Robert A. Wilcox

NEW DEVELOPMENTS IN THE MOLECULAR PHARMACOLOGY OF THE MYO-INOSITOL 1,4,5-TRISPHOSPHATE RECEPTOR

Receptor-mediated activation of phospholipase C to generate inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] is a ubiquitous signalling pathway in mammalian systems. A family of three IP3 receptor subtype monomers form functional tetramers, which act as effectors for Ins(1,4,5)P3, providing a ligand-gated channel that allows Ca2+ ions to move between cellular compartments. As IP3 receptors are located principally, although not exclusively, in the endoplasmic reticular membrane, Ins(1,4,5)P3 is considered to be a second messenger that mobilizes Ca2+ from intracellular stores. Ca2+ store mobilization by Ins(1,4,5)P3 can be shown to contribute to a variety of physiological and pathophysiological phenomena, and therefore the IP3 receptor represents a novel, potential pharmacological target. In this article, Rob Wilcox and colleagues review recent developments in IP3 receptor pharmacology, with particular emphasis on ligand molecular recognition by this receptor-channel complex. The potential for designing non-inositol phosphate-based agonists and antagonists is also discussed.

Whispering dysphonia (DYT4 dystonia) is caused by a mutation in the TUBB4 gene

A study was undertaken to identify the gene underlying DYT4 dystonia, a dominantly inherited form of spasmodic dysphonia combined with other focal or generalized dystonia and a characteristic facies and body habitus, in an Australian family.

Persistent abnormality detected in the non-ictal electroencephalogram in primary generalised epilepsy.

Objectives: Gamma oscillations (30–100 Hz gamma electroencephalographic (EEG) activity) correlate with high frequency synchronous rhythmic bursting in assemblies of cerebral neurons participating in aspects of consciousness. Previous studies in a kainic acid animal model of epilepsy revealed increased intensity of gamma rhythms in background EEG preceding epileptiform discharges, leading the authors to test for intensified gamma EEG in humans with epilepsy. Methods: 64 channel cortical EEG were recorded from 10 people with primary generalised epilepsy, 11 with partial epilepsy, and 20 controls during a quiescent mental state. Using standard methods of EEG analysis the strength of EEG rhythms (fast Fourier transformation) was quantified and the strengths of rhythms in the patient groups compared with with controls by unpaired t test at 1 Hz intervals from 1 Hz to 100 Hz. Results: In patients with generalised epilepsy, there was a threefold to sevenfold increase in power of gamma EEG between 30 Hz and 100 Hz (p<0.01). Analysis of three unmedicated patients with primary generalised epilepsies revealed an additional 10-fold narrow band increase of power around 35 Hz–40 Hz (p<0.0001). There were no corresponding changes in patients with partial epilepsy. Conclusions: Increased gamma EEG is probably a marker of the underlying ion channel or neurotransmitter receptor dysfunction in primary generalised epilepsies and may also be a pathophysiological prerequisite for the development of seizures. The finding provides a new diagnostic approach and also links the pathophysiology of generalised epilepsies to emerging concepts of neuronal correlates of consciousness.

Whispering dysphonia in an Australian family (DYT4): a clinical and genetic reappraisal.

The designation, DYT4, was assigned to an Australian family with whispering dysphonia. The role of known causes of dystonia has not been comprehensively investigated in this family, nor has the possible relationship with Wilson disease (WND) in 2 siblings. Eighteen family members were neurologically examined, and DNA samples were obtained. Linkage analysis was performed to DYT1, DYT6, DYT7, DYT11, DYT13, DYT15, and ATP7B with microsatellite markers and the THAP1 (DYT6), PRKRA (DYT16), and ATP7B (WND) genes were sequenced. Reevaluation of the family identified 9 living affected family members, 6 of whom are newly affected. Phenotypic expression was variable, ranging from isolated spasmodic dysphonia (often with mild craniocervical dystonia) to severe generalized dystonia. Two newly described features included an extrusional tongue dystonia and a unique “hobby horse gait.” Genetic analyses excluded all tested loci. Haplotype analysis of the ATP7B region resulted in three different combinations of the two parental alleles in the 8 investigated siblings of the 2 deceased WND patients, indicating that the fourth combination (of two mutated alleles) had occurred only in the deceased WND patients. On these two alleles, we identified a missense (c.2297C>G; p.T766R) and a splice‐site mutation (IVS5+1G>T). The c.2297C>G mutation was detected in 3 affected and 4 unaffected family members, whereas the IVS5+1G>T mutation was detected in 1 affected and unaffected family member. Five DYT4 patients carried neither mutation. DYT4 is a familial form of dystonia unrelated to known dystonia genes and loci. ATP7B mutations do not segregate with the dystonia phenotype, indicating two independent genetic diseases in this family.

The symbol of modern medicine: why one snake is more than two.

Western culture demands integrity, personal sacrifice, and compassion from its physician healers. This powerful social expectation predates Christianity and has its origins in the heroic and mythologic traditions of ancient Greece. The heroic, and later mythical, figure of Asklepios was a major focus of ancient Greco-Roman medical tradition from perhaps as early as 1200 BC (1, 2) until 500 AD (3-14). The mortal herophysician Asklepios, mentioned in Homers Iliad, exemplified the ideal Greek physician (2). Later, as Asklepios was deified and worshipped, these traditions of patient care spread throughout Greece and, subsequently, the vast Roman Empire (4-6). Asklepios came to be recognized as the god of medicine and the mythical son of Apollo whose healing power Asklepios had inherited and expanded (3-8). The cult of Asklepios and his family seems to have originated at Trikka in Thessaly; by Roman times, hundreds of ancient temple complexes, called Asklepieions, had been built throughout the Greco-Roman world (6). The Asklepieions of Epidavros, Kos, and Pergamon were particularly extensive and elaborate, resembling a cross between a sanatorium and a modern hospital. In times of illness, Asklepios was the focus of ancient Greco-Roman supplication, particularly for the poor and disregarded (4). Many early Greek physicians claimed direct descent from the herophysician Asklepios, proclaiming themselves a family of Asklepiades. Hippokrates (circa 460 to 377 BC) proudly claimed descent from Asklepios via Poldaleiros, the skillful physician son of Asklepios (4); indeed, Plato (circa 427 to 347 BC) often referred to Hippokrates as the Asklepiade (5). With the spread of the cult of the god Asklepios, the term Asklepiade was applied more generically, and Asklepios was seen as the patron of physicians and the guardian of the medical craft. The great physician Galen (circa 129 to 216 AD) began his training as an attendant at the Asklepieion of Pergamon (15) and in his writings referred to Asklepios as his ancestral God (4, 16). The opening lines of the Hippokratic Oath clearly reveal the central role occupied by Asklepios and his mythologic daughters, Hygieia and Panakeia, in the hearts and minds of the ancients: I swear by Apollo Physician and Asklepios and Hygieia and Panakeia and all the gods and goddesses, making them my witnesses, that I will fulfil according to my ability and judgement this oath and this covenant (17). Asklepios was commonly depicted on statues, reliefs, coins, and physicians rings holding his Asklepian emblem. Several myths describe how Asklepios chose his symbol (4). In perhaps the most popular tale, Asklepios is examining a man, Glaukos, whom Zeus had recently struck dead with a thunderbolt. During the examination, a snake gliding into the room surprised Asklepios, and he responded by killing it with a blow from his staff. Asklepios was subsequently intrigued by the arrival of a second serpent, which placed certain herbs in the mouth of the dead serpent and thereby restored it to life. Asklepios quickly perceived the lesson, revived Glaukos by recourse to the same herbs, and, as a mark of respect, adopted the serpent coiling about his staff as his emblem (4). The use of the Asklepian motif was very popular throughout antiquity. However, from the early Christian era to the Middle Ages, many of the ancient Greco-Roman gods and symbols were suppressed by the Catholic Church, and uroscopy (or water-casting) came to play an important role in medical diagnosis (18). Thus, from the 6th century until the Renaissance, the urine flask replaced the Asklepian as the symbol of the profession (19). The changes in religious imagination and values that took place after the Reformation in the Protestant countries of northern Europe had direct repercussions on the choice of medical patrons and symbols. As Catholic patron saints of medicine lost favor, they were replaced by the rediscovered symbols of antiquity (7). Subsequently, in countries such as England, the Netherlands, Norway, and Sweden, illustrations, art works, and statues of Asklepios began to proliferate; Asklepios was often accompanied by his mythical daughter, Hygieia, the goddess of health (7). Clearly, Asklepios was no longer worshipped as a divinity; however, because of the intense interest in the symbolism, learning, and traditions of the Greco-Roman period, the Asklepian was again recognized and firmly established as the symbol of medicine (Figure 1). Figure 1. Statues of Asklepios and Hygieia. From the beginning of the 17th century, the figure of Asklepios began appearing on medical medals and calling cards. The same pattern seen in antiquity emerged: The symbol was used only in a medical context, whereas the caduceus, although used by some medical organizations, was associated with other fields, especially commerce, communications, chemistry, and pharmacy (7, 13, 19). The Recent Adoption of the Caduceus as a Medical Symbol In most countries, the Asklepian is firmly established as the symbol of military and civilian medicine (20). Therefore, it is difficult to understand the widespread use of the caduceus in the United States, especially because it is used side by side with the Asklepian motif. For example, the emblem of the U.S. Public Health Service bears the caduceus, whereas the National Library of Medicine and American Medical Association prominently display the Asklepian. Within the military, the badge insignia of the U.S. Army Medical Corps (USAMC) is the caduceus, but its coat of arms, which is that of the U.S. Army Medical Department (USAMEDD) (adopted in 1818), bears the Asklepian (21, 22) (Figure 2). Figure 2. Symbols of the U.S. Army Medical Corps (USAMC). Top. Bottom. So why did the caduceus become inappropriately associated with medicine in the minds of North American doctors in the late 19th century? Some have hypothesized that the reason is related to the use of the caduceus motif by some European publishing houses. In particular, John Churchill of London, the prolific medical publisher, used a caduceus printers mark on the title page of many of the medical and scientific books he exported to the United States (13). The mark may have symbolized Churchills desire to unite medicine and literature because it consisted of two serpents labeled medicina and literis and a motto Irrupta Tenet Copula (unbreakable bond unites) (23). Nevertheless, John Churchill clearly saw the caduceus as his printers mark and not the symbol of medicine because several of his medical books also included prominent representations of the Asklepian (13). In the United States, however, an erroneous mental connection between Churchills caduceus and medical practice seems to have developed. By the late 19th century, several United Statesbased publishing houses, assuming that the caduceus was a symbol of medicine, had copied or adapted Churchills caduceus printers mark and were prominently displaying it in their medical books (13). Apparently, this misunderstanding was sufficiently widespread in the medical community in the United States to have stimulated the publication of papers condemning the adoption of the caduceus and the neglect of the Asklepian (24, 25). The important question to ask is how did the caduceus become popular so quickly in the United States. The role of the USAMC is crucial. In 1902, at the suggestion of an assistant surgeon, Captain Frederick Reynolds, a new uniform code was established, and the caduceus became a collar insignia for all personnel in the USAMC. From Captain Reynolds correspondence with the Surgeon Generals office, it is apparent that he was unaware of the distinction between the caduceus and Asklepian when he recommended the combined use of the cock of Aesculapius and the caduceus. His statement to the Surgeon General that the Medical Corps of several foreign powers, notably the English all displayed the caduceus was also erroneous. In fact, no other western medical military service of that time displayed the caduceus; they all used either the Asklepian or symbols based on the Christian cross (13). Thus, the adoption of the caduceus by the USAMEDD seems to have been simply a misunderstanding of classical mythologic iconography. Ironically, this mistake was almost avoided. In March 1902, when Captain Reynolds initially suggested the switch to the caduceus symbol, the Surgeon General, G.W. Sternberg, dismissed his request outright. However, Captain Reynolds was persistent and, later that year, he sent a second letter to the new Surgeon General, W.H. Forwood; this time, his proposal was approved. Thus, on 17 July 1902, the caduceus of gold was adopted as the branch insignia of the USAMC (13, 26). This faux pas did not go entirely unnoticed in the United States (21, 27, 28). In 1917, Lieutenant Colonel McCulloch, the librarian to the Surgeon General, discovered original documents showing that the coat of arms adopted by the USAMEDD a century earlier had displayed the Asklepian and not the caduceus. McCulloch lamented: I think that in this country we pay too little attention to the historical and humanistic side of things. The caduceus or wand of Mercury now used on the collar of the uniform blouse of the medical corps, has really no medical bearing whatever. It really should be replaced as a corps design by the Aesculapian staff and serpent (21). Why the Caduceus Is an Inappropriate Medical Symbol It is in and through symbols that man, consciously or unconsciously, lives, works and has his being (29). Symbols have power because of their associations and traditions. It is precisely for this reason that the symbol of the blameless physician Asklepios (2), and not the caduceus of Hermes (Latin, Mercury), is an appropriate emblem for the ideals of modern medicine. It is easy to appreciate the inaptness of the caduceus as a medical symbol, given an understanding of the role and attributes assigned to Hermes in ancient mytholo

Hashimoto’s encephalopathy masquerading as acute psychosis

Hashimotos encephalopathy (HE) is a relapsing, but exquisitely corticosteroid-responsive encephalopathy associated with autoimmune thyroiditis. Although a rare disease, with just over 100 cases reported, it may be under-recognised. Its presentation can be protean with prominent neuropsychiatric features, stroke-like episodes, seizures and myoclonic jerks. Prompt corticosteroid treatment usually leads to rapid recovery. Here we report a patient with HE, initially presenting with florid neuropsychiatric symptoms. Recent developments in the understanding of this condition are discussed.

Neuromyelitis optica (Devic's disease) in a patient with syphilis

The patient initially presented with bilateral optic neuritis and periventricular cranial MRI abnormalities in the context of syphilis. Blood was positive but cerebrospinal fluid testing was negative for specific syphilis markers and he was oligoclonal cerebrospinal fluid (CSF) band negative. He initially responded well to penicillin and corticosteriod treatment, but went on to develop the clinical syndrome of neuromyelitis optica (NMO). Testing for the presence of the serum autoantibody for aquaporin-4 was negative. This patient appears to represent another case of post-infectious NMO. Possible pathogenesis of this post-syphilis NMO syndrome in the patient is discussed. Multiple Sclerosis 2008; 14: 268—271. http://msj.sagepub.com

Inositol trisphosphate analogues selective for types I and II inositol trisphosphate receptors exert differential effects on vasopressin-stimulated Ca2+ inflow and Ca2+ release from intracellular stores in rat hepatocytes.

Previous studies have shown that adenophostin A is a potent initiator of the activation of SOCs (store-operated Ca2+ channels) in rat hepatocytes, and have suggested that, of the two subtypes of Ins(1,4,5)P3 receptor predominantly present in rat hepatocytes [Ins(1,4,5)P3R1 (type I receptor) and Ins(1,4,5)P3R2 (type II receptor)], Ins(1,4,5)P3R1s are required for SOC activation. We compared the abilities of Ins(1,4,6)P3 [with higher apparent affinity for Ins(1,4,5)P3R1] and Ins(1,3,6)P3 and Ins(1,2,4,5)P4 [with higher apparent affinities for Ins(1,4,5)P3R2] to activate SOCs. The Ins(1,4,5)P3 analogues were microinjected into single cells together with fura 2, and dose-response curves for the activation of Ca2+ inflow and Ca2+ release from intracellular stores obtained for each analogue. The concentration of Ins(1,4,6)P3 which gave half-maximal stimulation of Ca2+ inflow was substantially lower than that which gave half-maximal stimulation of Ca2+ release. By contrast, for Ins(1,3,6)P3 and Ins(1,2,4,5)P3, the concentration which gave half-maximal stimulation of Ca2+ inflow was substantially higher than that which gave half-maximal stimulation of Ca2+ release. The distribution of Ins(1,4,5)P3R1 and Ins(1,4,5)P3R2 in rat hepatocytes cultured under the same conditions as those employed for the measurement of Ca2+ inflow and release was determined by immunofluorescence. Ins(1,4,5)-P3R1s were found predominantly at the cell periphery, whereas Ins(1,4,5)P3R2s were found at the cell periphery, the cell interior and nucleus. It is concluded that the idea that a small region of the endoplasmic reticulum enriched in Ins(1,4,5)P3R1 is required for the activation of SOCs is consistent with the present results for hepatocytes.

Relapsing encephalopathy with headache: an unusual presentation of isolated intracranial neurosarcoidosis

We report a presentation of relapsing and remitting isolated intracranial neurosarcoidosis in a female patient who presented with episodic severe headache and behavioural disturbance initially misdiagnosed as psychosis. Eventually, several episodes were accompanied by visual disturbance secondary to papilloedema, ultimately leading to a diagnosis of neurosarcoidosis on meningeal biopsy. Sarcoidosis is a multisystem inflammatory disease of unknown aetiology, and is characterised by non-caseating granulomata. Pulmonary disease is the most common manifestation, occurring in 90% of patients. Clinical involvement of the nervous system is said to occur in 5–15% of patients.1 Isolated intracranial neurosarcoidosis is even rarer, with systemic sarcoidosis being detected in more than 95% of cases of sarcoidosis initially presenting with neurological symptoms.2 A woman presented initially at age 30 years, and then subsequently five times over 3 years with stereotyped episodes of headache, confusion and psychomotor agitation. In each instance, a history was given of a constant, severe bifrontal headache that was associated with nausea, vomiting, photophobia and/or visual field disturbance. As each presentation evolved, she became confused and encephalopathic. Early in the course of her illness these episodes were misinterpreted as acute psychosis because she exhibited pressured …

Genome sequencing identifies a novel mutation in ATP1A3 in a family with dystonia in females only

Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal movements or postures. Several genetic causes of dystonia have been elucidated but genetic causes of dystonia specifically affecting females have not yet been described. In the present study, we investigated a large dystonia family from New Zealand in which only females were affected. They presented with a generalized form of the disorder including laryngeal, cervical, and arm dystonia. We found a novel, likely disease-causing, three base-pair deletion (c.443_445delGAG, p.Ser148del) in ATP1A3 in this family by combining genome and exome sequencing. Mutations in ATP1A3 have previously been linked to rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and CAPOS syndrome. Therefore, we re-examined our patients with a specific focus on typical symptoms of these conditions. It turned out that all patients reported a rapid onset of dystonic symptoms following a trigger suggesting a diagnosis of RDP. Notably, none of the patients showed clear symptoms of parkinsonism or symptoms specific for AHC or CAPOS. The ATP1A3 gene is located on chromosome 19q13.2, thus, providing no obvious explanation for the preponderance to affect females. Interestingly, we also identified one unaffected male offspring carrying the p.Ser148del mutation suggesting reduced penetrance of this mutation, a phenomenon that has also been observed for other RDP-causing mutations in ATP1A3. Although phenotypic information in this family was initially incomplete, the identification of the p.Ser148del ATP1A3 mutation elicited clinical re-examination of patients subsequently allowing establishing the correct diagnosis, a phenomenon known as “reverse phenotyping”.