Heating induced near deep brain stimulation (DBS) lead electrodes during MRI with a 3T transceive head coil was measured, modeled, and imaged in three cadaveric porcine heads (mean body weight = 85.47±3.19 kg, mean head weight = 5.78±0.32 kg). The effect of the placement of the extra-cranial portion of the DBS lead on the heating was investigated by looping the extra-cranial lead on the top, side, and back of the head; and placing it parallel to the coil’s longitudinal axial direction. The heating was induced using a 641 s long turbo spin echo sequence with the mean whole head average SAR of 3.16 W/kg. Temperatures were measured using fluoroptic probes at the scalp, first and second electrodes from the distal lead tip, and 6 mm distal from electrode 1 (T6mm). The heating was modeled using the maximum T6mm and imaged using a proton resonance frequency shift based MR thermometry method. Results showed that the heating was significantly reduced when the extra-cranial lead was placed in the longitudinal direction compared to the other placements (peak temperature change = 1.5–3.2 °C vs 5.1–24.7 °C). Thermal modeling and MR thermometry may be used together to determine the heating and improve patient safety online.
MRI; Safety; DBS; Heating; 3T
Placentas are oxidatively stressed during preeclampsia and produce more TNFα and more thromboxane (TX) than normal. Oxidative stress may cause these abnormalities by activating NF-κB. We measured levels of activated NF-κB in normal and preeclamptic placentas and determined whether oxidative stress activates NF-κB in a trophoblast-like cell line.
We used immunohistochemistry to determine the percentage of the total tissue area that stained for the p65 subunit of NF-κB in placentas obtained from normal and preeclamptic pregnancies. In a second set of experiments, we used a reporter plasmid bearing the NF-κB binding site and transfected it into trophoblast-like cells. The cells were incubated with medium control, linoleic acid (LA), an oxidizing solution (Ox), or Ox enriched with linoleic acid (OxLA), TNFα, or OxLA plus TNFα for 20 hours. Cell lysates were analyzed using a dual luciferase assay kit.
Placentas obtained from women with preeclampsia showed nearly a 10-fold increase in the extent of area stained for activated NF-κB as compared to normal placentas. In cell culture experiments, Ox and OxLA induced a 3-fold increase in NF-κB activation as compared to medium control or LA. TNFα induced a 3-fold increase in NF-κB activation. The combination of TNFα with OxLA caused a 10-fold increase in NF-κB activation.
Placental NF-κB is activated nearly 10-fold in preeclampsia. Oxidative stress causes NF-κB activation in a trophoblast-like cell line, which is enhanced by TNFα. These data suggest that oxidative stress is likely an important in vivo activator of placental NF-κB in preeclampsia.
Nuclear factor-κB (NF-κB); trophoblast; placenta; oxidative stress; tumor necrosis factor α (TNFα)
Schizophrenia is characterized by deficits in executive control and impairments in emotion processing. This study assessed the nature and extent of potential alterations in the neural substrates supporting the interaction between cognitive control mechanisms and emotion attribution processes in people with schizophrenia.
Functional magnetic resonance imaging was performed during a verbal emotional go/no-go task. People with schizophrenia and healthy controls responded to word stimuli of a prespecified emotional valence (positive, negative or neutral) while inhibiting responses to stimuli of a different valence.
We enrolled 20 people with schizophrenia and 23 controls in the study. Healthy controls activated an extensive dorsal prefrontal–parietal network while inhibiting responses to negative words compared to neutral words, but showed deactivation of the midcingulate cortex while inhibiting responses to positive words compared to neutral words. People with schizophrenia failed to activate this network during response inhibition to negative words, whereas during response inhibition to positive words they did not deactivate the cingulate, but showed increased responsivity in the frontal cortex.
Sample heterogeneity is characteristic of studies of schizophrenia and may have contributed to more variable neural responses in the patient sample despite the care taken to control for potentially confounding variables.
Our results showed that schizophrenia is associated with aberrant modulation of neural responses during the interaction between cognitive control and emotion processing. Failure of the frontal circuitry to regulate goal-directed behaviour based on emotion attributions may contribute to deficits in psychosocial functioning in daily life.
Temperatures were measured in vivo in four pigs (mean animal weight = 110.75 kg and standard deviation = 6.13 kg) due to a continuous wave radiofrequency (RF) power irradiation with a 31.75 cm internal diameter and a 15.24 cm long, 7 T (296 MHz), eight channel, transverse electromagnetic head coil. The temperatures were measured in the subcutaneous layer of the scalp, 5, 10, 15, and 20 mm deep in the brain, and rectum using fluoroptic temperature probes. The RF power was delivered to the pig’s head for ~3 h (mean deposition time = 3.14 h and standard deviation = 0.06 h) at the whole head average specific absorption rate of = 3 W kg−1 (mean average specific absorption rate = 3.08 W kg−1 and standard deviation = 0.09 W kg−1). Next, simple bioheat transfer models were used to simulate the RF power induced temperature changes. Results show that the RF power produced uniform temperature changes in the pigs’ heads (mean temperature change = 1.68°C and standard deviation = 0.13°C) with no plateau achieved during the heating. No thermoregulatory alterations were detected due to the heating because the temperature responses of the pre-RF and post- RF epochs were not statistically significantly different. Simple, validated bioheat models may provide accurate temperature changes.
safety; radiofrequency; MRI; 7 T; bioheat
While hybridization based analysis of the cortical transcriptome has provided important insight into the neuropathology of schizophrenia, it represents a restricted view of disease-associated gene activity based on predetermined probes. By contrast, sequencing technology can provide un-biased analysis of transcription at nucleotide resolution. Here we use this approach to investigate schizophrenia-associated cortical gene expression.
The data was generated from 76 bp reads of RNA-Seq, aligned to the reference genome and assembled into transcripts for quantification of exons, splice variants and alternative promoters in postmortem superior temporal gyrus (STG/BA22) from 9 male subjects with schizophrenia and 9 matched non-psychiatric controls. Differentially expressed genes were then subjected to further sequence and functional group analysis. The output, amounting to more than 38 Gb of sequence, revealed significant alteration of gene expression including many previously shown to be associated with schizophrenia. Gene ontology enrichment analysis followed by functional map construction identified three functional clusters highly relevant to schizophrenia including neurotransmission related functions, synaptic vesicle trafficking, and neural development. Significantly, more than 2000 genes displayed schizophrenia-associated alternative promoter usage and more than 1000 genes showed differential splicing (FDR<0.05). Both types of transcriptional isoforms were exemplified by reads aligned to the neurodevelopmentally significant doublecortin-like kinase 1 (DCLK1) gene.
This study provided the first deep and un-biased analysis of schizophrenia-associated transcriptional diversity within the STG, and revealed variants with important implications for the complex pathophysiology of schizophrenia.
There is a paucity of therapies for gait impairment in Parkinson disease (PD). Open-label studies have suggested improved gait after treatment with methylphenidate (MPD).
To evaluate the efficacy of MPD for the treatment of gait impairment in PD.
Twenty-seven subjects with PD and moderate gait impairment were screened for this 6-month placebo-controlled, double-blind study. Subjects were randomly assigned to MPD (maximum, up to 80 mg/day) or placebo for 12 weeks and crossed over after a 3-week washout. The primary outcome measure was change in a gait composite score (stride length + velocity) between groups at 4 and 12 weeks. Secondary outcome measures included changes in motor function, as measured by the Unified Parkinson's Disease Rating Scale (UPDRS), Freezing of Gait Questionnaire (FOGQ), number of gait-diary freezing episodes, and measures of depression, sleepiness, and quality of life. Three-factor repeated-measures analysis of variance was used to measure changes between groups.
Twenty-three eligible subjects with PD were randomized and 17 completed the trial. There was no change in the gait composite score or treatment or time effect for any of the variables. Treatment effect was not modified by state or study visit. Although there was a trend for reduced frequency of freezing and shuffling per diary, the FOGQ and UPDRS scores worsened in the MPD group compared to placebo. There was a marginal improvement in some measures of depression.
MPD did not improve gait and tended to worsen measures of motor function, sleepiness, and quality of life.
Classification of evidence:
This study provides Class III evidence for the lack of benefit of MPD on PD-associated gait impairment. Clinical trial registration: NCT00526630.
To study the effect of the extra-cranial portion of a deep brain stimulation (DBS) lead on radiofrequency (RF) heating with a transmit and receive 9.4 tesla head coil.
Material and Methods
The RF heating was studied in four excised porcine heads (mean animal head weight = 5.46 ± 0.14 kg) for each of the following two extra-cranial DBS lead orientations: one, parallel to the coil axial direction; two, perpendicular to the coil axial direction (i.e., azimuthal). Temperatures were measured using fluoroptic probes at four locations: one, scalp; two, near the second DBS lead electrode-brain contact; three, near the distal tip of the DBS lead; and four, air surrounding the head. A continuous wave RF power was delivered to each head for 15 minutes using the coil. Net, delivered RF power was measured at the coil (mean whole head average specific absorption rate = 2.94 ± 0.08 W/kg).
RF heating was significantly reduced when the extra-cranial DBS lead was placed in the axial direction (temperature change = 0-5 °C) compared to the azimuthal direction (temperature change = 1-27 °C).
Development of protocols seems feasible to keep RF heating near DBS electrodes clinically safe during ultra-high field head imaging.
Safety; MRI; RF heating; DBS; high field
In vivo proton NMR spectroscopy allows non-invasive detection and quantification of a wide range of biochemical compounds in the brain. Higher field strength is generally considered advantageous for spectroscopy due to increased signal-to-noise and increased spectral dispersion. So far 1H NMR spectra have been reported in the human brain up to 7 Tesla. In this study we show that excellent quality short echo time STEAM and LASER 1H NMR spectra can be measured in the human brain at 9.4 Tesla. The information content of the human brain spectra appears very similar to that measured in the past decade in rodent brains at the same field strength, in spite of broader linewidth in human brain. Compared to lower fields, the T1 relaxation times of metabolites were slightly longer while T2 relaxation values of metabolites were shorter (< 100 ms) at 9.4 Tesla. The linewidth of the total creatine (tCr) resonance at 3.03 ppm increased linearly with magnetic field (1.35 Hz/Tesla from 1.5 T to 9.4 T), with a minimum achievable tCr linewidth of around 12.5 Hz at 9.4 Tesla. At very high-field, B0 microsusceptibility effects are the main contributor to the minimum achievable linewidth.
Proton NMR spectroscopy; brain; human; relaxation times; ultra-high field
Parallel excitation holds strong promises to mitigate the impact of large transmit B1 (B1+) distortion at very high magnetic field. Accelerated RF pulses, however, inherently tend to require larger values in RF peak power which may result in substantial increase in Specific Absorption Rate in tissues, which is a constant concern for patient safety at very high field. In this study, we demonstrate adapted rate RF pulse design allowing for SAR reduction while preserving excitation target accuracy. Compared with other proposed implementations of adapted rate RF pulses, our approach is compatible with any k-space trajectories, does not require an analytical expression of the gradient waveform and can be used for large flip angle excitation. We demonstrate our method with numerical simulations based on electromagnetic modeling and we include an experimental verification of transmit pattern accuracy on an 8 transmit channel 9.4 T system.
Urocortins are the endogenous ligands for the corticotropin-releasing factor receptor type 2 (CRFR2), which is implicated in regulating energy balance and/or glucose metabolism. We determined the effects of chronic CRFR2 activation on metabolism in vivo, by generating and phenotyping transgenic mice overproducing the specific CRFR2 ligand urocortin 3.
Body composition, glucose metabolism, insulin sensitivity, energy efficiency and expression of key metabolic genes were assessed in adult male urocortin 3 transgenic mice (Ucn3+) under control conditions and following an obesogenic high-fat diet (HFD) challenge.
Ucn3+ mice had increased skeletal muscle mass with myocyte hypertrophy. Accelerated peripheral glucose disposal, increased respiratory exchange ratio and hypoglycaemia on fasting demonstrated increased carbohydrate metabolism. Insulin tolerance and indices of insulin-stimulated signalling were unchanged, indicating these effects were not mediated by increased insulin sensitivity. Expression of the transgene in Crfr2 (also known as Crhr2)-null mice negated key aspects of the Ucn3+ phenotype. Ucn3+ mice were protected from the HFD-induced hyperglycaemia and increased adiposity seen in control mice despite consuming more energy. Expression of uncoupling proteins 2 and 3 was higher in Ucn3+ muscle, suggesting increased catabolic processes. IGF-1 abundance was upregulated in Ucn3+ muscle, providing a potential paracrine mechanism in which urocortin 3 acts upon CRFR2 to link the altered metabolism and muscular hypertrophy observed.
Urocortin 3 acting on CRFR2 in skeletal muscle of Ucn3+ mice results in a novel metabolically favourable phenotype, with lean body composition and protection against diet-induced obesity and hyperglycaemia. Urocortins and CRFR2 may be of interest as potential therapeutic targets for obesity.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-011-2205-6) contains supplementary material, which is available to authorised users.
CRFR2; Energy balance; Glucose uptake; IGF-1; Obesity; Skeletal muscle; Transgenic mice; Urocortin 3
Multidimensional spatially selective RF pulses have been proposed as a method to mitigate transmit B1 inhomogeneity in MR experiments. These RF pulses, however, have been considered impractical for many years because they typically require very long RF pulse durations. The recent development of parallel excitation techniques makes it possible to design multidimensional RF pulses that are short enough for use in actual experiments. However, hardware and experimental imperfections can still severely alter the excitation patterns obtained with these accelerated pulses. In this note, we report at 9.4 T on a human eight-channel transmit system, substantial improvements in 2D excitation pattern accuracy obtained when measuring k-space trajectories prior to parallel transmit RF pulse design (acceleration ×4). Excitation patterns based on numerical simulations closely reproducing the experimental conditions were in good agreement with the experimental results.
In vivo thermoregulatory temperature response to RF heating at 9.4 T was studied by measuring temperatures in nine anesthetized swine. Temperatures were measured in the scalp, brain, and rectum. The RF energy was deposited using a four loop head coil tuned to 400.2 MHz. Sham RF was delivered to three swine to understand thermal effects of anesthesia (animal weight = 54.16 kg, SD = 3.08 kg). Continuous wave RF energy was delivered to the other six animals for 2.5–3.4 hours (animal weight = 74.01 ± 26.0 kg, heating duration = 3.05 ± 0.29 hours). The whole head specific absorption rate (SAR) varied between 2.71 W/kg and 3.20 W/kg (SAR = 2.93 ± 0.18 W/kg). Anesthesia caused the brain and rectal temperatures to drop linearly. Altered thermoregulatory response was detected by comparing the difference in the temperature slopes before and after the RF delivery from zero. RF heating statistically significantly altered the rate of cooling down of the animal. The temperature slope changes correlated well with the RF energy per unit head weight and heating duration, and the maximum rectal temperature change during heating in heated animals. The temperature slope changes did not correlate well to the whole head average SARs.
RF safety; RF heating; MR safety; ultra high field MRI; MR heating; 9.4 T
The objective of this study was to investigate the feasibility of whole body imaging at 7 T. To achieve this objective, new technology and methods were developed. Radio frequency field distribution and specific absorption rate were first explored through numerical modeling. A body coil was then designed and built. Multi-channel transmit and receive coils were also developed and implemented. With this new technology in hand, an imaging survey of the “landscape” of the human body at 7 T was conducted. Cardiac imaging at 7 T appeared to be possible. The potential for breast imaging and spectroscopy was demonstrated. Preliminary results of the first human body imaging at 7 T suggest both promise and directions for further development.
7 T Body MRI; 7 T Cardiac MRI; 7 T Breast MRI; 7 T Breast MRS
Given the growing recognition of the importance of the life course approach for the determination of chronic diseases, birth cohort studies are becoming increasingly important. This paper describes the methods used in the 1982 Pelotas (Brazil) birth cohort study, one of the largest and longest studies of this type in developing countries. All 5,914 hospital births occurring in Pelotas in 1982 (over 99% of all deliveries) were studied prospectively. The main stages of the study took place in 1983, 1984, 1986, 1995, 1997, 2000, and 2001. More than two thousand variables are available for each subject who participated in all stages of the study. Recent phases of the study included the examination of 2,250 males when presenting for the army recruitment exam in 2000, the study of a 27% sample of men and women in 2001 through household visits, and the study of over 400 children born to the cohort women. Follow-up rates in the recent stages of the cohort were 78.9% for the army examination and 69.0% for the household visits. Ethnographic and oral health studies were conducted in sub-samples. Some recent results on blood pressure, adolescent pregnancy, and asthma are presented as examples of utilization of the data. Suggestions on lessons learned for other cohort studies are proposed.
Cohort Studies; Growth; Life Cycle Stages; Adolescent; Child
Influences from the visual (AEV), auditory (FAES) and somatosensory (SIV) divisions of the cat anterior ectosylvian sulcus (AES) play a critical role in rendering superior colliculus (SC) neurons capable of multisensory integration. However, it is not known whether this is accomplished via their independent sensory-specific action or via some cross-modal cooperative action that emerges as a consequence of their convergence on SC neurons. Using visual-auditory SC neurons as a model, we examined how selective and combined deactivation of FAES and AEV affected SC multisensory (visual-auditory) and unisensory (visual-visual) integration capabilities. As noted earlier, multisensory integration yielded SC responses that were significantly greater than those evoked by the most effective individual component stimulus. This multisensory ‘response enhancement’ was more evident when the component stimuli were weakly effective. Conversely, unisensory integration was dominated by the lack of response enhancement. During cryogenic deactivation of FAES and/or AEV, the unisensory responses of SC neurons were only modestly affected; however, their multisensory response enhancement showed a significant downward shift and was eliminated. The shift was similar in magnitude for deactivation of either AES subregion and, in general, only marginally greater when both were deactivated simultaneously. These data reveal that SC multisensory integration is dependent on the cooperative action of distinct subsets of unisensory corticofugal afferents; afferents whose sensory combination matches the multisensory profile of their midbrain target neurons, and whose functional synergy is specific to rendering SC neurons capable of synthesizing information from those particular senses.
Cross-modal; within-modal; enhancement; deactivation; ectosylvian; unisensory
A thermal model was needed to predict temperatures in a perfused tissue, which satisfied the following three criteria. One, the model satisfied conservation of energy. Two, the heat transfer rate from blood vessels to tissue was modeled without following a vessel path. Three, the model applied to any unheated and heated tissue. To meet these criteria, a generic bioheat transfer model (BHTM) was derived here by conserving thermal energy in a heated, vascularized, finite tissue and by making a few simplifying assumptions. Two linear, coupled differential equations were obtained with the following two variables: tissue volume averaged temperature and blood volume averaged temperature. The generic model was compared to the widely employed, empirical Pennes’ BHTM. The comparison showed that the Pennes’ perfusion term wCp(1−ε) should be interpreted as a local vasculature dependent heat transfer coefficient term. Suggestions are presented for further adaptations of the general BHTM for specific tissues using imaging techniques and numerical simulations.
To examine the thermal effects of physiological response to heating during exposure to radiofrequency (RF) electromagnetic fields in Magnetic Resonance Imaging (MRI) with a head-specific volume coil.
Materials and Methods
Numerical methods are used to calculate the temperature elevation in MRI of the human head within volume coils from 64 MHz to 400 MHz at different power levels both with and without consideration of temperature-induced changes in rates of metabolism, perspiration, radiation, and perfusion.
At the highest power levels currently allowed in MRI for head volume coils, there is little effect from physiological response as predicted with existing methods. This study does not rule out the possibility that at higher power levels or in different types of coils (such as extremity or whole-body coils) the physiological response may have more significant effects.
In modeling temperature increase during MRI of the human head in a head-sized volume coil at up to 3.0 W/kg head-average SAR, it may not be necessary to consider thermally-induced changes in rates of metabolism, perfusion, perspiration, and radiation.
model; SAR; temperature; head; physiology
In vivo temperatures were correlated to the whole head average specific absorption rate (SARavg) at 9.4T using 12 anesthetized swine (mean animal weight = 52 kg, standard deviation = 6.7 kg). Correlating the temperatures and SARavg is necessary to ensure safe levels of human heating during ultra-high field MR exams. The temperatures were measured at three depths inside the brain, in the rectum, and at the head-skin of swine. A 400 MHz, continuous wave RF power was deposited to the head using a volume coil. The SARavg values were varied between 2.7–5.8 W/kg. The RF power exposure durations were varied between 1.4 –3.7 hr. To differentiate the temperature response caused by the RF from that of the anesthesia, the temperatures were recorded in four unheated swine. To study the effect of the spatial distribution of the RF and tissue properties, the temperature probes were placed at two brain locations (n = 4 swine for each location). Results showed that the in vivo brain temperatures correlated to the SARavg in a geometry-dependent manner. Additionally, 1) the skin temperature change was not the maximum temperature change; 2) the RF heating caused an inhomogeneous brain temperature distribution; and 3) the maximum temperature occurred inside the brain.
RF safety; RF heating; bioheat thermal model; high field MRI
To evaluate brain activity associated with sexual arousal, fully conscious male marmoset monkeys were imaged during presentation of odors that naturally elicit high levels of sexual activity and sexual motivation.
Material and Methods
Male monkeys were lightly anesthetized, secured in a head and body restrainer with a built-in birdcage resonator and positioned in a 9.4-Tesla spectrometer. When fully conscious, monkeys were presented with the odors of a novel receptive female or an ovariectomized monkey. Both odors were presented during an imaging trial and the presentation of odors was counterbalanced. Significant changes in both positive and negative BOLD signal were mapped and averaged.
Periovulatory odors significantly increased positive BOLD signal in several cortical areas: the striatum, hippocampus, septum, periaqueductal gray, and cerebellum, in comparison with odors from ovariectomized monkeys. Conversely, negative BOLD signal was significantly increased in the temporal cortex, cingulate cortex, putamen, hippocampus, substantia nigra, medial preoptic area, and cerebellum with presentation of odors from ovariectomized marmosets as compared to periovulatory odors. A common neural circuit comprising the temporal and cingulate cortices, putamen, hippocampus, medial preoptic area, and cerebellum shared both the positive BOLD response to periovulatory odors and the negative BOLD response to odors of ovariectomized females.
These data suggest the odor-driven enhancement and suppression of sexual arousal affect neuronal activity in many of the same general brain areas. These areas included not only those associated with sexual activity, but also areas involved in emotional processing and reward.
BOLD technique; approach/avoidance; magnetic resonance imaging; functional imaging; common marmoset; cerebellum; neural circuit; sexual motivation; suppressed sexual activity
Background: Measurement of pH in exhaled breath condensate (EBC) is robust and simple. Acidic source fluid (airway lining fluid) traps bases while volatilising acids, leading to EBC acidification in many lung diseases. Lower airway ammonia is one determinant of airway lining fluid pH, raising the concern that addition of the base ammonia by contamination from the mouth might confound EBC pH assays.
Methods: Three discrete methods were used to limit oral ammonia contamination of EBC collections: endotracheal intubation, oral rinsing, and –40°C condenser temperatures. Separately, ammonia was removed from collected EBC samples by lyophilisation and resuspension. Intraweek and intraday variability of ammonia concentration was determined in 76 subjects, and ammonia and pH from a further 235 samples were graphically compared. Ammonia was assayed spectrophotometrically and pH was assessed after deaeration.
Results: Data from 1091 samples are presented. Ammonia was reduced in EBC by all methods. Endotracheal intubation decreased EBC ammonia from a mean (SD) of 619 (124) µM to 80 (24) µM (p<0.001, n = 32). Oral rinsing before collection also led to a decline in EBC ammonia from 573 (307) µM to 224 (80) µM (p = 0.016, n = 7). The colder the condensation temperature used, the less ammonia was trapped in the EBC. Lyophilisation removed 99.4 (1.9)% of ammonia. Most importantly, the pH of EBC never decreased after removal of ammonia by any of these methods. Intraweek and intraday coefficients of variation for ammonia were 64 (27)% and 60 (32)%, which is substantially more variable than EBC pH assays.
Conclusions: Although ammonia and pH appear to correlate in EBC, the oral ammonia concentration is not an important determinant of EBC pH. No precautions need to be taken to exclude oral ammonia when EBC pH is of interest. The low pH and low ammonia found in EBC from patients with lung diseases appear to be independent effects of volatile compounds arising from the airway.
Objective: To undertake a full genome-wide screen for Parkinson's disease susceptibility loci.
Methods: A genome-wide linkage study was undertaken in 227 affected sibling pairs from 199 pedigrees with Parkinson's disease. The pedigree sample consisted of 188 pedigrees from five European countries, and 11 from the USA. Individuals were genotyped for 391 microsatellite markers at ∼10 cM intervals throughout the genome. Multipoint model-free affected sibling pair linkage analyses were carried out using the MLS (maximum LOD score) test.
Results: There were six chromosomal regions with maximum MLS peaks of 1 or greater (pointwise p<0.018). Four of these chromosomal regions appear to be newly identified regions, and the highest MLS values were obtained on chromosomes 11q (MLS = 1.60, at 91 cM, D11S4175) and 7p (MLS = 1.51, at 5 cM, D7S531). The remaining two MLS peaks, on 2p11–q12 and 5q23, are consistent with excess sharing in regions reported by other studies. The highest MLS peak was observed on chromosome 2p11–q12 (MLS = 2.04, between markers D2S2216 and D2S160), within a relatively short distance (∼17 cM) from the PARK3 region. Although a stronger support of linkage to this region was observed in the late age of onset subgroup of families, these differences were not significant. The peak on 5q23 (MLS = 1.05, at 130 cM, D5S471) coincides with the region identified by three other genome scans. All peak locations fell within a 10 cM distance.
Conclusions: These stratified linkage analyses suggest linkage heterogeneity within the sample across the 2p11–q12 and 5q23 regions, with these two regions contributing independently to Parkinson's disease susceptibility.
INTRODUCTION—Symptoms of dyspepsia are common but most patients do not have major upper gastrointestinal pathology. Endoscopy is recommended for dyspeptic patients over the age of 45, or those with certain "alarm" symptoms. We have evaluated the effectiveness of age and "alarm" symptoms for predicting major endoscopic findings in six practising endoscopy centres.
METHODS—Clinical variables of consecutive patients with dyspepsia symptoms undergoing upper endoscopy examinations were recorded using a common endoscopy database. Patients who had no previous upper endoscopy or barium radiography were included. Stepwise multivariate logistic regression was used to identify predictors of endoscopic findings. The accuracy of these for predicting endoscopic findings was evaluated with receiver operating characteristic analysis. The sensitivity and specificity of age thresholds from 30 to 70 years were evaluated.
RESULTS—Major pathology (tumour, ulcer, or stricture) was found at endoscopy in 787/3815 (21%) patients with dyspepsia. Age, male sex, bleeding, and anaemia were found to be significant but weak independent predictors of endoscopic findings. A multivariate prediction rule based on these factors had poor predictive accuracy (c statistic=0.62). Using a simplified prediction rule of age ⩾45 years or the presence of any "alarm" symptom, sensitivity was 87% and specificity was 26%. Increasing or decreasing the age cut off did not significantly improve the predictive accuracy.
CONCLUSIONS—Age and the presence of "alarm" symptoms are not effective predictors of endoscopic findings among patients with dyspepsia. Better clinical prediction strategies are needed to identify patients with significant upper gastrointestinal pathology.
Keywords: dyspepsia; endoscopy; age
To evaluate the effect on morbidity and mortality of providing daily zinc for 14 days to children with diarrhoea.
Cluster randomised comparison.
Matlab field site of International Center for Diarrhoeal Disease Research, Bangladesh.
8070 children aged 3-59 months contributed 11 881 child years of observation during a two year period.
Children with diarrhoea in the intervention clusters were treated with zinc (20 mg per day for 14 days); all children with diarrhoea were treated with oral rehydration therapy.
Main outcome measures
Duration of episode of diarrhoea, incidence of diarrhoea and acute lower respiratory infections, admission to hospital for diarrhoea or acute lower respiratory infections, and child mortality.
About 40% (399/1007) of diarrhoeal episodes were treated with zinc in the first four months of the trial; the rate rose to 67% (350/526) in month 5 and to >80% (364/434) in month 7 and was sustained at that level. Children from the intervention cluster received zinc for about seven days on average during each episode of diarrhoea. They had a shorter duration (hazard ratio 0.76, 95% confidence interval 0.65 to 0.90) and lower incidence of diarrhoea (rate ratio 0.85, 0.76 to 0.96) than children in the comparison group. Incidence of acute lower respiratory infection was reduced in the intervention group but not in the comparison group. Admission to hospital of children with diarrhoea was lower in the intervention group than in the comparison group (0.76, 0.59 to 0.98). Admission for acute lower respiratory infection was lower in the intervention group, but this was not statistically significant (0.81, 0.53 to 1.23). The rate of non-injury deaths in the intervention clusters was considerably lower (0.49, 0.25 to 0.94).
The lower rates of child morbidity and mortality with zinc treatment represent substantial benefits from a simple and inexpensive intervention that can be incorporated in existing efforts to control diarrhoeal disease.
What is already known on this topicZinc deficiency is highly prevalent in children in developing countriesZinc supplements given during diarrhoea reduce the duration and severity of treated episodesIf given for 14 days during and after diarrhoea, zinc reduces the incidence of diarrhoea and pneumonia in the subsequent two to three monthsWhat this study addsZinc used as a treatment for diarrhoea reduces mortality in childrenZinc reduces admissions to hospital for diarrhoeaThe impact of zinc on mortality and morbidity can be achieved in a realistic large scale public health programme