Plaques and tangles and the pathogenesis of Alzheimer's disease

Since the earliest descriptions, senile plaques (SP) and neurofibrillary tangles (NFT) have been regarded as the pathological hallmarks of Alzheimer's disease (AD). Consequently, studies of the morphology, distribution, and molecular composition of SP and NFT have played an important role in developing theories as to the pathogenesis of AD; the most important being the 'Amyloid Cascade Hypothesis (ACH)'. Nevertheless, the significance of SP and NFT to the pathogenesis of AD remains controversial. This review examines three questions: 1) is there a relationship between the lesions and the degree of clinical dementia, 2) is the pathogenesis of the NFT linked to that of the SP, and 3) what is the relationship of SP and NFT to the pathogenesis of AD? These questions are discussed with reference to the morphology and molecular composition of SP and NFT, the effects of gene mutations, studies of head injury patients, experimental studies involving brain lesions and transgenes, and the degeneration of specific anatomical pathways. It was concluded that SP and NFT are not closely related to the developing dementia in AD, arise as relatively independent lesions, and may be the products of a degenerative process rather than being their cause.

Are pathological lesions in neurodegenerative disorders the cause or the effect of the degeneration?

Pathological lesions in the form of extracellular protein deposits, intracellular inclusions and changes in cell morphology occur in the brain in the majority of neurodegenerative disorders. Studies of the presence, distribution, and molecular determinants of these lesions are often used to define individual disorders and to establish the mechanisms of lesion pathogenesis. In most disorders, however, the relationship between the appearance of a lesion and the underlying disease process is unclear. Two hypotheses are proposed which could explain this relationship: (i) lesions are the direct cause of the observed neurodegeneration ('causal' hypothesis); and (ii) lesions are a reaction to neurodegeneration ('reaction' hypothesis). These hypotheses are considered in relation to studies of the morphology and molecular determinants of lesions, the effects of gene mutations, degeneration induced by head injury, the effects of experimentally induced brain lesions, transgenic studies and the degeneration of anatomical pathways. The balance of evidence suggests that in many disorders, the appearance of the pathological lesions is a reaction to degenerative processes rather than being their cause. Such a conclusion has implications both for the classification of neurodegenerative disorders and for studies of disease pathogenesis.

Sedation in paediatric intensive care

Paediatric intensive care is an expanding specialty that has been shown to improve the quality of care provided to critically ill children. An important aspect of the management of critically ill children includes the provision of effective sedation to reduce stress and anxiety during their stay in intensive care. However, to achieve effective and safe sedation in these children, is recognised as a challenge that is not without risk. Often children receive too much or too little sedation resulting in over sedation or under sedation respectively. These problems have arisen owing to a lack of information regarding altered pharmacokinetics and pharmacodynamics of medicines administered to critically ill children. In addition there are few validated sedation scoring systems in practice with which to monitor level of sedation and titrate medication appropriately. This study consisted of two stages. Stage 1 investigated the reproducibility and practicality of two observational sedation assessment scales for use in critically ill children. The two scales were different in design, the first being simple in design requiring a single assessment of the patient. The second was more complex in design requiring assessment of five patient parameters to obtain an overall sedation score. Both scales were found to achieve good reproducibility (kappa values 0.50 and 0.62 respectively). Practicality of each sedation scale was undertaken by obtaining nursing staff opinion about both scales using questionnaire and interview technique. It was established that nursing staff preferred the second, more complex sedation scale mainly because it was perceived to give a more accurate assessment of level of sedation and anxiety rather than merely level of sedation. Stage 2 investigated the pharmacokinetics and pharmacodynamics of midazolam in critically ill children. 52 children, aged between 0 and 18 years were recruited to the study and 303 blood samples taken to analyse midazolam and its metabolites, I-hydroxyrnidazolam (I-OR) and 4-hydroxymidazolam (4-0H). Analysis of plasma was undertaken using high performance liquid chromatography. A significant correlation was found between midazolam plasma concentration and sedative effect (r=0.598, p=O.OI). It was found that a midazolam plasma concentration of 223ng/ml (±31.9) achieved a satisfactory level of sedation. Only a poor correlation was found between dose of midazolam and plasma concentration of midazolam. Similarly only a poor correlation was found between sedative effect and dose of midazolam. Clearance of midazolam was found to be 6.3mllkglmin (±0.36), which is lower than that reported in healthy children (9.Il-13.3mllkg/min). Age related differences in midazolam clearance were observed in the study. Neonates produced the lowest clearance values (l.63mllkg/min), compared to children aged 1 to 12 months (8.52mllkg/min) who achieved the highest clearance values. Clearance was found to decrease after the age of 12 months to values of 5.34mllkglmin in children aged 7 years and above. Patients with renal (n=5) and liver impairment (n~4) were found to have reduced midazolam clearance (1.37 and 0.74ml/kg/min respectively). Plasma concentrations of I-OH and 4-0H ranged from 0-5 1 89nglml and 0-27 Inglml respectively. All children were found to be capable of producing both metabolites irrespective of age, although no trend was established between age and extent of production of either metabolite. Disease state was found to affect production of l-OH. Patients with renal impairment (n=5) produced the lowest I-OH midazolam plasma ratio (0.059) compared to patients with head injury (0.858). Patients with severe liver impairment were found to be capable of manufacturing both metabolites despite having a severely damaged liver.

The pathogenesis of Alzheimer's disease: a reevaluation of the "amyloid cascade hypothesis"

The most influential theory to explain the pathogenesis of Alzheimer's disease (AD) has been the "Amyloid Cascade Hypothesis" (ACH) first formulated in 1992. The ACH proposes that the deposition of ß-amyloid (Aß) is the initial pathological event in AD leading to the formation of senile plaques (SPs) and then to neurofibrillary tangles (NFTs) death of neurons, and ultimately dementia. This paper examines two questions regarding the ACH: (1) is there a relationship between the pathogenesis of SPs and NFTs, and (2) what is the relationship of these lesions to disease pathogenesis? These questions are examined in relation to studies of the morphology and molecular determinants of SPs and NFTs, the effects of gene mutation, degeneration induced by head injury, the effects of experimentally induced brain lesions, transgenic studies, and the degeneration of anatomical pathways. It was concluded that SPs and NFTs develop independently and may be the products rather than the causes of neurodegeneration in AD. A modification to the ACH is proposed which may better explain the pathogenesis of AD, especially of late-onset cases of the disease.

What causes alzheimer's disease?

Since the earliest descriptions of Alzheimer's disease (AD), many theories have been advanced as to its cause. These include: (1) exacerbation of aging, (2) degeneration of anatomical pathways, including the cholinergic and cortico-cortical pathways, (3) an environmental factor such as exposure to aluminium, head injury, or malnutrition, (4) genetic factors including mutations of amyloid precursor protein (APP) and presenilin (PSEN) genes and allelic variation in apolipoprotein E (Apo E), (5) mitochondrial dysfunction, (6) a compromised blood brain barrier, (7) immune system dysfunction, and (8) infectious agents. This review discusses the evidence for and against each of these theories and concludes that AD is a multifactorial disorder in which genetic and environmental risk factors interact to increase the rate of normal aging ('allostatic load'). The consequent degeneration of neurons and blood vessels results in the formation of abnormally aggregated 'reactive' proteins such as ß-amyloid (Aß) and tau. Gene mutations influence the outcome of age-related neuronal degeneration to cause early onset familial AD (EO-FAD). Where gene mutations are absent and a combination of risk factors present, Aß and tau only slowly accumulate not overwhelming cellular protection systems until later in life causing late-onset sporadic AD (LO-SAD). Aß and tau spread through the brain via cell to cell transfer along anatomical pathways, variation in the pathways of spread leading to the disease heterogeneity characteristic of AD.

What risk factors are associated with Alzheimer's disease?

A large number of risk factors have been associated with Alzheimer’s disease (AD). This article discusses the validity of the major risk factors that have been identified including age, genetics, exposure to aluminium, head injury, malnutrition and diet, mitochondrial dysfunction, vascular disease, immune system dysfunction, and infection. Rare forms of early-onset familial AD (FAD) are strongly linked to the presence of specific gene mutations, viz. mutations in amyloid precursor protein (APP) and presenilin (PSEN1/2) genes. By contrast, late-onset sporadic AD (SAD) is a multifactorial disorder in which age-related changes, genetic risk factors, such as allelic variation in apolipoprotein E (Apo E) gene, vascular disease, head injury and risk factors associated with diet, the immune system, mitochondrial function, and infection may all be involved. Life-style changes that may reduce the effect of these risk factors and therefore, the risk of AD are discussed.

Risk factors for Alzheimer's disease

A large number of possible risk factors have been associated with Alzheimer'sdisease (AD).This chapter discusses the validity of the major risk factors that have been identifiedincluding age, genetics, exposure to aluminum, head injury, malnutrition and diet,mitochondrial dysfunction, vascular disease, immune system dysfunction, and infectionand proposes a hypothesis to explain how these various risk factors may cause ADpathology.Rare forms of early-onset familial AD (FAD) are strongly linked to the presence ofspecific gene mutations, viz. mutations in amyloid precursor protein (APP) andpresenilin (PSEN1/2) genes. By contrast, late-onset sporadic AD (SAD) is amultifactorial disorder in which age-related changes, genetic risk factors, such as allelicvariation in apolipoprotein E (Apo E) gene, vascular disease, head injury and risk factorsassociated with diet, immune system, mitochondrial function, and infection may all beinvolved.These risk factors interact to increase the rate of normal aging (=allostatic load')which over a lifetime results in degeneration of neurons and blood vessels and as aconsequence, the formation of abnormally aggregated =reactive' proteins such as ß-amyloid (Aß) and tau leading to the development of senile plaques (SP) andneurofibrillary tangles (NFT) respectively. Life-style changes that may reduce theallostatic load and therefore, the risk of dementia are discussed.

Central Vestibulopathy in a Female Collegiate Basketball Player: A Case Study

We present a unique case of a collegiate athlete who suffered from a mild head injury following a multi-car motor vehicle accident and was later diagnosed with central vestibulopathy.

Reassembled, Slightly Askew:Composition & Sound Design

Reassembled, Slightly Askew is an autobiographical, immersive audio-based artwork based on Shannon Sickels’ experience of falling critically ill with a rare brain infection and her journey of rehabilitation with an acquired brain injury. Audience members experience Reassembled individually, listening to the audio via headphones while lying on a bed. The piece makes use of binaural microphone technology and spatial sound design techniques, causing listeners to feel they are inside Shannon’s head, viscerally experiencing her descent into coma, brain surgeries, early days in the hospital, and re-integration into the world with a hidden disability. It is a new kind of storytelling, never done before about this topic, that places the listener safely in the first-person perspective with the aim of increasing empathy and understanding. Reassembled… was made through a 5-year collaboration with an interdisciplinary team of artists led by Shannon Sickels (writer & performer), Paul Stapleton (composer & sound designer), Anna Newell (director), Hanna Slattne (dramaturgy), Stevie Prickett (choreography), and Shannon’s consultant neurosurgeon and head injury nurse. It’s development and production has been made possible with the support of a Wellcome Trust Arts Award, the Arts Council NI, Sonic Arts Research Centre, Belfast's Metropolitan Arts Centre, and grants from the Arts & Disability Award Ireland scheme. In its 2015 premiere year, Reassembled had 99 shows across Northern Ireland, including at the Cathedral Quarter Arts Festival (the MAC, Belfast) and BOUNCE Arts & Disability Forum Festival (Lyric Theatre, Belfast). It was awarded 5 stars in the Stage, a Hospital Club h100 Theatre & Performance Award, and been shared at medical conferences and trainings across the UK. It continues to be presented in diverse artistic and educational contexts, including as part of A Nation’s Theatre Festival in 2016 at Battersea Arts Centre in London where it was given 4 star reviews in the Guardian, Time Out London and the Evening Standard. "A real-life ordeal, captured by a daring, disorientating artistic collaboration, which works brilliantly on so many levels…It should be available on prescription.” — The Stage ★★★★★ www.reassembled.co.uk Audio clips and documentary footage available here: http://www.paulstapleton.net/portfolio/reassembled-slightly-askew

Modifications neurométaboliques et microstructurales à la suite d'une commotion cérébrale chez les athlètes féminines.

L’utilisation de méthodes d’investigation cérébrale avancées a permis de mettre en évidence la présence d’altérations à court et à long terme à la suite d’une commotion cérébrale. Plus spécifiquement, des altérations affectant l’intégrité de la matière blanche et le métabolisme cellulaire ont récemment été révélées par l’utilisation de l’imagerie du tenseur de diffusion (DTI) et la spectroscopie par résonance magnétique (SRM), respectivement. Ces atteintes cérébrales ont été observées chez des athlètes masculins quelques jours après la blessure à la tête et demeuraient détectables lorsque les athlètes étaient à nouveau évalués six mois post-commotion. En revanche, aucune étude n’a évalué les effets neurométaboliques et microstructuraux dans la phase aigüe et chronique d’une commotion cérébrale chez les athlètes féminines, malgré le fait qu’elles présentent une susceptibilité accrue de subir ce type de blessure, ainsi qu’un nombre plus élevé de symptômes post-commotionnels et un temps de réhabilitation plus long. Ainsi, les études composant le présent ouvrage visent globalement à établir le profil d’atteintes microstructurales et neurométaboliques chez des athlètes féminines par l’utilisation du DTI et de la SRM. La première étude visait à évaluer les changements neurométaboliques au sein du corps calleux chez des joueurs et joueuses de hockey au cours d’une saison universitaire. Les athlètes ayant subi une commotion cérébrale pendant la saison ont été évalués 72 heures, 2 semaines et 2 mois après la blessure à la tête en plus des évaluations pré et post-saison. Les résultats démontrent une absence de différences entre les athlètes ayant subi une commotion cérébrale et les athlètes qui n’en ont pas subie. De plus, aucune différence entre les données pré et post-saison a été observée chez les athlètes masculins alors qu’une diminution du taux de N-acetyl aspartate (NAA) n’a été mise en évidence chez les athlètes féminines, suggérant ainsi un impact des coups d’intensité sous-clinique à la tête. La deuxième étude, qui utilisait le DTI et la SRM, a révélé des atteintes chez des athlètes féminines commotionnées asymptomatiques en moyenne 18 mois post-commotion. Plus spécifiquement, la SRM a révélé une diminution du taux de myo-inositol (mI) au sein de l’hippocampe et du cortex moteur primaire (M1) alors que le DTI a mis en évidence une augmentation de la diffusivité moyenne (DM) dans plusieurs faisceaux de matière blanche. De iii plus, une approche par région d’intérêt a mis en évidence une diminution de la fraction d’anisotropie (FA) dans la partie du corps calleux projetant vers l’aire motrice primaire. Le troisième article évaluait des athlètes ayant subi une commotion cérébrale dans les jours suivant la blessure à la tête (7-10 jours) ainsi que six mois post-commotion avec la SRM. Dans la phase aigüe, des altérations neuropsychologiques combinées à un nombre significativement plus élevé de symptômes post-commotionnels et dépressifs ont été trouvés chez les athlètes féminines commotionnées, qui se résorbaient en phase chronique. En revanche, aucune différence sur le plan neurométabolique n’a été mise en évidence entre les deux groupes dans la phase aigüe. Dans la phase chronique, les athlètes commotionnées démontraient des altérations neurométaboliques au sein du cortex préfrontal dorsolatéral (CPDL) et M1, marquées par une augmentation du taux de glutamate/glutamine (Glx). De plus, une diminution du taux de NAA entre les deux temps de mesure était présente chez les athlètes contrôles. Finalement, le quatrième article documentait les atteintes microstructurales au sein de la voie corticospinale et du corps calleux six mois suivant une commotion cérébrale. Les analyses n’ont démontré aucune différence au sein de la voie corticospinale alors que des différences ont été relevées par segmentation du corps calleux selon les projections des fibres calleuses. En effet, les athlètes commotionnées présentaient une diminution de la DM et de la diffusivité radiale (DR) au sein de la région projetant vers le cortex préfrontal, un volume moindre des fibres de matière blanche dans la région projetant vers l’aire prémotrice et l’aire motrice supplémentaire, ainsi qu’une diminution de la diffusivité axiale (DA) dans la région projetant vers l’aire pariétale et temporale. En somme, les études incluses dans le présent ouvrage ont permis d’approfondir les connaissances sur les effets métaboliques et microstructuraux des commotions cérébrales et démontrent des effets délétères persistants chez des athlètes féminines. Ces données vont de pair avec la littérature scientifique qui suggère que les commotions cérébrales n’entraînent pas seulement des symptômes temporaires.

Lower limb and associated injuries in frontal-impact road traffic collisions.

Objectives: To study the relationship between severity of injury of the lower limb and severity of injury of the head, thoracic, and abdominal regions in frontal-impact road traffic collisions. Methods: Consecutive hospitalised trauma patients who were involved in a frontal road traffic collision were prospectively studied over 18 months. Patients with at least one Abbreviated Injury Scale (AIS) ≥3 or AIS 2 injuries within two AIS body regions were included. Patients were divided into two groups depending on the severity of injury to the head, chest or abdomen. Low severity group had an AIS < 2 and high severity group had an AIS ≥ 2. Backward likelihood logistic regression models were used to define significant factors affecting the severity of head, chest or abdominal injuries. Results: Eighty-five patients were studied. The backward likelihood logistic regression model defining independent factors affecting severity of head injuries was highly significant (p=0.01, nagelkerke r square = 0.1) severity of lower limb injuries was the only significant factor (p=0.013) having a negative correlation with head injury (Odds ratio of 0.64 (95% CI: 0.45-0.91). Conclusion: Occupants who sustain a greater severity of injury to the lower limb in a frontal-impact collision are likely to be spared from a greater severity of head injury.

Modifications neurométaboliques et microstructurales à la suite d'une commotion cérébrale chez les athlètes féminines

L’utilisation de méthodes d’investigation cérébrale avancées a permis de mettre en évidence la présence d’altérations à court et à long terme à la suite d’une commotion cérébrale. Plus spécifiquement, des altérations affectant l’intégrité de la matière blanche et le métabolisme cellulaire ont récemment été révélées par l’utilisation de l’imagerie du tenseur de diffusion (DTI) et la spectroscopie par résonance magnétique (SRM), respectivement. Ces atteintes cérébrales ont été observées chez des athlètes masculins quelques jours après la blessure à la tête et demeuraient détectables lorsque les athlètes étaient à nouveau évalués six mois post-commotion. En revanche, aucune étude n’a évalué les effets neurométaboliques et microstructuraux dans la phase aigüe et chronique d’une commotion cérébrale chez les athlètes féminines, malgré le fait qu’elles présentent une susceptibilité accrue de subir ce type de blessure, ainsi qu’un nombre plus élevé de symptômes post-commotionnels et un temps de réhabilitation plus long. Ainsi, les études composant le présent ouvrage visent globalement à établir le profil d’atteintes microstructurales et neurométaboliques chez des athlètes féminines par l’utilisation du DTI et de la SRM. La première étude visait à évaluer les changements neurométaboliques au sein du corps calleux chez des joueurs et joueuses de hockey au cours d’une saison universitaire. Les athlètes ayant subi une commotion cérébrale pendant la saison ont été évalués 72 heures, 2 semaines et 2 mois après la blessure à la tête en plus des évaluations pré et post-saison. Les résultats démontrent une absence de différences entre les athlètes ayant subi une commotion cérébrale et les athlètes qui n’en ont pas subie. De plus, aucune différence entre les données pré et post-saison a été observée chez les athlètes masculins alors qu’une diminution du taux de N-acetyl aspartate (NAA) n’a été mise en évidence chez les athlètes féminines, suggérant ainsi un impact des coups d’intensité sous-clinique à la tête. La deuxième étude, qui utilisait le DTI et la SRM, a révélé des atteintes chez des athlètes féminines commotionnées asymptomatiques en moyenne 18 mois post-commotion. Plus spécifiquement, la SRM a révélé une diminution du taux de myo-inositol (mI) au sein de l’hippocampe et du cortex moteur primaire (M1) alors que le DTI a mis en évidence une augmentation de la diffusivité moyenne (DM) dans plusieurs faisceaux de matière blanche. De iii plus, une approche par région d’intérêt a mis en évidence une diminution de la fraction d’anisotropie (FA) dans la partie du corps calleux projetant vers l’aire motrice primaire. Le troisième article évaluait des athlètes ayant subi une commotion cérébrale dans les jours suivant la blessure à la tête (7-10 jours) ainsi que six mois post-commotion avec la SRM. Dans la phase aigüe, des altérations neuropsychologiques combinées à un nombre significativement plus élevé de symptômes post-commotionnels et dépressifs ont été trouvés chez les athlètes féminines commotionnées, qui se résorbaient en phase chronique. En revanche, aucune différence sur le plan neurométabolique n’a été mise en évidence entre les deux groupes dans la phase aigüe. Dans la phase chronique, les athlètes commotionnées démontraient des altérations neurométaboliques au sein du cortex préfrontal dorsolatéral (CPDL) et M1, marquées par une augmentation du taux de glutamate/glutamine (Glx). De plus, une diminution du taux de NAA entre les deux temps de mesure était présente chez les athlètes contrôles. Finalement, le quatrième article documentait les atteintes microstructurales au sein de la voie corticospinale et du corps calleux six mois suivant une commotion cérébrale. Les analyses n’ont démontré aucune différence au sein de la voie corticospinale alors que des différences ont été relevées par segmentation du corps calleux selon les projections des fibres calleuses. En effet, les athlètes commotionnées présentaient une diminution de la DM et de la diffusivité radiale (DR) au sein de la région projetant vers le cortex préfrontal, un volume moindre des fibres de matière blanche dans la région projetant vers l’aire prémotrice et l’aire motrice supplémentaire, ainsi qu’une diminution de la diffusivité axiale (DA) dans la région projetant vers l’aire pariétale et temporale. En somme, les études incluses dans le présent ouvrage ont permis d’approfondir les connaissances sur les effets métaboliques et microstructuraux des commotions cérébrales et démontrent des effets délétères persistants chez des athlètes féminines. Ces données vont de pair avec la littérature scientifique qui suggère que les commotions cérébrales n’entraînent pas seulement des symptômes temporaires.

Fratura traumática do osso temporal : diagnóstico, sequelas e tratamento

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

Biceps femoris long-head architecture: A reliability and retrospective injury study

Purpose: To determine i) the reliability of two-dimensional ultrasonography for the assessment of biceps femoris long head (BFlh) architectural characteristics; ii) if limbs with a history of strain injury in the BFlh display different architecture and eccentric strength compared to uninjured limbs. Methods: This case-control study (control [n=20], injured group [n=16], males) assessed the BFlh architecture at rest and during graded isometric contractions using two-dimensional ultrasonography. The control group were assessed three times (>24hrs apart) to determine reliability. Previously injured individuals were evaluated once. Results The assessment of BFlh architecture was highly reliable (intraclass correlations >0.90). Fascicle length (p<0.001; d range: 0.67 to 1.34) and fascicle length relative to muscle thickness (p<0.001; d range: 0.58 to 0.85) of the previously injured BFlh were significantly less than the contralateral uninjured BFlh at all intensities. Pennation angle of the previously injured BFlh was significantly greater (p<0.001; d range: 0.62 to 0.88) than the contralateral uninjured BFlh at all intensities. Eccentric strength in the previously injured limb was significantly lower than the contralateral limb (-15.4%; -52.5N; 95% CI=-28.45 to -76.23; p<0.001, d=0.56). Conclusion These data indicate that two-dimensional ultrasonography is reliable for assessing BFlh architecture at rest and during graded isometric contractions. Fascicle length, fascicle length relative to muscle thickness and pennation angle are significantly different in previously injured BFlh compared to an uninjured contralateral BFlh. Eccentric strength of the previously injured limb is also significantly lower than the uninjured contralateral limb. These findings have implications for rehabilitation and injury prevention practices which should consider altered architectural characteristics.

X-ray studies on crystalline complexes involving amino acids and peptides. Part XIV: Closed conformation and head-to-tail arrangement in a new crystal form of L-histidine L-aspartate monohydrate

A new form of L-histidine L-aspartate monohydrate crystallizes in space group P22 witha = 5.131(1),b = 6.881(1),c= 18.277(2) Å,β= 97.26(1)° and Z = 2. The structure has been solved by the direct methods and refined to anR value of 0.044 for 1377 observed reflections. Both the amino acid molecules in the complex assume the energetically least favourable allowed conformation with the side chains staggered between the α-amino and α-scarboxylate groups. This results in characteristic distortions in some bond angles. The unlike molecules aggregate into alternating double layers with water molecules sandwiched between the two layers in the aspartate double layer. The molecules in each layer are arranged in a head-to-tail fashion. The aggregation pattern in the complex is fundamentally similar to that in other binary complexes involving commonly occurring L amino acids, although the molecules aggregate into single layers in them. The distribution of crystallographic (and local) symmetry elements in the old form of the complex is very different from that in the new form. So is the conformation of half the histidine molecules. Yet, the basic features of molecular aggregation, particularly the nature and the orientation of head-to-tail sequences, remain the same in both the forms. This supports the thesis that the characteristic aggregation patterns observed in crystal structures represent an intrinsic property of amino acid aggregation.