Alzheimer's Disease Biomarker Decision-Making among Patients with Mild Cognitive Impairment and Their Care Partners.

BACKGROUND: Alzheimer's disease (AD) biomarker tests can be ordered as part of the diagnostic workup of patients with mild cognitive impairment (MCI). Little is known about how patients with MCI and their care partners decide whether to pursue testing. OBJECTIVE: To examine factors that influence AD biomarker testing decisions among patients with MCI and their care partners. DESIGN: We performed structured research interviews with patients with MCI and their study partners to assess the importance of eight factors in the decision whether to undergo AD biomarker testing (6-point Likert scale; 1-extremely unimportant to 6-extremely important): cost, fear of testing procedures, learning if AD is the cause of cognitive problems, concern about health insurance, instructing future planning, informing treatment decisions, family members' opinions, and doctor recommendation. SETTING: Two researchers administered interviews with participants in-person (i.e., participant home, research center) or remotely (i.e., telephone, video-conference). PARTICIPANTS: We completed interviews with 65 patients with a diagnosis of MCI and 57 study partners, referred by dementia specialist clinicians from the University of California, Irvine health system. MEASUREMENTS: We used generalized estimating equations (GEE) to examine the mean importance of each factor among patients and study partners, and the mean difference in importance of each factor within dyads. RESULTS: One third of participants reported the patient had previously undergone AD biomarker testing. Fifty-five percent of patients and 65% of study partners who reported no previous testing indicated a desire for the patient to be tested. GEE analyses found that patients and study partners rated the following factors with highest importance: informing treatment decisions (mean score 5.29, 95% CI: 5.06, 5.52 for patients; mean score 5.56, 95% CI: 5.41, 5.72 for partners); doctor recommendation (4.94, 95% CI: 4.73, 5.15 for patients; 5.16, 95% CI: 4.97, 5.34 for partners); and instructing future planning (4.88, 95% CI: 4.59, 5.16 for patients; 5.11, 95% CI: 4.86, 5.35 for partners). High dyadic agreement was observed for all factors except fear of testing, which patients rated with lower importance than their study partners. CONCLUSIONS: Biomarker testing for AD in patients with MCI is a rapidly evolving practice and limited data exist on patient perspectives. In this study, most patients and their care partners were interested in testing to help inform treatment decisions and to plan for the future. Participants placed high importance on clinician recommendations for biomarker testing, highlighting the need for clear communication and education on the options, limitations, risks, and benefits of testing.

Cohort Effects in Alzheimer's Disease Trials: An Empirical Assessment Utilizing Data from the Alzheimer's Disease Cooperative Study.

BACKGROUND: Cohort effects in study populations can impact clinical trial conclusions and generalizability, particularly in trials with planned interim analyses. Long recruitment windows may exacerbate these risks in Alzheimer's disease (AD) trials. OBJECTIVES: To investigate the presence of cohort effects mild-to-moderate AD trials. DESIGN: Retrospective analysis using pooled participant-level data from nine randomized, placebo-controlled trials conducted by the Alzheimer's Disease Cooperative Study (ADCS). SETTING: Trials were multicenter studies conducted by an academic trial network. PARTICIPANTS: The trials enrolled participants with mild, mild-to-moderate, or moderate AD who were over age 50 and had mini mental state exam scores between 12 and 26. Interventions/Exposure: We defined a participant's site-standardized enrollment time as the number of days between their screening date and the first screening date among randomized participants at their site within their study. MAIN OUTCOME(S) AND MEASURE(S): Our primary outcome was the 12-month change in the AD assessment scale - cognitive subscale (ADAS-Cog). Secondary outcomes were participant demographics and time to study discontinuation. RESULTS: The pooled sample consisted of N=2,754 at baseline with N=2,191 participants completing a 12-month visit. We found no meaningful differences in the distributions of sex, race and ethnicity, age, years of education or baseline ADAS-Cog score across enrollment time. We found a significant association between enrollment time and 12-month change in ADAS-Cog, with participants enrolling 100 days later tending to experience an increase on the ADAS-Cog of 0.16 points greater (reflecting greater cognitive decline; 95% CI: (0.021, 0.294), p = 0.02), after controlling for potential confounding factors. CONCLUSION: We found minimal evidence of clinically relevant cohort effects in ADCS trials. Our results reinforce the original findings of these trials.

Diversifying Recruitment Registries: Considering Neighborhood Health Metrics.

BACKGROUND: Disparities in clinical research participation perpetuate broader health disparities. Recruitment registries are novel tools to address known challenges in accrual to clinical research. Registries may accelerate accrual, but the utility of these tools to improve generalizability is unclear. OBJECTIVE: To examine the diversity of a local on-line recruitment registry using the Area Deprivation Index (ADI), a publicly available metric of neighborhood disadvantage. DESIGN: Retrospective analysis. SETTING: Data were collected in the University of California Irvine Consent-to-Contact Registry. PARTICIPANTS: We categorized N=2,837 registry participants based on the ADI decile (collapsed into quintiles) using a state-based rankings. MEASUREMENTS: We examined the proportion of enrollees per ADI quintile and quantified the demographics of these groups. We assessed willingness to participate in studies involving unique research procedures among the ADI groups. RESULTS: Although registry enrollees represented the full spectrum of the ADI, they disproportionately represented less disadvantaged neighborhoods (lowest to highest quintiles: 42%, 30%, 15%, 6%, 7%). Compared to participants from less disadvantaged neighborhoods, participants from more disadvantaged neighborhoods were more often female, of non-white race, and Hispanic ethnicity. Despite demographic differences, ADI groups were observed to have similar willingness to participate in research studies. CONCLUSIONS: People from more disadvantaged neighborhoods may be underrepresented in recruitment registries, increasing the risk that they will be underrepresented when using these tools to facilitate prospective recruitment to clinical research. Once enrolled in registries, participants from more disadvantaged neighborhoods may be equally willing to participate in research. Efforts to increase representation of participants from disadvantaged neighborhoods in registries could be an important first step toward increasing the generalizability of clinical research.

Anxiety and Depressive Symptoms and Cortical Amyloid-ß Burden in Cognitively Unimpaired Older Adults.

BACKGROUND: There is evidence of relationships between behavioral symptoms and increased risk for Alzheimer's Disease and/or Alzheimer's Disease biomarkers. However, the nature of this relationship is currently unknown. OBJECTIVES: To evaluate the relationship between anxiety and depressive symptoms and amyloid-ß deposition in cognitively unimpaired older adults, and to assess mediating effects of either objective or subjective cognitive skills. DESIGN: Cross-sectional analysis of screening data from participants enrolled in the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study (ClinicalTrials.gov Identifier: NCT02008357). SETTING: Data analysis. PARTICIPANTS: 4492 cognitively unimpaired adults, age 65-85, enrolled in the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study. MEASUREMENTS: We used linear regression to estimate the associations between amyloid-ß standard uptake value ratio (SUVR) and Geriatric Depression Scale (GDS) and State Trait Anxiety Inventory (STAI) scores while adjusting for potential confounding factors as well as for Cognitive Function Index (CFI) or Preclinical Alzheimer's Cognitive Composite (PACC) scores as possible mediational variables. RESULTS: 4399 subjects with complete covariates were included (mean age: 71.3, 59% female), GDS ranged 0-13 (mean: 1.0), and STAI ranged 6-24 (mean: 9.9). Amyloid-ß SUVR was modestly associated with STAI; mean STAI score was estimated to be 0.275 points higher (95% CI: 0.038, 0.526; p-value = 0.023) for each 0.5-point increase in cortical amyloid-ß SUVR. Subjective cognitive decline (CFI) attenuated the relationship between SUVR and STAI, while objective cognitive function (PACC) did not. No statistically significant relationship between SUVR and GDS was observed (p = 0.326). CONCLUSIONS: In cognitively unimpaired adults with low levels of depression and anxiety, cortical amyloid-ß deposition is associated with anxiety but not depressive symptoms. Attenuation of this relationship by subjective cognitive difficulties suggests that anxiety may be partly due to such a perception resulting from cortical amyloid-ß deposition.

Is Reluctance to Share Alzheimer's Disease Biomarker Status with a Study Partner a Barrier to Preclinical Trial Recruitment?

BACKGROUND: Preclinical Alzheimer's disease clinical trials test candidate treatments in individuals with biomarker evidence but no cognitive impairment. Participants are required to co-enroll with a knowledgeable study partner, to whom biomarker information is disclosed. OBJECTIVE: We investigated whether reluctance to share biomarker results is associated with viewing the study partner requirement as a barrier to preclinical trial enrollment. DESIGN: We developed a nine-item assessment on views toward the study partner requirement and performed in-person interviews based on a hypothetical clinical trial requiring biomarker testing and disclosure. SETTING: We conducted interviews on campus at the University of California, Irvine. PARTICIPANTS: Two hundred cognitively unimpaired older adults recruited from the University of California, Irvine Consent-to-Contact Registry participated in the study. MEASUREMENTS: We used logistic regression models, adjusting for potential confounders, to examine potential associations with viewing the study partner requirement as a barrier to preclinical trial enrollment. RESULTS: Eighteen percent of participants reported strong agreement that the study partner requirement was a barrier to enrollment. Ten participants (5%) agreed at any level that they would be reluctant to share their biomarker result with a study partner. The estimated odds of viewing the study partner requirement as a barrier to enrollment were 26 times higher for these participants (OR=26.3, 95% CI 4.0, 172.3), compared to those who strongly disagreed that they would be reluctant to share their biomarker result. Overall, participants more frequently agreed with positive statements than negative statements about the study partner requirement, including 76% indicating they would want their study partner with them when they learned biomarker results. CONCLUSIONS: This is one of the first studies to explore how potential preclinical Alzheimer's disease trial participants feel about sharing their personal biomarker information with a study partner. Most participants viewed the study partner as an asset to trial enrollment, including having a partner present during biomarker disclosure.

Using clinical risk factors and bone mineral density to determine who among patients undergoing bone densitometry should have vertebral fracture assessment.

SUMMARY: Vertebral fracture assessment (VFA) is a new method for imaging thoracolumbar spine on bone densitometer. Among patients referred for bone densitometry, the selection of patients for VFA testing can be optimized using an index derived from clinical risk factors and bone density measurement. PURPOSE: VFA, a method for imaging thoracolumbar spine on bone densitometer, was developed because vertebral fractures, although common and predictive of future fractures, are often not clinically diagnosed. The study objective was to develop a strategy for selecting patients for VFA. METHODS: A convenience sample from a university hospital bone densitometry center included 892 subjects (795 women) referred for bone mineral density (BMD) testing. We used questionnaires to capture clinical risk factors and dual-energy X-ray absorptiometry to obtain BMD and VFA. RESULTS: Prevalence of vertebral fractures was 18% in women and 31% in men (p = 0.003 for gender difference). In women, age, height loss, glucocorticoid use, history of vertebral and other fractures, and BMD T-score were significantly and independently associated with vertebral fractures. A multivariate model which included above predictors had an area under the receiver operating curve of 0.85 with 95% confidence interval (CI) of 0.81 to 0.89. A risk factor index was derived from the above multivariate model. Using a level of 2 as a cut-off yielded 93% sensitivity (95% CI 87, 96) and 48% specificity (95% CI 69, 83). Assuming a 15% prevalence of vertebral fractures, this cut-off value had a 24% positive and 97% negative predictive value and required VFA scanning of three women at a cost of $60 (assuming a $20 cost/VFA scan) to detect one with vertebral fracture(s). CONCLUSIONS: Selecting patients for VFA can be optimized using an index derived from BMD measurement and easily obtained clinical risk factors.

Paradox of gastric cardia: it becomes more acidic following meals while the rest of stomach becomes less acidic.

INTRODUCTION: The proximal cardia region of the stomach has a high incidence of inflammation, metaplasia and neoplasia. It demonstrates less acid buffering following meals than the more distal stomach. Novel high definition pHmetry was employed to investigate acidity at the cardia under fasting conditions and in response to a meal. METHODS: 15 healthy subjects were studied. A custom-made 12-electrode pH catheter was clipped at the squamocolumnar junction with four electrodes recording proximal to and eight distal to the squamocolumnar junction. The most distal pH electrode was located at the catheter tip, and nine electrodes in the region of the squamocolumnar junction were 11 mm apart. RESULTS: The electrode situated in the cardia 5.5 mm distal to the squamocolumnar junction differed from all other intragastric electrodes during fasting in recording minimal acidity (pH <4 = 2.2%) while all other intragastric electrodes recorded high intragastric acidity (pH <4 =or>39%) (p<0.05). The cardia also differed from the rest of the stomach, showing a marked increase in acidity in response to the meal (from 2.2% fasting to 58.4% at 60-70 min after the meal; p<0.05) while the electrodes distal to the cardia all showed a marked decrease in acidity (p<0.05). These changes in acidity at the cardia following the meal caused the gastric acidity to extend 10 mm closer to the squamocolumnar junction. CONCLUSION: Whereas the rest of the stomach shows a marked fall in acidity on ingesting a meal, the cardia paradoxically increases in acidity to become the most acidic region throughout the postprandial period.

Repeated respiratory hospital encounters among children with asthma and residential proximity to traffic.

OBJECTIVE: The prevalence of adverse respiratory outcomes among children has been frequently associated with measurements of traffic-related exposures, and other data suggest asthma severity is worsened with residence near heavy traffic. We examined the association between neighbourhood traffic burden and repeated acute respiratory illnesses that required emergency department visits and/or hospitalisation for children with a primary or secondary diagnosis of asthma (89% acute bronchitis or pneumonia). METHODS: This is a hospital-based longitudinal study of a southern California urban catchment area around two adjacent children's hospitals. Subjects' home addresses were geocoded and linked to nearby traffic data. Recurrent event proportional hazard analysis was used to estimate the hazard of repeated hospital encounters. RESULTS: We found living within 300 metres of arterial roads or freeways increased risk of repeated hospital encounters in 3297 children age 18 years or less. At highest risk were children in the top quintile of traffic density (HR = 1.21; 95% CL 0.99 to 1.49) and those who had 750 metres or more of arterial road and freeway length within 300 metres of their residence (HR = 1.18; 95% CL 0.99 to 1.41). Associations between repeated hospital encounters and residence near heavy traffic were stronger in females than males and in children without insurance or who required government sponsored insurance than children with private insurance. The gender disparity was most notable among infants (age 0) and children ages 6-18 years. CONCLUSIONS: Results suggest exposure to traffic-related air pollution increases asthma severity as indicated by hospital utilisation. The finding in infants suggests this is an especially vulnerable population, although the validity of asthma diagnosis at this age is unknown. Females and children who do not have private insurance may also be more vulnerable to air pollution from traffic.

The relationship of respiratory and cardiovascular hospital admissions to the southern California wildfires of 2003.

OBJECTIVE: There is limited information on the public health impact of wildfires. The relationship of cardiorespiratory hospital admissions (n = 40 856) to wildfire-related particulate matter (PM(2.5)) during catastrophic wildfires in southern California in October 2003 was evaluated. METHODS: Zip code level PM(2.5) concentrations were estimated using spatial interpolations from measured PM(2.5), light extinction, meteorological conditions, and smoke information from MODIS satellite images at 250 m resolution. Generalised estimating equations for Poisson data were used to assess the relationship between daily admissions and PM(2.5), adjusted for weather, fungal spores (associated with asthma), weekend, zip code-level population and sociodemographics. RESULTS: Associations of 2-day average PM(2.5) with respiratory admissions were stronger during than before or after the fires. Average increases of 70 microg/m(3) PM(2.5) during heavy smoke conditions compared with PM(2.5) in the pre-wildfire period were associated with 34% increases in asthma admissions. The strongest wildfire-related PM(2.5) associations were for people ages 65-99 years (10.1% increase per 10 microg/m(3) PM(2.5), 95% CI 3.0% to 17.8%) and ages 0-4 years (8.3%, 95% CI 2.2% to 14.9%) followed by ages 20-64 years (4.1%, 95% CI -0.5% to 9.0%). There were no PM(2.5)-asthma associations in children ages 5-18 years, although their admission rates significantly increased after the fires. Per 10 microg/m(3) wildfire-related PM(2.5), acute bronchitis admissions across all ages increased by 9.6% (95% CI 1.8% to 17.9%), chronic obstructive pulmonary disease admissions for ages 20-64 years by 6.9% (95% CI 0.9% to 13.1%), and pneumonia admissions for ages 5-18 years by 6.4% (95% CI -1.0% to 14.2%). Acute bronchitis and pneumonia admissions also increased after the fires. There was limited evidence of a small impact of wildfire-related PM(2.5) on cardiovascular admissions. CONCLUSIONS: Wildfire-related PM(2.5) led to increased respiratory hospital admissions, especially asthma, suggesting that better preventive measures are required to reduce morbidity among vulnerable populations.

Survival advantage of pediatric recipients of a first kidney transplant among children awaiting kidney transplantation.

The mortality rate in children with ESRD is substantially lower than the rate experienced by adults. However, the risk of death while awaiting kidney transplantation and the impact of transplantation on long-term survival has not been well characterized in the pediatric population. We performed a longitudinal study of 5961 patients under age 19 who were placed on the kidney transplant waiting list in the United States. Of these, 5270 received their first kidney transplant between 1990 and 2003. Survival was assessed via a time-varying nonproportional hazards model adjusted for potential confounders. Transplanted children had a lower mortality rate (13.1 deaths/1000 patient-years) compared to patients on the waiting list (17.6 deaths/1000 patient-years). Within the first 6 months of transplant, there was no significant excess in mortality compared to patients remaining on the waiting list (adjusted Relative Risk (aRR) = 1.01; p = 0.93). After 6 months, the risk of death was significantly lower: at 6-12 months (aRR = 0.37; p < 0.001) and at 30 months (aRR 0.26; p < 0.001). Compared to children who remain on the kidney transplant waiting list, those who receive a transplant have a long-term survival advantage. With the potential for unmeasured bias in this observational data, the results of the analysis should be interpreted conservatively.

Association of ultrasound-based measures of fetal body composition with newborn adiposity.

BACKGROUND: Newborns exhibit substantial variation in gestational age-adjusted and sex-adjusted fat mass proportion. The antecedent characteristics of fetal body composition that are associated with newborn fat mass proportion are poorly understood. OBJECTIVE: The aim of this study was to determine whether a composite measure of fetal fat mass is prospectively associated with newborn adiposity. METHODS: In a longitudinal study of 109 low-risk pregnancies, fetal ultrasonography was performed at approximately 12, 20 and 30 weeks gestation. Estimated fetal adiposity (EFA) was derived by integrating cross-sectional arm and thigh per cent fat area and anterior abdominal wall thickness. Newborn per cent body fat was quantified by Dual Energy X-Ray Absorptiometry. The association between EFA and newborn per cent body fat was determined by multiple linear regression. RESULTS: After controlling for confounding factors, EFA at 30 weeks was significantly associated with newborn per cent body fat (standardized ß = 0.41, p < 0.001) and explained 24.0% of its variance, which was substantially higher than that explained by estimated fetal weight (8.1%). The observed effect was driven primarily by arm per cent fat area. CONCLUSIONS: A composite measure of fetal adiposity at 30 weeks gestation may constitute a better predictor of newborn per cent body fat than estimated fetal weight by conventional fetal biometry. Fetal arm fat deposition may represent an early indicator of newborn adiposity. After replication, these findings may provide a basis for an improved understanding of the ontogeny of fetal fat deposition, thereby contributing to a better understanding of its intrauterine determinants and the development of potential interventions.

Gastric histology, serological markers and age as predictors of gastric acid secretion in patients infected with Helicobacter pylori.

BACKGROUND: Acid secretion is intimately associated with most upper gastrointestinal diseases. Helicobacter pylori infection is a major environmental factor modifying acid secretion. AIM: To study the association between the pattern of H pylori gastritis and gastric secretory function in a large number of subjects without specific upper gastrointestinal disease. METHODS AND MATERIALS: Maximal acid output (MAO) was measured in 255 patients with dyspepsia showing normal endoscopy. Activity and severity of gastritis, atrophy and H pylori infection were assessed in body and antral biopsies. The correlations of histological parameters as well as age, sex, height, weight, smoking, serum gastrin, pepsinogen I and II, and their ratio with MAO were determined. Multiple linear regression was used to show the best possible predictors of MAO. RESULTS: Negative relationships: Body atrophy and body-combined (active and chronic) inflammatory scores showed a potent inverse correlation with MAO (correlation coefficients (CC) 0.59 and 0.50, respectively). Body:antral chronic gastritis ratio and body:antral combined inflammation ratio (both with CC = 0.49) and age (CC = 0.44) were also inversely correlated with MAO. Intestinal metaplasia at both antral and body sites had negative relationships with acid output with CC = 0.23 and 0.20, respectively. Positive relationships: Serum pepsinogen I, body H pylori density:combined inflammation ratio and pepsinogen I:II ratio with CC of 0.38, 0.38 and 0.30, respectively, correlated with MAO. The H pylori density: combined inflammation of both antrum and body positively correlated with MAO (CC = 0.29 and 0.38, respectively). Male sex and patient height also positively correlated with acid output. Modelling showed that body combined inflammatory score, body atrophy, age and serum pepsinogen I are independent predictors of acid output (R(2) = 0.62). CONCLUSION: Combination of body gastritis, body atrophy, age and serum pepsinogen I can be used as predictors of acid-secretory state in populations infected with H pylori.

Effect of simple analgesics on quantitative sensation test threshold.

Twenty individuals underwent quantitative sensation testing (QST) before and after 1 dose of aspirin, acetaminophen, or acetaminophen with codeine to determine the effect of analgesics on QST results. There was no significant change from baseline when mean QST results after placebo were compared to mean QST results after analgesics. We conclude that the effect of small doses of simple analgesics on QST results is either not present or is too small to necessitate withholding analgesics before sensory testing.

A 4, 2, and 1 stepping algorithm for quick and accurate estimation of cutaneous sensation threshold.

In quantitative sensory testing, certain methods may lead to incorrect estimates of vibratory (VDT), cool (CDT), or warm (WDT) detection thresholds. We have shown that the specific forced-choice algorithm of testing employed in our Computer-Assisted Sensory Examination (CASE IV) system, when compared with other tests of nerve dysfunction, provides accurate and reproducible estimates of these thresholds. Because this forced-choice algorithm is time consuming and performance might be made worse by drowsiness or boredom, we explored other algorithms that might provide estimates of threshold similar to those obtained with the forced-choice algorithm, but more quickly. In a trial of 25 healthy subjects and 25 patients with neuropathy, the 4, 2, and 1 stepping algorithm with null stimuli, based in part on comparative data from computer simulation and insights from patient decision making, provides an accurate estimate of threshold. On average, the time needed for forced-choice testing was 12.8 +/- 2.9 minutes (mean +/- SD). For 4, 2, and 1 stepping testing, it was 2.7 +/- 2.5 minutes--a large saving of time. Since null stimuli were employed in the 4, 2, and 1 stepping algorithm, it was possible to monitor for spurious responses and repeat the test if they occurred at an excessive rate. The algorithm appears to be sufficiently robust to be recommended for clinical use and for some controlled clinical and epidemiologic trials.

Cool, warm, and heat-pain detection thresholds: testing methods and inferences about anatomic distribution of receptors.

We recently found that vibratory detection threshold is greatly influenced by the algorithm of testing. Here, we study the influence of stimulus characteristics and algorithm of testing and estimating threshold on cool (CDT), warm (WDT), and heat-pain (HPDT) detection thresholds. We show that continuously decreasing (for CDT) or increasing (for WDT) thermode temperature to the point at which cooling or warming is perceived and signaled by depressing a response key ("appearance" threshold) overestimates threshold with rapid rates of thermal change. The mean of the appearance and disappearance thresholds also does not perform well for insensitive sites and patients. Pyramidal (or flat-topped pyramidal) stimuli ranging in magnitude, in 25 steps, from near skin temperature to 9 degrees C for 10 seconds (for CDT), from near skin temperature to 45 degrees C for 10 seconds (for WDT), and from near skin temperature to 49 degrees C for 10 seconds (for HPDT) provide ideal stimuli for use in several algorithms of testing and estimating threshold. Near threshold, only the initial direction of thermal change from skin temperature is perceived, and not its return to baseline. Use of steps of stimulus intensity allows the subject or patient to take the needed time to decide whether the stimulus was felt or not (in 4, 2, and 1 stepping algorithms), or whether it occurred in stimulus interval 1 or 2 (in two-alternative forced-choice testing). Thermal thresholds were generally significantly lower with a large (10 cm2) than with a small (2.7 cm2) thermode.(ABSTRACT TRUNCATED AT 250 WORDS)

Intradermal recombinant human nerve growth factor induces pressure allodynia and lowered heat-pain threshold in humans.

Nerve growth factor (NGF) plays a biologic role in the development and maintenance of sympathetic and small sensory neurons. Because it facilitates nerve fiber regeneration, lowers heat-pain threshold (hyperalgesia), and prevents or improves nerve dysfunction in experimental neuropathy, it is being considered as a putative treatment for certain human polyneuropathies. In 16 healthy subjects, we tested whether intradermal injection of minute doses of recombinant human NGF (1 or 3 micrograms) compared with saline induces hyperalgesia or alters cutaneous sensation (at the site of injection) as measured by symptom scores, clinical examination, or quantitative sensory testing with Computer Assisted Sensory Examination (CASE IV). Most subjects had, as their only symptom, localized tenderness of the NGF-injected site and only when the site was bumped or compressed. Slight discomfort developed in volar wrist structures (with flexion of fingers) or tenderness of deep structures to palpation over the bicipital groove or supraclavicular region. The Neuropathy Symptoms and Change questionnaire indicated that pressure allodynia was significantly localized to the NGF-injected side from 3 hours to 21 days after injections. Light stroking of the skin did not induce tactile allodynia. Compression of injected sites induced pressure allodynia that occurred more frequently and significantly on the NGF-injected side after 3 hours and was maintained for several weeks. No abnormality of vibratory or cooling detection threshold developed from NGF injection. By contrast, heat-pain threshold (HP 0.5, p = 0.003) and an intermediate level of heat-pain (HP 5.0, p < 0.001) were significantly lowered 1, 3, and 7 days (and in some cases at 3 hours and 14 and 21 days) after NGF injection. The time course of pressure allodynia and heat-pain hyperalgesia is too rapid to be explained by uptake of NGF by nociception terminals, retrograde transport, and upregulation of pain modulators. Local tissue mechanisms appear to be implicated. It remains to be tested whether recombinant human NGF prevents, stabilizes, or ameliorates small fiber human neuropathies.

Comparison of algorithms of testing for use in automated evaluation of sensation.

Estimates of vibratory detection threshold may be used to detect, characterize, and follow the course of sensory abnormality in neurologic disease. The approach is especially useful in epidemiologic and controlled clinical trials. We studied which algorithm of testing and finding threshold should be used in automatic systems by comparing among algorithms and stimulus conditions for the index finger of healthy subjects and for the great toe of patients with mild neuropathy. Appearance thresholds obtained by linear ramps increasing at a rate less than 4.15 microns/sec provided accurate and repeatable thresholds compared with thresholds obtained by forced-choice testing. These rates would be acceptable if only sensitive sites were studied, but they were too slow for use in automatic testing of insensitive parts. Appearance thresholds obtained by fast linear rates (4.15 or 16.6 microns/sec) overestimated threshold, especially for sensitive parts. Use of the mean of appearance and disappearance thresholds, with the stimulus increasing exponentially at rates of 0.5 or 1.0 just noticeable difference (JND) units per second, and interspersion of null stimuli, Békésy with null stimuli, provided accurate, repeatable, and fast estimates of threshold for sensitive parts. Despite the good performance of Békésy testing, we prefer forced choice for evaluation of the sensation of patients with neuropathy.

Utility of thermography in the diagnosis of lumbosacral radiculopathy.

We performed infrared telethermography in 55 patients with the clinical diagnosis of lumbosacral radiculopathy and in 37 normal controls. Five readers interpreted the thermograms in a blinded fashion. A moderate degree of agreement was noted in tests of intraobserver and interobserver variability. The sensitivity of thermography ranged from 78% to 94% compared with 81% to 92% for imaging studies and 77% for EMG. The specificity of thermography ranged from 20% to 44%. Thermography predicted the level of the radiculopathy correctly in less than 50% of cases. Thermography has little or no utility in the diagnosis of lumbosacral radiculopathy.

Anthropometric measures and risk of death in children with end-stage renal disease.

We evaluated the association between anthropometric measurements and death among pediatric patients with end-stage renal disease (ESRD) using data from the Pediatric Growth and Development Special Study (PGDSS) from the US Renal Data System. Height, growth velocity, and body mass index (BMI) were used for the analysis of 1,949 patients in the PGDSS. To standardize these measurements, SD scores (SDSs) were calculated using population data from the Third National Health and Nutrition Examination Survey. Using Cox proportional hazards models, we assessed the association between anthropometric measures and death, controlling for demographic factors and stratifying by age. Multivariate analysis showed that each decrease by 1 SDS in height was associated with a 14% increase in risk for death (adjusted relative risk [aRR], 1.14; 95% confidence interval [CI], 1.02 to 1.27; P = 0.017). For each 1 SDS decrease in growth velocity among patients in our sample, the risk for death increased by 12% (aRR, 1.12; 95% CI, 1.00 to 1.25; P = 0.043). There was a statistically significant U-shaped association between BMI and death (P = 0.001), with relatively low and high BMIs associated with an increased risk for death. In children with ESRD, growth delay and extremes in BMI are associated with an increased risk for mortality.

Problems related to acid rebound and tachyphylaxis.

Rebound acid hypersecretion after taking histamine H(2)-receptor antagonists is a now well-established class phenomenon. It has been demonstrated both basally and in response to meal and gastrin-releasing peptide stimulation, but not in response to peak pentagastrin stimulation. It is present by 3 days after treatment but has resolved by 10 days. A recent study in previously asymptomatic healthy volunteers has suggested that this phenomenon may be clinically relevant. Tachyphylaxis/tolerance after the use of H(2)-receptor antagonists is also now well established. It manifests as a loss of acid inhibitory efficacy and is also a class effect. It is present within a few doses but is not progressive after 29 days. Rebound acid hypersecretion after proton pump inhibitors has been shown for both basal and maximal acid output by 14 days after treatment. It is found in Helicobacter pylori -negative, but not positive, subjects, probably owing to the influence of the enhanced oxyntic gastritis that occurs during proton pump inhibitor therapy. It is a prolonged phenomenon, lasting for at least 2 months after a 2-month treatment course. This duration is likely to reflect its development as a result of trophic effects on the oxyntic mucosa. This trophism is caused by the marked hypergastrinaemia that occurs secondary to the profound acid suppression during proton pump inhibitor treatment. The clinical relevance of this phenomenon remains at present unknown. Tachyphylaxis/tolerance has not yet been shown in several short-term studies after taking proton pump inhibitors. A recent clinical study has, however, suggested that this phenomenon may merit longer-term evaluation.