The Golden Retriever Lifetime Study: establishing an observational cohort study with translational relevance for human health.

The Golden Retriever Lifetime Study (GRLS) is the first prospective longitudinal study attempted in veterinary medicine to identify the major dietary, genetic and environmental risk factors for cancer and other important diseases in dogs. The GRLS is an observational study that will follow a cohort of 3000 purebred Golden Retrievers throughout their lives via annual online questionnaires from the dog owner and annual physical examinations and collection of biological samples by the primary care veterinarian. The field of comparative medicine investigating naturally occurring disorders in pets is specifically relevant to the many diseases that have a genetic basis for disease in both animals and humans, including cancer, blindness, metabolic and behavioural disorders and some neurodegenerative disorders. The opportunity for the GRLS to provide high-quality data for translational comparative medical initiatives in several disease categories is great. In particular, the opportunity to develop a lifetime dataset of lifestyle and activity, environmental exposure and diet history combined with simultaneous annual biological sample sets and detailed health outcomes will provide disease incidence data for this cohort of geographically dispersed dogs and associations with a wide variety of potential risk factors. The GRLS will provide a lifetime historical context, repeated biological sample sets and outcomes necessary to interrogate complex associations between genes and environmental influences and cancer.

Toe to hand transfer in children: ten year follow up of psychological aspects.

Our previous study found positive psychosocial effects from hand reconstruction in children, by microsurgical toe transfer. The aim of the current study was to determine whether these are enduring at ten years or more postoperatively. Twenty-five patients with congenital (n=21) or post-traumatic (n=4) hand anomalies underwent transfer of either one or two toes. (Nineteen of the patients had taken part in the previous study while six had not.) All families had undergone preoperative counselling. Ten years or more after surgery, the patients and their parents underwent review to assess the long-term psychosocial outcome of the surgery. As in the previous study, a high level of satisfaction was reported, in terms of function, appearance, donor site, psychosocial well-being and the reactions of others. This was true regardless of the gender of the child. Patient and parent responses were more similar to each other than they had been in the earlier study. It was concluded that the positive effects of toe transfer surgery are enduring at long-term follow-up.

An evaluation of two self-report screening measures for mood in an out-patient chronic heart failure population.

OBJECTIVE: To examine the criterion validity of the Hospital Anxiety and Depression Scale (HADS) and the Geriatric Depression Scale 15-item (GDS-15) in a community sample of Chronic Heart Failure (CHF) out-patients. METHODS: Eighty-eight of 203 older adults with confirmed CHF responded to a postal survey and participated in a face-to-face interview. The GDS-15 and HADS were compared to diagnoses from the Structured Clinical Interview for DSM-IV (SCID-I), using a receiver operating characteristic (ROC) analysis and positive and negative predictive values, sensitivity and specificity for various cut-off points. RESULTS: For all depressive disorders, the area under the ROC curve for the GDS-15 was 0.883 and a cut-off of 5 gave a sensitivity of 0.818 and a specificity of 0.833. The area under the ROC curve for the HADS Depression (D) and Anxiety (A) were 0.889 and 0.941 respectively. At a cut-off of 7, the HADS-A gave a sensitivity of 0.938 and a specificity of 0.847. At a cut-off of 4, the HADS-D gave a sensitivity of 0.864 and a specificity of 0.788. CONCLUSIONS: The GDS-15 and HADS are valid screening tools for detecting depression in aged CHF out-patients. However, use of the HADS requires reduced cut-points to ensure that patients with mood disorder are not missed in this population.

Perceptions of medical school graduates and students regarding their academic preparation to teach.

PURPOSE: How medical students learn and develop the characteristics associated with good teaching in medicine is not well known. Information about this process can improve the academic preparation of medical students for teaching responsibilities. The purpose of this study was to determine how different experiences contributed to the knowledge, skills, and attitudes of medical school graduates and students regarding medical teaching. METHODS: A questionnaire was developed, addressing reliability and validity considerations, and given to first year residents and third year medical students (taught by those residents). Completed questionnaires were collected from 76 residents and 110 students (81% of the sample group). Item responses were analysed using descriptive and inferential statistics. RESULTS: Most residents (n = 54; 71%) positively viewed opportunities they had to practice teaching when they were seniors. Residents rated three activities for learning to teach highest: (1) observing teachers as they teach; (2) reviewing the material to be taught; and (3) directly teaching students; representing both individual and participatory ways of learning. Residents' self ratings of teaching behaviours improved over time and this self assessment by the residents was validated by the students' responses. Comparison between residents' self ratings and students' views of typical resident teaching behaviours showed agreement on levels of competence, confidence, and motivation. The students rated characteristics of enthusiasm, organisation, and fulfilment lower (p<0.002) than residents rated themselves. CONCLUSIONS: The residents and students in this study viewed academic preparation for teaching responsibilities positively and showed agreement on characteristics of good teaching that may be helpful indicators in the process of developing medical teachers.

Prevalence and predictors of anxiety and depression in a sample of chronic heart failure patients with left ventricular systolic dysfunction.

OBJECTIVE: To determine the prevalence and predictors of anxiety and depression in patients with heart failure due to Left Ventricular Systolic Dysfunction (LVSD). BACKGROUND: Psychological adjustment to Chronic Heart Failure (CHF) can be poor, with the prevalence of depression in out-patients ranging from 13% to 48%. The prevalence of anxiety disorders in this population is unknown and the factors that predict anxiety and depression are not well understood. METHODS: 100 out-patients from a community heart failure programme completed a clinical diagnostic interview--the Structured Clinical Interview (SCID-I), to evaluate anxiety and depression. Mean age was 67+/-11 years, 17% were women and 91% were NYHA Class II or III. Other standardised measures were of cognition, biomedical status, social support and previous physical and mental health history. RESULTS: The prevalence rates of anxiety and depression (all subtypes) were 18.4% and 28.6%, respectively. Predictors of depression included a reported history of mental ill-health and NYHA class. Predictors of anxiety included a reported history of mental ill-health, co-morbid physical illness (diabetes and angina) and NYHA class. Severity of LVSD did not predict either anxiety or depression. CONCLUSIONS: Both anxiety and depression are common in CHF patients. The data on the predictors of poor psychological adjustment might assist in targeting bio-psychosocial intervention for patients who are at most at risk of anxiety and depression, within community CHF disease management programmes.

Neuropsychological prediction of conversion to dementia from questionable dementia: statistically significant but not yet clinically useful.

BACKGROUND: Verbal memory impairment, one of the earliest signs of Alzheimer's disease (AD), may help identify people with cognitive impairment, insufficient for a diagnosis of dementia (questionable dementia: QD), at risk of developing AD. Other cognitive parameters have been found that may indicate which people with QD will go on to develop dementia. Nevertheless, some researchers have reported only partial success in differentiating between mild AD and age related cognitive impairment. OBJECTIVES: To discover if there are early, pre-clinical cognitive markers that could help identify patients attending our memory clinic who were at risk of developing dementia. METHODS: Multidisciplinary assessment of a consecutive sample of 195 patients with QD seen in a National Health Service hospital outpatient clinic; 135 seen for a mean follow up of 24.5 months. RESULTS: Conversion rate to dementia was 27.4% (37 of 135). A diagnosis of probable or possible AD was made in 15.6% (21 of 135) of cases. Despite statistically significant differences in some cognitive tasks between those who did and those who did not go on to dement, Cox regression analyses failed to improve prediction rates markedly above base rates and were unstable. CONCLUSION: A large number of studies claim good prediction of conversion to dementia using cognitive test scores. Although this study produced similarly good sensitivity and specificity values, proper consideration of the statistical analyses and their clinical significance suggested that these prediction methods are currently too imprecise for clinical use. Use of cognitive indicators combined with neuroradiological, neuropathological, and genetic factors for predicting conversion to dementia might prove more reliable but may be beyond the scope of many geriatric services.

Evaluation of the toxicity of concentrated barley beta-glucan in a 28-day feeding study in Wistar rats.

Beta-glucans are water-soluble cell-wall polysaccharides consisting of (1-->3,1-->4)-linked beta-D-glucopyranosyl monomers that comprise a considerable proportion of soluble fiber from certain grains including oats and barley. Consumption of foods containing beta-glucan or beta-glucan-enriched fractions prepared from these grains lower serum cholesterol concentrations in humans and in animal models of hypercholesterolemia. The present study was conducted to evaluate the toxicity of beta-glucan-enriched soluble fiber from barley in Wistar rats on dietary administration at concentrations of 0.7, 3.5 and 7% beta-glucan for 28 days. There were no adverse effects on general condition and behavior, growth, feed and water consumption, feed conversion efficiency, red blood cell and clotting potential parameters, clinical chemistry values, and organ weights. Necropsy and histopathology findings revealed no treatment-related changes in any organ evaluated. A dose-dependent increase in full and empty cecum weight was observed. This is a common physiological response of rodents to high amounts of poorly digestible, fermentable carbohydrates, and was of no toxicological concern. The only finding of possible biological relevance was an increase in the number of circulating lymphocytes observed in males. However, the increase was not dose-dependent and was not observed in females. Results of this study demonstrated that consumption of concentrated barley beta-glucan was not associated with any obvious signs of toxicity in Wistar rats even following consumption of large quantities.

Outcome of the first 3-years of a DNA-based neonatal screening program for glutaric acidemia type 1 in Manitoba and northwestern Ontario, Canada.

Glutaric acidemia type 1 (GA1) is overrepresented in the aboriginal population of Island Lake, Manitoba, and northwestern Ontario who speak the Ojibway-Cree (Oji-Cree) dialect. The carrier frequency in these communities has been predicted to be as high as 1 in 10 individuals. Prior to beginning newborn screening for GA1 in May 1998, 18 of 20 affected patients diagnosed at this center have been from these high-risk communities. Most have followed an acute encephalopathic course with permanent neurologic sequelae and high mortality. They excrete small amounts of glutaric acid and 3-hydroxyglutaric acid and have significant residual enzyme activity. A single homozygous mutation in glutaryl-CoA-dehydrogenase (GCDH IVS-1 + 5g right arrow t) has been identified in this population. DNA-based newborn screening targeted to our high-risk communities was begun in order to provide presymptomatic detection and treatment of affected patients. Of the first 1176 newborns screened, 4 affected infants were identified and treated with a low-protein diet, carnitine, and riboflavin. All 4 infants have required numerous hospitalizations for treatment of intercurrent illnesses. Eventually, 3 infants presented with acute dystonic encephalopathy and seizures along with permanent neurological sequelae. One of these infants died unexpectedly at home at 18 months of age. The fourth, now 9 months old, has had a gastrostomy tube placed to facilitate fluid replacement in addition to a standard treatment protocol and is doing well. The reasons for our initial disappointing outcomes in the first 3 of 4 affected babies are likely multiple. Based on our early experience and that of other centers screening newborns for GA1, current therapeutic strategies may be insufficient in preventing the occurrence of neurologic sequelae in some children. An incomplete understanding of the neurotoxic mechanisms underlying this devastating disorder hampers effective management.

Celiac disease in a patient with a congenital deficiency of intestinal enteropeptidase.

We report on a 40-yr-old man with both primary enteropeptidase deficiency and celiac disease. He suffered from severe intestinal malabsorption and growth failure as a child. Enteropeptidase deficiency was found and pancreatic enzyme replacement therapy resulted in a growth spurt. Enteropeptidase levels in his intestinal mucosa and intraluminal fluid remained very low throughout childhood and early adult life. Celiac disease was confirmed by characteristic abnormalities in tests of intestinal function and in mucosal biopsies, which recovered when he instituted a gluten-free diet. He remains clinically intolerant to gluten as an adult. Enteropeptidase levels have remained abnormally low whether or not his intestinal mucosa has been normal in response to gluten restriction. Enteropeptidase levels have previously been shown to be normal in untreated celiac patients. The relationship between the two disorders remains unclear.

Hepatic carnitine palmitoyl transferase 1 (CPT1 A) deficiency in North American Hutterites (Canadian and American): evidence for a founder effect and results of a pilot study on a DNA-based newborn screening program.

We describe six patients with hepatic carnitine palmitoyl transferase (CPT1 A) deficiency who are members of a large extended Hutterite kindred living in widely scattered communities in the United States and Canadian Prairies. Two patients have significant neurological impairment due to severe recurrent hypoglycemic crises. The remaining four patients with earlier detection and treatment have near normal outcomes. The Canadian and American Hutterite families share two common ancestors who married in 1812, about 60 years before the Hutterites arrived in North America and prior to their subdivision into the three groups (Schmiedeleut, Dariusleut, and the Lehrerleut). These patients share a common haplotype on chromosome 11q13 and are all homozygous for a common CPT1 A G710E mutation, suggesting a founder effect. The clustering of such a rare disorder of fatty acid oxidation prompted us to initiate a pilot DNA-based neonatal screening program to determine the carrier frequency of this mutation in Hutterite newborns with the participation and support of the community. To date our carrier frequency is 1/16, close to the predicted frequency based on diagnosed patients and number of births. We believe our newborn screening program for CPT1 A deficiency in the Hutterite community will serve as a prototype model for delivery of targeted genetic services to other similar unique genetic isolates.

Molecular and enzymatic characterization of a unique carnitine palmitoyltransferase 1A mutation in the Hutterite community.

Hepatic carnitine palmitoyltransferase 1 (CPT1A) deficiency is a rare disorder of mitochondrial fatty acid oxidation inherited as an autosomal recessive trait. Symptomatology comprises attacks of hypoketotic hypoglycemia with risk of sudden death or neurological sequelae. Only one CPT1A mutation has been reported so far. Identification of the disease-causing mutations allows both insights into the structure-function relationships of CPT1A and management of the patients and their relatives. The molecular analysis of CPT1A deficiency in a large Hutterite kindred illustrates this point. Both cDNA and genomic DNA analysis demonstrate that the affected patients are homozygous for a 2129G>A mutation predicting a G710E substitution. Studies in fibroblasts from one patient as well as heterologous expression of the mutagenized CPT1A in yeast show that the G710E mutation alters neither mitochondrial targeting nor stability of the CPT1A protein. By contrast, kinetic studies conclusively establish that the mutant CPT1A is totally inactive, indicating that the G710E mutation dramatically impairs the catalytic function of CPT1A. Finally, due to a strongly suspected founder effect for the origin of CPT1A deficiency in this Hutterite kindred, identification of this disease-causing mutation allows the setup of a targeted DNA-based newborn screening in this at-risk population.

The pupillary light reflex in aging and Alzheimer's disease.

The pupillary light reflex is reported to be reduced in amplitude in Alzheimer's disease (AD). The purpose of this study was to determine whether this effect is measurable under conditions typical of clinical rather than laboratory settings. A head-mounted infra-red videopupillometer was used to measure the amplitude of pupillary constriction in 12 patients with probable AD, 12 healthy age-matched older adults and 12 young adults. The constriction to the onset of bright light relative to the resting amplitude was significantly reduced in AD compared with both control groups. This result is consistent with an acetylcholine-related deficit in AD and supports the findings of Prettyman et al. and Fotiou et al. The impairment is likely to be caused by degeneration in relays in the midbrain but cholinergic deficits in the peripheral parasympathetic pathway cannot be excluded. The variation in pupillary response between individuals may preclude its use for diagnostic purposes. However, if the changes in pupillary response in AD are related to change in neurotransmitter status, then the value of such a technique may be in its use in providing an objective, non-invasive monitor of physiological abnormality with which to follow disease progression and treatment efficacy.

Maintaining good dental practice: the East Lancashire approach to dentists whose performance gives cause for concern.

The Consultant in Dental Public Health and the Local Dental Committee in East Lancashire have developed a local system, similar to that being set up for general medical practitioners, to help general dental practitioners whose performance is causing concern. GDPs approved it at an open meeting of practitioners. A Dental Performance and Assessment Group has been set up and one problem has already been resolved to everyone's satisfaction. The model is recommended to dentists in other areas.

Effect of dose of prostaglandin F(2alpha) on steroidogenic components and oligonucleosomes in ovine luteal tissue.

To determine whether prostaglandin (PG) F(2alpha) had a dose-dependent effect upon secretion of progesterone, oligonucleosome formation, or loss of luteal weight, ewes on Day 9 or 10 of the estrous cycle were administered 0, 3, 10, or 30 mg PGF(2alpha) per 60 kg BW (i.v.), and luteal tissue was collected 9 and 24 h after injection. All doses of PGF(2alpha) decreased (P < 0. 05) concentrations of progesterone in sera by 9 h; however, in ewes treated with 3 mg PGF(2alpha), concentrations of progesterone were similar to control values at 24 h and higher (P < 0.05) than those in the 10- or 30-mg groups. Concentrations of progesterone in sera over all dose levels were highly correlated to luteal concentrations of mRNA encoding steroidogenic acute regulatory protein (P < 0.001), cytochrome P450 side-chain cleavage (P < 0.02), and 3beta-hydroxysteroid dehydrogenase (P < 0.01). Corpora lutea collected at 24 h from ewes treated with the 10- and 30-mg doses of PGF(2alpha) weighed less (P < 0.05) than those from controls. Oligonucleosomes were not present in luteal tissues from control ewes. Surprisingly, all doses of PGF(2alpha)-induced oligonucleosomes in a majority of animals at 9 h and in a majority of ewes treated with 10 and 30 mg of PGF(2alpha) at 24 h. In conclusion, 3 mg of PGF(2alpha) per 60 kg BW transiently decreased serum concentrations of progesterone and induced oligonucleosome formation, but did not result in reduced luteal weight. The 10- and 30-mg doses of PGF(2alpha) decreased secretion of progesterone and induced oligonucleosome formation and luteolysis.

Amerindian pyruvate carboxylase deficiency is associated with two distinct missense mutations.

We characterized the pyruvate carboxylase (PC) gene by PCR amplification, subcloning, and sequencing. The coding region has 19 exons and 18 introns spanning approximately 16 kb of genomic DNA. Screening both the cDNA and the gene of individuals with the simple A form of PC deficiency revealed an 1828G-->A missense mutation in 11 Ojibwa and 2 Cree patients and a 2229G-->T transversion mutation in 2 brothers of Micmac origin. Carrier frequency may be as high as 1/10 in some groupings. The two point mutations are located in a region of homology conserved among yeast, rat, and human PC, in the vicinity of the carboxylation domain of the enzyme. These data provide the first characterization of the human PC gene structure, the identification of common pathogenic mutations, and the demonstration of a founder effect in the Ojibwa and Cree patients.

Messenger ribonucleic acid encoding monocyte chemoattractant protein-1 is expressed by the ovine corpus luteum in response to prostaglandin F2alpha.

To investigate expression of monocyte chemoattractant protein-1 (MCP-1) in the ovine corpus luteum, a partial cDNA was produced by reverse transcription-polymerase chain reaction. This cDNA was 89% identical to that reported for bovine MCP-1 mRNA. In experiment 1, steady-state concentrations of mRNA encoding MCP-1 were measured in pools of luteal tissue collected on Days 3, 6, 9, 12, and 15 of the estrous cycle (estrus = O; n = 4/day). There were no differences in mRNA concentrations for MCP-1 among any of the days studied (p = 0.43). In experiment 2, midluteal-phase corpora lutea were collected from ewes at 0 (untreated), 2, 4, 8, and 16 h after administration of a luteolytic dose of prostaglandin F2alpha (PGF2alpha; n = 4/time point). Concentrations of MCP-1 mRNA were undetectable in untreated controls, were detectable at 2 h post-treatment, had increased 4 and 8 h after administration of PGF2alpha when compared to those at 2 h (p < 0.05), and were decreased 16 h after administration of PGF2alpha when compared to those at 4 h (p < 0.05). In situ hybridization for MCP-1 mRNA combined with immunocytochemical labeling of tissue inhibitor of metalloproteinase-1 (TIMP-1) in large luteal cells was used to determine whether the steroidogenic cells that have PGF2alpha receptors express MCP-1 mRNA in response to PGF2alpha. Messenger RNA encoding MCP-1 and TIMP-1 were not colocalized, indicating that MCP-1 was not expressed by large steroidogenic luteal cells during luteolysis.