A double-blind, placebo-controlled randomized trial of creatine for the cancer anorexia/weight loss syndrome (N02C4): an Alliance trial.

BACKGROUND: Multiple pilot studies, including one in colorectal cancer patients, suggest that creatine, an amino acid derivative, augments muscle, improves strength, and thereby could palliate the cancer anorexia/weight loss syndrome. PATIENTS AND METHODS: In this randomized, double-blind, placebo-controlled trial, incurable patients with this syndrome were assigned creatine (20 g/day load×5 days followed by 2 g/day orally) versus identical placebo. Patients were weighed once a week for 1 month and then monthly. Patients were also assessed over 1 month for appetite and quality of life (validated questionnaires), fist grip strength, body composition (bioelectrical impedance), and adverse events. The primary endpoint was 10% or greater weight gain from baseline during the first month. RESULTS: Within this combined cohort of 263 evaluable patients (134 received creatine and 129 placebo), only 3 gained ≥10% of their baseline weight by 1 month: two creatine-treated and the other placebo-exposed (P = 1.00). Questionnaire data on appetite, quality of life, and activities of daily living showed no statistically significant differences between groups. Similarly, no statistically significant differences between groups were observed for fist-grip strength or body composition. Rates and severity of adverse events were comparable between groups. Finally, a median survival of 230 and 239 days were observed in the creatine and placebo groups, respectively (P = 0.70). CONCLUSION: Creatine, as prescribed in this trial, had no effect on the cancer anorexia/weight loss syndrome.

5-Year Update of a Multi-Institution, Prospective Phase 2 Hypofractionated Postmastectomy Radiation Therapy Trial.

PURPOSE: Hypofractionation in the setting of postmastectomy radiation (PMRT) is not currently the standard of care in most countries. Here we present a 5-year update of our multi-institutional, phase 2 prospective trial evaluating a novel 15-day hypofractionated PMRT regimen. METHODS AND MATERIALS: Patients were enrolled to receive 3.33 Gy daily to the chest wall (or reconstructed breast) and regional lymphatics in 11 fractions with an optional 4-fraction mastectomy scar boost. The primary endpoint was freedom from grade 3 or higher late non-reconstruction-related radiation toxicities. Toxicities were scored using Common Terminology Criteria for Adverse Events v4.0. Secondary endpoints included local and locoregional recurrence rates, cosmesis, and reconstruction complications. RESULTS: After enrolling 69 patients with stage II-IIIa breast cancer, 67 women were eligible for analysis. At a median follow up of 54 months, there were no acute or late grade 3 and 4 nonreconstruction reported toxicities. The grade 2 or greater late toxicity rate was only 12% and comprised grade 2 pain, fatigue, and lymphedema that persisted beyond 6 months after completion of radiation therapy. Only 3 women (4.6%) experienced a chest wall or nodal recurrence as a first site of relapse. Freedom from local failure, including local failure after distant relapse, was 92% at 5 years, and the 5-year overall survival was 90%. CONCLUSIONS: This is the first prospective trial conducted in the United States to demonstrate the safe and effective use of hypofractionated PMRT. We have demonstrated a low complication rate while achieving excellent local control. Toxicity was better than anticipated based on previously published series of PMRT toxicities. Although our fractionation was novel, the radiobiological equivalent dose is similar to other hypofractionation schedules. This trial was the basis for the creation of Alliance A221505 (RT CHARM), which is currently accruing patients in a phase 3 randomized design.

Simultaneous magnetically directed drug convection and MR imaging.

Superparamagnetic iron oxide nanoparticles (IO NPs) are of interest for their usefulness in biomedical applications. In this work, we have synthesized iron oxide nanocomposites surface-modified with different biocompatible polymers. Bovine serum albumin (BSA) was physisorbed onto these IO NPs along with an excipient during freeze-drying. The mass transport of the protein attached to the iron oxide core-shell nanoparticles (IO cs-NPs) under a gradient magnetic field of an MRI instrument was observed in vitro and in an egg as a model system for a biological fluid. From the in vitro experiments in agarose gels, it was observed that the protein gets separated from the core during mass transport for some cs-IO, but co-migration was observed for PEG-modified IO cs-NPs. These experiments demonstrated proof-of-concept for the use of IO cs-NPs in magnetically directed drug convection.

Using strain typing to characterise a fluoroquinolone-resistant Neisseria gonorrhoeae transmission network in southern California.

OBJECTIVE: We investigated the initial outbreak of fluoroquinolone-resistant Neisseria gonorrhoeae (QRNG) in southern California with analysis of transmission using strain typing. METHODS: Surveillance for QRNG was conducted between 2000 and 2002 in southern California, including epidemiology and strain typing by a combination of antibiogram, auxotype, serovar, Lip type and amino acid alteration patterns in the quinolone-resistance determining region of GyrA and ParC. Combining epidemiological data with strain typing, we describe the emergence of QRNG outbreak strains using risk factor analysis and transmission networks. RESULTS: Two outbreak strains accounted for 82% of isolates. Both strains required proline, were Lip type 17c, had amino acid alterations 91> Phe in GyrA and 87> Arg in ParC, but they differed by their serovar, IB-3C8 versus IB-2H7, 2G2. Outbreak strains were positively associated with men who have sex with men (MSM), adjusted odds ratio (AOR) 23.9 (95% confidence interval (CI) 2.2 to 261) and negatively associated with travel history: AOR 0.05, (95% CI 0.0 to 0.6). Network analysis demonstrated that 17 cases were connected by sexual contacts and/or public venues including bars, bathhouses/sex clubs, and internet sites. CONCLUSIONS: QRNG may have become established among Californian MSM through an identified transmission network of southern Californian bars, bathhouses and internet sites.

Neuropathic and cerebrovascular correlates of hearing loss in Fabry disease.

Fabry disease, OMIM 301500, is a progressive multisystem storage disorder due to the deficiency of alpha-galactosidase A (GALA). Neurological and vascular manifestations of this disorder with regard to hearing loss have not been analysed quantitatively in large cohorts. We conducted a retrospective cross sectional analysis of hearing loss in 109 male and female patients with Fabry disease who were referred to and seen at the Clinical Center of the National Institutes of Health, Bethesda, MD, USA on natural history and enzyme replacement study protocols. There were 85 males aged 6-58 years (mean 31 years, SD 13) and 24 females aged 22-72 years (mean 42 years, SD 12). All patients underwent a comprehensive audiological evaluation. In addition, cerebral white matter lesions, peripheral neuropathy, and kidney function were quantitatively assessed. HL(95), defined as a hearing threshold above the 95th percentile for age and gender matched normal controls, was present in 56% [95% CI (42.2-67.2)] of the males. Prevalence of HL(95) was lower in the group of patients with residual GALA enzyme activity compared with those without detectable activity (33% versus 63%) HL(95) was present in the low-, mid- and high-frequency ranges for all ages. Male patients with HL(95) had a higher microvascular cerebral white matter lesion load [1.4, interquartile range (IQR) 0-30.1 +/- versus 0, IQR 0-0], more pronounced cold perception deficit [19.4 +/- 5.5 versus 13.5 +/- 5.5 of just noticeable difference (JND) units] and lower kidney function [creatinine: 1.6 +/- 1.2 versus 0.77 +/- 0.2 mg/dl; blood urea nitrogen (BUN): 20.1 +/- 14.1 versus 10.3 +/- 3.28 mg/dl] than those without HL(95) (P < 0.001). Of the females, 38% had HL(95). There was no significant association with cold perception deficit, creatinine or BUN in the females. Word recognition and acoustic reflexes analyses suggested a predominant cochlear involvement. We conclude that hearing loss involving all frequency regions significantly contributes to morbidity in patients with Fabry disease. Our quantitative analysis suggests a correlation of neuropathic and vascular damage with hearing loss in the males. Residual GALA activity appears to have a protective effect against hearing loss.

Species distribution and antimicrobial resistance of enterococci isolated from surface and ocean water.

AIMS: The species identification and antimicrobial resistance profiles were determined for enterococci isolated from Southern California surface and ocean waters. METHODS AND RESULTS: Species identification was determined for 1413 presumptive Enterococcus isolates from urban runoff, bay, ocean and sewage water samples. The most frequently isolated species were Enterococcus faecalis, Enterococcus faecium, Enterococcus hirae, Enterococcus casseliflavus and Enterococcus mundtii. All five of these species were isolated from ocean and bay water with a frequency ranging from 7% to 36%. Enterococcus casseliflavus was the most frequently isolated species in urban runoff making up 36-65% of isolates while E. faecium was the most frequently isolated species in sewage making up 53-78% of isolates. The similar distribution of species in urban runoff and receiving water suggests that urban runoff may be the source of Enterococcus. No vancomycin or high level gentamycin resistance was detected in E. faecalis and E. faecium isolates. CONCLUSIONS: Enterococcus faecalis, E. faecium, E. casseliflavus and E. mundtii are the most commonly isolated Enterococcus species from urban runoff and receiving waters in Southern California. SIGNIFICANCE AND IMPACT OF THE STUDY: Determination of the Enterococcus species isolated from receiving waters and potential pollution sources may assist in determining the sources of pollution.

Stroke surveillance in Manitoba, Canada: estimates from administrative databases.

This study investigated the use of population-based administrative databases for stroke surveillance. First, a meta-analysis was conducted of four studies, identified via a PubMed search, which estimated the sensitivity and specificity of hospital data for ascertaining cases of stroke when clinical registries or medical charts were the gold standard. Subsequently, case-ascertainment algorithms based on hospital, physician and prescription drug records were developed and applied to Manitoba's administrative data, and prevalence estimates were obtained for fiscal years 1995/96 to 2003/04 by age group, sex, region of residence and income quintile. The meta-analysis results revealed some over-ascertainment of stroke cases from hospital data when the algorithm was based on diagnosis codes for any type of cerebrovascular disease (Mantel-Haenszel Odds-Ratio [OR] - 1.70 [95% confidence interval (CI): 1.53 - 1.88]). Analyses of Manitoba administrative data revealed that while the total number of stroke cases varied substantially across the algorithms, the trend in prevalence was stable regardless of the algorithm adopted.

Solar particle event storm shelter requirements for missions beyond low Earth orbit.

Protecting spacecraft crews from energetic space radiations that pose both chronic and acute health risks is a critical issue for future missions beyond low Earth orbit (LEO). Chronic health risks are possible from both galactic cosmic ray and solar energetic particle event (SPE) exposures. However, SPE exposures also can pose significant short term risks including, if dose levels are high enough, acute radiation syndrome effects that can be mission- or life-threatening. In order to address the reduction of short term risks to spaceflight crews from SPEs, we have developed recommendations to NASA for a design-standard SPE to be used as the basis for evaluating the adequacy of proposed radiation shelters for cislunar missions beyond LEO. Four SPE protection requirements for habitats are proposed: (1) a blood-forming-organ limit of 250 mGy-equivalent for the design SPE; (2) a design reference SPE environment equivalent to the sum of the proton spectra during the October 1989 event series; (3) any necessary assembly of the protection system must be completed within 30 min of event onset; and (4) space protection systems must be designed to ensure that astronaut radiation exposures follow the ALARA (As Low As Reasonably Achievable) principle.

Glutathione S-transferase activity and glutathione S-transferase mu expression in subjects with risk for colorectal cancer.

The glutathione S-transferases (alpha, mu, and pi), a family of Phase II detoxication enzymes, play a critical role in protecting the colon mucosa by catalyzing the conjugation of dietary carcinogens with glutathione. We investigated the efficacy of using the glutathione S-transferase (GST) activity of blood lymphocytes and GST-mu expression as biomarkers of risk for colorectal cancer. GST activity was measured in the blood lymphocytes of control individuals (n = 67) and in the blood lymphocytes (n = 60) and colon tissue (n = 34) of individuals at increased risk for colon cancer. Total GST activity was determined spectrophotometrically with the use of 1-chloro-2,4-dinitrobenzene as a substrate. The ability to express the um subclass of GST was determined with the use of an ELISA. Although interindividual variability in the GST activity of blood lymphocytes was greater than 8-fold (range, 16.7-146.8 nmol/min/mg), the GST activity of blood lymphocytes and colon tissue within an individual was constant over time and was unrelated to sex, age, or race. The GST activity of blood lymphocytes from high-risk individuals was significantly lower than that of blood lymphocytes from control individuals (P < or = 0.004). No association was observed between the frequency of GST-mu phenotype and risk for colorectal cancer. Blood lymphocytes from high-risk individuals unable to express GST-mu had lower levels of GST activity than did those from control subjects with the GST-mu null phenotype; however, this difference was significant in male subjects only (P < or = 0.006). Analysis of paired samples of blood lymphocytes and colon tissue indicated a strong correlation between the GST activity of the two tissue types (Spearman's rank correlation, r = 0.87; P < or = 0.0001). The GST activity of blood lymphocytes may be used to identify high-risk individuals with decreased protection from this Phase II detoxication enzyme who may benefit from clinical trials evaluating GST modulators as chemopreventive agents for colorectal cancer. The GST activity of blood lymphocytes may also be used in colorectal cancer chemoprevention trials to monitor the responsiveness of colon tissue to regimens that modify Phase II detoxication enzymes.

Regional cerebral hyperperfusion and nitric oxide pathway dysregulation in Fabry disease: reversal by enzyme replacement therapy.

BACKGROUND: Fabry disease is an X-linked lysosomal deficiency of alpha-galactosidase A that results in cellular accumulation of galacto-conjugates such as globotriosylceramide, particularly in blood vessels. It is associated with early-onset stroke and kidney and heart failure. METHODS AND RESULTS: Using [(15)O] H(2)O and PET, we found increased resting regional cerebral blood flow in Fabry disease without evidence of occlusive vasculopathy or cerebral hypoperfusion. Because nitric oxide is known to play an important role in vascular tone and reactivity, we studied plasma nitrate, nitrite, and low-molecular-weight S-nitrosothiol levels by chemiluminescence. Skin biopsy specimens and archived brain tissue were also examined immunohistochemically for nitrotyrosine. Plasma nitrate, nitrite, and low-molecular-weight S-nitrosothiol were in the normal range; however, enhanced nitrotyrosine staining was observed in dermal and cerebral blood vessels. After a double-blind, placebo-controlled trial of alpha-galactosidase A therapy, the resting regional cerebral blood flow in the treated group was significantly reduced, with a notable decrease of nitrotyrosine staining in dermal blood vessels. CONCLUSIONS: These findings suggest a chronic alteration of the nitric oxide pathway in Fabry disease, with critical protein nitration that is reversible with enzyme replacement therapy.

Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non--small-cell lung cancer: a Southwest Oncology Group trial.

PURPOSE: This randomized trial was designed to determine whether paclitaxel plus carboplatin (PC) offered a survival advantage over vinorelbine plus cisplatin (VC) for patients with advanced non--small-cell lung cancer. Secondary objectives were to compare toxicity, tolerability, quality of life (QOL), and resource utilization. PATIENTS AND METHODS: Two hundred two patients received VC (vinorelbine 25 mg/m(2)/wk and cisplatin 100 mg/m(2)/d, day 1 every 28 days) and 206 patients received PC (paclitaxel 225 mg/m(2) over 3 hours with carboplatin area under the curve of 6, day 1 every 21 days). Patients completed QOL questionnaires at baseline, 13 weeks, and 25 weeks. Resource utilization forms were completed at five time points through 24 months. RESULTS: Patient characteristics were similar between the groups. The objective response rate was 28% in the VC arm and 25% in the PC arm. Median survival was 8 months in both arms, with 1-year survival rates of 36% and 38%, respectively. Grade 3 and 4 leukopenia (P =.002) and neutropenia (P =.008) occurred more frequently on the VC arm. Grade 3 nausea and vomiting were higher on the VC arm (P =.001, P =.007), and grade 3 peripheral neuropathy was higher on the PC arm (P <.001). More patients on the VC arm discontinued therapy because of toxicity (P =.001). No difference in QOL was observed. Overall costs on the PC arm were higher than on the VC arm because of drug costs. CONCLUSION: PC is equally efficacious as VC for the treatment of advanced non--small-cell lung cancer. PC is less toxic and better tolerated but more expensive than VC. New treatment strategies should be pursued.

Familial associations with EEG variants in manic-depressive disease.

Electroencephalographic (EEG) studies of 60 patients with bipolar manic-depressive disease disclosed an incidence of small sharp spikes plus a few other variations in 47% of the sample. In women these EEG features were significantly associated with a history of mental illness in the patient's mother or the maternal side of the family and an absence of mental disorder in the fathers. The reverse was true of women probands without these EEG characteristics. In the men small sharp spikes did not relate to parental psychopathology but half of the sisters of men with these EEG characteristics were found to be mentally ill. On the basis of these observations and previous work, we hypothesize that the small sharp spike EEG pattern might be an inherited characteristic related in some way to the familal transmission of manic-depressive disease.

Primary radiotherapy vs conservative management for localized prostate cancer--a population-based study.

BACKGROUND: Radiotherapy is the most common curative cancer therapy used for elderly patients with localized prostate cancer. However, the effectiveness of this approach has not been established. The purpose of this study is to evaluate the long-term outcomes of primary radiotherapy compared with conservative management in order to facilitate treatment decisions. METHOD: This population-based study consisted of 57,749 patients with T1-T2 prostate cancers diagnosed during 1992-2007. We utilized an instrumental variable (IV) analytical approach with competing risk models to evaluate the outcomes of primary radiotherapy vs conservative management. The IV was comprised of combined health service areas with high- and low-use areas corresponding to the top and bottom tertile in radiotherapy usage rates. RESULTS: In patients with low-/intermediate-risk prostate cancer, 10-year prostate cancer-specific and overall survival was similar in high- and low-radiotherapy use areas (96.1 vs 95.4% and 56.6 vs 56.3%, respectively). In patients with high-risk disease, however, areas with high-radiotherapy use had a higher 10-year cancer-specific survival (90.2 vs 88.1%, difference 2.1%; 95% CI 0.3-4.0%) and 10-year overall survival (53.3 vs 50.2%, difference 3.1%; 95% CI 1.3-6.3%). Results were similar irrespective of the type of radiotherapy used. To assess the robustness of our choice of IV, we repeated the IV analytical approach using different IVs (using the median utilization rate as the cutoff) and found the results to be similar. CONCLUSIONS: Among men >65 years of age, the benefit of primary radiotherapy for localized disease is largely confined to patients with high-risk prostate cancer (Gleason scores 7-10).

Enhanced endothelium-dependent vasodilation in Fabry disease.

BACKGROUND AND PURPOSE: Fabry disease is an X-linked lysosomal storage disease secondary to deficiency of alpha-galactosidase A with resulting glycolipid accumulation, particularly globotriaosylceramide in arterial smooth muscle and endothelial cells. A systemic vasculopathy, including early-onset stroke, is prevalent without a clear pathogenesis. METHODS: Seventeen normotensive and normocholesterolemic hemizygous Fabry patients (aged 21 to 49 years) and 13 control subjects (aged 21 to 48 years) were investigated by venous plethysmography, allowing assessment of forearm blood flow. Plethysmographic measurements were obtained at baseline and during intra-arterial infusion of acetylcholine and sodium nitroprusside both with and without N(G)-monomethyl-L-arginine (L-NMMA). RESULTS: Forearm blood flow was significantly higher in patients than in control subjects at all 3 acetylcholine doses (P=0.014). Patients had a greater response to acetylcholine even after the addition of L-NMMA (P=0.036). CONCLUSIONS: These results demonstrate an increased endothelium-mediated vascular reactivity in Fabry disease. The increased vessel response to acetylcholine with and without L-NMMA suggests altered functionality of non-NO endothelium-dependent vasodilatory pathways.

Follow-up of stereotaxic amygdalotomy for seizure and behavior disorders.

Stereotaxic amygdalotomy for the control of unmanageable behavior and/or intractable seizures is a controversial treatment approach with unknown risk-to-benefit ratios. Information about this subject was obtained from a retrospective follow-up study of 58 patients who received this form of treatment 1 to 11 years earlier (average 6 years). Assessments of the patients were made by invesgators external to the surgical treatment system, using structured psychiatric interviews, neuropsychological tests, and EEGs. In addition, global assessments were made, comparing pre- versus postoperative status. The objective data revealed no indication of worsening or damage with similar pre- and postoperative test scores and EEG features. Computer-scored interviews revealed considerable psychopathology in the ambulatory patients. Overall judgments of behavior, seizures, and functional levels indicated that more than a third of the group was probably improved, although the relationship of outcome to the surgery was indeterminate.

Evidence for neuroaxonal injury in patients with proteolipid protein gene mutations.

The authors used proton MRS to investigate neuropathologic correlates in nine patients with proteolipid protein (PLP) gene mutations who did not show cerebral atrophy on cranial MRI. When compared with 16 age-matched control participants, patients with PLP mutations had significant and widespread decreased brain N-acetyl aspartate, a neuronal marker. The authors conclude that PLP mutations cause neuroaxonal injury, which in turn contributes to the neurologic deficit observed in these patients.

The neurogenetics of mucolipidosis type IV.

BACKGROUND: Mucolipidosis type IV (MLIV) is an autosomal recessive disease caused by mutations in the MCOLN1 gene that codes for mucolipin, a member of the transient receptor potential (TRP) gene family. OBJECTIVE: To comprehensively characterize the clinical and genetic abnormalities of MLIV. METHODS: Twenty-eight patients with MLIV, aged 2 to 25 years, were studied. Ten returned for follow-up every 1 to 2 years for up to 5 years. Standard clinical, neuroimaging, neurophysiologic, and genetic techniques were used. RESULTS: All patients had varying degrees of corneal clouding, with progressive optic atrophy and retinal dystrophy. Twenty-three patients had severe motor and mental impairment. Motor function deteriorated in three patients and remained stable in the rest. All had a constitutive achlorhydria with elevated plasma gastrin level, and 12 had iron deficiency or anemia. Head MRI showed consistent characteristic findings of a thin corpus callosum and remained unchanged during the follow-up period. Prominent abnormalities of speech, hand usage, and swallowing were also noted. Mutations in the MCOLN1 gene were present in all patients. Correlation of the genotype with the neurologic handicap and corpus callosum dysplasia was found. CONCLUSIONS: MLIV is both a developmental and a degenerative disorder. The presentation as a cerebral palsy-like encephalopathy may delay diagnosis.

Clinical trials of fluorouracil with alpha-interferon in advanced colorectal carcinomas.

Three clinical trials have been conducted with fluorouracil (5-FU) and recombinant interferon alfa-2a (rIFN-alpha 2a) in the treatment of advanced colorectal carcinoma. The regimen consisted of 5-FU (750 mg/m2/d) as an intravenous continuous infusion for 5 consecutive days followed by a week's rest. Weekly bolus 5-FU (750 mg/m2) was subsequently administered. Nine million units of rIFN-alpha 2a was administered subcutaneously three times weekly. The initial clinical trial conducted by investigators from the Albert Einstein Cancer Center (New York, NY) reported a 76% response rate with 13 of 17 patients responding. When this clinical trial was extended to 32 patients, 20 patients (63%) achieved partial responses. Investigators from the University of Texas M.D. Anderson Cancer Center (Houston, TX) enrolled 45 evaluable patients and reported 15 partial responses and one clinical complete response (response rate, 36%). A similar trial was conducted at Memorial Sloan-Kettering Cancer Center (New York, NY) with nine of 35 patients (26%) experiencing partial responses. Grades 3 to 4 toxicities in these three trials included mucositis, diarrhea, leukopenia, and neurotoxicity. Four treatment-related deaths were reported, with three of these deaths ascribed to profuse watery diarrhea associated with leukopenia. Current randomized trials are comparing this regimen with 5-FU plus folinic acid. Future strategies will examine alternative schedules of 5-FU with interferon, and will attempt to better define the mechanism of interaction.

Modulation of fluorouracil with recombinant alfa interferon: M. D. Anderson Clinical trial.

Clinical trials have been initiated examining the combination of fluorouracil (5-FU) and recombinant interferon alfa-2a (rIFN-2a) in the treatment of advanced colorectal carcinomas. An early trial reported a response rate of 76%, encouraging further investigation. Clinical trials have used 5-FU administered as a continuous intravenous infusion, 750 mg/m2 per day for 5 consecutive days, followed by weekly bolus administration of 5-FU 750 mg/m2. Recombinant interferon alfa-2a, 9 million units, was administered subcutaneously three times weekly. Of 45 evaluable patients treated at The University of Texas M. D. Anderson Cancer Center, a response rate of 35% (95% confidence interval, 22%, 50%) was observed. Twenty-five percent of patients developed grade 4 toxicity and 82% developed grade 3 toxicity. The median survival was 16 months. Investigation of this combination will require randomized trials to further assess activity in relation to alternative treatments.

Pica, iron deficiency, and the medical history.

We describe two new forms of pica associated with iron deficiency and a new variant of a third. Previous reports on pica are tabulated. The value of a sympathetic, nonjudgmental approach to eliciting the medical history is emphasized.