Molecular genetic, cardiac and neurodevelopmental findings in cases of prenatally diagnosed rhabdomyoma associated with tuberous sclerosis complex.

OBJECTIVE: Rhabdomyoma is the most common type of cardiac tumor in fetuses and is often associated with tuberous sclerosis complex (TSC) with neurologic sequelae. The purpose of this study was to investigate the cardiac and neurodevelopmental outcomes of fetal rhabdomyoma. METHODS: We reviewed the clinical characteristics of 23 cases of cardiac rhabdomyoma diagnosed prenatally by fetal echocardiography at the Asan Medical Center between January 1998 and December 2009. We also reviewed postnatal results of brain magnetic resonance imaging, echocardiography, renal ultrasound examination and molecular genetic analysis to confirm the presence of cardiac rhabdomyoma with or without TSC. RESULTS: Among 23 cases, outcome data were available for 17 (73.9%) and six cases (26.1%) were lost to follow-up. The survival rate was 100.0% (17/17). Among the 17 cases with outcome data, spontaneous tumor regression occurred in eight (47.1%), and no change in tumor size and number was observed in the remaining nine cases (52.9%). There was no evidence of long-term cardiac dysfunction caused by persisting rhabdomyomas, regardless of tumor size. TSC was found in nine patients (52.9%), of whom five (55.6%) showed neurodevelopmental morbidity. We identified mutations in one of the TSC1 or TSC2 genes in four of nine TSC infants whose parents allowed us to perform molecular genetic analysis. Three of these (75.0%) were found to have neurologic impairment. Seven (77.8%) of nine TSC cases were non-familial. CONCLUSIONS: The overall outcome of isolated cardiac rhabdomyoma appears to be favorable. We suggest that systematic postnatal evaluation of TSC be performed even in cases of cardiac rhabdomyoma without a family history of TSC. Molecular characterization of TSC1 and TSC2 might be helpful in predicting short- and long-term neurodevelopmental outcomes.

Protective effect of fetal pulmonary sequestration in two cases of postnatal manifestation of congenital diaphragmatic hernia.

We describe two cases of postnatally diagnosed congenital diaphragmatic hernia (CDH) combined with pulmonary sequestration, both of which were diagnosed as isolated pulmonary sequestration on prenatal ultrasound. In these cases, prenatal ultrasonography demonstrated only a hyperechoic mass on the left lower lung and the diaphragm seemed intact. In each case both lungs showed otherwise normal development throughout pregnancy. Pulmonary sequestration may serve as a 'protector', preventing herniation of abdominal contents into the thoracic cavity. The co-occurrence of CDH may be obscured by a lung mass, especially on the left lower lung, and therefore it is necessary to deliver these infants at a tertiary center and parents should be counseled about the possibility of postnatal CDH.

Evaluation of the usefulness of the fetal femur length with respect to gestational age to detect Down syndrome in Korean subjects.

OBJECTIVE: We investigated the usefulness of shortening of the fetal femur length (FL) to predict Down syndrome at different gestational ages in Korean subjects. METHODS: This study involved 110 Korean Down syndrome fetuses and 602 randomly selected euploid controls. The expected FL for any biparietal diameter (BPD) was calculated based on the control group data. Subjects were divided into four groups according to gestational age periods: 14-18 weeks; 19-23 weeks; 24-28 weeks and 29-36 weeks. The value of measured/expected FL ratio to predict Down syndrome was analyzed for each group. RESULTS: The values of FL for any BPD in Down syndrome patients were significantly different from those in the control group (p < 0.001). A low ratio of measured/expected FL increased the risk of fetal Down syndrome (p < 0.001) with a mean measured/expected FL in Down syndrome of 0.907 (SD 0.075). At a fixed false positive rate of 5%, the sensitivities of FL were lower than 32.8% (95% CI 0.705-0.915) in three second trimester groups, and 71.1% (95% CI 0.924-0.997) in the third trimester group. CONCLUSION: Short FL is a poor marker of Down syndrome in the second trimester in Korean subject. It may be used as a screening marker only in the third trimester.

Profile of volatile compounds during papaya juice fermentation by a mixed culture of Saccharomyces cerevisiae and Williopsis saturnus.

This study investigated the formation and utilization of volatile compounds during papaya juice fermentation by a mixed culture of Saccharomyces cerevisiae and Williopsis saturnus. Time-course papaya juice fermentations were carried out using pure cultures of S. cerevisiae var. bayanus R2 and W. saturnus var. mrakii NCYC2251 and a mixed culture of the two yeasts at a ratio of 1:1000 (R2:NCYC2251). Changes in S. cerevisiae cell population, Brix, sugar consumption and pH were similar in the mixed culture and in the S. cerevisiae monoculture. There was an early growth arrest of W. saturnus in the mixed culture fermentation. A range of volatile compounds were produced during fermentation including fatty acids, alcohols, aldehydes and esters and some volatile compounds including those initially present in the juice were utilized. The mixed culture fermentation of S. cerevisiae and W. saturnus benefited from the presence of both yeasts, with more esters being produced than the S. cerevisiae monoculture and more alcohols being formed than the W. saturnus monoculture. The study suggests that papaya juice fermentation with a mixed culture of S. cerevisiae and W. saturnus may be able to result in the formation of more complex aroma compounds and higher ethanol level than those using single yeasts.

TRPM8 Mediates Hyperosmotic Stimuli-Induced Nociception in Dental Afferents.

Hyperosmolar sweet foods onto exposed tooth dentin evoke sudden and intense dental pain, called dentin hypersensitivity. However, it remains unclear how hyperosmolar stimuli excite dental primary afferent (DPA) neurons and thereby lead to dentin hypersensitivity. This study elucidated whether TRPM8, which is well known as a cold temperature- or menthol-activated receptor, additionally mediates nociception in response to hyperosmolar stimuli in adult mouse DPA neurons, which are identified by a fluorescent retrograde tracer: DiI. Single-cell reverse transcription polymerase chain reaction revealed that TRPM8 was expressed in subsets of DPA neurons and that TRPM8 was highly colocalized with TRPV1 and Piezo2. Immunohistochemical analysis also confirmed TRPM8 expression in DPA neurons. By using Fura-2-based calcium imaging, application of hyperosmolar sucrose solutions elicited calcium transients in subsets of the trigeminal ganglion neurons, which was significantly abolished by a selective TRPM8 antagonist: N-(3-Aminopropyl)-2-[(3-methylphenyl)methoxy]-N-(2-thienylmethyl)benzamide (AMTB) hydrochloride. When we further examined changes of c-fos expression (a neuronal activation marker) in the spinal trigeminal nucleus after hyperosmolar stimulation onto exposed tooth dentin, c-fos mRNA and protein expression were increased and were also significantly reduced by AMTB, especially in the spinal trigeminal interpolaris-caudalis transition zone (Vi/Vc). Taken together, our results provide strong evidence that TRPM8 expressed in DPA neurons might mediate dental pain as a hyperosmosensor in adult mice.

Diagnostic value of the matrix metalloproteinase-8 rapid test for detecting microbial invasion of the amniotic cavity.

The purpose of this paper was to compare the MMP-8 PTD Check (MPC) test with other indirect tests for detecting microbial invasion of the amniotic cavity (MIAC). Amniotic fluid (AF) was analyzed in 155 women for white blood cell (WBC) count, glucose concentration, and an MPC test and evaluated for MIAC using cultures for aerobic/anaerobic bacteria and mycoplasmas and polymerase chain reaction (PCR) of chlamydia. The median AF glucose concentration was lower and the median AF WBC count was higher in women with MIAC than in women without MIAC (p < 0.01 and p < 0.001, respectively). Also, the positive rate of the MPC test was higher in women with MIAC than in women without MIAC (p < 0.001). The sensitivities of AF glucose concentration, AF WBC count, and the MPC test for the detection of MIAC were 58.6%, 75.9%, and 86.2%, respectively. The specificities for the detection of MIAC were 76.2%, 80.2%, and 74.6%, respectively. We conclude that the MPC test is a rapid, easily performed, and accurate indirect method for detecting MIAC.

TRPM7 Mediates Mechanosensitivity in Adult Rat Odontoblasts.

Odontoblasts, with their strategic arrangement along the outermost compartment of the dentin-pulp complex, have been suggested to have sensory function. In addition to their primary role in dentin formation, growing evidence shows that odontoblasts are capable of sensing mechanical stimulation. Previously, we found that most odontoblasts express TRPM7, the nonselective mechanosensitive ion channel reported to be critical in Mg2+ homeostasis and dentin mineralization. In line with this finding, we sought to elucidate the functional expression of TRPM7 in odontoblasts by pharmacological approaches and mechanical stimulation. Naltriben, a TRPM7-specific agonist, induced calcium transient in the majority of odontoblasts, which was blocked by TRPM7 blockers such as extracellular Mg2+ and FTY720 in a dose-dependent manner. Mechanical stretch of the odontoblastic membrane with hypotonic solution also induced calcium transient, which was blocked by Gd3+, a nonselective mechanosensitive channel blocker. Calcium transient induced by hypotonic solution was also blocked by high extracellular Mg2+ or FTY720. When TRPM7-mediated calcium transients in odontoblasts were analyzed on the subcellular level, remarkably larger transients were detected in the distal odontoblastic process compared with the soma, which was further verified with comparable immunocytochemical analysis. Our results demonstrate that TRPM7 in odontoblasts can serve as a mechanical sensor, with its distribution to facilitate intracellular Ca2+ signaling in the odontoblastic process. These findings suggest TRPM7 as a mechanical transducer in odontoblasts to mediate intracellular calcium dynamics under diverse pathophysiological conditions of the dentin.

Piezo2 Expression in Mechanosensitive Dental Primary Afferent Neurons.

Mechanosensitive ion channels have been suggested to be expressed in dental primary afferent (DPA) neurons to transduce the movement of dentinal fluid since the proposal of hydrodynamic theory. Piezo2, a mechanosensitive, rapidly inactivating (RI) ion channel, has been recently identified in dorsal root ganglion (DRG) neurons to mediate tactile transduction. Here, we examined the expression of Piezo2 in DPA neurons by in situ hybridization, single-cell reverse transcriptase polymerase chain reaction, and whole-cell patch-clamp recordings. DPA neurons with Piezo2 messenger RNA (mRNA) or Piezo2-like currents were further characterized based on their neurochemical and electrophysiological properties. Piezo2 mRNA was found mostly in medium- to large-sized DPA neurons, with the majority of these neurons also positive for Nav1.8, CGRP, and NF200, whereas only a minor population was positive for IB4 and peripherin. Whole-cell patch-clamp recordings revealed Piezo2-like, RI currents evoked by mechanical stimulation in a subpopulation of DPA neurons. RI currents were pharmacologically blocked by ruthenium red, a compound known to block Piezo2, and were also reduced by small interfering RNA-mediated Piezo2 knockdown. Piezo2-like currents were observed almost exclusively in IB4-negative DPA neurons, with the current amplitude larger in capsaicin-insensitive DPA neurons than the capsaicin-sensitive population. Our findings show that subpopulation of DPA neurons is indeed mechanically sensitive. Within this subpopulation of mechanosensitive DPA neurons, we have identified the Piezo2 ion channel as a potential transducer for mechanical stimuli, contributing to RI inward currents. Piezo2-positive DPA neurons were characterized as medium- to large-sized neurons with myelinated A-fibers, containing nociceptive peptidergic neurotransmitters.

Drug promotion and labeling in developing countries: an update.

Recent studies of drug promotion and labeling in Third World countries since 1972 have observed important changes in the policies of multinational corporations. Earlier studies found that multinational and national drug companies often grossly exaggerated the indications for the drugs and minimized or ignored the hazards. In the latest study, initiated in 1987, considerable improvement in promotional practices of the multinational corporations has been found, but little or no improvement on the part of the national companies. As a result, physicians are still provided with grossly exaggerated claims and the hazards of prescription drugs are covered up or glossed over. A very serious problem--the marketing of fraudulent drug products--has been identified in a number of Third World countries. Drug products are shaped and colored to resemble the original multinational company product, but contain only a small percentage of the active ingredient stated on the label, or perhaps none at all. In Indonesia fraudulent drug products may represent 20-30% of all drug products in the market. Similar fraudulent products have been reported in Brazil, Thailand, Bangladesh and Malaysia.

Thyroid hormone regulation of N-methyl-D-aspartic acid receptor subunit mRNA expression in adult brain.

Thyroid hormone is an essential modulator of brain development, but little is known about its actions in the adult brain. Hypothyroidism is associated with gene expression changes in both central and peripheral nervous tissue. Functional consequences of adult-onset hypothyroidism include an inability to produce long-term potentiation in rat hippocampus and impaired learning and memory in both rats and man. Long-term potentiation is a form of learning that is dependent on functional N-methyl-d-aspartic acid (NMDA)-preferring ionotropic glutamate receptors. This work examines the expression of ionotropic glutamate receptor subunit mRNA following surgical thyroidectomy with or without thyroid hormone replacement. In situ hybridization histochemistry was used to determine the mRNA levels of the NMDA receptor subunits NR1, NR2A, NR2B, the AMPA receptor subunit GluR1, and the kainate receptor subunit KA2. Reducing circulating concentrations of thyroid hormone by surgical removal of the thyroid gland 2 weeks before sacrifice decreased the expression of NR1 mRNA exclusively in the hippocampus. Conversely, hyperthyroidism selectively reduced NR2B mRNA expression in the dorsal hippocampus. Altering thyroid hormone status had no effect on the expression of KA2 or GluR1 subunit mRNA. The regulation of expression of NR1 and NR2B mRNA by thyroid hormone is a novel mechanism for explaining the relationship between thyroid hormone and cognitive function.

Socioeconomic status and health. Policy implications in research, public health, and medical care.

The role of public policy in research, public health, and medical care is discussed as well as the extent to which public policy has been informed by increased knowledge about the relationship between SES and health and to what extent policy has affected SES-related health disparities. Observations on current healthcare policy and recommendations for the future are offered.

Health system reform and the generalist physician.

The quality of primary care services is central to reforming the health care system of the United States. The well-trained generalist is essential in a delivery system that emphasizes high-quality, cost-effective care. Several analyses estimate that within a few years the United States will have 100,000-150,000 too many specialists, and some estimates show a shortage of perhaps 35,000 generalists. Residents and residency programs in nongeneralist areas continue to increase, and two-thirds of graduates enter careers as specialists. Academic medical centers must assume major responsibility for changing their programs to produce the types of practitioners that U.S. society needs. Among the changes recommended or directed by advisory bodies and professional organizations are establishing a workforce commission to set long-term goals, limiting the number of first-year residency positions and allocating them to generalist and nongeneralist specialties, establishing a national payment system to support residency training, setting up transition payments to teaching hospitals that reduce their number of residency positions, and initiatives to graduate more minority and generalist physicians, improve geographic distribution, and expand the capacity for primary-care teaching.

Case management of persons with acquired immunodeficiency syndrome in San Francisco.

The acquired immunodeficiency syndrome (AIDS) epidemic represents a growing challenge for the health care system and for case management models applied to persons with AIDS. The experience of San Francisco highlights some of the issues involved in developing a case management system appropriate to the needs of persons with AIDS, as well as providers, and payers. Dramatic growth in the size and complexity of the AIDS caseload and the involvement of public, health maintenance organization, and community providers has required the increasing formalization and centralization of case management roles. Persistent questions about the definition and goals of case management complicate development of these services.

Nutrition policy--from neglect and uncertainty to debate and action.

Until recent years, nutrition has received little attention in U.S. agriculture, food, and health policies. This circumstance is changing. In the late sixties and early seventies, reports of hunger and malnutrition sparked public reaction and a shift in policy. The White House Conference on Food, Nutrition and Health in 1971 prompted the Senate select Committee on Nutrition and Human Needs to address itself to this problem, with the result that the Food Stamp, child nutrition, WIC, and Nutrition for the Elderly programs were initiated or expanded. Then, in the mid-seventies, the Select Committee turned its attention to broader issues of nutrition and health and declared that the goal of any food system is the maintenance and improvement of nutritional health of the population. This objective emerged as public policy in the Food and Agriculture Act of 1977. As the Select Committee continued its work, problems of overnutrition became more apparent. The culmination of its studies was the issuance early in 1977 of the "Dietary Goals for the United States," designed to improve the nutrition and reduce health problems of the population. To that same end, the Select Committee has also made recommendations regarding food labeling and nutrition education.

HLA antigens in childhood onset schizophrenia.

Evidence of immune system abnormalities in adult schizophrenia has prompted examination of the human leukocyte antigen (HLA) system. Childhood onset schizophrenia offers a unique opportunity to test neurodevelopmental hypotheses of schizophrenia, including those which implicate components of the immune system. In the present study, class I and II HLA antigens were typed using sequence-specific primers and the polymerase chain reaction in 28 childhood onset schizophrenics and 51 ethnically matched healthy subjects. Groups were compared for frequencies of HLA antigens reported to be associated with schizophrenia and/or autoimmune disorders. We hypothesized that antigen frequencies would differ between schizophrenic and healthy children, suggesting that some dimension of the neurodevelopmental disturbance experienced by these children may be mediated by subtle abnormalities of immune function. There were no significant differences between schizophrenic and healthy subjects in the frequency of any antigen tested. These findings do not support HLA-associated pathology in childhood onset schizophrenia.

Evaluation of the Heart To Heart Project: lessons from a community-based chronic disease prevention project.

PURPOSE: To present an evaluation of a 5-year, community-based, chronic disease prevention project managed by a state health department to determine whether the department could replicate similar previous projects that had received more funding and other resources. DESIGN: The evaluation used a matched comparison design and a review of archive and interview data. SETTING: Florence, South Carolina (population: 56,240). SUBJECTS: A random sample of 1642 persons in Florence (and 1551 in the comparison) who responded to a risk factor questionnaire and underwent a physical assessment; 70.7% of baseline subjects participated in the postintervention. Forty key persons were interviewed concerning project effectiveness. INTERVENTIONS BY PROJECT: Walk-a-thons, a speakers' bureau, media messages, restaurant food labeling, and cooking seminars. More than 31,000 participants were involved in 585 activities. MEASURES: Questionnaires focused on hypertension, obesity, high cholesterol, smoking, and exercise. Physical assessments determined lipid, lipoprotein, apolipoprotein, and blood pressure levels. Analysis of covariance was used for baseline and postintervention comparisons. Content analysis was used on archive and interview data. RESULTS: The project had a slightly favorable intervention effect on cholesterol and smoking, but failed to have an effect on other risk factors for cardiovascular disease. The project influenced community awareness, enlisted influential community members, and fostered linkages among local health services. CONCLUSIONS: Health departments can be instrumental in community risk reduction programming; however, they may not replicate projects having greater resources.

Key components of a statewide Healthy Communities effort.

The Healthy Cities/Healthy Communities movement is in its second decade. Examples of both successful and unsuccessful Healthy Communities efforts can be found in large and small communities across the country. What are the key components of a successful effort? Movement leaders from California, Massachusetts, Pennsylvania, and South Carolina as well as the Centers for Disease Control (CDC) and Prevention have contributed their collective experience to identifying the key components of a statewide Healthy Communities effort. Assessing the degree to which a state has these key components in place can help the state take steps to assure support for Healthy Communities.

Assets-oriented community assessment.

Determining how to promote community health requires that community health workers first assess where the community stands. The authors maintain that Healthy Communities initiatives are better served by assets-oriented assessment methods than by standard "problem-focused" or "needs-based" approaches. An assets orientation allows community members to identify, support, and mobilize existing community resources to create a shared vision of change, and encourages greater creativity when community members do address problems and obstacles.

The federal response to the AIDS epidemic.

The response of the U.S. government to the AIDS epidemic is reviewed within the context of health policy making in the U.S.A. in general and the reduced role of the federal government in domestic social programs in particular. This review involves multiple levels of government, the relationship of government to the private sector, the diffusion of authority within a federal system, the long delays in policy implementation because of the absence of mechanisms to deal with emergency situations, the tendency to fund the response to AIDS from reallocation of appropriated funds, thereby creating financial distress for existing programs. The federal response to AIDS is considered uncoordinated, insufficient and inadequate in particular with respect to the support of public health education and the financing of health care for AIDS patients. These are needed while a vaccine may still be years away.