An Anatomical Study of the Foramen Ovale for Neuromodulation of Trigeminal Neuropathic Pain.

OBJECTIVE: Neuromodulation for trigeminal pain syndromes such as trigeminal neuropathic pain (TNP) necessitates accurate localization of foramen ovale (FO). The Härtel-type approach is very well-established and safe, ideal for temporary cannulation of the FO for ablative procedures such as balloon microcompression. A key shortcoming of the Hartel approach for placement of neuromodulation leads is the limited opportunity for secure anchoring. The aim of this study is to introduce a novel surgical approach for the treatment of TNP by investigating key osseous landmarks and their spatial relationships to the FO. MATERIALS AND METHODS: Sixteen sides of cadaver heads were dissected to investigate a surgical route of the FO via transoral gingival buccal approach. Alveolar arch of the maxilla and zygomaticomaxillary suture were selected to serve as an osseous landmark for the surgical guidance to the FO. Through the intraoral route, a needle simulating electrode was traversed to aim the FO from the inferior lateral to the superior medial direction to target specific fibers of the aimed division of the nerve. RESULTS: Visual identification and access to the trigeminal nerve at the external opening of FO was successful in all 16 hemifacial cadavers. A needle successfully targeted different regions of the trigeminal nerve by changing the angle of the trajectory allowing the needle to reach a specific division of the trigeminal nerve. CONCLUSIONS: This study provides a novel means of approaching the FO via transoral gingival buccal access.

Applicability of the dual isotopes δ15N and δ18O to identify nitrate in groundwater beneath irrigated cropland.

Identification of the nitrate sources that adversely impact groundwater quality is a necessary first step in the control of this major worldwide pollutant. The impact of nitrate leachate from urea-ammonium nitrate (UAN) (50% urea-N, 25% ammonium-N, 25% nitrate-N) fertilizer, whose use has increased dramatically in the last three decades largely because it can be applied through sprinkler irrigation systems to corn in all growth stages, is investigated. The dual isotopes δ15NNO3 and δ18ONO3 were measured in groundwater samples from 39 irrigation wells in two intensively sprinkler-irrigated, corn-growing areas of Nebraska with nitrate-contaminated (N > 10 mg/L) groundwater and documented UAN use to ascertain whether nitrified ammonia and nitrate fertilizers can be distinguished in the High Plains aquifer. The areas, which are highly vulnerable to nitrate leaching and differ only in the composition and thickness of their unsaturated zones, are uniquely suited to provide scientific evidence of the feasibility of identifying nitrate fertilizer leachate in groundwater and thereby add significantly to the small body of existing and inconclusive data. The dual isotope method (DIM) results indicate that the nitrate contamination in 38 wells is mostly nitrified ammonium fertilizer. Most importantly, nitrate fertilizer from UAN was not identified isotopically in groundwater beneath almost all fields with documented heavy UAN use. This could be a potentially valuable finding for fertilizer management or it could convey limitations on the appropriateness of the DIM for nitrate fertilizer source identification in groundwater. Slightly enriched δ15NNO3 values in a few wells coincide with the practice of wintering cattle on corn stubble, which reportedly occurred more frequently in one focus area. The absence of natural soil-N leachates and denitrification in groundwater enabled an apparently reliable identification of manure leachates in both areas.

Factors underlying metastatic breast cancer patients' perceptions of symptom importance: a qualitative analysis.

The symptom literature in cancer has primarily examined symptom severity, frequency and distress. Assessing cancer patients' perceptions of symptom importance-how important it is for them to see improvement in a symptom following an intervention-and factors influencing these judgments would also inform patient-centred care, but this analysis has not been undertaken. This qualitative study aimed to identify factors underlying perceptions of symptom importance among 25 symptomatic metastatic breast cancer (MBC) patients. Participants were recruited from a cancer centre in the Midwestern USA. Semi-structured interviews focused on patients' rationale for considering common symptoms (i.e., anxiety, sadness, sleep problems, pain or fatigue) to be important. Thematic analyses revealed five interrelated factors underlying MBC patients' perceptions of symptom importance: activity restriction, concentration difficulties, exacerbation of other physical symptoms, symptom-related long-term health concerns and negative impact on their relationships with others. Patients most frequently stated that a physical or psychological symptom was important because of the resulting activity restriction. Additionally, some patients considered pain to be important because it signalled potential long-term health concerns, such as worsening metastatic disease. Findings suggest that clinicians should take into account MBC patients' perceptions of symptom importance and factors underlying these judgments when making shared treatment decisions.

The influence of patient's sex, race and depression on clinician pain treatment decisions.

BACKGROUND: Pain treatments often vary across patients' demographic and mental health characteristics. Most research on this topic has been observational, has focused on opioid therapy exclusively and has not examined individual differences in clinician decision making. The current study examined the influence of patient's sex, race and depression on clinicians' chronic pain treatment decisions. METHODS: We used virtual human technology and lens model methodology to enhance study realism and facilitate a richer understanding of treatment decisions. Clinicians and trainees (n = 100) made treatment decisions (opioid, antidepressant, pain specialty referral, mental health referral) for 16 computer-simulated patients with chronic low back pain. Patients' sex, race and depression status were manipulated across vignettes (image and text). RESULTS: Individual- and group-level analyses indicated that patient's depression status had the strongest and most consistent influence on treatment decisions. Although less influential overall, patient's sex and race were significantly influential for a subset of participants. Furthermore, the results indicated that participants who were influenced by patient's race had less experience in treating chronic pain than those who were not influenced by patient's race [t(11.59) = 4.75; p = 0.001; d = 1.20]. CONCLUSIONS: The results of this study indicated considerable variability in participants' chronic pain treatment decisions. These data suggest that interventions to reduce variability in treatment decision making and improve pain care should be individually tailored according to clinicians' decision profiles.

Using virtual human technology to capture dentists' decision policies about pain.

Healthcare professionals use race, gender, and age cues when making pain management decisions. Use of these demographic cues, therefore, is an important topic in the study of healthcare disparities. This study used virtual human (VH) technology to investigate the effects of VH patients' demographic cues on dentists' pain management decisions. Eighty-nine dentists viewed patients with different demographic cues. Analyses revealed that dentists rated pain intensity higher and were more willing to prescribe opioids to female, African-American, and younger patients than to their demographic counterparts. Results also found significant 2-way interactions between race and age for both pain assessment and treatment decisions. The interaction results suggest that the race difference (Caucasian < African American) was more pronounced for younger than for older patients. This is the first study to examine demographic cue use in dentists' decision-making for pain. The study found that dentists used demographic cues when making pain management decisions. Currently, there are no guidelines for decision- making practices for gender-, race-, or age-related pain. Since dentists see thousands of patients during their careers, the use of demographic cues could affect a substantial portion of the population. The findings could improve future training programs for dentists and dental students.

Evidence-based recommendations for bowel cleansing before colonoscopy in children: a report from a national working group.

BACKGROUND: There are no current recommendations for bowel cleansing before colonoscopy in children. The Israeli Society of Pediatric Gastroenterology and Nutrition (ISPGAN) established an iterative working group to formulate evidence-based guidelines for bowel cleansing in children prior to colonoscopy. METHOD: Data were collected by systematic review of the literature and via a national-based survey of all endoscopy units in Israel. Based on the strength of evidence, the Committee reached consensus on six recommended protocols in children. Guidelines were finalized after an open audit of ISPGAN members. RESULTS: Data on 900 colonoscopies per year were accrued, which represents all annual pediatric colonoscopies performed in Israel. Based on the literature review, the national survey, and the open audit, several age-stratified pediatric cleansing protocols were proposed: two PEG-ELS protocols (polyethylene-glycol with electrolyte solution); Picolax-based protocol (sodium picosulphate with magnesium citrate); sodium phosphate protocol (only in children over the age of 12 years who are at low risk for renal damage); stimulant laxative-based protocol (e. g. bisacodyl); and a PEG 3350-based protocol. A population-based analysis estimated that the acute toxicity rate of oral sodium phosphate is at most 3/7320 colonoscopies (0.041 %). Recommendations on diet and enema use are provided in relation to each proposed protocol. CONCLUSION: There is no ideal bowel cleansing regimen and, thus, various protocols are in use. We propose several evidence-based protocols to optimize bowel cleansing in children prior to colonoscopy and minimize adverse events.

The clinical impact of an early decline in kidney function in patients following heart transplantation.

Renal dysfunction is a well-known complication following heart transplantation. We examined an early decline in kidney function as a predictor of progression to end-stage renal disease and mortality in heart transplant recipients. We performed a retrospective cohort study of 233 patients who received a heart transplant between July 1985 and July 2004, and who survived >1 month. The decline in estimated creatinine clearance (CrCl) was used to predict the outcomes of need for chronic dialysis or mortality >1-year posttransplant. The earliest time to chronic dialysis was 484 days. A 30% decline in CrCl between 1 month and 12 months predicted the need for chronic dialysis (p = 0.01), all-cause mortality (p < 0.0001) and time to first CrCl 1-year posttransplant (p = 0.02). A 30% decline in CrCl between 1 month and 3 months also independently predicted the need for chronic dialysis (p = 0.04) and time to first CrCl 1-year posttransplant (p = 0.01). In conclusion, an early drop in CrCl within the first year is a strong predictor of chronic dialysis and death >1-year postheart transplantation. Future studies should focus on kidney function preservation in those identified at high risk for progression to end-stage kidney disease and mortality.

Detecting putative orthologs.

We developed an algorithm that improves upon the common procedure of taking reciprocal best blast hits(rbh) in the identification of orthologs. The method-reciprocal smallest distance algorithm (rsd)-relies on global sequence alignment and maximum likelihood estimation of evolutionary distances to detect orthologs between two genomes. rsd finds many putative orthologs missed by rbh because it is less likely than rbh to be misled by the presence of a close paralog.

The CF salt controversy: in vivo observations and therapeutic approaches.

There is controversy over whether abnormalities in the salt concentration or volume of airway surface liquid (ASL) initiate cystic fibrosis (CF) airway disease. In vivo studies of CF mouse nasal epithelia revealed an increase in goblet cell number that was associated with decreased ASL volume rather than abnormal [Cl(-)]. Aerosolization of osmolytes in vivo failed to raise ASL volume. In vitro studies revealed that osmolytes and pharmacological agents were effective in producing isotonic volume responses in human airway epithelia but were typically short acting and less effective in CF cultures with prolonged volume hyperabsorption and mucus accumulation. These data show that (1) therapies can be designed to normalize ASL volume, without producing deleterious compositional changes in ASL, and (2) therapeutic efficacy will likely depend on development of long-acting pharmacologic agents and/or an increased efficiency of osmolyte delivery.

[Single-stage implants in areas of maxillary sinuses that were augmented with allograft. Case reports].

Demineralized freezed dried bone allograft (DFDBA) is known as a bone inductive material, and used widely in periodontal and bone regeneration procedures. DFDBA can also be used for sinus floor augmentation prior or with implant placement. The present manuscript described cases of single-stage implants that were used successfully in areas where the maxillary sinus was augmented with DFDBA simultaneously with implant placement (Case 1) or in a second procedure, 18 months following grafting of the sinus (Case 2). These cases demonstrated the ability to use single-stage implants in the augmented maxillary sinus, in a separated or simultaneous procedure.

Protein dispensability and rate of evolution.

If protein evolution is due in large part to slightly deleterious amino acid substitutions, then the rate of evolution should be greater in proteins that contribute less to individual fitness. The rationale for this prediction is that relatively dispensable proteins should be subject to weaker purifying selection, and should therefore accumulate mildly deleterious substitutions more rapidly. Although this argument was presented over twenty years ago, and is fundamental to many applications of evolutionary theory, the prediction has proved difficult to confirm. In fact, a recent study showed that essential mouse genes do not evolve more slowly than non-essential ones. Thus, although a variety of factors influencing the rate of protein evolution have been supported by extensive sequence analysis, the relationship between protein dispensability and evolutionary rate has remained unconfirmed. Here we use the results from a highly parallel growth assay of single gene deletions in yeast to assess protein dispensability, which we relate to evolutionary rate estimates that are based on comparisons of sequences drawn from twenty-one fully annotated genomes. Our analysis reveals a highly significant relationship between protein dispensability and evolutionary rate, and explains why this relationship is not detectable by categorical comparison of essential versus non-essential proteins. The relationship is highly conserved, so that protein dispensability in yeast is also predictive of evolutionary rate in a nematode worm.

Ligand-mediated protection against phage lysis as a positive selection strategy for the enrichment of epitopes displayed on the surface of E. coli cells.

We present a novel strategy, termed CISTEM, which allows direct in vivo screening of polypeptides displayed on the surface of E. coli cells by a combination of ligand-mediated protection and phage-mediated selection. The effectiveness of this new approach was demonstrated by displaying the T7.tag on the surface of E. coli as a fusion with the outer membrane protein A, the receptor for bacteriophage K3. A monoclonal T7.tag antibody was used as protective ligand for T7.tag-displaying cells and phage K3 for the elimination of unprotected cells. When populations of bacteria, containing between 6 to 10,000 cells displaying the T7.tag and approximately 10(8) cells displaying an unrelated OmpA fusion protein, were infected with phage K3, specific and antibody-dependent survival of T7.tag displaying cells was observed, yielding an enrichment factor of up to 10(7)-fold. The CISTEM technology was used to select sequences from a T7.tag-based, randomised library and the results were compared to those obtained from selection by MACS with the same library. Together, these results reveal a novel in vivo screening strategy in which an E. coli phage receptor is used as display plafform and selection is performed in suspension upon addition of a protective ligand and a bacteriophage. Extentions and modifications of the basic strategy should lead to novel applications for the identification of protein-ligand interactions.

Fluorescence ratio intrinsic basis states analysis: a novel approach to monitor and analyze protein unfolding by fluorescence.

Fluorescence ratio intrinsic basis states analysis (FRIBSTA) is a novel method allowing quantitative estimation of the stability of proteins in aqueous solution as a function of temperature. In FRIBSTA emission fluorescence spectra are repeatedly recorded while ramping temperature from < or =-15 to > or =100 degrees C. Subsets of these are identified as reference spectra of the protein in either its folded or in its heat denatured configuration. Each reference spectrum of both sets is normalized by its own integrated fluorescence intensity to give a fractional area spectrum. Linear extrapolations of these normalized reference spectral shapes over the entire temperature range of measurement are then used to deconvolute each experimental emission spectrum to give a fraction of emission from native state and a fraction from denatured state. Additionally, the integrated emission fluorescence intensity for the native configuration is fitted and extrapolated over the temperature range of measurement. Division of the deconvoluted native integrated fluorescence intensity by the fitted-extrapolated integrated emission fluorescence intensity yields the fraction folded. The free energy functions derived from fraction unfolded are presented for beta-lactoglobulin and phosphoglycerate kinase. According to these results both proteins are considerably less stable than heretofore assumed at ambient temperatures and partially denatured at temperatures < or =0 degrees C. The method is employed to study the effect of denaturants on these proteins as well. The major usefulness of FRIBSTA is that one can directly measure the protein stability at ambient and subambient temperatures in the absence of denaturants rather than predicting it by extrapolation from heat denaturation data.

The role of Helicobacter pylori and gastritis in children with recurrent abdominal pain.

BACKGROUND: Recurrent abdominal pain is a common pediatric diagnostic problem. Endoscopy is sometimes performed as part of the evaluation. Although gastritis and/or Helicobacter pylori infection is often present, it is not known if they contribute to the symptomatology. OBJECTIVES: To evaluate the role of either gastritis or H. pylori infection in the symptomatology of children with RAP. PATIENTS AND METHODS: We retrospectively studied two groups of patients, 70 children in each, who had undergone endoscopy. One group was evaluated endoscopically for RAP and the other was a heterogeneous group that underwent endoscopy for indications other than RAP. Biopsies were taken during endoscopy and Giemsa staining was performed for the presence of H. pylori. Triple therapy was given as indicated, and the children were followed for an average of 6 months. RESULTS: Microscopic gastritis was diagnosed in 39 patients (55.7%) of the RAP group and in 31 of the heterogeneous group (44.2%) (NS), and H. pylori was found in 32 patients of the RAP group and in 16 of the heterogeneous group (45.7% vs. 22.8%, P < 0.01). All children with H. pylori, except one in the heterogeneous group, had accompanying gastritis. On the other hand, gastritis without H. pylori infection was seen in 7 children in the RAP group and in 15 of the other. Endoscopy revealed macroscopic abnormalities in 52 of the 70 children with microscopic gastritis. There was a clinical improvement after triple therapy in 28 of 33 children with H. pylori-associated gastritis (84.85%), in 4 of 8 children with gastritis unassociated with H. pylori (50%), and in 8 of 15 without gastritis or H. pylori (53.3%) (P < 0.01 between the H. pylori-associated gastritis and each of the other groups). CONCLUSIONS: H. pylori infection and gastritis may be associated with RAP in a selected subgroup of children. We recommend a complete work-up, including endoscopy and invasive or non-invasive diagnostic modalities for H. pylori, and treatment of the infection.

Botulinum toxin type A for the treatment of axillary Hailey-Hailey disease.

BACKGROUND: Hailey-Hailey disease is an inherited acantholytic disorder affecting the intertriginous areas of the body which is exacerbated by sweat, moisture, and friction. The disease is frequently resistant to conventional nonsurgical treatment. OBJECTIVE: To evaluate whether chemodenervation of sweat glands would improve the course of the disease in a patient with Hailey-Hailey. METHODS: We used low-dose treatment of the left axilla with botulinum toxin type A, the right axilla being used as a control, followed by treatment of both axillae with the optimal dose routinely used for the treatment of axillary hyperhidrosis. RESULTS: After one treatment with a low dose of botulinum toxin type A, we observed partial improvement of the treated axilla. With subsequent treatment of both axillae with the recommended dose for axillary hyperhidrosis, we observed a sustained complete remission of the disease in the treated axillae. CONCLUSION: Botulinum toxin type A may be an effective and safe nonsurgical alternative for the treatment of benign familial pemphigus in intertriginous areas such as the axillae.

Cholecystokinin decreases intestinal hexose absorption by a parallel reduction in SGLT1 abundance in the brush-border membrane.

The dual lumenaly and vascularly perfused small intestine was used to determine the mechanism by which cholecystokinin octapeptide (CCK-8) decreases the rate of glucose absorption. With CCK-8 in the vascular perfusate the rate of 3-O-methyl-D-glucose absorption decreased, whereas the rate of D-fructose absorption was unaffected. The substrate pool size within the tissue during steady-state transport, in the presence and absence of CCK-8, was estimated by compartmental analysis of the 3-O-methyl-D-glucose washout into the vascular bed. When CCK-8 was included in the vascular perfusate, the absorptive cell pool size decreased when compared with untreated tissue. Both the steady-state hexose absorption data and the washout studies indicated that the locus of action of CCK-8 was the SGLT1 transporter located in the brush-border membrane. The SGLT1 protein abundance in isolated brush-border membranes, as quantified by Western blotting, showed a decrease that paralleled the decrease in the steady-state transport rate induced by CCK-8. These results indicate that CCK-8 diminishes the rate of intestinal hexose absorption by decreasing SGLT1 protein abundance in the brush-border membrane of the rat jejunum and therefore provides evidence for acute enteric hormonal regulation of the rate of glucose absorption across the small intestine.

Inhibition of glucose absorption in the rat jejunum: a novel action of alpha-D-glucosidase inhibitors.

BACKGROUND & AIMS: alpha-D-Glucosidase inhibitors act primarily by decreasing disaccharide hydrolysis and thus reduce the amount of free monosaccharides available for absorption. A novel action of alpha-D-glucosidase inhibitors is presented, indicating a direct effect on free glucose absorption by the rat jejunum. METHODS: The jejunum was isolated and free hexose was measured using in vivo single-pass luminal perfusion and dual vascular and luminal single-pass in vitro perfusion. Xenopus oocytes were injected with RNA transcript encoding recombinant sodium-glucose cotransporter 1, and uptake of 3H-labeled 3-O-methyl-D-glucopyranose (3-O-MG) was assessed. RESULTS: Acarbose (0.1 mg/mL), added to the lumen, decreased D-glucose absorption by 20% in vivo. Addition of 0.1 or 1.0 mg/mL acarbose to the lumen in vitro decreased the appearance of 3-O-MG in the vascular effluent by 28% and 60%, respectively. Accumulation of D-glucose within the enterocytes was decreased significantly by 67% and 79% when acarbose (1 mg/mL) or phloridzin (2 mmol/L), respectively, were present in the luminal perfusate. In contrast, acarbose did not affect the transport rate of free D-fructose and did not inhibit 3-O-MG uptake in oocytes expressing sodium-glucose cotransporter 1. CONCLUSIONS: The findings indicate that alpha-D-glucosidase inhibitors act specifically on the entry of free glucose into the enterocyte, an additional means by which they can reduce postprandial hyperglycemia.

Effect of cholecystokinin and related peptides on jejunal transepithelial hexose transport in the Sprague-Dawley rat.

An in situ dual vascular and luminal perfusion technique was used to study the effect of cholecystokinin octapeptide (CCK-8) on the transport of hexoses by the jejunum of the Sprague-Dawley rat from the lumen to the vascular bed. The lumen of the jejunum was perfused with hexoses in oxygenated Krebs buffer, while the superior mesenteric artery was infused with Krebs buffer containing Ficoll 70 as a plasma expander. CCK-8 (0.8-8 pM) in the vascular infusate selectively reduced hexose transport in a dose-dependent manner by 20-47%, although having no effect on L-glucose or L-leucine absorption. Vascular tetrodotoxin did not block CCK-8 inhibition, whereas a specific CCK-A receptor antagonist, lorglumide, did. The CCK-B receptor agonist cholecystokinin tetrapeptide had a small effect on hexose absorption, whereas somatostatin-14 and -28 had no effect. These results suggest that cholecystokinin can decrease intestinal absorption of hexoses in the small intestine, acting via CCK-A-type receptors.

Stem cell factor potentiates histamine secretion by multiple mechanisms, but does not affect tumour necrosis factor-alpha release from rat mast cells.

The effect of stem cell factor (SCF) on histamine and tumour necrosis factor-alpha (TNF-alpha) release from rat peritoneal mast cells (PMC) was determined and the intracellular pathways involved in the potentiation of histamine secretion were investigated. The effects of SCF (2-100 ng/ml) were examined following both short-term (0 and 20 min) and long-term (up to 24hr) preincubations with SCF. Pretreatment of PMC with SCF for 0 min (concurrent) or 20 min did not induce histamine secretion directly, but significantly increased antigen (Ag)-induced histamine secretion. SCF potentiated Ag-induced intracellular Ca2+ increase and calcium ionophore A23187-induced histamine secretion. Pertussis toxin (PT) inhibited SCF-induced potentiation of IgE-dependent histamine secretion, indicating that PT-sensitive G-proteins are involved in the immediate effects of SCF. In long-term incubation experiments, SCF pretreatment for 18-24 hr significantly enhanced Ag-induced histamine secretion, but did not affect Ag-induced intracellular Ca2+ levels. The effects of long-term incubation with SCF, but not the short-term effects, were blocked by cycloheximide. Interestingly, spontaneous and Ag-induced TNF-alpha release from rat PMC were not affected by pretreatment with SCF (2-500 ng/ml) for 1 to 24 hr. Thus, through immediate and delayed mechanisms, SCF potentiates histamine release from PMC, but has not effect on TNF-alpha release. The regulation of MC by SCF may be important in allergic and other inflammatory diseases.