The effect of a therapeutic trial of high-dose rabeprazole on symptom response of patients with non-cardiac chest pain: a randomized, double-blind, placebo-controlled, crossover trial.

BACKGROUND: Therapeutic trials with high-dose lansoprazole and omeprazole have been shown to be sensitive clinical tools for diagnosing patients with gastro-oesophageal reflux disease-related non-cardiac chest pain. AIM: To determine the clinical value of a therapeutic trial of high-dose rabeprazole over 7 days in detecting patients with gastro-oesophageal reflux disease-related non-cardiac chest pain. METHODS: Double-blind, randomized, placebo-controlled, crossover study. Patients referred by a cardiologist after a comprehensive cardiac work-up were enrolled into the study. Oesophageal mucosal disease was determined by upper endoscopy and 24-h oesophageal pH monitoring assessed acid exposure. Patients were then randomized to either placebo or rabeprazole 20 mg am and 20 mg pm for 7 days. After a washout period of 1 week, patients crossed over to the other arm of the study for an additional 7 days. Patients completed a daily diary assessing severity and frequency of chest pain throughout the baseline, treatment and wash-out periods. The rabeprazole therapeutic trial was considered as a diagnostic tool, if chest pain scores improved > or =50% from baseline. RESULTS: Of the 35 patients enrolled, 16 (46%) were diagnosed as gastro-oesophageal reflux disease-positive and 19 (54%) as gastro-oesophageal reflux disease-negative. Of the gastro-oesophageal reflux disease-positive patients, 12 of 16 (75%) had a significant symptom improvement on rabeprazole when compared with 3 of 16 (19%) on placebo (P = 0.029). Of the gastro-oesophageal reflux disease-negative group, only two of 19 (11%) improved significantly on the medication and four of 19 (21%) on placebo (P = 0.6599). The calculated sensitivity and specificity of the rabeprazole therapeutic trial was 75% and 90%, respectively. CONCLUSIONS: A rabeprazole therapeutic trial is highly sensitive and specific for diagnosing gastro-oesophageal reflux disease-related non-cardiac chest pain patients.

Axial patterning of C. elegans male sensilla identities by selector genes.

The fan and rays of the C. elegans male tail constitute a compound sensory organ essential for mating. Within this organ, the individual sensilla, known as rays, have unique identities. We show that ray identities are patterned by a selector gene mechanism in a manner similar to other serially homologous axial structures. One selector gene that promotes the identities of a subset of the rays is the Hox gene egl-5. Within EGL-5-expressing rays, further patterning is provided by a Pax-6 homolog and a signal of the TGFbeta family. These genes and pathway coordinately specify multiple ray properties affecting all three terminal ray cell types. These properties include complex patterns of FMRFamide-like (FaRP) neuropeptides, serotonin (5HT) and dopamine expression, and ray morphology. Differences in these differentiated characteristics give each sensillum a unique identity and potentially endow the compound ray organ with a higher-order information gathering capacity.

Recurrent giant Gartner's duct cysts. A report of two cases.

BACKGROUND: Gartner's duct cysts are cystically dilated wolffian duct remnants found in the upper anterolateral part of the vagina. Many such giant cysts are diagnosed during childhood and result from ectopic communication with the ureter or cervix. There is a paucity of literature on recurrent and giant cysts presenting among older women. CASES: A 43-year-old woman presented in 1981 with a 7 x 14-cm, left, paravaginal, cystic mass. This was initially drained vaginally, then marsupialized vaginally. Following marsupialization, the patient began to note large gushes of fluid from the vagina. Ultrasound demonstrated a 3-cm cyst thought to arise within the broad ligament. The patient required total abdominal hysterectomy/bilateral salpingo-oophorectomy for endometrial hyperplasia. Exploration revealed neither a broad ligament nor vaginal mass. Postoperatively, vaginal drainage continued. Computed tomography demonstrated a multiloculated, cystic mass left of the vaginal cuff. Exploratory laparotomy revealed the mass to be within the paravaginal space. The cyst was marsupialized into the peritoneal cavity. A 32-year-old woman was diagnosed in 1992 with an 8 x 10-cm right pelvic mass found on examination and confirmed by computed tomography. At exploratory laparotomy the mass was found to be within the paravaginal space and was resected vaginally. In 1999 the patient returned, complaining of rectal pain. Examination and ultrasound revealed a right, multiloculated pelvic mass displacing the rectum, uterus and vagina. Magnetic resonance imaging demonstrated that the mass was entirely inferior to the levator plate. The cyst was resected vaginally. CONCLUSION: Giant Gartner's cysts tend to be misdiagnosed as pelvic masses. Magnetic resonance imaging is the best imaging modality for localizing these cysts. Recurrences of giant cysts tend to be multiloculated. Management strategies for multiloculated recurrences include periodic surveillance, schlerotherapy and marsupialization into the peritoneal cavity.

Imagery rehearsal therapy for chronic nightmares in sexual assault survivors with posttraumatic stress disorder: a randomized controlled trial.

CONTEXT: Chronic nightmares occur frequently in patients with posttraumatic stress disorder (PTSD) but are not usually a primary target of treatment. OBJECTIVE: To determine if treating chronic nightmares with imagery rehearsal therapy (IRT) reduces the frequency of disturbing dreams, improves sleep quality, and decreases PTSD symptom severity. DESIGN, SETTING, AND PARTICIPANTS: Randomized controlled trial conducted from 1995 to 1999 among 168 women in New Mexico; 95% had moderate-to-severe PTSD, 97% had experienced rape or other sexual assault, 77% reported life-threatening sexual assault, and 58% reported repeated exposure to sexual abuse in childhood or adolescence. INTERVENTION: Participants were randomized to receive treatment (n = 88) or to the wait-list control group (n = 80). The treatment group received IRT in 3 sessions; controls received no additional intervention, but continued any ongoing treatment. MAIN OUTCOME MEASURES: Scores on the Nightmare Frequency Questionnaire (NFQ), Pittsburgh Sleep Quality Index (PSQI), PTSD Symptom Scale (PSS), and Clinician-Administered PTSD Scale (CAPS) at 3- and 6-month follow-up. RESULTS: A total of 114 participants completed follow-up at 3 and/or 6 months. Comparing baseline to follow-up (n = 97-114), treatment significantly reduced nights per week with nightmares (Cohen d = 1.24; P<.001) and number of nightmares per week (Cohen d = 0.85; P<.001) on the NFQ and improved sleep (on the PSQI, Cohen d = 0.67; P<.001) and PTSD symptoms (on the PSS, Cohen d = 1.00; P<.001 and on the CAPS, Cohen d = 1.53; P<.001). Control participants showed small, nonsignificant improvements for the same measures (mean Cohen d = 0.21). In a 3-point analysis (n = 66-77), improvements occurred in the treatment group at 3-month follow-up (treatment vs control group, Cohen d = 1.15 vs 0.07 for nights per week with nightmares; 0.95 vs -0.06 for nightmares per week; 0.77 vs 0.31 on the PSQI, and 1.06 vs 0.31 on the PSS) and were sustained without further intervention or contact between 3 and 6 months. An intent-to-treat analysis (n = 168) confirmed significant differences between treatment and control groups for nightmares, sleep, and PTSD (all P<.02) with moderate effect sizes for treatment (mean Cohen d = 0.60) and small effect sizes for controls (mean Cohen d = 0.14). Posttraumatic stress symptoms decreased by at least 1 level of clinical severity in 65% of the treatment group compared with symptoms worsening or not changing in 69% of controls (chi(2)(1) = 12.80; P<.001). CONCLUSIONS: Imagery rehearsal therapy is a brief, well-tolerated treatment that appears to decrease chronic nightmares, improve sleep quality, and decrease PTSD symptom severity.

The novel C. elegans gene sop-3 modulates Wnt signaling to regulate Hox gene expression.

We describe the properties of a new gene, sop-3, that is required for the regulated expression of a C. elegans Hox gene, egl-5, in a postembryonic neuroectodermal cell lineage. Regulated expression of egl-5 in this cell lineage is necessary for development of the sensory rays of the male tail. sop-3 encodes a predicted novel protein of 1475 amino acids without clear homologs in other organisms. However, the sequence contains motifs consisting of homopolymeric runs of amino acids found in several other transcriptional regulators, some of which also act in Hox gene regulatory pathways. The genetic properties of sop-3 are very similar to those of sop-1, which encodes a component of the transcriptional Mediator complex, and mutations in the two genes are synthetic lethal. This suggests that SOP-3 may act at the level of the Mediator complex in regulating transcription initiation. In a sop-3 loss-of-function background, egl-5 is expressed ectopically in lineage branches that normally do not express this gene. Such expression is dependent on the Hox gene mab-5, as it is in branches where egl-5 is normally expressed. Ectopic egl-5 expression is also dependent on the Wnt pathway. Thus, sop-3 contributes to the combinatorial control of egl-5 by blocking egl-5 activation by MAB-5 and the Wnt pathway in inappropriate lineage branches.

The basic helix-loop-helix transcription factors LIN-32 and HLH-2 function together in multiple steps of a C. elegans neuronal sublineage.

bHLH transcription factors function in neuronal development in organisms as diverse as worms and vertebrates. In the C. elegans male tail, a neuronal sublineage clonally gives rise to the three cell types (two neurons and a structural cell) of each sensory ray. We show here that the bHLH genes lin-32 and hlh-2 are necessary for the specification of multiple cell fates within this sublineage, and for the proper elaboration of differentiated cell characteristics. Mutations in lin-32, a member of the atonal family, can cause failures at each of these steps, resulting in the formation of rays that lack fully-differentiated neurons, neurons that lack cognate rays, and ray cells defective in the number and morphology of their processes. Mutations in hlh-2, the gene encoding the C. elegans E/daughterless ortholog, enhance the ray defects caused by lin-32 mutations. In vitro, LIN-32 can heterodimerize with HLH-2 and bind to an E-box-containing probe. Mutations in these genes interfere with this activity in a manner consistent with the degree of ray defects observed in vivo. We propose that LIN-32 and HLH-2 function as a heterodimer to activate different sets of targets, at multiple steps in the ray sublineage. During ray development, lin-32 performs roles of proneural, neuronal precursor, and differentiation genes of other systems.

A C. elegans mediator protein confers regulatory selectivity on lineage-specific expression of a transcription factor gene.

The Caenorhabditis elegans caudal homolog, pal-1, is required for neurogenesis in the male tail. We show that expression of pal-1 in the postembryonic neuroblast cell V6 can be initiated by two alternate pathways. One pathway, acting in wild type, requires a regulatory element in the fifth pal-1 intron. The other pathway, independent of this element, is normally repressed by the newly identified gene sop-1, which encodes a homolog of the mammalian Mediator complex protein TRAP230. In sop-1 mutants, pal-1 is activated by a pathway that is stimulated by bar-1/beta-catenin, a component of the Wnt signal transduction pathway. The results support a physiological role of the Mediator complex in conveying regulatory signals to the transcriptional apparatus.

Somatic polyploidization and cellular proliferation drive body size evolution in nematodes.

Most of the hypodermis of a rhabditid nematode such as Caenorhabditis elegans is a single syncytium. The size of this syncytium (as measured by body size) has evolved repeatedly in the rhabditid nematodes. Two cellular mechanisms are important in the evolution of body size: changes in the numbers of cells that fuse with the syncytium, and the extent of its acellular growth. Thus nematodes differ from mammals and other invertebrates in which body size evolution is caused by changes in cell number alone. The evolution of acellular syncytial growth in nematodes is also associated with changes in the ploidy of hypodermal nuclei. These nuclei are polyploid as a consequence of iterative rounds of endoreduplication, and this endocycle has evolved repeatedly. The association between acellular growth and endoreduplication is also seen in C. elegans mutations that interrupt transforming growth factor-beta signaling and that result in dwarfism and deficiencies in hypodermal ploidy. The transforming growth factor-beta pathway is a candidate for being involved in nematode body size evolution.

Patterning of dopaminergic neurotransmitter identity among Caenorhabditis elegans ray sensory neurons by a TGFbeta family signaling pathway and a Hox gene.

We have investigated the mechanism that patterns dopamine expression among Caenorhabditis elegans male ray sensory neurons. Dopamine is expressed by the A-type sensory neurons in three out of the nine pairs of rays. We used expression of a tyrosine hydroxylase reporter transgene as well as direct assays for dopamine to study the genetic requirements for adoption of the dopaminergic cell fate. In loss-of-function mutants affecting a TGFbeta family signaling pathway, the DBL-1 pathway, dopaminergic identity is adopted irregularly by a wider subset of the rays. Ectopic expression of the pathway ligand, DBL-1, from a heat-shock-driven transgene results in adoption of dopaminergic identity by rays 3-9; rays 1 and 2 are refractory. The rays are therefore prepatterned with respect to their competence to be induced by a DBL-1 pathway signal. Temperature-shift experiments with a temperature-sensitive type II receptor mutant, as well as heat-shock induction experiments, show that the DBL-1 pathway acts during an interval that extends from two to one cell generation before ray neurons are born and begin to differentiate. In a mutant of the AbdominalB class Hox gene egl-5, rays that normally express EGL-5 do not adopt dopaminergic fate and cannot be induced to express DA when DBL-1 is provided by a heat-shock-driven dbl-1 transgene. Therefore, egl-5 is required for making a subset of rays capable of adopting dopaminergic identity, while the function of the DBL-1 pathway signal is to pattern the realization of this capability.

Spire contains actin binding domains and is related to ascidian posterior end mark-5.

Spire is a maternal effect locus that affects both the dorsal-ventral and anterior-posterior axes of the Drosophila egg and embryo. It is required for localization of determinants within the developing oocyte to the posterior pole and to the dorsal anterior corner. During mid-oogenesis, spire mutants display premature microtubule-dependent cytoplasmic streaming, a phenotype that can be mimicked by pharmacological disruption of the actin cytoskeleton with cytochalasin D. Spire has been cloned by transposon tagging and is related to posterior end mark-5, a gene from sea squirts that encodes a posteriorly localized mRNA. Spire mRNA is not, however, localized to the posterior pole. SPIRE also contains two domains with similarity to the actin monomer-binding WH2 domain, and we demonstrate that SPIRE binds to actin in the interaction trap system and in vitro. In addition, SPIRE interacts with the rho family GTPases RHOA, RAC1 and CDC42 in the interaction trap system. Thus, our evidence supports the model that SPIRE links rho family signaling to the actin cytoskeleton.

Normalizing results of 13C-urea breath testing for CO2 production rates in children.

BACKGROUND: The 13C-urea breath test detects the presence of Helicobacter pylori from an enrichment of breath 13CO2, which, in turn, is critically dependent on the amount of dilution by endogenous CO2 production. The production of CO2 differs according to age (adults > children), sex (male > female) weight, and height. The cutoff value of 2.4 delta%(delta over baseline, DOB) for the 13C-urea breath test, defined in adults, does not take into account actual CO2 production. Therefore, this cutoff value (2.4 delta%) may or may not be appropriate for children. The purpose of this study was to determine a cutoff value that would provide accurate results in pediatric patients, independent of their differences in anthropometric parameters. METHODS: Estimates of CO2 production were combined with DOB values to calculate the host-dependent urea hydrolysis rate. RESULTS: Calculated as urea hydrolysis rate, the cutoff range for adults was 10.4 to 10.9 microg/min. Individual ranges were concentric (men, 9.6-10.9 microg/min; women, 8.5-12.2 microg/min). Results in studies of 312 children show that a urea hydrolysis rate of more than 10 m microg/min may also be appropriate to predict H. pylori infection. CONCLUSION: Calculating 13C-urea breath test values as urea hydrolysis rate removes the effect of individual anthropometric differences on test outcome and provides a single cutoff value for pediatric patients of all ages.

Patterning of Caenorhabditis elegans posterior structures by the Abdominal-B homolog, egl-5.

The Caenorhabditis elegans body axis, like that of other animals, is patterned by the action of Hox genes. In order to examine the function of one C. elegans Hox gene in depth, we determined the postembryonic expression pattern of egl-5, the C. elegans member of the Abdominal-B Hox gene paralog group, by means of whole-mount staining with a polyclonal antibody. A major site of egl-5 expression and function is in the epithelium joining the posterior digestive tract with the external epidermis. Patterning this region and its derived structures is a conserved function of Abd-B paralog group genes in other animals. Cells that initiate egl-5 expression during embryogenesis are clustered around the presumptive anus. Expression is initiated postembryonically in four additional mesodermal and ectodermal cell lineages or tissues. Once initiated in a lineage, egl-5 expression continues throughout development, suggesting that the action of egl-5 can be regarded as defining a positional cell identity. A variety of cross-regulatory interactions between egl-5 and the next more anterior Hox gene, mab-5, help define the expression domains of their respective gene products. In its expression in a localized body region, function as a marker of positional cell identity, and interactions with another Hox gene, egl-5 resembles Hox genes of other animals. This suggests that C. elegans, in spite of its small cell number and reproducible cell lineages, may not differ greatly from other animals in the way it employs Hox genes for regional specification during development.

Regulated nuclear entry of the C. elegans Pax-6 transcription factor.

It is shown that the C. elegans Pax-6 locus encodes two protein isoforms. One contains a Paired DNA binding domain as well as a homeodomain; the other consists only of the carboxy-terminal portion of the locus encoding the homeodomain. These two isoforms are expressed in a variety of postembryonic cell lineages. In one set of lineages, nuclear localization of a homeodomain-only form (MAB-18 isoform) appears to be under temporal and spatial control. Nuclear localization of MAB-18 is correlated with the genetic requirement for mab-18 and with activation of a reporter gene driven by a mab-18 promoter. Reporter gene expression is dependent on mab-18 gene activity. It is hypothesized that a positive feedback loop is activated by regulated nuclear entry.

Quantifying faculty teaching time in a department of obstetrics and gynecology.

OBJECTIVE: The goal of this project was to develop a reproducible system that measures quantity and quality of teaching in unduplicated hours, such that comparisons of teaching activities could be drawn within and across departments. Such a system could be used for allocating teaching monies and for assessing teaching as part of the promotion and tenure process. METHODS: Various teaching activities, including time spent in clinic, rounds, and doing procedures, were enumerated. The faculty were surveyed about their opinions on the proportion of clinical time spent in teaching. The literature also was reviewed. RESULTS: Based on analysis of the faculty survey and the literature, a series of calculations were developed to divide clinical time among resident teaching, medical student teaching, and patient care. The only input needed was total time spent in the various clinical activities, time spent in didactic activities, and the resident procedure database. CONCLUSION: This article describes a simple and fair database system to calculate time spent teaching from activities such as clinic, ward rounds, labor and delivery, and surgery. The teaching portfolio database calculates teaching as a proportion of the faculty member's total activities. The end product is a report that provides a reproducible yearly summary of faculty teaching time per activity and per type of learner.

Paraplegia: prolonged closed-loop standing with implanted nucleus FES-22 stimulator and Andrews' foot-ankle orthosis.

Our object is to develop a reliable, implantable and closed-loop functional electrical stimulator (FES) hybrid system for safe prolonged standing in paraplegic individuals. Open-loop FES systems rapidly induce muscle fatigue that limits paraplegic standing to less than 20 and typically 10 min. Since December 1991, a paraplegic male (CS: 23 years old, T10 level, Asia: A) has been implanted with the first Nucleus FES-22 channel stimulating system (Cochlear Ltd., Lane Cove, N.S.W., Australia). Epineural platinum disc electrodes (2.5 mm) were placed on branches of the femoral, gluteal and sciatic nerves, which can be activated to produce controlled lower extremity movements for exercise and standing. No medical complications have occurred during these 5 1/2 years of implantation. The ankles are stabilized with Andrews' ankle-foot braces, the knees are free to flex. With bilateral knee goniometers fitted to sense a 10 degrees angle flexion, this hybrid closed-loop stimulation system allows the patient to achieve safe uninterrupted standing for over 60 min. The stimulator has needed to be activated 'on' for 8% (range: 3-17%) of the standing times, preventing muscle fatigue, with little or no changes found in the vital signs. The patient can manipulate and transfer objects at arm length up to 2.2 kg with good stability. New, less obstrusive sensors are currently being tested for a safer and more reliable closed-loop system.