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1.  Description of 3,180 Courses of Chelation with Dimercaptosuccinic Acid in Children ≤5 y with Severe Lead Poisoning in Zamfara, Northern Nigeria: A Retrospective Analysis of Programme Data 
PLoS Medicine  2014;11(10):e1001739.
Jane Greig and colleagues from the medical humanitarian organization Médecins Sans Frontières describe the use of the oral chelating agent dimercaptosuccinic acid (DMSA) in several thousand young children with severe lead poisoning as a result of an environmental disaster in Zamfara, northern Nigeria.
Please see later in the article for the Editors' Summary
In 2010, Médecins Sans Frontières (MSF) discovered extensive lead poisoning impacting several thousand children in rural northern Nigeria. An estimated 400 fatalities had occurred over 3 mo. The US Centers for Disease Control and Prevention (CDC) confirmed widespread contamination from lead-rich ore being processed for gold, and environmental management was begun. MSF commenced a medical management programme that included treatment with the oral chelating agent 2,3-dimercaptosuccinic acid (DMSA, succimer). Here we describe and evaluate the changes in venous blood lead level (VBLL) associated with DMSA treatment in the largest cohort of children ≤5 y of age with severe paediatric lead intoxication reported to date to our knowledge.
Methods and Findings
In a retrospective analysis of programme data, we describe change in VBLL after DMSA treatment courses in a cohort of 1,156 children ≤5 y of age who underwent between one and 15 courses of chelation treatment. Courses of DMSA of 19 or 28 d duration administered to children with VBLL ≥ 45 µg/dl were included. Impact of DMSA was calculated as end-course VBLL as a percentage of pre-course VBLL (ECP). Mixed model regression with nested random effects was used to evaluate the relative associations of covariates with ECP. Of 3,180 treatment courses administered, 36% and 6% of courses commenced with VBLL ≥ 80 µg/dl and ≥ 120 µg/dl, respectively. Overall mean ECP was 74.5% (95% CI 69.7%–79.7%); among 159 inpatient courses, ECP was 47.7% (95% CI 39.7%–57.3%). ECP after 19-d courses (n = 2,262) was lower in older children, first-ever courses, courses with a longer interval since a previous course, courses with more directly observed doses, and courses with higher pre-course VBLLs. Low haemoglobin was associated with higher ECP. Twenty children aged ≤5 y who commenced chelation died during the period studied, with lead poisoning a primary factor in six deaths. Monitoring of alanine transaminase (ALT), creatinine, and full blood count revealed moderate ALT elevation in <2.5% of courses. No clinically severe adverse drug effects were observed, and no laboratory findings required discontinuation of treatment. Limitations include that this was a retrospective analysis of clinical data, and unmeasured variables related to environmental exposures could not be accounted for.
Oral DMSA was a pharmacodynamically effective chelating agent for the treatment of severe childhood lead poisoning in a resource-limited setting. Re-exposure to lead, despite efforts to remediate the environment, and non-adherence may have influenced the impact of outpatient treatment.
Please see later in the article for the Editors' Summary
Editors' Summary
Lead, a toxic metal that occurs naturally in the earth's crust, is now present throughout the environment because of human activities. For many years, lead was added to paint and gasoline and used in solder for water pipes. In addition, the mining, smelting, and refining of some metallic ores releases lead into the environment. Inhalation of contaminated air, consumption of contaminated food and water, and contact with dust that contains lead raises venous blood lead levels (VBLLs) and causes many health problems, particularly in children. Children who ingest large amounts of lead can develop anemia, muscle weakness, kidney damage, and life-threatening encephalopathy (brain swelling). Although fatal lead poisoning is now rare in resource-rich countries, it nevertheless remains a major global health problem. Over a three-month period in early 2010, for example, about 400 young children died in Zamfara State, Nigeria, from unexplained, intractable fits. By May 2010, it was clear that recently expanded gold mining had caused widespread environmental lead contamination in the region, and an environmental management program was begun to reduce lead levels in the surface soils.
Why Was This Study Done?
In response to the lead poisoning outbreak, the not-for-profit organization Médecins Sans Frontières (MSF) began a medical management program to reduce VBLLs that included treatment with the oral chelation agent dimercaptosuccinic acid (DMSA). Chelation agents bind metal ions and facilitate their removal from the body, thereby reducing the likelihood of lead moving from the blood to the brain. Lead encephalopathy has been commonly treated by injecting another chelator called CaNa2EDTA, but the discovery of more than 1,000 cases of childhood lead poisoning in rural villages in Nigeria meant that MSF needed a chelation approach that could be applied rapidly in a remote resource-limited setting. Additionally, although CaNa2EDTA has been in common use for severe lead poisoning for longer than DMSA, and is commonly recommended in guidelines, the evidence base does not support one treatment as superior. Here, in a retrospective analysis of MSF program data, the researchers evaluate the changes in VBLLs before and after courses of oral DMSA treatment in children aged five years and below living in Zamfara to gain new insights into this understudied treatment for severe childhood lead poisoning.
What Did the Researchers Do and Find?
The researchers measured VBLLs before and after treatment with DMSA in 1,156 children (inpatient and outpatient) with high amounts of lead in their blood who underwent one or more courses of chelation treatment lasting 19 or 28 days by calculating each child's end-course VBLL as a percentage of the child's pre-course VBLL (ECP). Considering all the treatment courses given between June 2010 and June 2011, the mean (average) ECP was 74.5%. That is, on average, VBLLs measured at the end of treatment courses were reduced by a quarter compared to VBLLs at the start of treatment courses. Among 159 inpatient courses of DMSA, the ECP was 47.7% (a halving of pre-course VBLLs). The ECP after 19-day courses was lower in older children, after first-ever courses, after courses with a longer interval since a previous course, after courses that included more directly observed doses (DMSA given in the presence of a health-care worker), and in children with higher pre-course VBLLs. Nine of the children included in this analysis died during the study period; lead poisoning was probably involved in three of these deaths. Importantly, no clinically severe adverse effects related to DMSA were seen during the study period, and no laboratory findings were recorded that required treatment discontinuation.
What Do These Findings Mean?
Because many changes were made to the treatment given to the affected children in Zamfara during the study period and because no information is presented here on clinical outcomes, these findings cannot be used to reach any definitive conclusions about the effectiveness or safety of oral DMSA as a treatment for lead poisoning in young children. However, these findings show that chelation was associated with a large reduction in the death rate among probable or suspected cases of childhood lead poisoning in Zamfara and provide new information about oral chelation that may help agencies such as MSF provide urgent treatment for lead poisoning in resource-limited settings where intravenous chelation is not feasible. Moreover, the finding of a lower ECP after inpatient treatment courses compared to after outpatient courses suggests that re-exposure to lead and non-adherence to treatment may have influenced the impact of outpatient treatments. Thus, it is essential that medical management of lead poisoning in resource-limited settings be accompanied by environmental remediation and that efforts are made to support adherence to treatment in the community by implementing directly observed treatment wherever possible.
Additional Information
Please access these websites via the online version of this summary at
A related PLOS ONE Research Article by Greig et al. provides information about the association between VBLLs and neurological features in children affected by the acute lead poisoning outbreak in Zamfara
MSF provides information about the lead poisoning crisis in Zamfara State
Human Rights Watch, an international organization that works to uphold human dignity and advance the cause of human rights for all, also provides information about lead poisoning in Zamfara State, including photographs and a video
Tox Town, an interactive site about environmental health concerns from the US National Library of Medicine, provides information on exposure to lead (in English and Spanish)
The US Environmental Protection Agency provides information on lead and lead poisoning (in English and Spanish)
The US Centers for Disease Control and Prevention provides information about lead in the environment and about its lead poisoning prevention program
MedlinePlus provides a list of links to further information about lead poisoning (in English and Spanish)
PMCID: PMC4188566  PMID: 25291378
2.  Lead Poisoning-Induced Hypertensive Crisis Managed by Prazosin: A Case Report 
Chronic lead exposure is known to be a risk factor for hypertension (HTN). No specific medication is recommended for the treatment of lead-induced hypertension (LIHTN).
Case Presentation
Our patient was a male admitted with the chief complaint of chronic abdominal pain. His whole blood lead level was reported to be 1961 µg/L. He also mentioned a previous history of HTN managed by propranolol (10 mg, TDS). He discharged himself by giving written consent and 19 days later, he was re-admitted due to high blood pressure of 220/140 mmHg. His Blood pressure (BP) was decreased to 180/110 mmHg with sublingual captopril; but, in maintenance therapy, higher doses of captopril could not further decrease BP. Amlodipine was tried which was discontinued due to the patient intolerance. Prazosin was then administered in gradual increasing doses up to 1 mg twice a day and captopril was tapered.
We would like to suggest that LIHTN may better be managed by alpha blockers compared with converting enzyme inhibitors
PMCID: PMC3840843  PMID: 24349754
Lead; Hypertension; Prazosin
3.  Radiolabeled fragments of monoclonal antibodies against carcinoembryonic antigen for localization of human colon carcinoma grafted into nude mice 
Four monoclonal antibodies against carcinoembryonic antigen (CEA) have been selected from 32 hybrids that produce antibodies against this antigen, by the criteria of high affinity for CEA and low cross- reactivity with granulocyte glycoprotein(s). The specificity of tumor localization in vivo of the four MAb, and their F(ab')2 and Fab fragments was compared in nude mice bearing grafts of a serially transplanted, CEA-producing, human colon carcinoma. The distribution of radiolabeled MAb and their fragments after intravenous injection was analyzed by direct measurement of radioactivity in tumor and normal organs, as well as by whole-body scanning and by autoradiography of tumor sections. Paired labeling experiments, in which 131I-labeled antibody or fragments and 125I-labeled control IgG are injected simultaneously, were undertaken to determine the relative tumor uptakes of each labeled protein. The tumor antibody uptake divided by that of control IgG defines the specificity index of localization. Tumor antibody uptakes (as compared with the whole mouse), ranging between 7 and 15, and specificity indices ranging between 3.4 and 6.8, were obtained with the four intact MAb at day 4-5 after injection. With F(ab')2 fragments of the four MAb, at day 3, the tumor antibody uptakes ranged between 12 and 24 and the specificity indices between 5.3 and 8.2. With the Fab fragments prepared from the two most promising MAb, the antibody uptakes reached values of 34 and 82 at day 2-3 and the specificity indices were as high as 12 and 19. The scanning results paralleled those obtained by direct measurement of radioactivity. With intact MAb, tumor grafts of 0.5-1 g gave very contrasted positive scans 3 d after injection. Using MAb fragments, tumors of smaller size were detectable earlier. The best results were obtained with Fab fragments of MAb 35, which gave clear detections of tumors weighing only 0.1 g as early as 48 h after injection. Autoradiographs of tumor sections from mice injected with 125I-labeled MAb demonstrated that the radioactivity was localized in the tumor tissues and not in the stromal connective tissue of mouse origin. The highest radioactivity concentration was localized in areas known to contain CEA such as the pseudolumen of glands and the apical side of carcinoma cells. The penetration of radioactivity in the central part of tumor nodules and the pseudolumen appeared to be increased with the use of MAb fragments.
PMCID: PMC2187333  PMID: 6886623
4.  Distribution of radioactivity from 14C-formaldehyde in pregnant mice and their fetuses. 
The distribution of 14C after the administration of 14C-formaldehyde was studied in pregnant mice by a whole body low temperature autoradiographic technique. The concentrations of formaldehyde and its metabolites in maternal and fetal blood and tissues were determined in unsectioned tissues by liquid scintillation spectrophotometry. The binding of 14C from 14C-formaldehyde to cells and DNA in maternal and fetal mouse liver was also measured. Radioactivity of 14C deriving from 14C-formaldehyde was found immediately after injection, and showed strong accumulation and retention three hours after injection. The organs that had high concentrations at all studied survival intervals were maternal liver, intestinal mucosa, bone marrow, kidneys, and salivary glands. Considerable amounts of radioactivity were found in the fetuses at six hours after injection, and the concentrations were almost the same as in the maternal tissues. The elimination of 14C-formaldehyde and metabolites from the placenta and fetus occurred more slowly than from maternal tissue.
PMCID: PMC1061257  PMID: 8435351
5.  Distribution of aztreonam into fetuses and milk of rats. 
Subcutaneous administration of [14C]aztreonam (150 mg/kg) to pregnant rats was followed by the appearance of radioactive moieties in fetuses and amniotic fluid. Concentrations of both total radioactivity and unchanged aztreonam in maternal serum declined more rapidly than those in fetuses and amniotic fluid. [14C]aztreonam (150 mg/kg) was also administered subcutaneously to lactating rats. Radioactivity and unchanged aztreonam were found in the suckling pups and in the serum and milk of the dam. Results obtained by whole-body autoradiography were generally consistent with these obtained by measuring radioactivity present in the excised tissues. Autoradiographs of the pups showed detectable amounts of radioactivity in the brain; since no radioactivity was detectable in the brain of the dam, it appears that the blood-brain barrier was not fully developed in 7-day-old pups.
PMCID: PMC284105  PMID: 6541451
To determine the role of RLIP76 in providing protection from radiation and chemotherapy. In the present report, we used RLIP76 to refer to both the mouse (Ralbp1) and the human (RLIP76) 76-kDa splice variant proteins (RLIP76) for convenience and to avoid confusion. In other reports, Ralbp1 refers to the mouse enzyme (encoded by the Ralbp1 gene), which is structurally and functionally homologous to RLIP76, the human protein encoded by the human RALBP1 gene.
Methods and Materials
Median lethal dose studies were performed in RLIP76-/- and RLIP76+/+ C57B mice after treatment with a single dose of RLIP76 liposomes 14 h after whole body radiation. The radiosensitivity of the cultured mouse embryonic fibroblasts and the effects of buthionine sulfoximine (BSO), amifostine, c-jun N-terminal kinase (JNK), protein kinase B (Akt), and MAPK/ERK kinase (MEK) were determined by colony-forming assays. Glutathione-linked enzyme activities were measured by spectrophotometric assays, glutathione by dithiobis-2-nitrobenzoic acid (DTNB), lipid hydroperoxides by iodometric titration, and aldehydes and metabolites by thiobarbitauric acid reactive substances and liquid chromatography-mass spectrometry (LCMS).
RLIP76-/- mice were significantly more sensitive to radiation than were the wild-type, and RLIP76 liposomes prolonged survival in a dose-dependent manner in both genotypes. The levels of 4-hydroxynonenal and glutathione-conjugate of 4-hydroxynonenal were significantly increased in RLIP76-/- tissues compared with RLIP76+/+. RLIP76-/- mouse embryonic fibroblasts were markedly more radiosensitive than RLIP76+/+ mouse embryonic fibroblasts, despite increased glutathione levels in the former. RLIP76 augmentation had a remarkably greater protective effect compared with amifostine. The magnitude of effects of RLIP76 loss on radiation sensitivity was greater than those caused by perturbations of JNK, MEK, or Akt, and the effects of RLIP76 loss could not be completely compensated for by modulating the levels of these signaling proteins.
The results of our study have shown that RLIP76 plays a central role in radiation resistance.
PMCID: PMC2664086  PMID: 18793957
RLIP76; Ralbp1; Radiation-resistance; Embryonic fibroblasts
7.  Intestinal absorption, organ distribution, and urinary excretion of the rare sugar D-psicose 
The purpose of this study was to evaluate intestinal absorption, organ distribution, and urinary elimination of the rare sugar D-psicose, a 3-carbon stereoisomer of D-fructose that is currently being investigated and which has been found to be strongly effective against hyperglycemia and hyperlipidemia.
This study was performed using radioactive D-psicose, which was synthesized enzymatically from radioactive D-allose. Concentrations in whole blood, urine, and organs were measured at different time points until 2 hours after both oral and intravenous administrations and 7 days after a single oral administration (100 mg/kg body weight) to Wistar rats. Autoradiography was also performed by injecting 100 mg/kg body weight of 14C-labeled D-psicose or glucose intravenously to C3H mice.
Following oral administration, D-psicose easily moved to blood. The maximum blood concentration (48.5±15.6 μg/g) was observed at 1 hour. Excretion to urine was 20% within 1 hour and 33% within 2 hours. Accumulation to organs was detected only in the liver. Following intravenous administration, blood concentration was decreased with the half-life=57 minutes, and the excretion to urine was up to almost 50% within 1 hour. Similarly to the results obtained with oral administration, accumulation to organs was detected only in the liver. Seven days after the single-dose oral administration, the remaining amounts in the whole body were less than 1%. Autoradiography of mice showed results similar to those in rats. High signals of 14C-labeled D-psicose were observed in liver, kidney, and bladder. Interestingly, no accumulation of D-psicose was observed in the brain.
D-psicose was absorbed well after oral administration and eliminated rapidly after both oral and intravenous administrations, with short duration of action. The study provides valuable pharmacokinetic data for further drug development of D-psicose. Because the findings were mainly based on animal study, it is necessary to implement human trials to study the metabolism pathway, which would give an important guide for human intake and food application of D-psicose.
PMCID: PMC4207542  PMID: 25378908
14C-labeled D-psicose; organ accumulation; pharmacokinetics; autoradiography
8.  Differences in Susceptibility to Okadaic Acid, a Diarrhetic Shellfish Poisoning Toxin, between Male and Female Mice 
Toxins  2012;5(1):9-15.
The mouse bioassay (MBA) for diarrhetic shellfish poisoning (DSP) toxins has been widely used in many countries of the world. In the Japanese and EU methods, male mice are designated to be used for MBA. Female mice were described to be less susceptible than male mice. To the best of our knowledge, however, there have been no reports on the details of sex differences in susceptibility to DSP toxins. In this study, we investigated whether, and to what extent, female mice are less sensitive to DSP toxins. A lethal dose of okadaic acid (OA), one of the representative DSP toxins, was injected intraperitoneally into mice. The mice were observed until 24 hours after injection. Both male and female mice of ICR and ddY strains, which are designated in the Japanese official method, were compared. All the mice were four weeks old and weighed 18–20 g. The experiments were repeated twice. The lethality was 70%–100%. Survival analysis showed no sex differences in susceptibility to OA, but ICR female mice showed significant resistance compared with other groups in one out of two trials. These results indicate that sex differences were not clear but, nonetheless, male mice showed more stable results.
PMCID: PMC3564064  PMID: 23271638
sex difference; okadaic acid; mouse bioassay; diarrhetic shellfish poisoning (DSP) toxin
9.  Brighter-colored paper wasps (Polistes dominula) have larger poison glands 
Frontiers in Zoology  2012;9:20.
Aposematism is a defense system against predators consisting of the toxicity warning using conspicuous coloration. If the toxin production and aposematic coloration is costly, only individuals in good physical condition could simultaneously produce abundant poison and striking coloration. In such cases, the aposematic coloration not only indicates that the animal is toxic, but also the toxicity level of individuals. The costs associated with the production of aposematic coloration would ensure that individuals honestly indicate their toxicity levels. In the present study, we examine the hypothesis that a positive correlation exists between the brightness of warning coloration and toxicity level using as a model the paper wasp (Polistes dominula).
We collected wasps from 30 different nests and photographed them to measure the brightness of warning coloration in the abdomen. We also measured the volume of the poison gland, as well as the length, and the width of the abdomen. The results show a positive relationship between brightness and poison-gland size, which remained positive even after controlling for the body size and abdomen width.
The results suggest that the coloration pattern of these wasps is a true sign of toxicity level: wasps with brighter colors are more poisonous (they have larger poison glands).
PMCID: PMC3495029  PMID: 22901602
Paper wasp; Poison glands; Aposematic coloration; Warning signals
10.  Distribution of [14C]aztreonam in rat tissue. 
[14C]aztreonam was administered intramuscularly (50 mg/kg) to male and female rats. Groups of 10 rats (five male and five female) were sacrificed at 0.25, 2, 6, and 24 h after dosing. Blood and various tissues were removed from six rats (three male and three female) in each group for determination of total radioactivity and unchanged aztreonam by liquid scintillation counting and thin-layer radiochromatography. The remaining rats were prepared for whole-body autoradiography. Radioactivity was distributed rapidly to most tissues and was rapidly eliminated from blood into urine and bile. Concentrations of total radioactivity in kidney, liver, small and large intestines and their contents, and urinary bladder were higher than those in serum at all the times examined. Concentrations of unchanged aztreonam in serum, kidney, liver, and lung declined at about the same rate as did that of total radioactivity in the same tissues. The results of whole-body autoradiography essentially confirmed the results of the distribution of [14C]aztreonam as determined by liquid scintillation counting. No major differences between males and females were observed when concentrations in organs common to both were compared.
PMCID: PMC284104  PMID: 6541450
11.  In vivo SPECT and ex vivo autoradiographic brain imaging of the novel selective CB1 receptor antagonist radioligand [125I]SD7015 in CB1 knock-out and wildtype mouse 
Brain research bulletin  2013;91:46-51.
We aimed to evaluate the novel high-affinity and relatively lipophilic CB1 receptor (CB1R) antagonist radioligand [125I]SD7015 for SPECT imaging of CB1Rs in vivo using the multiplexed multipinhole dedicated small animal SPECT/CT system, NanoSPECT/CTPLUS (Mediso, Budapest, Hungary), in knock-out CB1 receptor knock-out (CB1R-/-) and wildtype mice. In order to exclude possible differences in cerebral blood flow between the two types of animals, HMPAO SPECT scans were performed, whereas in order to confirm the brain uptake differences of the radioligand between knock-out mice and wildtype mice, in vivo scans were complemented with ex vivo autoradiographic measurements using the brains of the same animals. With SPECT/CT imaging, we measured the brain uptake of radioactivity, using %SUV (% standardised uptake values) in CB1R-/- mice (n = 3) and C57BL6 wildtype mice (n = 7) under urethane anaesthesia after injecting [125I]SD7015 intravenously or intraperitoneally. The Brookhaven Laboratory mouse MRI atlas was fused to the SPECT/CT images by using a combination of rigid and non-rigid algorithms in the Mediso Fusion™ (Mediso, Budapest, Hungary) and VivoQuant (inviCRO, Boston, MA, USA) softwares. Phosphor imager plate autoradiography (ARG) was performed on 4 μm-thin cryostat sections of the excised brains. %SUV was 8.6 ± 3.6 (average ± SD) in CB1R-/- mice and 22.1 ± 12.4 in wildtype mice between 2 and 4 h after injection (p < 0.05). ARG of identically taken sections from wildtype mouse brain showed moderate radioactivity uptake when compared with the in vivo images, with a clear difference between grey matter and white matter, whereas ARG in CB1R(-/-) mice showed practically no radioactivity uptake. [125I]SD7015 enters the mouse brain in sufficient amount to enable SPECT imaging. Brain radioactivity distribution largely coincides with that of the known CB1R expression pattern in rodent brain. We conclude that [125I]SD7015 should be a useful SPECT radioligand for studying brain CB1R in mouse and rat disease models.
PMCID: PMC4182908  PMID: 23318272
Endocannabinoid CB1 receptor (CB1R); Single photon emission computed tomography (SPECT); Molecular imaging biomarker; [125I]SD7015; Knock-out CB1R-/- mouse; Multiplexed multipinhole dedicated small animal SPECT/CT system
12.  In vitro incorporation of (3H)threonine and (3H)glucose by the mucous and serous cells of the human bronchial submucosal gland. A quantitative electron microscope study 
The Journal of Cell Biology  1975;67(2):320-344.
Incorporation of [3H]threonine and [3H]glucose by the mucous and serous cells of the human bronchial submucosal gland has been studied over 8 h using, for the first time in vitro pulse labeling and electron microscope autoradiography. In assessing the autoradiographs, two methods were compared, the circle analysis and the recently described hypothetical grain analysis. Preliminary studies showed formaldehyde to be the most suitable fixative. Chemical analysis of tissue revealed that [3H]threonine was incorporated into the polypeptide moiety of the bronchial gland product and that metabolites of [3H]-glucose were incorporated into the carbohydrate. Tritiated threonine was first localized in the endoplasmic reticulum of both mucous and serous cells and later migrated to the Golgi apparatus, while metabolites of [3H]glucose localized first mainly in the Golgi apparatus. From here, both radioactive precursors were next identified in vacuoles and, finally, in secretory granules. The mucous cell incorporated strikingly more of both radioactive precursors than the serous cell. Thus, it seems that oligosaccharides of mucous and serous cell glycoproteins are synthesized mainly in the Golgi apparatus and added there to the polypeptide core which is synthesized in the endoplasmic reticulum. The relationship of the mucous cell to the serous cell is discussed. It seems that under "normal" conditions each cell represents a different line but that injury may transform a serous cell into a mucous cell.
PMCID: PMC2109595  PMID: 1194352
A method has been worked out for the measurement of the volume of sweat produced by individual glands. A special paper, impregnated with iodine, absorbs water in a uniform way and shows the area of wetting by a sharply defined blue dot. Indirect calibrations showed that 1 cm.3 of water would form a spot of 700 cm.2 area, and that this relation of volume to area was a constant one over a wide range. The actual volumes encountered in prints of the sweat glands were from 5 x 10–9 to 4 x 10–6 cm.3. The relative activity of glands at any instant of time can be expressed by the statistical distribution of log diameter of the dots on the print. This distribution, which might at first sight seem rather artificial, has the advantage of being unaffected by a proportionate change in the output of water from each gland. Thus it is independent of the duration of contact between print paper and skin, and of changes in the average flow from the field as a whole. It is sensitive only to changes in the activity of glands relative to each other. The methods of printing and statistical analysis were used to study the relative activity of glands in a field of 22 mm. diameter. Glands of the forearm and back were studied both under direct stimulation with mecholyl and under the reflex stimulation of environmental heat, similar results being obtained with the two kinds of stimuli. Glands of the abdomen and leg, stimulated with mecholyl, were studied in one experiment. Detailed comparison of the dots in consecutive prints showed that the large dots remained large and the small dots continued to be small. These persistent differences in the outflow of water from adjacent glands were interpreted as being due to differences in the functional power of the glands. Repeated prints of the glands during a period of 75 minutes, in which the sweat flow was declining, showed that the relative activity of the glands remained constant. This meant that the set of glands, although differing greatly in power, varied together as a functional unit. Different regions of the body show not only the variation of glandular power within each small area, but also marked differences in the average power of glands belonging to the different regions. Glands of the back, for instance, show a much greater outflow than glands of the forearm when stimulated equally with a local injection of mecholyl. Equal rates of outflow, therefore, do not mean equal states of functional activity, unless the regions being compared are of equal functional power.
PMCID: PMC2136283  PMID: 13069656
14.  Absorption, disposition, and urinary metabolism of 14C-rifabutin in rats. 
14C-rifabutin was given orally (25 mg/kg) and intravenously (i.v.) (10 mg/kg) to female Sprague-Dawley rats. Radioactivity was eliminated by both the renal and fecal routes, amounting to 44.49 and 43.39% of the dose, respectively, in urine and feces at 96 h after the oral dose and to 47.81 and 40.76% of the dose, respectively, in urine and feces after the i.v. dose. Differences between the two routes of administration were negligible. Tissue distribution of radioactivity after the oral dose was investigated by the combustion technique. At 2 h, the highest concentration of radioactivity was observed in the liver, followed by the lung, abdominal adipose tissue, and spleen, whereas at 72 h, the sequence was abdominal adipose tissue, liver, spleen, bone marrow, and lung. Brain levels of radioactivity were very low. The results of whole-body autoradiography after i.v. administration confirmed the above. Whole-body autoradiography of pregnant rats showed higher concentrations of radioactivity in the uterus than in the placenta and trace levels in the fetuses up to 8 h. Radioactivity was absent in the amniotic fluid. The urinary metabolism was studied by radio-high-pressure liquid chromatography. Rifabutin accounted for 7.4 and 7.2% of the dose in 0- to 48-h urine after oral and i.v. administration, respectively. Metabolites 31-OH rifabutin and 25-O-deacetyl rifabutin amounted to 4.3 and 1.6% of the dose, respectively, after oral administration and to 2.6 and 0.7% of the dose, respectively, after i.v. administration. The remaining urinary radioactivity was mainly due to polar compounds.
PMCID: PMC245178  PMID: 1656861
15.  Reduced brain glucose with normal plasma glucose in salicylate poisoning 
Journal of Clinical Investigation  1970;49(11):2139-2145.
After the intraperitoneal injection into young mice of 700-800 mg/kg of salicylate, brain glucose fell to one-third or less of control values despite normal plasma glucose levels; brain lactate was nearly doubled and there were small decreases in phosphocreatine (18%) and in glycogen (17%). ATP, pyruvate, α-ketoglutarate, and glutamate were unchanged. In liver, glycogen was reduced 79% and lactate was five times higher than in control animals; glucose, glucose-6-phosphate, and ATP were unchanged.
Since salicylate uncouples oxidative phosphorylation, it is postulated that high energy phosphate in the brain is maintained near normal levels by a compensatory increase in cerebral glycolysis. Apparently the brain glucose level falls because the rate of utilization exceeds the rate at which glucose can be supplied from the blood. Concurrent administration of glucose with salicylate elevated brain glucose concentration and was associated with striking improvement in the condition and the increased survival of the animals. These findings stress the fact that in salicylate poisoning the supply of glucose to the brain may be inadequate even when blood glucose levels are normal.
PMCID: PMC535789  PMID: 4319971
16.  Interrupted Time-Series Analysis of Regulations to Reduce Paracetamol (Acetaminophen) Poisoning 
PLoS Medicine  2007;4(4):e105.
Paracetamol (acetaminophen) poisoning is the leading cause of acute liver failure in Great Britain and the United States. Successful interventions to reduced harm from paracetamol poisoning are needed. To achieve this, the government of the United Kingdom introduced legislation in 1998 limiting the pack size of paracetamol sold in shops. Several studies have reported recent decreases in fatal poisonings involving paracetamol. We use interrupted time-series analysis to evaluate whether the recent fall in the number of paracetamol deaths is different to trends in fatal poisoning involving aspirin, paracetamol compounds, antidepressants, or nondrug poisoning suicide.
Methods and Findings
We calculated directly age-standardised mortality rates for paracetamol poisoning in England and Wales from 1993 to 2004. We used an ordinary least-squares regression model divided into pre- and postintervention segments at 1999. The model included a term for autocorrelation within the time series. We tested for changes in the level and slope between the pre- and postintervention segments. To assess whether observed changes in the time series were unique to paracetamol, we compared against poisoning deaths involving compound paracetamol (not covered by the regulations), aspirin, antidepressants, and nonpoisoning suicide deaths. We did this comparison by calculating a ratio of each comparison series with paracetamol and applying a segmented regression model to the ratios. No change in the ratio level or slope indicated no difference compared to the control series. There were about 2,200 deaths involving paracetamol. The age-standardised mortality rate rose from 8.1 per million in 1993 to 8.8 per million in 1997, subsequently falling to about 5.3 per million in 2004. After the regulations were introduced, deaths dropped by 2.69 per million (p = 0.003). Trends in the age-standardised mortality rate for paracetamol compounds, aspirin, and antidepressants were broadly similar to paracetamol, increasing until 1997 and then declining. Nondrug poisoning suicide also declined during the study period, but was highest in 1993. The segmented regression models showed that the age-standardised mortality rate for compound paracetamol dropped less after the regulations (p = 0.012) but declined more rapidly afterward (p = 0.031). However, age-standardised rates for aspirin and antidepressants fell in a similar way to paracetamol after the regulations. Nondrug poisoning suicide declined at a similar rate to paracetamol after the regulations were introduced.
Introduction of regulations to limit availability of paracetamol coincided with a decrease in paracetamol-poisoning mortality. However, fatal poisoning involving aspirin, antidepressants, and to a lesser degree, paracetamol compounds, also showed similar trends. This raises the question whether the decline in paracetamol deaths was due to the regulations or was part of a wider trend in decreasing drug-poisoning mortality. We found little evidence to support the hypothesis that the 1998 regulations limiting pack size resulted in a greater reduction in poisoning deaths involving paracetamol than occurred for other drugs or nondrug poisoning suicide.
Analysis of mortality rates for paracetamol poisoning in England and Wales does not support the view that regulations limiting pack size have been responsible for a reduction in deaths.
Editors' Summary
Paracetamol—known as acetaminophen in the United States—is a cheap and effective painkiller. It is widely used to relieve minor aches and pains as well as fevers and headaches. Recommended doses of paracetamol are considered safe in humans, but overdoses are toxic and can cause liver failure and death. Because this drug is very easy to get hold of, there are many overdoses each year, either accidental or deliberate. In the UK, paracetamol poisoning is the most common cause of acute liver failure. Toward the end of 1998, new laws were introduced in the UK to try to reduce the number of paracetamol overdoses. These laws said that pharmacies could not sell packs of paracetamol containing more than 32 tablets and other shops could not sell packs with more than 16 tablets. One of the reasons behind the introduction of this law was that many suicides are not preplanned and, therefore, if it was harder for people to get hold of or keep large quantities of tablets, they might be less likely to attempt suicide or accidentally overdose.
Why Was This Study Done?
Following the introduction of these new laws, the number of deaths caused by paracetamol overdose in the UK dropped. However, it is possible that the drop in deaths came about for a variety of different reasons and not just as a result of the new laws on paracetamol pack size. For example, the suicide rate might have been falling anyway due to other changes in society and the fall in death rate from paracetamol might just have been part of that trend. It is important to find out whether the legal changes that were introduced to address a public health problem did in fact bring about a change for the better. This knowledge would also be relevant to other countries that are considering similar changes.
What Did the Researchers Do and Find?
The researchers used data from the Office of National Statistics, which holds information on drug poisoning deaths in England and Wales. These data were then broken down by the type of drug that was mentioned on the death certificate. The researchers compared death rates involving the following drugs: paracetamol; paracetamol-containing compounds (which were not subject to the new pack size laws); aspirin; antidepressant drugs; and then finally non-drug poisoning suicides. The reason for comparing death rates involving paracetamol against death rates involving other drugs, or non-drug suicide, was that this method would allow the researchers to see if the drop in paracetamol deaths followed overall trends in the poisoning or suicide rates or not. If the paracetamol death rate dropped following introduction of the new laws but the rates of other types of poisoning or suicide did not, then there would be a link between the new laws and a fall in paracetamol suicides. The researchers compared these death data within specific time periods before the end of 1998 (when the new laws on paracetamol pack size were introduced) and after.
Overall, there were nearly 2,200 deaths involving paracetamol between 1993 and 2004. The number of deaths per year involving paracetamol dropped substantially when comparing the periods of time before the end of 1998 and after it. However, the number of deaths per year involving any drug, and the non-drug suicides, also fell during this period of time. When comparing the trends for paracetamol deaths with other poisoning or suicide deaths, the researchers did not find any statistical evidence that the fall in paracetamol deaths was any different to the overall trend in poisoning or suicide death rates.
What Do These Findings Mean?
Although the paracetamol death rate fell immediately following the new laws on pack size, this study suggests the link might just be coincidence. The researchers could not find any data supporting the idea that the new laws caused a drop in paracetamol deaths. However, this was an observational study, not a true experimental one: the researchers here were clearly not able to set up equivalent “experimental” and “control” groups for comparison. It is very difficult to prove or disprove conclusively that new laws such as this are, or are not, effective.
Additional Information.
Please access these Web sites via the online version of this summary at
Information is available from Medline Plus about suicide
Wikipedia has an entry on paracetamol (note that Wikipedia is an internet encyclopedia anyone can edit)
Information about regulation of drugs in the UK is available from the Medicines and Healthcare Regulatory Agency
The Office for National Statistics provides key economic and social data about the UK, and is involved in many other important projects
PMCID: PMC1845154  PMID: 17407385
17.  Effects of acute organophosphate poisoning on pituitary target gland hormones at admission, discharge and three months after poisoning: A hospital based pilot study 
Organophosphate compound (OPC) poisoning is common in the developing countries such as India. The acute and later effects of OPC poisoning on pituitary and target gland hormones is largely unknown.
Materials and Methods:
This prospective study was conducted at Postgraduate Institute of Medical Education and Research between January 2012 and March 2013. Fourteen patients (8 males, age 18-50 years) with acute OPC poisoning were included in the study based on the history and clinical features, documented decreased in plasma cholinesterase activity or presence of the OPC in gastric lavage/blood samples. The hormonal parameters were done at baseline, at the time of discharge and at three months of follow-up.
A total of 14 patients out of 46 with the mean age of 30.1 ± 10.3 years were finally eligible for the study. Hormonal alterations at admission were similar to sick euhormonal syndrome. Overall 7 of them had nine hormonal deficits at three months of follow up, 4 having sub normal basal cortisol level and two each had low testosterone and growth hormone and only one had thyroxine deficiency.
Acute organophosphate poisoning results in endocrine dysfunction akin to sick euhormonal syndrome. However, in a small subset of patients, varying level of hormonal insufficiency may occur either at admission or later. These observations need re-validation in a larger group of patients with specific OPC.
PMCID: PMC4287755  PMID: 25593838
Endocrine dysfunction; organophosphate poisoning; pituitary
18.  Hyperglycemia Is a Strong Prognostic Factor of Lethality in Methanol Poisoning 
Journal of Medical Toxicology  2011;7(3):189-194.
Methanol poisoning is seen in the form of isolated episodes, or intentional ingestion and epidemics. Despite its efficient treatment, methanol poisoning has high morbidity and mortality rates. So far, several studies have been performed to identify the prognostic factors in methanol poisoning. Recently, during the treatment of patients with methanol poisoning, we observed that patients’ blood glucose levels were high on presentation to the hospital, particularly in those who expired. Through a literature search, we found that no studies have been performed on blood glucose levels or hyperglycemia in methanol poisoning. Therefore, the present retrospective study was done as a preliminary investigation to understand whether there was a meaningful relationship between methanol poisoning and blood glucose level on presentation, and also if hyperglycemia could be considered as a prognostic factor for mortality. In this retrospective study, a review of the hospital charts was performed for all patients who were treated for methanol poisoning from March 2003 to March 2010 in two hospitals in Tehran, Iran. Those with definitive diagnosis of methanol poisoning, no history of diabetes mellitus, and normal or low body mass index (<25) were included. Patients’ demographic information, clinical manifestations, time elapsed between ingestion and presentation, blood glucose level on presentation (before treatment), results of arterial blood gas analysis, and the clinical outcome were recorded. Statistical analysis was done using SPSS software (version 17, Chicago, Illinois, USA) and application of Mann–Whitney U test, Pearson's chi-square test, Pearson correlation coefficient (r), receiver operating characteristic (ROC) curve, and logistic regression. P values less than 0.05 were considered as the statistically significant levels. Ninety-five patients with methanol poisoning met the inclusion criteria and were included in the study. Of these, 91 (96%) were male and 4 (4%) were female. Mean age was 31.61 ± 14.3 years (range, 13 to 75). Among the 95 patients, 68 survived (72%) and 27 expired (28%). Median blood glucose level was 144 mg/dL (range, 75 to 500). There was no significant statistical correlation between blood glucose level and time of treatment, age, pCO2, or serum bicarbonate concentration, but blood glucose level had a statistically significant correlation with pH (r = −0.242, P = 0.02) and base deficit (r = 0.230, P = 0.03). The mean blood glucose level was 140 ± 55 and 219 ± 99 mg/dL in the survivor and non-survivor patients, respectively (P < 001). Considering the cutoff level of 140 mg/dL for blood glucose and using logistic regression analysis, and adjusting according to the admission data with significant statistical difference in the two study groups, the odds ratio for hyperglycemia as a risk factor for death was 6.5 (95% confidence interval = 1.59–26.4). Our study showed that blood glucose levels were high in methanol poisoning and even higher in those who died in comparison with the survivors. Therefore, hyperglycemia might be a new prognostic factor in methanol poisoning, but further studies are needed to determine whether controlling hyperglycemia has therapeutic consequences.
PMCID: PMC3550199  PMID: 21336799
Methanol poisoning; Prognosis; Hyperglycemia; Mortality
19.  Distribution of pimonidazole and RSU 1069 in tumour and normal tissues. 
British Journal of Cancer  1990;62(6):915-918.
The tritium-labelled analogues of pimonidazole and RSU 1069 were injected into mice bearing the KHT murine sarcoma which has a hypoxic cell fraction of approximately 10%. The distribution of activity at 24 h was recorded using autoradiography and measurement of tissue activity. Autoradiographs with both drugs showed high activity in particular cells within tumour, eye (melanin-associated cells), eyelid (Meibomian gland), liver (centrilobular area), skin (sebaceous gland and melanin), stomach (squamous area), footpad, oesophagus, labial gland, Zymbal's gland, preputial gland, parotid gland (intralobular ducts) and airway epithelium. These tissues had previously been identified as sites of binding of misonidazole. The measurement of total tissue radioactivity showed significantly higher activity in liver, eyelid (Meibomian gland), oesophageal lining, kidney and labial gland than was found in the tumour.
PMCID: PMC1971577  PMID: 2257219
20.  Permeability of Oral Tissues to Blood-borne Coxsackievirus B-1 
Applied Microbiology  1967;15(2):296-299.
The ability of coxsackievirus B-1 to pass the barriers of the circulatory system into whole saliva has been shown previously. In this investigation, the major salivary glands and the oral mucosa were studied, and their role as participants in the excretion of coxsackievirus B-1 during viremia was evaluated. The effect of the salivary-gland stimulant pilocarpine nitrate on both the salivary flow rate and the recovery of virus during viremia was determined. A comparison was made between the amount of virus recovered from whole saliva during viremia in animals deficient in one or both of the major salivary-gland pairs and animals with a complete complement of salivary glands. The salivary glands in other animals were cannulated, and pure glandular secretions were collected during viremia and assayed for the presence of virus The amount of virus passing from the capillaries of the oral mucosa to the surface was also determined to evaluate this route as a possible site for the excretion of virus into saliva during viremia. The major salivary glands did not excrete appreciable quantities of virus during viremia. The submaxillary-gland secretions did not contain virus, and the parotid-gland secretions showed virus only at extremely high blood virus levels. Either removal of the major salivary glands or decreased salivary flow rates increased the concentration of virus in whole saliva. This observation suggested that the production of saliva by the major salivary glands tends to dilute the virus in the oral cavity. A 0.88-cm2 sample of the oral mucosa excreted significantly large amounts of virus during viremia and suggested that the passage of virus through the oral mucosa was the major route for the excretion of virus into saliva during viremia.
PMCID: PMC546894  PMID: 6029830
21.  Cobinamide is superior to other treatments in a mouse model of cyanide poisoning 
Cyanide is a rapidly acting cellular poison, primarily targeting cytochrome c oxidase, and is a common occupational and residential toxin, mostly via smoke inhalation. Cyanide is also a potential weapon of mass destruction, with recent credible threats of attacks focusing the need for better treatments, since current cyanide antidotes are limited and impractical for rapid deployment in mass casualty settings.
We have used mouse models of cyanide poisoning to compare the efficacy of cobinamide, the precursor to cobalamin (vitamin B12), to currently approved cyanide antidotes. Cobinamide has extremely high affinity for cyanide and substantial solubility in water.
Materials and Methods
We studied cobinamide in both an inhaled and intraperitoneal model of cyanide poisoning in mice.
We found cobinamide more effective than hydroxocobalamin, sodium thiosulfate, sodium nitrite, and the combination of sodium thiosulfate-sodium nitrite in treating cyanide poisoning. Compared to hydroxocobalamin, cobinamide was 3 and 11 times more potent in the intraperitoneal and inhalation models, respectively. Cobinamide sulfite was rapidly absorbed after intramuscular injection, and mice recovered from a lethal dose of cyanide even when given at a time when they had been apneic for over two minutes. In range finding studies, cobinamide sulfite at doses up to 2000 mg/kg exhibited no clinical toxicity.
Discussion and Conclusion
These studies demonstrate that cobinamide is a highly effective cyanide antidote in mouse models, and suggest it could be used in a mass casualty setting, because it can be given rapidly as an intramuscular injection when administered as cobinamide sulfite. Based on these animal data cobinamide sulfite appears to be an antidote worthy of further testing as a therapy for mass casualties.
PMCID: PMC3119202  PMID: 20704457
Antidote; Poisoning management; Poisoning; Hydroxocobalamin
22.  Clinical Chemistry of Staphylococcal Enterotoxin Poisoning in Monkeys 
Applied Microbiology  1966;14(3):445-450.
Clinical chemistry values were examined in 90 monkeys administered a purified preparation of staphylococcal enterotoxin, type B, intravenously. These studies showed an early release of epinephrine accompanied by a mild increase in blood glucose. This was followed by progressively developing prolonged hypoglycemia. An early increase in bloodurea nitrogen occurred, presumably as a result of both prerenal azotemia and functional renal failure seen in association with the observed hypotension. Serum protein, Ca, and Cl concentrations decreased with time. Pi levels increased, whereas Na and K concentrations in serum remained unchanged. Serum enzyme concentrations were unchanged, with the exception of serum glutamic oxaloacetic transaminase, which rose rapidly when compared with prechallenge control observations or with values from sham-challenged monkeys. These changes were statistically significant. These results suggested that enterotoxin administered intravenously produced early change in glucose metabolism, possibly related initially to catecholamine release and later to increased utilization of glucose and metabolic acidosis. Other findings were compatible with tissue breakdown at as yet undetermined locations and with loss of endothelial membrane integrity, as evidenced by loss of protein from the vascular space.
PMCID: PMC546739  PMID: 4961554
23.  Variety and complexity of fluorine-18-labelled fluoro-2-deoxy-d-glucose accumulations in the oral cavity of patients with oral cancers 
Dentomaxillofacial Radiology  2013;42(7):20130014.
To elucidate the points that require attention when interpreting fluorine-18-labelled fluoro-2-deoxy-d-glucose (18F-FDG)/positron emission tomography (PET) images by demonstration of 18F-FDG accumulation in various areas of the oral cavity other than primary lesions in patients with oral cancers.
18F-FDG accumulations with a maximal standardized uptake value of over 2.5 in various areas of the oral cavity other than primary lesions were identified in 82 patients with oral cancers.
18F-FDG/PET-positive areas, excluding primary tumours, included the front intrinsic muscles of the tongue (89.0%), upper and lower marginal parts of the orbicularis oris muscle (64.6%), sublingual glands, palatine tonsil, pharyngeal tonsil, and lingual tonsil. In addition, some areas in the jaws also showed accumulation.
In patients with oral cancers, areas of 18F-FDG accumulation in the oral cavity should be precisely identified and appropriately diagnosed, because accumulations can be seen in areas other than the primary tumour.
PMCID: PMC3699977  PMID: 23610089
fluorine-18-labelled fluoro-2-deoxy-d-glucose; positron emission tomography computerized tomography; tongue; oral cancer; oral cavity; mimetic muscles
24.  Distribution and metabolism of intravenously administered trefoil factor 2/porcine spasmolytic polypeptide in the rat 
Gut  1998;43(2):240-247.
Background—Trefoil peptides are secreted by mucus producing cells in the gastrointestinal tract and are supposed to be involved in oligomerisation processes of the mucin glycoproteins in the lumen. Endocrine functions have also been suggested. 
Aims—To target possible binding sites for iodine-125 labelled porcine spasmolytic polypeptide (pSP) in an in vivo rat model. 
Methods—125I-pSP was given by intravenous injection to female Spraque-Dawley rats. The distribution of 125I-pSP was assessed by gamma counting of samples of organs and by autoradiography of paraffin wax embedded sections. The degradation of 125I-pSP was studied by trichloroacetic acid precipitation, and the saturability of binding by administration of excess unlabelled peptide. 
Results—125I-pSP was taken up in the kidneys and the gastrointestinal tract and was excreted almost unmetabolised in the urine. In the stomach, it could be displaced by unlabelled pSP in a dose dependent manner. Autoradiography showed grains in mucous neck cells, parietal cells, the mucus layer, and the pyloric glands of the stomach; in Brunner's glands and the Paneth cells in the small intestine; and in cells in the lower part of the crypts in the colon. 
Conclusions—125I-pSP from the circulatory system is taken up by mucus producing cells in the gastrointestinal tract. The binding can be displaced by non-radioactive pSP, suggesting the presence of a receptor. 

Keywords: trefoil peptides; trefoil factor 2; spasmolytic polypeptide; metabolism; autoradiography; rat
PMCID: PMC1727199  PMID: 10189851
25.  Impaired Neurotransmitter Release from Lacrimal and Salivary Gland Nerves of a Murine Model of Sjögren's Syndrome 
To determine whether lacrimal and salivary gland nerves of an animal model of Sjögren's syndrome, the MRL/lpr mouse, are able to release acetylcholine. The second purpose was to determine whether activation of the lacrimal gland nerves of the MRL/lpr mouse leads to protein secretion.
Total saliva was collected for 10 minutes from the oral cavity of male and female MRL/lpr and MRL/+ mice, after intraperitoneal stimulation with pilocarpine and isoproterenol. Lacrimal and salivary gland lobules prepared from 18-week-old MRL/lpr and MRL/+ mice were incubated in the presence of depolarizing KCl (75 mM) solution. Acetylcholine release and peroxidase secretion (a protein secreted by the lacrimal gland) were measured using a spectrofluorometric assay.
Female, but not male, MRL/lpr mouse salivary glands were hyper-responsive to in vivo injection of secretagogues. These mice produced significantly higher amounts of saliva than did age-matched MRL/+ mice. Lacrimal and salivary gland nerves from 18-week-old MRL/+ mice released acetylcholine in response to a depolarizing KCl solution. In contrast, nerves in glands from 18-week-old MRL/lpr mice did not increase acetylcholine release in response to the depolarizing solution. Moreover, lacrimal glands from 18-week-old MRL/+ mice were able to secrete peroxidase in response to a depolarizing KCl solution, whereas those from 18-week-old MRL/lpr could not. This was not due to a defect in the secretory process, because addition of an exogenous secretagogue elicited peroxidase secretion from 18-week-old MRL/lpr as well as MRL/+ mice lacrimal glands.
The results show that activation of nerves of lacrimal and salivary glands infiltrated with lymphocytes does not increase the release of neurotransmitters, which results in impaired secretion from these glands. (Invest Ophthalmol Vis Sci.
PMCID: PMC3241007  PMID: 11274068

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