located in Florida elementary schools (kindergarten through third grade) during academic year 1992-1993 (n = 9943). Educational disability was operationalized as placement into eight mutually exclusive types of special education (SE) classifications determined by statewide standardized eligibility criteria: physically impaired, sensory impaired (SI), profoundly mentally handicapped, trainable mentally handicapped, educable mentally handicapped, specific learning disabilities, emotionally handicapped, and speech and language impaired (SLI). Logistic regression was used to estimate the odds of placement in SE for selected perinatal and sociodemographic variables. RESULTS: Placement into SE ranged from .8% for SI to 9.9% for SLI. Placement was related to four perinatal factors (birth weight, transport, medical conditions [congenital anomalies, seizures or intraventricular hemorrhage] and ventilation), and five sociodemographic factors (child's sex, mother's marital status, mother's race, mother's educational level, and family income). Perinatal factors primarily were associated with placement in physically impaired, SI, profoundly mentally handicapped, and trainable mentally handicapped. Perinatal and sociodemographic factors both were associated with placement in educable mentally handicapped and specific learning disabilities whereas sociodemographic factors primarily were associated with placement in emotionally handicapped and SLI. CONCLUSIONS: Educational disabilities of NICU graduates are influenced differently by perinatal and sociodemographic variables. Researchers must take into account both sets of these variables to ascertain the long-term risk of educational disability for NICU graduates. Birth weight alone should not be used to assess NICU morbidity outcomes.

Educational outcome of neonatal intensive care graduates.

Studies of developmental outcome of neonatal intensive care unit graduates have generally been limited to the first 2 to 3 years of life, with outcome determined by psychometric tests. This study followed neonatal intensive care unit graduates born 1975 through 1983 (n = 457) into the public school system and compared their educational outcomes with those of newborn nursery graduates (n = 656). Outcomes were evaluated by placement in four academic categories: regular classroom, academic problems, speech/language impairment, and major impairment. Educational outcomes for children of both groups were essentially the same. Their placement in the four academic categories were equally affected by nonmedical variables, primarily income (below/above poverty level), race, and sex. Seventy percent of poverty-level children were in one of the three problem categories, compared with 40% of children above poverty level. Neither neonatal intensive care unit treatment nor low birth weight were major predictors of educational outcome. The only clear-cut neonatal intensive care unit effect occurred among children born with sensory or physical impairments. Therefore, in order to reduce poor educational outcomes, follow-up and intervention programs should be targeted primarily to children with diagnosable handicaps and from minority, low-income families.

Assessment and diagnostic utility of the cytotoxic T-lymphocyte phenotype using the specific markers granzyme-B and TIA-1 in esophageal mucosal biopsies.

Most esophageal intraepithelial lymphocytes (IELs) express T-cell markers. Increased numbers of esophageal IELs have been shown in reflux esophagitis. The cytotoxic potential and activity of esophageal IELs have not as yet been examined. Our objectives were to determine whether esophageal IELs express the recently described cytotoxic T-cell (CTLs) markers, TIA-1 and granzyme-B, and whether the number of CTLs correlates with well-defined endoscopic, clinical, and histological features of esophagitis. In this study, most CD-3+ esophageal IELs exhibit the CD-8+/TIA-1+ T cell with cytotoxic potential phenotype in both histologically normal biopsy specimens and in biopsy specimens with esophagitis. A subpopulation of esophageal IELs that express cytotoxic activity was identified by granzyme-B immunostaining. A significant positive association was found between the number of esophageal IELs seen by light microscopy in biopsy specimens with histological features of reflux (21 IELs/HPF) and Candida esophagitis (31 IELs/HPF) as compared with normal-appearing biopsy specimens (10 IELs/HPF) (P< or =.05). Furthermore, the number of TIA-1 or granzyme-B-positive IELs were significantly increased in biopsy specimens with reflux esophagitis (34 and 15 cells/HPF) and Candida esophagitis (44 and 18 cells/HPF) as compared with normal (11 and 2 cells/HPF) (P< or =.05). Granzyme-B and CD-3-positive IELs were also significantly elevated in biopsy specimens with reflux-associated squamous hyperplasia (P< or =.05). Finally, biopsy specimens of patients with dysphagia and to a lesser extent dyspepsia/heartburn exhibited increased numbers of IELs bearing the cytotoxic phenotype when compared with asymptomatic patients. In conclusion, we provide immunohistochemical evidence that most esophageal IELs exhibit the cytotoxic phenotype and that activated cytotoxic IELs are increased in reflux and Candida esophagitis.

MN antigen expression in normal, preneoplastic, and neoplastic esophagus: a clinicopathological study of a new cancer-associated biomarker.

Recently, a novel tumor-associated protein, termed MN, has been described in carcinomas of the uterine cervix, where its expression has been shown to be associated with malignant transformation. Because malignant transformation in the esophagus develops through a dysplasia-carcinoma sequence similar to that which occurs in the cervix, this study was performed to evaluate MN expression in normal, preneoplastic, and neoplastic tissues of the esophagus. Esophageal tumor resection specimens from 27 patients (12 squamous cell carcinomas, one multifocal squamous dysplasia, 10 Barrett's-associated adenocarcinomas, two Barrett's esophagus with dysplasia, two adenosquamous carcinomas) were immunohistochemically stained with a monoclonal antibody (clone M75) directed against the MN antigen. The localization of MN antigen, as well as the proportion of positively stained cells, were determined in sections of normal, dysplastic, and carcinomatous tissues. The staining characteristics were correlated with the pathological features of the tumors. Weak intracellular MN expression was detected only in the basal cells of normal squamous epithelium. However, inflamed and reactive squamous epithelium showed increased staining in the basal layer and in the overlying mature squamous cells. MN expression was significantly increased in dysplastic squamous epithelium (P < .001). All esophageal squamous cell carcinomas (100%) stained positively for MN antigen, where the pattern of staining was predominantly membranous. However, the degree of MN staining did not correlate with any of the pathological features of the tumors. In Barrett's epithelium, MN stained positively in all types of metaplastic cells and showed no difference in dysplastic epithelium. In contrast to squamous cell carcinomas, only 80% of esophageal adenocarcinomas were positive for MN, but the degree of MN expression was inversely correlated with histological tumor differentiation (P < .015). The results of this study suggest that (1) the tumor-associated MN antigen may play a role in proliferation and regeneration in esophageal squamous epithelium, and (2) loss of MN expression may be related to cancer progression in Barrett's-associated adenocarcinomas.

Changes in survival patterns of very low-birth-weight infants from 1980 to 1993.

OBJECTIVE: To determine changes in survival patterns among very low-birth-weight ( < 1500 g) infants between 1980 and 1993. METHODS: The records of 12,960 infants treated in nine perinatal intensive care centers in Florida were analyzed on the basis of survival (discharged alive from hospital) according to four independent variables: birth weight, race, sex, and transport status. Survival curves were generated using log linear regression techniques for each race by sex by transport status group. RESULTS: Race, sex, and transport status correlated significantly with survival: survival percentages were higher among black infants, female infants, and infants transported to the perinatal intensive care centers than among white infants, male infants, and those admitted initially to the tertiary care centers. After 1985, 95% of neonates with birth weights between 1200 and 1500 g survived. In addition, survival of 500- to 500-g transported black male infants increased from zero to near 80% during the 13-year period; that of 500- to 550-g inborn white female infants rose from 35% to 70%. CONCLUSIONS: These results illustrate the value of taking into account race, sex, and transport status in efforts to understand the contribution that neonatal intensive care of extremely low-birth-weight infants makes to the lowering of infant mortality, and of using multivariable statistical procedures to generate predicted survival probabilities for different subpopulations. These probabilities can be applied to (1) predicting survival for specific subgroups of extremely low-birth-weight infants, and (2) helping physicians develop clinical guidelines for extending care to infants at the threshold of viability.

The effect of low-frequency ultrasound on immersed pig lungs.

Acoustic models suggest that high-intensity, low-frequency ultrasound (US) at 21-31 kHz, could cause damage to divers' lungs. The purpose of the study was to investigate lung tissue changes secondary to water-borne low-frequency US produced by commonly used underwater acoustic beacons (pingers). Explanted pig lungs were immersed and exposed to four different modes of low-frequency US pinger transmission. In each trial, 5 pairs of lungs were exposed to sound and 5 pairs served as controls. One central and one peripheral section were taken from each lung and evaluated microscopically for location and extent of damage. When present, microhaemorrhages were primarily found in a patchy alveolar distribution, as well as in the septal and subpleural regions. Only rare focal microhaemorrhages could be found in the Control Group. The results demonstrate a potential hazard to the immersed lungs of large mammals on exposure to prolonged transmission by commercially available underwater pingers. The relevance of these findings to human exposure should be further evaluated.

Multifocal adenocarcinoma in situ with underlying carcinoid tumor of the gallbladder.

We describe a case of combined multifocal carcinoma in situ and carcinoid tumor of the gallbladder. Morphologic and immunohistochemical studies revealed two distinct neoplastic patterns without clear evidence of transition between the two processes.

Developmental intervention program for high-risk premature infants: effects on development and parent-infant interactions.

Developmental follow-up studies have documented that low birth weight infants are at high risk for mental and physical disabilities, despite recent advances in neonatal intensive care. Moreover, parent-infant bonding is hampered by the barriers created by technical equipment. This study evaluated a program of hospital and home-based developmental interventions designed to enhance the development of high-risk, preterm infants and the quality of communication between infants and their caregivers. Treatment and contrast groups consisted of 41 premature infants weighing less than 1800 g at birth. Treatment took a preventive approach, consisting of daily multimodal interventions in-hospital and twice-monthly interventions by child development specialists in the child's home, through 12 months adjusted age. Infants in the contrast group received traditional, remedially oriented care. The Bayley Scales of Infant Development were used to measure mental and psychomotor development, and the Greenspan-Lieberman Observations System (GLOS) was used to analyze the behavioral characteristics of infant-caregiver interactions. Developmental interventions had positive, significant effects on mental development and on the quality of caregiver-infant interactions. Changes in mental development were not independent of changes in the GLOS.

Promotion of cytoplasmic mislocalization of p27 by Helicobacter pylori in gastric cancer.

The cyclin-dependent kinase (CDK) inhibitor p27 has an important role in cell cycle regulation. Reduced expression of p27 is commonly associated with poor prognosis in many malignancies, including gastric cancer. Cytoplasmic p27 mislocalization may be an additional indicator of high-grade tumors and poor prognosis in cancer. As chronic infection by Helicobacter pylori is the most important risk factor for gastric cancer development, we evaluated the effects of H. pylori on p27 expression and localization in gastric cancer cells. Co-culture of gastric cells with H. pylori induced cytoplasmic p27 expression and reduced nuclear p27 expression in vitro. Cytoplasmic p27 expression was associated with and dependent upon phosphorylation of p27 at T157 and T198: wild-type p27 accumulated in the cytoplasm, but non-phosphorylatable mutants affecting T157 or T198 were nuclear in H. pylori-infected cells. These post-translational p27 changes were secondary to activation of cellular phosphoinositide-3 kinase (PI3K) and AKT signaling pathways, and dependent upon a functional H. pylori cag pathogenicity island. We investigated the clinical significance of cytoplasmic p27 mislocalization in 164 cases of resected gastric cancer in tissue microarrays. In 97 cases (59%), cytoplasmic p27 mislocalization was observed, and this was associated with increased mortality in multivariate analysis. These results show that H. pylori infection induces AKT/PI3K-mediated phosphorylation of p27 at T157 and T198 to cause cytoplasmic p27 mislocalization in gastric cancer, and that p27 mislocalization is an adverse prognostic feature in gastric cancer. This is the first demonstration of the translocation of a specific bacterial virulence factor that post-translationally regulates a host cell CDK inhibitor. This is of particular significance, because p27 has both tumor-suppressive and oncogenic activities, depending upon its subcellular localization. Cytoplasmic mislocalization of p27 induced by H. pylori may be an important mechanistic link between H. pylori infection and gastric carcinogenesis.