Our lives unfold in space and time—we are able to be aware not only of the present instant but also to recollect the past and imagine the future, and our memories tend to be not instantaneous snapshots but rather bear a temporal, sequential dimension. This faculty of time travel allows us to adjust our current actions in light of what we have previously learned and with respect to what we aspire to become. It depends upon faithful records of our personal experiences, termed episodic memory. While over the last century we have learned a great deal about the molecular changes that support this kind of learning, the circuit-level mechanisms with which the brain implements the formation of episodic memory remain to be discovered. Failures of episodic memory can be catastrophic, and unfortunately, such dysfunction is commonplace in a number of human pathologies. In the neuropsychiatric syndrome of schizophrenia, the capacity to form and utilize episodic memory is compromised, a state of affairs that likely contributes to the difficulty people with schizophrenia have adjusting their actions to meet desired goals. Attempts to understand the pathogenesis of schizophrenia’s memory deficits at the molecular level have yielded frustratingly few leads, making circuit-level inquiries a rational next step. Utilizing a genetic mouse model of schizophrenia susceptibility (Df(16)A+/- mice), we have taken a three-pronged approach to the analysis of the circuit mechanisms and missteps of episodic memory. We first developed a behavioral model of episodic memory, a variation on classical ‘trace’ fear conditioning, which involves the formation of an association between an innocuous stimulus (conditioned stimulus, CS) and a temporally separate aversive stimulus (unconditioned stimulus, US). Next, we turned to a region of the brain known to be required for trace fear conditioning and implicated in the pathogenesis of schizophrenia, dorsal CA1 of the hippocampus. Because network coordination and plasticity in dorsal hippocampal CA1 relies heavily on the activity of soma-targeting, parvalbumin-positive interneurons (PV+ INs), we hypothesized that they may be mediators of the associations built during trace fear conditioning. We therefore sought to characterize their activity during temporal association learning in both wild-type (WT) and Df(16)A+/- mice using two-photon calcium imaging. We simultaneously recorded local field potentials in the contralateral dorsal hippocampus to pair the discrete transformations captured through imaging with information about more global states of hippocampal activity. Finally, we manipulated the activity PV+ INs during various epochs of freely-moving trace fear conditioning to test hypotheses regarding their necessity for trace fear conditioning in healthy and schizophrenia-susceptible mice. We found that Df(16)A+/- mice have severe deficits in trace fear conditioning when compared to mice that do not carry their defining mutation. Calcium imaging of PV+, peri-somatic boutons in dorsal CA1 over the course of trace fear conditioning revealed a marked increase in the number of detected boutons that initiate activity during the presentation of the CS and that sustain their activity across the time gap preceding delivery of the US. This shift in activity was notably absent in recordings from Df(16)A+/- mice. Consistent with the observations of others, analysis of local field potentials indicated that successful learning was associated with modulation of amplitude and theta-phase relation in mid- and fast-gamma frequency oscillations. This modulation was compromised in Df(16)A+/- mice. Finally, we found that inhibition of PV+ INs during encoding in Df(16)A+/- mice restores their response to the CS to near-WT levels of fear expression. Our results support the thesis that temporary downregulation of PV+ IN activity during encoding is essential for the formation of complex, hippocampus-dependent associations including temporal association memory. We suggest that this transient disinhibition may serve to allow for the generation of new pyramidal cell ensembles to represent the associated stimuli. The heightened, sustained inhibition observed during post-learning trials in the calcium imaging experiments is consistent with a transition of the PV+ INs into a role of stabilizing the fledgling memory trace during consolidation. Our results also support the hypothesis that in our model of schizophrenia susceptibility, impairments in learning complex associations may be due to the inability of PV+ INs to modulate their activity appropriately over the changing phases of memory formation. We identify PV+ INs as a promising therapeutic target for schizophrenia as we were able to restore behavior of the susceptible mice during our assay of temporal association memory. Further studies combining pharmacogenetic or optogenetic manipulations with calcium imaging and LFP recording could shed light on the mechanisms of these shifts in network plasticity and may help to identify new approaches to the treatment of the debilitating cognitive deficits associated with schizophrenia.

No description available.

Data of 1338 respondents from the Priority Toxicant Reference Range Study were analyzed to examine exposure to volatile organic compounds (VOCs). Self-reported contact to chemical products and blood concentrations of specific chemicals were analyzed. Neurobehavioral function was assessed by simple reaction time test (SRTT), symbol digit substitution test (SDST), and serial digit learning test (SDLT). Prevalence of exposure to VOC products was, for instance, air freshener/room deodorant - 34.7%, gasoline - 29.2%, finger nail polish - 16.2%, and diesel fuel/ kerosene - 10.6%. The 95th percentiles of blood VOCs (μg/L) were calculated for 41 chemicals including Benzene - 0.476, 1,1,1-Trichloroethane - 0.799, o-Xylene - 0.271, and Styrene - 0.177. Significant correlation coefficients included 0.216* with SRTT and 0.130* with SDST for 1,4-Dichlorobenzene, 0.097* with SDST for 1,1,2-Trichloroethane, 0.098* with SDLT for Chloroform, and 0.115* with SDLT for Dibromochloromethane (* p<0.05) suggesting possible neurobehavioral effects. Study results provided pilot data of exposure status and reference ranges of VOCs for the US population.

Complex social connections are essential for health and survival, and memory-impacting disorders like schizophrenia and Alzheimer’s disease can be debilitating for the relationships between patients and loved ones. To form and sustain relationships requires the ability to, first, identify strangers versus familiar individuals (identification) and, second, revise one’s representations of them based on past experience (learning). This ability is called social memory. A range of evidence confirms that the CA2 subregion of the hippocampus is crucial for social memory, and CA2-specific abnormalities are linked to social memory deficits in disease mouse models. However, the specific social cues that CA2 processes to inform social memory—as well as how CA2 adapts its responses to representations of other individuals through learning and experience—remains unclear.Since mice rely most heavily on olfaction to investigate conspecifics, odor sensory cues likely inform the basis of social identification processes in the murine brain. Furthermore, the hippocampus receives information from the olfactory bulb through the entorhinal cortex, suggesting that CA2 may be capable of processing odor sensory information for memory storage. It is already known the neighboring hippocampal subregion CA1 processes nonsocial odor cues and encodes the relationship between nonsocial odors and positive valence through learned experience. Therefore, since CA2 is necessary for social recognition overall, and since it is possible CA2 receives odor information through the same circuits as CA1, I hypothesized that CA2 processes social odor cues for social identification and combines this information with contextual information to develop and maintain social memory. In my thesis, I used two-photon calcium imaging to confirm that CA2 indeed encodes and distinguishes social odors belonging to unique individuals, as well as nonsocial odors. I also found that CA2 neurons adapt their responses to odor stimuli when a reward contingency is introduced—pairing some odors and not others with an artificial reward. Intensive decoding analyses further revealed that CA2 is capable of forming a generalized or abstract representation of social versus nonsocial and rewarded versus unrewarded social odor stimuli. Finally, with archaerhodopsin-mediated CA2 silencing, I confirmed that CA2 is necessary for social—but not nonsocial—odor-reward associative learning, further promoting the specificity of this brain region in the encoding of socially-relevant episodic memory. A link exists between CA2-specific dysfunction (namely, poor CA2 neuronal excitability) and social recognition deficits in the Df(16)A+/- microdeletion mouse model of the human 22q11.2 Deletion Syndrome—in which nearly a third of patients develop schizophrenia. I next hypothesized that CA2 in this model has a deficit in processing social sensory cues and forming the appropriate association between those cues and learned valence. Indeed, I discovered behavioral deficits in both social and nonsocial odor-reward associative learning in the Df(16)A+/- model. I further showed that CA2 is important in this impairment because selective expression of a dominant negative TREK-1 potassium channel subunit, which has been shown to improve CA2 function in these mice, rescued the deficits in social and nonsocial odor-reward learning. With two-photon imaging, I found that CA2 neurons in Df(16)A+/- mice were able to discriminate between social and nonsocial odors with an accuracy that was similar to that seen in wild-type mice, which was surprising given the CA2-dependent deficit in odor-reward learning in the Df(16)A+/- mice. However, the Df(16)A+/- mice did show a reduced fraction of neurons that were selectively activated by the rewarded odor compared to the wild-type mice. Perhaps the most salient finding is that CA2 representations in Df(16)A+/- mice showed a reduced generalized or abstract coding of odor-reward across the social and nonsocial odor categories. This suggests that the Df(16)A+/- mice failed to generalize the task variable of reward, but rather learned separate rules for social and nonsocial odor-reward association. This is reminiscent of a reduction in abstract thought in individuals with schizophrenia. Overall, my thesis provides evidence for the first time that CA2 encodes social odors and odor-reward learned experiences, that these identification and learning-related adaptation mechanisms are impaired in a disease model harboring social memory deficits, and that specific manipulations to restore CA2 function can rescue abnormal learning in this model. These results reinforce the notion that CA2 may provide a novel target for therapeutic intervention in restoring cognitive function associated with neuropsychiatric disease.

Myriad small molecule compounds targeting metabotropic glutamate receptors (mGluRs) have been investigated for the treatment of various neuropsychiatric diseases and displayed promise in preclinical studies. At the clinical level, many of these compounds have been well tolerated by human subjects but have eluded success as promising therapeutics. There are eight subtypes of mGluRs, which express as constitutive dimers. This dimerization can occur between identical (homodimerization) or different (heterodimerization) mGluR protomer subtypes, which are subject to pairing-specific signaling mechanisms. Subtype expression of mGluRs is heterogenous between brain regions and cell types, yielding probable cell-specific homo- and heterodimer combinations that respond differently to certain drugs. While G protein recruitment to active mGluR dimers has been studied extensively, little is known about arrestin recruitment to these receptors. I used bioluminescence resonance energy transfer (BRET) assays, which provide a quantitative measure of protein-protein proximity, to observe and quantify arrestin recruitment to specific mGluR subtype pairings upon ligand administration in heterologous cells. I studied how select allosteric ligands affect communication between protomers to enhance arrestin recruitment to dimers. My findings indicate that arrestin recruitment occurs only at select mGluR homodimers upon orthosteric stimulation but is frequently stimulated or enhanced by administration of activating allosteric ligands. Additionally, I found that trans-protomer communication is highly specific to mGluR protomer subtype pairings, the ligand administered,a nd inter-protomer signal direction. Lastly, my findings reveal a cooperative effect of mGluR2 and 3 heterodimerization on arrestin recruitment that is dependent on the functional ability of each protomer to bind orthosteric agonist and responds distinctively from homodimers to stimulation by certain allosteric ligands. Taken together, this work shows that mGluR signaling can be tuned using strategic pharmacology and energizes hope for future clinical success of mGluR-targeting ligands.

Accurate, early diagnosis of Alzheimer's Disease is becoming increasingly important in light of its growing prevalence among the expanding older-aged adult population. Due to its ability to assess multiple domains of cognitive functioning and provide a profile of impairment rather than a simple global score, the Neurobehavioral Cognitive Status Examination (NCSE) is suggested to better assess such patterns of cognitive deficit for the purpose of diagnosis. The performance of the NCSE was compared with that of the Mini-Mental State Examination (MMSE) for diagnostic sensitivity in a sample of patients diagnosed as having probable Alzheimer's Disease. The strength of correlation between severity of cognitive impairment on these tests and report of behavior problems on the Memory and Behavior Problems Checklist (MBPC) was also explored, as was performance on the NCSE and report of behavior problems using the MBPC in predicting Single Photon Emission Computed Tomography (SPECT) scan results. The NCSE was found to exhibit greater sensitivity to physician diagnosis of probable Alzheimer's Disease relative to two versions (Serial 7's or WORLD) of the MMSE (.90, .77 and .68, respectively). While both measures were found to correlate significantly with the report of behavior problems, only a moderate proportion (NCSE = .22 and MMSE = .33) of the explained variance was accounted for by either test. Severity of cognitive impairment on the NCSE was found to be significant, though small in estimate of its effect size, for predicting the absence/presence of pathognomic findings on SPECT scans. In contrast, the report of behavior problems on the MBPC did not significantly predict SPECT scan outcomes. The NCSE would appear to be a sensitive tool for the identification of the extent and severity of cognitive impairment found among demented individuals; however, it may be "over"-sensitive to such diagnosis. Although relationships between cognitive impairment and behavior problems and/or neuroradiological findings are observed, their meaningfulness remains with the need for further, more detailed, study using standardized criteria for comparison purposes.

Lee Nga Lan. / Thesis submitted in: June 1997. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1998. / Includes bibliographical references. / Abstract also in Chinese. / Abstract --- p.i / Acknowledgment --- p.iii / Table of contents --- p.iv / List of tables --- p.viii / List of figures --- p.x / Glossary of abbreviations --- p.xi / Chapter CHAPTER 1. --- INTRODUCTION --- p.1 / Chapter CHAPTER 2. --- BACKGROUND --- p.3 / Chapter 2.1 --- OUTBREAKS OF SOLVENT INDUCED NEUROPATHY IN MAN --- p.3 / Chapter 2.2 --- WORLD-WIDE INVESTIGATIONS ON ORGANIC SOLVENTS HAZARDS --- p.5 / Chapter 2.3 --- HEALTH EEFECTS OF ORGANIC SOLVENTS --- p.8 / Chapter 2.3.1 --- Effects on the Nervous System --- p.9 / Chapter (a) --- Peripheral Nervous System / Chapter (b) --- Central Nervous System / Chapter 2.3.2 --- Other Effects --- p.13 / Chapter 2.4 --- METHODOLOGICAL ISSUES IN THE INVESTIGATION OF SOLVENT NEUROTOXICITY --- p.14 / Chapter 2.4.1 --- Study Design --- p.15 / Chapter 2.4.2 --- Exposure Measurements --- p.17 / Chapter 2.4.3 --- Outcome Effects Measurements --- p.18 / Chapter 2.5 --- UNSOLVED PROBLEMS IN THE STUDY OF SOLVENT NEUROTOXICITY --- p.20 / Chapter 2.6 --- ORGANIC SOLVENTS IN THE PRINTING INDUSTRY --- p.21 / Chapter 2.7 --- PRINTING METHODS --- p.25 / Chapter 2.8 --- OFFSET LITHOGRAPHY --- p.27 / Chapter 2.8.1 --- Principles of Offset Lithography --- p.28 / Chapter 2.8.2 --- Image Carriers for Offset Lithography --- p.29 / Chapter 2.8.3 --- Lithographic Presses --- p.32 / Chapter 2.8.4 --- Printing Process --- p.34 / Chapter CHAPTER 3. --- STUDY OBJECTIVES AND METHODS --- p.37 / Chapter 3.1 --- OBJECTIVES --- p.37 / Chapter 3.2 --- METHODS --- p.38 / Chapter 3.2.1 --- Study Population --- p.38 / Chapter 3.2.2 --- Visits --- p.41 / Chapter 3.2.3 --- Workers' Health Assessment --- p.42 / Chapter 3.2.4 --- Air Sampling --- p.44 / Chapter 3.2.5 --- Definition of Exposures --- p.48 / Chapter 3.3 --- DATA ANALYSIS --- p.49 / Chapter CHAPTER 4. --- RESULTS --- p.51 / Chapter 4.1 --- RESPONSE RATE --- p.51 / Chapter 4.2 --- CHARACTERISTICS OF THE STUDY POPULATION --- p.53 / Chapter 4.2.1 --- Printing Companies --- p.53 / Chapter 4.2.2 --- Study Subjects --- p.56 / Chapter 4.3 --- HEALTH PROBLEMS OF STUDY SUBJECTS --- p.60 / Chapter 4.3.1 --- Sick Leave --- p.60 / Chapter 4.3.2 --- Prevalence of Subjective Symptoms --- p.61 / Chapter 4.3.3 --- Mean Number of Symptoms --- p.64 / Chapter 4.4 --- AIR SAMPLING RESULTS --- p.66 / Chapter 4.4.1 --- Mean Concentration Levels of Solvents --- p.71 / Chapter 4.4.2 --- Mean Concentration Levels of Solvents by Printing Plants --- p.73 / Chapter 4.4.3 --- Mean Concentration Levels of Solvents by Locations --- p.75 / Chapter 4.5 --- EXPOSURE-RESPONSE RELATIONSHIPS BETWEEN ORGANIC SOLVENTS AND SYMPTOMS --- p.77 / Chapter 4.6 --- RISK FACTORS FOR SUBJECTIVE SYMPTOMS --- p.85 / Chapter CHAPTER 5. --- DISCUSSIONS --- p.90 / Chapter 5.1 --- RESPONSE RATE --- p.90 / Chapter 5.2 --- SOURCES OF BIAS --- p.91 / Chapter 5.3 --- STUDY SUBJECTS --- p.92 / Chapter 5.4 --- SOLVENT EXPOSURES --- p.93 / Chapter 5.4.1 --- Occupational Hygiene --- p.93 / Chapter 5.4.2 --- Exposure Classification --- p.95 / Chapter 5.4.3 --- Chemical Interaction --- p.98 / Chapter 5.5 --- HEALTH PROBLEMS --- p.99 / Chapter CHAPTER 6. --- CONCLUSION --- p.103 / REFERENCES --- p.105 / APPENDICES --- p.120 / Appendices A1 to A9: Newspaper reports on polyneuropathy induced by organic solvents in a Hong Kong printing factory --- p.120 / Appendix B: Telephone follow up form --- p.129 / Appendix C: Letter to the printing factory employer --- p.130 / Appendix D: Subjective symptom questionnaire for solvent workers --- p.131 / Appendix E: Questionnaire for exposed group workers --- p.132 / Appendix F: Questionnaire for non-exposed group workers --- p.140 / Appendix G: NIOSH Sampling and Analytical Method 1400 --- p.145 / Appendix H: NIOSH Sampling and Analytical Method 1500 --- p.150 / "Appendix I: Chemical Analytical Method from Department of Hygiene, School of Public Health, Sun Yat Sen University of Medical Sciences" --- p.157 / Appendix J: Air Sampling Worksheet --- p.159 / BIBLIOGRAPHY --- p.162

Song Hong. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2000. / Includes bibliographical references (leaves ). / Abstracts in English and Chinese; questionnaire in Chinese. / Abstract (English) --- p.i / Abstract (Chinese) --- p.iv / Acknowledgments --- p.vi / Table of Contents --- p.vii / List of tables --- p.x / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- Printing industry and organic solvents exposure --- p.1 / Chapter 1.2 --- Risk of low level exposures to organic solvents --- p.2 / Chapter 1.3 --- Using neurobehavioral methods to study the subclinical effects --- p.3 / Chapter Chapter 2 --- Literature review --- p.4 / Chapter 2.1 --- Organic solvents and neurobehavioral impairment --- p.4 / Chapter 2.2 --- Methodology of Neurobehavioral Test --- p.6 / Chapter 2.2.1 --- Criteria for selecting test battery --- p.7 / Chapter 2.2.2 --- Standardization of neurobehavioral test battery --- p.8 / Chapter 2.2.3 --- Reliability and validity --- p.9 / Chapter 2.2.4 --- Confounding factors of neurobehavioral test --- p.10 / Chapter 2.3 --- Neurobehavioral effects of different levels of solvent exposures --- p.12 / Chapter 2.3.1 --- Positive results in field studies --- p.12 / Chapter 2.3.2 --- Negative results in field studies --- p.17 / Chapter 2.3.3 --- Dose-response relationship in the field studies --- p.18 / Chapter 2.3.4 --- To separate acute and chronic effects --- p.20 / Chapter 2.3.5 --- The long-term effects of solvent exposure --- p.21 / Chapter 2.4 --- Limitations of these studies --- p.23 / Chapter 2.5 --- Summary --- p.26 / Chapter Chapter 3 --- Aims and Objectives --- p.31 / Chapter 3.1 --- Aims of the present research --- p.31 / Chapter 3.2 --- Position of this study cm this research domain --- p.32 / Chapter Chapter 4 --- Subjects and Method --- p.33 / Chapter 4.1 --- Study design --- p.33 / Chapter 4.2 --- Study population and sampling --- p.33 / Chapter 4.2.1 --- Participation --- p.33 / Chapter 4.2.2 --- Exposed group --- p.34 / Chapter 4.2.3 --- Reference group --- p.34 / Chapter 4.2.4 --- Sample size estimation --- p.34 / Chapter 4.3 --- Data collection --- p.36 / Chapter 4.3.1 --- Exposure assessment --- p.36 / Chapter 4.3.1.1 --- Air sample measurements --- p.36 / Chapter 4.3.1.2 --- Biological monitoring --- p.38 / Chapter 4.3.2. --- Medical assessment --- p.38 / Chapter 4.3.2.1 --- Pre-test questionnaire --- p.39 / Chapter 4.3.2.2 --- Neurobehavioral assessment --- p.39 / Chapter 4.4 --- Data Analysis --- p.43 / Chapter 4.4.1 --- Data Processing --- p.43 / Chapter 4.4.2 --- Statistical analysis --- p.44 / Chapter 4.4.2.1 --- Descriptive analysis --- p.44 / Chapter 4.4.2.2 --- Identifying the main confounding factories --- p.44 / Chapter 4.4.2.3 --- Comparing the tests score adjusted for confounding --- p.45 / Chapter 4.4.2.4 --- Dose-response analysis --- p.45 / Chapter Chapter 5 --- Results --- p.47 / Chapter 5.1 --- Demographic characteristics of the subjects --- p.47 / Chapter 5.2 --- Comparison of the basic characteristics between the exposed group and the reference group --- p.48 / Chapter 5.3 --- Comparison of the symptoms between the exposed group and the reference group --- p.49 / Chapter 5.4 --- Comparison of the scores of neurobehavioral tests between the exposed group and the reference group --- p.51 / Chapter 5.5 --- Identifying potential confounding of neurobehavioral test --- p.51 / Chapter 5.5.1 --- Main confounding factors of NCTB test on performance tests --- p.51 / Chapter 5.5.2 --- Main confounding factors of Profile of Mood States --- p.54 / Chapter 5.6 --- Groups comparison of the neurobehavioral effects --- p.57 / Chapter 5.6.1 --- Comparison of the adjusted mean scores between the exposed group and the reference group --- p.57 / Chapter 5.6.2 --- Groups comparison of the adjusted tests score in Factories C and G respectively --- p.58 / Chapter 5.7 --- Exposure assessment --- p.61 / Chapter 5.7.1 --- Air sampling results of the printing factories --- p.62 / Chapter 5.7.2 --- Relationship between results of active and passive sampling systems --- p.63 / Chapter 5.7.3 --- Biological monitoring --- p.63 / Chapter 5.8 --- Dose-response relationship --- p.65 / Chapter Chapter 6 --- Discussion --- p.69 / Chapter 6.1 --- Findings of this study --- p.69 / Chapter 6.1.1 --- Subjective symptoms --- p.69 / Chapter 6.1.2 --- Neurobehavioral effects --- p.70 / Chapter 6.1.3 --- Exposure intensity --- p.72 / Chapter 6.1.4. --- Dose-response relationship --- p.75 / Chapter 6.2 --- Applications of the study results --- p.76 / Chapter 6.2.1 --- The need for prevention measures --- p.77 / Chapter 6.2.2 --- Contributing to re-setting of OELs --- p.77 / Chapter 6.2.3. --- The evidence on neurotoxicology --- p.78 / Chapter 6.3 --- Limitations of the study --- p.79 / Chapter 6.3.1. --- Possibility of bias --- p.79 / Chapter 6.3.2. --- Lack of historical hygiene measurement data --- p.80 / Chapter 6.3.3. --- Influence of workshift --- p.81 / Chapter 6.3.4. --- Combined exposures to noise and organic solvents --- p.82 / Chapter 6.4 --- Conclusion --- p.83 / Appendices --- p.84 / Appendix 1 --- p.84 / Appendix 2 --- p.97 / Appendix 3 --- p.102 / Appendix 4 --- p.103 / Appendix 5 The Administration of The WHO-NCTB Tests --- p.114 / Test 1 Profile of Mood States Test --- p.115 / Test 2. Simple Reaction Time Test --- p.116 / Test 3. Digit Span Test Test --- p.119 / Test 4. Santa Ana Test --- p.120 / Test 5. Digit Symbol Test --- p.122 / Test 6. Benton Visual Retention Test --- p.123 / Test 7. Pursuit Aiming Test --- p.125 / Appendix 6 --- p.126 / Reference List --- p.127

Thesis (M.A.)--The University of North Carolina at Greensboro, 2008. / Directed by Thomas Kwapil; submitted to the Dept. of Psychology. Title from PDF t.p. (viewed Jan. 28, 2010). Includes bibliographical references (p. ).

Thesis (Ph. D.)--University of California, San Diego, 2000. / Vita. Includes bibliographical references (leaves 148-160).