Common Presentations, Diagnostic Strategies, and Principles of Treatment

Michael A. Gardam MSc, MD, CM, FRCPC
Medical Director,
Tuberculosis Clinic,
Associate Hospital Epidemiologist,
University Health Network,Toronto.

The elderly are one of four sub populations in Canada, which also include the foreign born, homeless persons, and Native Canadians, that are at high risk for developing active tuberculosis. There are several reasons why tuberculosis is common among the elderly: Firstly, today's elderly have a high possibility of being infected with M. tuberculosis. They are survivors of the earlier part of the twentieth century in which an estimated three-quarters or more of the population were infected with tuberculosis by the time they were 30 years of age. Secondly, the elderly often suffer from other conditions which predispose them to reactivation of tuberculosis, such as diabetes mellitus, chronic renal failure, malnutrition, and diseases requiring prolonged corticosteroid therapy. Finally, residents of nursing homes and long-term care facilities may become infected or reinfected through contact with other residents with active disease.

Symptoms
While the clinical symptoms of tuberculosis may be vague and non-specific in any age group, this is particularly true in elderly persons. Fever, malaise, weakness, and failure to thrive are the most consistent symptoms.

Hearing Loss Traced to Age-related Changes in Cochlear Function and Central Auditory Processing

Nadège Chéry, PhD

In a society that extols the virtues of youth, hearing impairment in the elderly is often perceived as a graceless symbol of old age. Unfortunately, because of this attitude, most seniors would rather deny that, upon reaching their aged ears, even the most vibrant sounds fail to be heard. Hearing impairment affects over 50% of Canadians aged 60 years and over.¹ The incidence of hearing loss increases considerably with age, reaching 81% among persons 80 years of age or over.¹ Importantly, hearing impairment can have devastating consequences on the social life of an older person, and may profoundly alter their emotional wellbeing.^1,3,7 Although common among older adults, auditory processing defects are not an inevitable side effect of aging.^5,9 In fact, in most cases, hearing problems can be resolved,³ and yet, many older persons afflicted with hearing loss are unaware of this or simply choose not to deal with the problem.

Normal hearing is a complex mechanism that involves the transfer and subsequent conversion of sound into electrical impulses to be processed by the brain.

Target for a New Generation of Therapeutic Agents

Kimby N. Barton, MSc
Assistant Editor,
Geriatrics & Aging

The small southern Italian village of Nicastro, once again made it into International headlines when researchers at the University of Toronto discovered a new protein, nicastrin, which is involved in Alzheimer's disease (AD). Nicastrin was so named to honour a large family in Nicastro that has been plagued with AD for generations and played a key role in the 1995 discovery of two genes that cause early onset Alzheimer's. The same team, led by Peter St. George Hyslop, has found that nicastrin is a functional component of the g-secretase, which is involved in the formation of toxic plaques found in the brains of AD patients. More importantly, they have found an exposed and highly conserved domain of this protein that affects production of the amyloid-b (Ab) peptide and may serve as a potential target for pharmaceutical modulation of Ab production in patients with AD and other related disorders.

Much of the research into AD has been focused on the mechanism underlying the formation of the (Ab) peptide, which is a key component of the toxic amyloid plaques that are characteristic of brain tissue from patients with AD. In 1995, it was discovered that a mutation in a previously unknown protein could lead to an early-onset form of familial AD. This protein was subsequently discovered to be presenilin, a highly conserved, polytopic membrane protein. However, several studies have demonstrated that although mutations in presenilin may result in overproduction of the toxic Ab derivative, it is unlikely that the protein acts alone.

The Ab peptide is generated from a large precursor protein, the amyloid precursor protein (APP) in a two-step proteolytic pathway. Initially, the protein is cleaved near the cell surface in an extracellular domain either by a b- or a a-secretase to generate C-terminal stubs of the protein. These stubs are then further cleaved in their transmembrane domains by the presenilin-linked g-secretase to generate two different isoforms of the Ab peptide, one that is benign and one that is neurotoxic. The b-secretase enzyme appears to have a benign role; during development it may cleave a protein called Notch, which releases a fragment that activates gene transcription. Unfortunately it has been difficult to determine which proteins are directly responsible for the g-secretase activity, although evidence suggests that the presenilins are involved.

St. George-Hyslop's tream found that nicastrin binds to presenilins 1 and 2 and interacts with the APP carboxy terminal 'stub', the fragment that is produced by the initial, b-secretase cleavage. Mutations in an exposed and conserved domain of nicastrin, increase the production of both forms of the Ab peptide and deletions inhibit their production. The team also found that nicastrin is required for processing of the protein Notch, which is involved in gene activation.

So, nicastrin is structurally part of the g-secretase complex, but how does it interact with the other proteins? The team has suggested that nicastrin may bind to the APP stub and align it in the correct way to presenilin, so that it is cleaved at the right position. Another possibility is that nicastrin regulates the cleavage activity, in which case, compounds that interact with either nicastrin or the presenilins should effectively alter g-secretase and APP turnover; hence a site for pharmaceutical intervention.

Whether or not genetic variants in nicastrin are associated with inherited susceptibility to AD remains to be determined. Research in this field will be ongoing, but in the meantime pharmaceutical companies will no doubt devote a great deal of attention to this little 'Italian' protein.

Fayaaz Jaffer
Faculty of Dentistry,
University of Toronto.

David W. Matear
Associate Professor,
Director of Clinics,
Faculty of Dentistry,
University of Toronto.

Introduction
The oral health status of older adults is generally poorer than that of the rest of the population. In particular, those residing in institutions have very poor oral health.^1,2 The prevalence of systemic infection among the elderly is becoming an increasingly important health care issue, especially since age-related demographics show an increase in the numbers of aging and elderly individuals.

One of the primary portals of entry into the body for infectious agents is the oral cavity, which is home to over 500 bacterial species alone.³ Although most oral microbes are non-pathogenic, decreased host resistance and/or environmental factors, such as institutionalization, can increase the risk of systemic infection among the elderly. Furthermore, once a focal infection has been established, it can open the way to colonization by more virulent organisms. Some of the systemic diseases reported to result from oral infections include pneumonia, meningitis, osteomyelitis, bacterial endocarditis, as well as abcesses of the brain, lung, and liver. This article will provide examples of the impact of oral diseases on general health in the elderly.

Among Seniors there is a High Prevalence of Hearing Loss but Low Incidence of Disclosure

Nadia Sandor, MSc
Audiologist, Mt. Sinai Hospital

Elderly listeners often have difficulties with their hearing in typical, everyday situations. For example, they may fail to hear faint sounds, especially in an area with a great deal of background noise. They may also have difficulty ascertaining the direction from which a sound is coming--for instance, determining whether the telephone is ringing in the kitchen or whether the ringing is coming from a television program.¹ Finally, they may have trouble distinguishing between or understanding persons talking in a restaurant or at the dinner table. Moreover, these difficulties with hearing become more apparent and more debilitating when the listening environment is more complex (such as at a large noisy gathering in a highly reverberant room).¹

Hearing loss starts as early as the third or fourth decade of life, and it is well known that both its incidence and prevalence increase with advancing age.² Auditory deficits, which differ from hearing loss in that they encompass hearing threshold changes and changes in temporal and spectral resolution, also increase markedly with age, beginning in the fourth decade. Hearing loss has been identified as the most prevalent chronic disability among older adults, exceeded only by arthritis and hypertension.

Rachel L. Panton¹,
Catharine Ramsey, Brenda L. Gallie^1,2,3
1Department of Ophthalmology,
²The Hospital for Sick Children; Cancer Informatics, Ontario Cancer Institute/Princess Margaret Hospital, University Health Network;
³Departments of Ophthalmology and Molecular and Medical Genetics, University of Toronto.

Only as a grandmother, did Catharine Ramsey learn what had caused the loss of her eye in infancy, information that was to change the life of her entire family.

"I was born on January 19, 1939, adopted as an infant and raised in Kirkland Lake, Ontario. On September 26, 1940 my left eye was removed due to 'eye problems'. Throughout my life, I was told 'you were sick when you were a baby and had to have your eye out!'

I often asked my ophthalmologist why this had happened to me, but I did not receive any clear answers. When my daughter Margaret married, I asked again if there was any information I needed to pass along to my children. I was told that there wasn't any.

My beautiful granddaughter, Jennifer, was born November 6, 1988. She was perfect, or so we thought. My daughter repeatedly questioned the baby's doctor about why Jennifer's eyes were not tracking together. This appearance was barely noticeable and the doctor assured her that 'the baby was only trying to look at the bridge of her nose and would grow out of it.

Mark Mandelcorn, MD, FRCS(C)
Vitreo-retinal Surgeon
Toronto Western Hospital

Macular degeneration (MD) is the leading cause of legal blindness in the Western world, the leading cause of poor eyesight in Canada, and has been described as one of the great 'epidemics' of the twentieth century. The Canadian National Institute for the blind registers almost 50,000 people as legally blind as a result of MD. This month, Geriatrics & Aging is very pleased to present an article by Dr. Mark Mandelcorn, a leading vitreo-retinal surgeon, on the various treatment options that are available for patients suffering from MD.

Macular degeneration is the most likely diagnosis when an elderly patient has poor reading vision that cannot be corrected with either glasses or cataract surgery. Not all cases presenting in this way, however, constitute true macular degeneration, currently referred to as age-related macular degeneration (AMD). Some may, in fact, be cases of macular hole; others could be premacular fibrosis; finally, a case resembling macular degeneration may actually be related to a systemic disorder, such as, diabetic macular edema.

It is important to be certain that the disorder is true age-related macular degeneration. In the case of AMD, the prognosis and management of the affected eye are entirely different and perhaps more difficult, and the fate of the other eye more uncertain, than would be the case with any of the other disorders mentioned above.

Physiological Aging Occurs throughout the Eye and can bring about the Loss of Vision

Cindy M.L. Hutnik, MD, PhD, FRCSC
Department of Ophthalmology,
University of Western Ontario
Active Staff, St. Joseph's Health Centre, London, ON

Introduction
In 1942, Sir W. Stewart Duke-Elder published his classic ophthalmic text series.¹ The first paragraph eloquently describes his thoughts on the genesis of vision and the evolution of the eye "from remote and lowly origins, far removed in form and in function from the highly specialized mechanism we find in man; indeed, it is no easy matter to decide where its origin lay or when the sense of vision first became a factor in conscious behaviour." He begins by stating that "either in fact or in fiction there are few stories more fascinating than the history of the evolution of the visual apparatus from primitive undifferential protoplasm into a system of the highest delicacy and intricacy of structure." Recognizing the complexity of the human eye, the following is a summary of how this intricate structure withstands the physiological stresses of a normal human life span.

The eye is not exempt from the relentless process of aging. Structurally, changes can be observed in all parts of the eye, both macroscopically and microscopically. The key is to recognize when these structural changes begin to threaten function.

Bioinformatics--Role in Future of Science and Medicine in Canada

Dr. Jamie Cuticchia is the Head of the Bioinformatics program at the Hospital for Sick Children in Toronto. Since 1997, Dr. Cuticchia has actively and successfully developed this program, which is designed to turn trillions of pieces of biological information into usable knowledge. In the June issue of Geriatrics & Aging, Dr. Cuticchia shared his thoughts on the Human Genome Project and Canada's role in this project. This month he has shared his thoughts on the field of bioinformatics and its role in the future of science and medicine in Canada.

Q: What is meant by the term 'bioinformatics'?

A: Bioinformatics is the joining together of hardware, software, and communications devices with the objective of solving a biological question.

Q: What are the origins of bioinformatics and what have been some of the critical milestones in the development of this field?

A: The origins of the field are rooted in the human genome project. Most of the funding for bioinformatics has been attained for purposes of collecting, disseminating, assembling, and analyzing human genomic data (and those of model organisms). There have been several milestones to date. These include: The creation of large databases, such as GenBank and the Genome Database (GDB); the production of rapid-comparison tools, such as BLAST, which is used to determine sequence homology; the current milestone is that phase of bioinformatics which looks to co-ordinate data from hundreds of widely distributed biological databases.

Q: Do you see biology and medicine becoming increasingly driven by computation?

A: The position of biology today is similar to where physics stood over a decade ago. The field of physics underwent a shift, splitting research into two directions. There were the large centres that acted as the providers of massive amounts of data (the light sources) and the smaller research groups who pooled information from them and worked on analysis and theories. In the field of biology, the independent, small research lab with a technician, a post-doc, and a student, will no longer be competitive research-wise. There will have to be either larger groups, such as the genome centres in the US, with hundreds of researchers, or, alternatively, smaller groups that will rely on the Internet data and software tools to make new discoveries.

Q: How did the Supercomputing Centre for Bioinformatics come to be established here in Toronto? What has your role in all of this been?

A: Luck. I came to Toronto in August, 1997 to form a small group whose mandate was to set up an infrastructure enabling the hospital researchers to handle more effectively scientific data and to use bioinformatic tools. Canada was very far behind the US in acknowledging the importance of this field, and after a few attempts at fund-raising it became clear that bioinformatics programs couldn't be funded through any traditional granting programs in Canada. However, the philanthropists of the hospital's foundation, and members of the information technology industry, had enough vision to see the important role bioinformatics would play in the future of research. With the first endowments coming in from companies like SGI, IBM, and Oracle we were off to the races. Eventually infrastructure monies from the Federal and Provincial governments of Canada were awarded and I went from $200,000 of funding to $50,000,000 in about 2 years.

Q: Did the prominence of the role of Canada and Toronto (and in particular, that of The Hospital for Sick Children) in genetic research play a part in the establishment of the Centre? How significant is this genetic work in the international context?

A: HSC has been recognized worldwide as a place for discovery of genetic information. Given its level of funding, it is probably the most efficiently run genetic group in the world. However, with groups in the US and Europe getting $10 or even $20 for every $1 the Canadian genomics group receives, it is only a matter of time before its reputation drops unless significant Canadian funding is provided.

Q: What is the capacity of the Supercomputer facility? Why is bioinformatics so computationally intensive?

A: We have a 128 cpu Origin 2800 supercomputer and an IBM-SP3 supercomputer. The combined performance of these systems is about the same as having 3000 desktop PCs working in unison. An example: We recently performed a clustering of DNA sequences (1.5 million) and it took over 5 days using the entire supercomputer. If we tried to do this on a PC the program would still be running long after the genome project was completed!

Q: How much information is being generated by the Human Genome Project? Are the means of organizing this data sufficient to meet the demands and the complexity of the task?

A: Right now, very little "information" is being generated; however, it is generating a great deal of data. We generated over 1 billion bases of DNA in one year and, in the end, we will have over 3 billion in total. The organization of this data is not particularly complex when compared to the analysis of this data, which will be going on for the next 5-15 years.

Q: The Supercomputer Centre was established to house the GDB. What function does the GDB serve in the overall Genome project?

A: There has always been some confusion about GDB. GenBank is a database of raw sequences of all sequenced organisms and is merely a listing of the nucleotide bases. GDB is the repository for biological knowledge and maps about the human genome. Using the GDB, researchers can see what probes are available for a gene or region of the genome, what mutations exists, and what polymorphisms have been studied. Best of all, unlike MOST biological databases, GDB is curated by a group of nearly 100 leading researchers in the genome field. Our data are high quality.

Q: What database source is of greatest value to physicians and clinicians?

A: That would probably be OMIM, the online version of Victor McKusick's Mendelian Inheritance in Man. It is a free text version of the catalogue, which has been a staple for medical geneticists for decades. GDB provides links to OMIM where appropriate.

Q: What role do you see Canada playing in Genomics and bioinformatics ten years down the road?

A: I fear that Canada will take its investments in these areas and, because of the enforced socialism within research, dilute them so much that we will have a greater number of 2nd class scientists. The body of research will be bigger, but will not necessarily improve. Unless the funding agencies, or the venture capitalists, see that the "big science" requires significant investment, we will continue to plod along. However, if investments are made in select groups with significant intellectual capital, I have no doubt Canada could be a worldwide leader in both of these fields.

Chris Overgaard, MD, MSc

Introduction
Pressure ulcers are common in elderly patients who suffer from an acute illness causing immobility, and for those patients with chronic disabilities who are confined to a bed at home, or in a chronic care facility.¹ The development of these ulcers represents a major medical problem that can, by itself, necessitate admission to hospital, or significantly prolong the length of stay in a hospital in patients who were admitted with other illnesses. In this brief review, the scope of the medical problem associated with pressure ulcers is examined, etiology and risk factors are discussed, and preventative measures and treatment options, based on recently published consensus guidelines, are summarized.