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Angiotensinogen gene-inducible enhancer-binding protein 1, a member of a new family of large nuclear proteins that recognize nuclear factor kappa B-binding sites through a zinc finger motif.

Transcriptional activation of the rat angiotensinogen gene during the acute-phase response is dependent on a previously characterized acute-phase response element (APRE) that binds at least two types of nuclear proteins: a cytokine-inducible activity indistinguishable from nuclear factor kappa-B (NF kappa B) and a family of C/EBP-like proteins. We screened a rat liver cDNA expression library with a labeled APRE DNA probe and isolated a single clone that encodes a sequence-specific APRE-binding protein. This new protein, the angiotensinogen gene-inducible enhancer-binding protein 1 (AGIE-BP1), is encoded by a large continuous open reading frame and contains a zinc finger motif virtually identical to the DNA-binding domain of a recently described human protein, MBP-1/PRDII-BF1, and a homologous mouse protein, alpha A-CRYBP1. Outside the binding domain, the sequences diverged considerably. Southern blot analysis indicated that AGIE-BP1 and alpha A-CRYBP1 are encoded by separate genes, thus defining a new family of DNA-binding proteins. Electrophoretic mobility shift assays, methylation interference, and DNase I footprint protection assays with the bacterially expressed DNA-binding domain of AGIE-BP1 demonstrated a binding specificity indistinguishable from that of purified NF kappa B. Antiserum raised against the bacterially expressed DNA-binding domain of AGIE-BP1 detected on immunoblots of cellular proteins a large (greater than 250-kDa) nuclear protein. Northern (RNA) blot analysis of RNAs from different rat tissues and cell lines indicated different levels of expression of the large (greater than 10-kb) AGIE-BP1 transcript in different tissues. The potential role of AGIE-BP1 in the regulation of gene expression is discussed.

Amino Acid Sequence↗

Medical genetics in Paraguay.

Paraguay is a developing country with low levels of health coverage, with 81% of the population without health insurance, a proportion that reaches 98.1% among the poor, 93% among the rural population and 91.7% among the mainly Guarani-speaking population. The infant mortality rate is 19.4 per 1,000, although there is gross under-reporting. Maternal mortality rate is alarmingly high at 110.9 per 100,000 livebirths, reaching 420.5 in rural areas. There are only two clinical geneticists and four biochemists trained in human genetics, and virtually all genetic services in the country are concentrated in the 'Instituto de Investigaciones en Ciencias de la Salud' (IICS) from the National University. The teaching of medical genetics in medical schools is included in physiology and pathology courses, while at the postgraduate level, training in medical genetics is limited to pediatrics and gynecology. In 1999, a pilot newborn screening program was initiated to determine the frequency of congenital hypothyroidism and phenylketonuria and to provide early treatment for affected babies. Another pilot project recently launched by the Ministry of Health is the Program for the Prevention of Neural Tube Defects, mandating folic acid fortification of flour, but as of the end of 2003 it had not been implemented. Paraguay lacks adequate resources to provide accurate diagnoses and treatment of genetic conditions.

Congenital Abnormalities↗

[Three-dimensional medical images for upper gastrointestinal lesions].

Virtual endoscopy (VE), three-dimensional endoscopic ultrasonography(3-DEUS) and three-dimensional ultrasonography(3D-US) have been utilized for three-dimensional medical images of upper gastrointestinal lesions. VE images are similar to endoscopic images. But because the detection rate of early gastric cancers is from 39.6% to 78%, it is difficult to use for the screening of gastric lesions now. 3-DEUS has been used for assessment of depth of cancerous invasion or treatment for esophageal and gastric cancer. Accuracy of cancerous invasion has been improved by 3-DEUS because both radial images and lineal images are able to be observed simultaneously. One of benefit in 3D-US is not invasive. These methods are thought to be improved and to be popularized.

Endosonography↗

Applied nanotechnology for the management of breakthrough cancer pain.

Pain, often considered the 5th vital sign, plays a significant role in the pathophysiology of cancer. Often addressed as an afterthought, untreated or under-treated cancer-related pain can have deleterious effects on a patient's physical and psychological well-being. Additionally, patients with breakthrough cancer pain tend to have more intense and more frequent background pain than patients without breakthrough pain. Currently, only oral transmucosal fentanyl citrate (OTFC) has reached the market for the treatment of cancer-related breakthrough pain. OTFC is an excellent first step in addressing the unmet need for symptomatic relief of breakthrough cancer pain; however, there is much room for improvement. Nanoscale science and engineering advancements have the long-term potential to bring revolutionary changes in society and across virtually all physical, biological and engineering disciplines, particularly medicine. Nanotechnology offers the potential to address multiple, major unmet problems in the diagnosis, treatment and symptom management of a large variety of diseases and conditions, including cancer. Nanotechnology can engender transformational progress in crucial aspects of the fight against cancer, spanning the continuum that ranges from prevention, to early detection, screening and monitoring, to innovative diagnostics and therapeutic modalities in the era of patient-centered, molecular medicine. Specifically, the authors will discuss their current research in the field of biomedical nanotechnology and its application to the management of breakthrough cancer pain.

Animals↗

Humoral immune response against melanoma antigens induced by vaccination with cytokine gene-modified autologous tumor cells.

Although the existence of a humoral response against tumor-associated antigens is well appreciated, a systematic analysis of its possible induction by the tumor remains missing. We compared the specific IgG response of Stage IV melanoma patients during vaccination. Patients had been treated within 2 clinical trials with autologous tumor cells gene-modified for IL-7 or IL-12. A panel of 27 tumor-associated antigens (HD-MM-01 to HD-MM-27) was isolated by a SEREX screening of a testis cDNA library using a pool of 5 sera from patients after vaccination. All antigens were retested with individual sera of 12 patients both pre- and post-vaccination. A serological response was induced during vaccination against 18 antigens. Remarkably, induction was detected only in patients included in the screening pool. The low overlap between sero-reactivity of the 12 patients suggested a very individualized immunological reaction. Two of 5 sera included in the screening pool exhibited a high frequency of induced humoral responses. The same patients had been shown to have a high Karnovsky index and had generated lytic cytotoxic T cells against the tumor. Besides 2 known cancer-germline genes (SCP-1 and PLU-1), the other isolated antigens were expressed in a non-tumor-specific fashion as analyzed by virtual Northern blot or RT-PCR. The properties of homologues to several of the identified tumor-antigens, especially PLU-1, SCP-1, DNEL2, CLOCK, and PIASx-alpha, suggest further investigation of their possible function in malignant melanoma. We conclude that a strong humoral response against tumor-associated antigens is inducible by tumor cells and that this response is very individual.

Antibodies, Neoplasm↗

Activity spectra of Bacillus thuringiensis delta-endotoxins against eight insect cell lines.

Eight continuous insect cell lines were tested for susceptibility to the delta-endotoxins of several lepidopteran-active strains and cloned-gene products of Bacillus thuringiensis. The assays were performed on cells suspended in agarose gel, which allowed the toxins activated at pH 10.5 to be applied directly in a high-pH buffer without causing solvent toxicity to the cells. The responses of the cell lines to the various toxins produced activity spectra that were used to identify functionally similar and dissimilar toxin proteins. IPRI-CF-1 and FPMI-MS-5, derived from neonate larvae of Choristoneura fumiferana and Manduca sexta, respectively, exhibited the greatest sensitivity to the toxins tested, whereas B. thuringiensis subsp. entomocidus had the broadest in vitro host range. Analysis of activity spectra led to the identification of the particular Cry protein that was responsible for the broad toxicity of this subspecies and demonstrated a distinct difference in toxin composition between two strains of subsp. sotto. The identical spectra observed for subsp. kurstaki HD-1 and NRD-12 is consistent with insect bioassay data obtained previously by other workers and supports the conclusion that there is virtually no difference in activity between these two strains. The in vitro assay system, referred to as the "lawn assay" and used to test B. thuringiensis activated toxins against insect cell lines, is particularly useful in mode-of-action studies and as a rapid, preliminary test for the presence of specific cytolytic proteins, rather than as a method for screening toxins of wild-type strains for insecticidal activity. The response of cells in vitro to B. thuringiensis toxins is often very different from that of the insect from which the cells were derived.

Animals↗

Bias to experience approaching motion in a three-dimensional virtual environment.

We used two-frame apparent motion in a three-dimensional virtual environment to test whether observers had biases to experience approaching or receding motion in depth. Observers viewed a tunnel of tiles receding in depth, that moved ambiguously either toward or away from them. We found that observers exhibited biases to experience approaching motion. The strengths of the biases were decreased when stimuli pointed away, but size of the display screen had no effect. Tests with diamond-shaped tiles that varied in the degree of pointing asymmetry resulted in a linear trend in which the bias was strongest for stimuli pointing toward the viewer, and weakest for stimuli pointing away. We show that the overall bias to experience approaching motion is consistent with a computational strategy of matching corresponding features between adjacent foreshortened stimuli in consecutive visual frames. We conclude that there are both adaptational and geometric reasons to favor the experience of approaching motion.

Adaptation, Physiological↗

MIST VR. A laparoscopic surgery procedures trainer and evaluator.

The key bimanual instrument tasks involved in laparoscopic surgery have been abstracted for use in a virtual reality surgical skills evaluator and trainer. The trainer uses two laparoscopic instruments mounted on a frame with position sensors which provide instrument movement data that is translated into interactive real time graphics on a PC (P133, 16 Mb RAM, graphics acceleration card). An accurately scaled operating volume of 10 cm3 is represented by a 3D cube on the computer screen. "Camera" position and size of target objects can be varied for different skill levels. Targets appear randomly within the operating volume according to the skill task and can be grasped and manipulated with the instruments. Accuracy and errors during the tasks and time to completion are logged. Mist VR has tutorial, training, examination, analysis and configuration modes. Six tasks have been selected and include combinations of instrument approach, target acquisition, target manipulation and placement, transfer between instruments, target contact with optional diathermy, and controlled instrument withdrawal/replacement. Tasks can be configured for varying degrees of difficulty and the configurations saved to a library for reuse. Specific task configurations can be assigned to individual students. In the examination mode the supervisor can select the tasks, repetitions and order and save to a specific file for that trainee. Progress can be assessed and there is the option for playback of the training session or examination. Data analyses permit overall, including task, and right or left hand performances to be quantified. Mist VR represents a significant advance over the subjective assessment of training performances with existing "plastic box" basic trainers.

Computer-Assisted Instruction↗

[Combined alpha and beta thalassemia in a Chinese family in The Netherlands].

In a Chinese family living in The Netherlands alpha 0- and beta-thalassaemia occur singly and in combined form. All members of the family are moderately anaemic and show the characteristic haematological abnormalities of thalassaemia carriers. The nature of the alpha 0-thalassaemia defect was shown at the molecular level to be a deletion of the South East Asian type, which removes about 20 kb of DNA spanning both alpha genes in cis. The chromosome carrying the beta-thalassaemia mutation was identified using RFLPs (restriction enzyme fragment length polymorphisms). The combined heterozygosity for alpha 0- and beta-thalassaemia results in a phenotype virtually indistinguishable from heterozygous beta-thalassaemia, except for the almost balanced globin chain synthesis.

Adolescent↗

Virtual colonography: identification and differentiation of colorectal lesions using multi-detector computed tomography.

OBJECTIVE: Early detection of precancerous or malignant lesions may be decisive for prognosis of patients with colorectal cancer. In this prospective feasibility study, multi-detector spiral computed tomography (CT) colonography was compared with conventional colonoscopy for the detection of colorectal polyps. MATERIAL AND METHODS: Seventy-eight patients underwent CT colonography (standard colonoscopy preparation, distension with room air, prone and supine position) immediately before colonoscopy. Sixty-five (83%) were asymptomatic screening subjects, while the rest had symptoms suggestive of colorectal disease. Presence, location, and size of lesions were prospectively assessed. Sensitivity, specificity, and positive and negative predictive values of CT colonography were calculated using conventional colonoscopy as the reference standard. RESULTS: Conventional colonoscopy was normal in 52 patients. In 26 patients a total of 49 polyps and 3 carcinomas were identified. All three carcinomas and 39 polyps (80%) were identified by CT colonography. Seven of 7 polyps > or = 10 mm (100%), 13 of 16 polyps of 6 to 9 mm (81%), and 19 of 26 polyps < or = 5 mm (73%) in diameter were identified. Fourteen false-positive findings (10 of which were < or = 5 mm in diameter) were related to 8 patients (specificity at the patient level was 86%). In 10 patients, a total of 10 polyps were missed by CT colonography, 7 of which were < or = 5 mm in diameter. CONCLUSIONS: In this feasibility study, multi-detector spiral CT colonography allows accurate detection of polyps > 5 mm in diameter, but at the expense of low specificity in the small size range.

Colonic Polyps↗

Systematic screening for mutations in the glycine receptor alpha2 subunit gene (GLRA2) in patients with schizophrenia and other psychiatric diseases.

The glycine receptor, which is a member of the ligand-gated ion channel superfamily, mediates synaptic inhibition in the spinal cord and other brain regions. This superfamily has been implicated in the pathogenesis of schizophrenia and other psychiatric diseases. The complete coding sequence and splice junctions of the GLRA2 gene were scanned by DOVAM-S, a form of SSCP analysis with sufficient redundancy to detect virtually all mutations. Those analyses were performed in 113 patients with schizophrenia, and in pilot studies of patients with bipolar illness, alcoholism, puerperal psychosis, autism, and attention-deficit hyperactivity disorder (533 kb total scanned sequences). We detected three sequence changes in the coding region, all resulting in silent mutations: C894T in exon 5, C1134T in exon 7, and C1476T in exon 9. These do not alter the structure or the expression of the protein. It is unlikely that mutations in the coding region and splice junction of GLRA2 gene are associated with schizophrenia and other psychiatric diseases.

Alcoholism↗

A longitudinal study of the prevalence of voice disorders in children from a rural school division.

In a mass screening of children ages 6-10 in a rural school division, 203 children were identified as showing a voice deviation. One year later a retesting of 178 of these children showed that 39.9% still showed a voice disorder. Four years later 50 of these children were still available in the same school system; 38% of them still showed a voice disorder. Virtually none of these children were referred to the otolaryngologist for an ENT evaluation or to the speech-language pathologist for voice rehabilitation. Results indicate that, for many of these children, the voice disorders do not "clear up" through maturation alone.

Child↗

Ophthalmologic disorders in minority populations.

Race- and ethnicity-related differences in prevalence of a number ofophthalmologic disorders have been documented. More importantly, blackand Hispanic Americans share a disproportionate share of morbidity, asmeasured by visual impairment and blindness, when compared with whiteAmericans. The reasons for this health disparity are complex andmultifactorial. If the unequal, individual, and societal burden of avoidable vision lossamong black and Hispanic Americans is to be decreased, it is essential tounderstand the apparent barriers to accessing timely and appropriateophthalmologic monitoring and care for these minority populations. Forthose who do gain access to ophthalmologic care, it is important tounderstand better the determinants leading to different treatment of blackand Hispanic Americans compared with white Americans. Opportunities for decreasing vision-related morbidity caused by cataract,diabetic retinopathy, and glaucoma for these minority groups clearly exist. Strategies for each of these ophthalmologic disorders may differ. Cataract isa reversible cause of visual impairment and removal of cataract improvesquality of life. Cataract surgery should be offered to all who can potentiallybenefit from this treatment. Earlier diagnosis, before the disease hasprogressed to loss of vision, should be a goal in both glaucoma and diabeticretinopathy. Strategies for screening high-risk groups may be particularlyrelevant in this regard. Additionally, with diabetic retinopathy, improvedmanagement of contributing risk factors, such as blood glucose control andblood pressure control, is important. Asian Americans are increasingly becoming a sizable minority group inthe United States. It is projected that by 2070, the Asian population willreach 11% of the total population of the United States. Virtually all of thepopulation-based data relating to ophthalmologic disorders in Asians havebeen performed in Asia. The reported relative proportion of PACG versusPOAG, however, among some Asian populations and of normal-tensionglaucoma versus high-tension glaucoma among the Japanese seems to applyto the United States Asian population. This assertion is based onwidespread clinical impression and analysis of Medicare claims data [56]. Understanding the differences is important for optimal treatment of theseminority populations as the proportion of Asians in the United Statescontinues to grow. The common denominator in all of these diseases is the role of thephysician and patient. Educational programs aimed at the physician tofacilitate cultural competence and at the patient to increase level of knowledgeabout their disease are appropriate and enthusiastically endorsed.

Eye Diseases↗

Rhinoscopy.

This article presents a diagnostic protocol for nasal disease evaluation that provides consistent success in diagnosis of chronic cases. The protocol includes history, physical examination, blood clinical pathology assessment, radiographs, culture and sensitivity tests, rhinoscopy, histopathology, fungal serology, and allergy screening. The sequence of diagnostic procedures and their techniques are discussed, and rhinoscopic appearance of the normal nasal cavity is presented, along with findings of commonly seen nasal diseases, including neoplasia, mycotic rhinitis and sinusitis, foreign body obstruction, dental disease, allergic rhinitis, bacterial rhinitis, and idiopathic rhinitis. Rhinoscopy is a highly effective diagnostic technique with minimal morbidity and mortality that has virtually eliminated the need for exploratory rhinotomy.

Animals↗

NSCL-1 and NSCL-2 synergistically determine the fate of GnRH-1 neurons and control necdin gene expression.

To study the role of the bHLH genes NSCL-1 and NSCL-2 in the development of GnRH-1 neurons, we have generated compound mutant mice. Mutant animals die at birth and show a virtually complete absence of GnRH-1 neurons in the posterior parts of the brain at E18.5 and an aberrant morphology of the remaining GnRH-1 neurons in the anterior parts of the brain indicating that NSCL-1 and NSCL-2 might concomitantly control differentiation/migration of GnRH-1 neurons in a cell autonomous manner. To gain further insights into this process, we screened for NSCL target genes using DNA array hybridization and detected necdin, which is deleted in the human Prader-Willi syndrome phenotypically resembling the NSCL-2 mutation. Using chromatin immunoprecipitation and site-directed mutagenesis of the necdin promoter, we demonstrate that NSCLs together with additional cofactors directly control transcription of the necdin gene. NSCL-dependent control of necdin expression might be instrumental for proper neuronal cell differentiation and enable GnRH-1 neurons to migrate.

Animals↗

Sexually transmissible diseases and travel.

Sexually transmissible diseases (STDs) continue to be the most common notifiable infectious conditions worldwide. Their unacceptably high incidence is underlined by the recent emergence of a (presently) incurable and lethal STD, human immunodeficiency virus (HIV) infection, which merits its description as a pandemic, and with which other STDs interact in an epidemiological synergy. Certain travellers, by virtue of their behavioural interactions with 'core-groups' of efficient transmitters, may have a high relative risk of acquisition of an STD. This risk can be virtually eliminated by avoiding penetrative sexual intercourse with casual partners, especially injecting drug users and persons who have had multiple sexual partners (particularly prostitutes), or reduced by the use of condoms. The risk of parenteral exposure can be reduced by avoiding parenteral drug use and behaviour that is likely to lead to injury and by seeking facilities with adequate capabilities to screen blood donors and to sterilize instruments.

Female↗

Evaluation of intravascular hemolysis by haptoglobin administration after prosthetic valve replacement.

Although the measurement of serum haptoglobin (S-Hp) is of great use for evaluation of intravascular hemolysis, it is not applicable in patients with mechanical prosthetic valves because S-Hp is virtually absent. We administered haptoglobin preparation to 10 patients with Björk-Shiley mitral prosthetic valves and 10 patients with the same aortic prosthetic valves. Serum haptoglobin levels were measured periodically afterwards. The maximum haptoglobin levels (Hp (max)), serum, haptoglobin reducing rate ((Hp-delta Hp)/delta t) and expected haptoglobin disappearing time (hours) were obtained from the subsequent samples. The screening studies which were performed at the same time were not predictors of difference in the 2 groups. On the other hand, serum haptoglobin reducing rate and expected haptoglobin disappearing time indicated that hemolysis is higher in patients with an aortic prosthetic valve than with a mitral prosthetic valve. This haptoglobin administration test seems to be useful for the comparative examination of the intravascular hemolysis caused by the difference in the position of the prosthetic valve.

Adult↗

Inverse relationship between trk expression and N-myc amplification in human neuroblastomas.

We examined the expression of the trk protooncogene in a series of 82 neuroblastomas to determine its relationship to N-myc amplification and expression, disease stage, patient age, and survival. We found that virtually all stage I, II, and IV-S patients had moderate to high levels of trk expression, whereas most advanced stage neuroblastomas had low or absent levels. All but one tumor with N-myc amplification had low or absent trk expression, and the one exception was regressing at the time it was resected. Conversely, all neuroblastomas identified by mass screening had moderate to high expression of trk, and all these patients are surviving. Thus, trk expression was associated with an absence of N-myc amplification, lower disease stage, lower patient age, and favorable outcome. Tumors with high trk expression may be more likely to differentiate, regress spontaneously, or respond well to therapy.

Gene Amplification↗