Assessment and outcomes of firefighter applicants with possible asthma.

BACKGROUND: Firefighter applicants (FFAs) with a history of asthma may be refused entry to the fire service because of potentially putting themselves and others at risk. AIMS: We undertook a service evaluation to identify respiratory and employment outcomes of FFAs with a history of asthma who had undergone additional respiratory assessment at our specialist occupational lung disease clinic during 2005-19. METHODS: We reviewed FFA medical records and categorized them as having either no current asthma or definite/probable asthma at the time of clinic assessment. 'No current asthma' was defined as negative non-specific bronchial hyper-responsiveness (BHR) to histamine/methacholine, and no symptoms or treatment within the 2 years before clinic. 'Definite/probable current asthma' was defined as either positive BHR, or negative BHR with symptoms and/or treatment within the previous 2 years. Around 1 year later, we contacted FFAs to enquire about their application outcome and current respiratory symptoms. RESULTS: Data were available on 116 applicants; of whom, 45% (n = 52) had definite/probable current asthma and were significantly more likely to be older, atopic to common aeroallergens, report atopic disease and have a lower forced expiratory volume in one second/forced vital capacity ratio compared with applicants with no current asthma. Only two individuals' applications were rejected due to asthma. At follow-up, just 2 (2%) of the 90 operational firefighters reported any recent trouble with asthma. CONCLUSIONS: A history of asthma alone is not sufficient to determine current asthma in FFAs. Even with a diagnosis of current asthma, FFAs are mostly successful in their application to join the fire service.

Maternity Healthcare Chaplains and Perinatal Post-Mortem Support and Understanding in the United Kingdom and Ireland: An Exploratory Study.

Perinatal autopsy rates have declined significantly in recent decades. There is a lack of consensus concerning the potential religious influences for bereaved parents in their decision making process for post-mortem. This online study of British and Irish maternity healthcare chaplains explored their understanding of general and local perinatal post-mortem procedures and their experiences in the support of parents. Participants included Christian, Muslim and non-faith chaplains. No chaplain identified any religious prohibition to perinatal post-mortem. A majority of chaplains reported that they had been asked about post-mortem by parents; only a minority felt adequately prepared. A key recommendation is that following appropriate training chaplains may be well placed to support colleagues and parents during the decision making process.

Follow-up survey of patients with occupational asthma.

BACKGROUND: Occupational asthma (OA) is often associated with a poor prognosis and the impact of a diagnosis on an individual's career and income can be significant. AIMS: We sought to understand the consequences of a diagnosis of OA to patients attending our clinic. METHODS: Using a postal questionnaire, we surveyed all patients attending our specialist occupational lung disease clinic 1 year after having received a diagnosis of OA due to a sensitizer (n = 125). We enquired about their current health and employment status and impact of their diagnosis on various aspects of their life. Additional information was collected by review of clinical records. RESULTS: We received responses from 71 (57%) patients; 77% were referred by an occupational health (OH) provider. The median duration of symptoms prior to referral was 18 months (interquartile range (IQR) 8-48). At 1 year, 79% respondents were no longer exposed to the causal agent. Whilst the unexposed patients reported an improvement in symptoms compared with those still exposed (82% versus 53%; P = 0.023), they had poorer outcomes in terms of career, income and how they felt treated by their employer; particularly those not currently employed. Almost all (>90%) of those still employed had been referred by an OH provider compared with 56% of those currently unemployed (P = 0.002)x. CONCLUSIONS: The negative impact of OA on people's careers, livelihood and quality of life should not be underestimated. However, with early detection and specialist care, the prognosis is often good and particularly so for those with access to occupational health.

Support mothers in poverty need: Lessons learned from Mom2Mom.

Childhood stress leads to adverse developmental and health outcomes in adulthood, and childhood poverty is perhaps the most significant source of stress that exists today for Canadian children. Previously, three key factors were identified that are important in improving developmental outcomes in children: reducing the stress of poverty; connecting the mother to the child's education; and connecting the mother to social support. The Mom2Mom Child Poverty Initiative was established as a model to improve developmental outcomes for vulnerable children. Mom2Mom combines current evidence regarding the social and biological determinants of child health with direct advocacy. It provides mentorship, and financial and practical support to families, with the goal of improving outcomes for children living in poverty.

Le stress vécu pendant l'enfance s'associe à des problèmes de développement et de santé à l'âge adulte. À l'heure actuelle, la pauvreté est peutêtre la plus grande source de stress pour les enfants canadiens. Trois facteurs clés déjà établis sont essentiels pour améliorer l'issue des enfants sur le plan du développement : réduire le stress causé par la pauvreté, engager la mère dans l'éducation de l'enfant et orienter la mère vers un soutien social. La Mom2Mom Child Poverty Initiative Society a été créée comme modèle pour améliorer l'issue des enfants vulnérables sur le plan du développement. Mom2Mom combine des données probantes à jour sur les déterminants sociaux et biologiques de la santé des enfants avec de la défense d'intérêts directe. Elle offre du mentorat et un soutien financier et pratique aux familles, afin d'améliorer le sort des enfants qui vivent dans la pauvreté.

Occupational asthma from tafenoquine in the pharmaceutical industry: implications for QSAR.

We report occupational asthma and rhinitis in a formulation pharmacist, employed in the development of tafenoquine. Tafenoquine is a new anti-malarial drug in development; the pure drug substance has an asthma hazard index of zero and previously was not known to be a respiratory sensitizing agent. The implications of this finding for the refinement of quantitative structural analysis of asthmagenic chemicals are discussed.

Mesoscale modeling of shear-thinning polymer solutions.

We simulate the linear and nonlinear rheology of two different viscoelastic polymer solutions, a polyisobutylene solution in pristane and an aqueous solution of hydroxypropylcellulose, using a highly coarse-grained approach known as Responsive Particle Dynamics (RaPiD) model. In RaPiD, each polymer has originally been depicted as a spherical particle with the effects of the eliminated degrees of freedom accounted for by an appropriate free energy and transient pairwise forces. Motivated by the inability of this spherical particle representation to entirely capture the nonlinear rheology of both fluids, we extended the RaPiD model by introducing a deformable particle capable of elongation. A Finite-Extensible Non-Linear Elastic potential provides a free energy penalty for particle elongation. Upon disentangling, this deformability allows more time for particles to re-entangle with neighbouring particles. We show this process to be integral towards recovering the experimental nonlinear rheology, obtaining excellent agreement. We show that the nonlinear rheology is crucially dependent upon the maximum elongation and less so on the elasticity of the particles. In addition, the description of the linear rheology has been retained in the process.

Leptin is differentially expressed and epigenetically regulated across monochorionic twin placenta with discordant fetal growth.

Severely growth-discordant monochorionic (MC) twins offer a unique opportunity to study fetal and placental growth based on a similar genetic background and maternal host environment where the healthy twin serves as an ideal control. Differences in development of MC twins may therefore be due to differential epigenetic regulation of genes involved in placental development and function. Growth-discordant twins are known for abnormal angio-architecture in the placenta of the smaller twin. Since the reasons for this phenotype are mostly unknown this study was aimed to investigate the expression and regulation of genes known to be involved in angiogenesis. We studied 10 severely growth-discordant MC twin placentas (birthweight difference ≥20%) without twin-twin-transfusion syndrome and 5 growth-concordant MC twin placentas. Growth-discordant twin placentas were phenotyped by histology. Placental mRNA expression of 88 angiogenesis-related genes was measured by PCR array. ELISA assay and immunohistochemistry were used to confirm PCR results. EpiTYPTER for DNA methylation was used to determine if methylation ratios were responsible for differential gene expression. The PCR array analysis showed significant mRNA up-regulation in the placental share of the smaller twin for several genes. These included leptin (24.6-fold, P = 0.017), fms-like tyrosine kinase 1 (Flt1, 2.4-fold, P = 0.016) and Endoglin (Eng, 1.86-fold, P = 0.078). None of the other 84 angiogenesis-related genes showed significant differences. ELISA confirmed significantly increased leptin protein expression (49.22 versus 11.03 pg/ml, P = 0.049) in the smaller twin of the discordant growth cohort. Leptin expression in smaller twins' placentas was associated with elevated DNA methylation of the leptin promotor region suggesting the inhibition of binding of a transcriptional activator/inhibitor in that region. We attempted to overcome the limitation of sample size by careful patient selection. We minimized any bias in placental sampling by random sampling from two different sites and by avoiding sampling from areas with grossly visible abnormalities using a standardized sampling protocol. In conclusion, the smaller twin's placenta is characterized by differentially increased gene expressions for Flt1 and Eng mRNA that may be causally associated with the villous pathology driven by abnormal feto-placental angiogenesis. The substantial up-regulation of leptin mRNA may be epigenetically conferred and relevant to the post-natal risk of metabolic syndrome in intrauterine growth restriction offspring with placental pathology. Growth-discordant MC twins offer unique insights into the epigenetic basis of perinatal programming.

Placental hyperinflation and the risk of adverse perinatal outcome.

OBJECTIVES: To determine the pathological basis and clinical associations of excessively thick placentae observed at second-trimester ultrasound examination. METHODS: In a retrospective cohort of 19 singleton high-risk second-trimester pregnancies noted to have a placental length-to-maximum thickness ratio ≤ 2.0, maximum sonographic placental thickness was correlated with clinical outcome, maximum placental thickness after delivery and placental pathological findings. Results were compared with those of an intermediate group of 21 high-risk pregnancies with normal placental dimensions and a control group of 18 low-risk pregnancies also with normal placental dimensions. Increased maximum placental thickness (> 28 mm) and abnormal placental deflation following delivery (pathology - sonography difference in maximum placental thickness < -2 mm) were defined by the upper and lower quartile values, respectively, in the control group. RESULTS: The study group exhibited significantly more adverse outcomes and gross pathological placental features compared with both intermediate and control groups. Despite increased sonographic maximum placental thickness in the study group (median, 55 (range, 40-75) mm compared with both the intermediate group (median, 27 (range, 22-41) mm, P < 0.0001) and the control group (median 26 (range, 23-36) mm, P < 0.0001)), all three groups had similar maximal placental thickness following delivery (study group: median, 24 (range, 10-50) mm vs intermediate group: median, 27 (range, 15-40) mm, P = 0.82 and vs control group: median, 28.5 (range, 18-44), P = 0.42). Pathology-sonography difference in maximum placental thickness in the study group (median, -30 (range, -42 to 0) mm) was significantly greater than that in either the intermediate (median, -2 (range, -11 to 9) mm, P < 0.0001) or the control (median, 1.5 (range, -10 to 18) mm, P < 0.0001) group and was significantly associated with abnormal development of the gas-exchanging placental villi (distal villous hypoplasia) (P = 0.0001). CONCLUSIONS: Increased second-trimester sonographic maximum placental thickness represents a pathological finding associated with severe adverse perinatal outcome. This observation is due to overinflation of the intervillous space by maternal blood rather than to adaptive formation of functional placental tissue.

Proper understanding of recurrent stress urinary incontinence treatment in women (PURSUIT): a randomised controlled trial of endoscopic and surgical treatment.

BACKGROUND: Women with stress urinary incontinence (SUI) experience urine leakage with physical activity. Currently, the interventional treatments for SUI are surgical, or endoscopic bulking injection(s). However, these procedures are not always successful, and symptoms can persist or come back after treatment, categorised as recurrent SUI. There are longstanding symptoms and distress associated with a failed primary treatment, and currently, there is no consensus on how best to treat women with recurrent, or persistent, SUI. METHODS: A two-arm trial, set in at least 20 National Health Service (NHS) urology and urogynaecology referral units in the UK, randomising 250 adult women with recurrent or persistent SUI 1:1 to receive either an endoscopic intervention (endoscopic bulking injections) or a standard NHS surgical intervention, currently colposuspension, autologous fascial sling or artificial urinary sphincter. The aim of the trial is to determine whether surgical treatment is superior to endoscopic bulking injections in terms of symptom severity at 1 year after randomisation. This primary outcome will be measured using the patient-reported International Consultation on Incontinence Questionnaire - Urinary Incontinence - Short Form (ICIQ-UI-SF). Secondary outcomes include assessment of longer-term clinical impact, improvement of symptoms, safety, operative assessments, sexual function, cost-effectiveness and an evaluation of patients' and clinicians' views and experiences of the interventions. DISCUSSION: There is a lack of high-quality, randomised, scientific evidence for which treatment is best for women presenting with recurrent SUI. The PURSUIT study will benefit healthcare professionals and patients and provide robust evidence to guide further treatment and improve symptoms and quality of life for women with this condition. TRIAL REGISTRATION: International Standard Randomised Controlled Trials Number (ISRCTN) registry ISRCTN12201059. Registered on 09 January 2020.

Congenital megalourethra: prenatal diagnosis and postnatal/autopsy findings in 10 cases.

OBJECTIVE: Congenital megalourethra is a rare urogenital malformation characterized by dilation and elongation of the penile urethra associated with absence or hypoplasia of the corpora spongiosa and cavernosa. Postnatal complications include voiding and erectile dysfunction as well as renal insufficiency and pulmonary hypoplasia. To date, only a few prenatally diagnosed cases have been reported. We report on 10 cases diagnosed prenatally and their postnatal/autopsy findings. METHODS: The study involved retrospective chart review of all cases diagnosed antenatally in three tertiary care centers over 5 years. Antenatal ultrasound images and medical records from obstetrics, genetics, urology and nephrology were reviewed. RESULTS: Ten fetuses with megalourethra were identified at a median gestational age of 19 (range, 13-24) weeks and all were confirmed postnatally or at autopsy. Three pregnancies were terminated and seven continued. All cases presented with a distended bladder and megalourethra and all cases had normal karyotype. Of seven liveborn babies, one died neonatally of pulmonary hypoplasia. All six infants alive at the time of writing had a dysfunctional urethra and three suffered from impaired or end-stage renal disease. Associated anomalies were found in half of the cases. CONCLUSION: Congenital megalourethra is caused by abnormal development or hypoplasia of the penile erectile tissue, secondary to distal urethral obstruction. When the amniotic fluid volume is normal, survival is possible. However, all liveborn infants have voiding and renal dysfunction and sexual dysfunction is expected. Megalourethra should be considered in all male fetuses presenting prenatally with megacystis and detailed fetal ultrasonography should look for an elongated and/or distended phallic structure as well as any associated anomalies.

Optimal assessment of residual disease after neo-adjuvant therapy for locally advanced and inflammatory breast cancer--clinical examination, mammography, or magnetic resonance imaging?

PURPOSE: Accurate assessment of residual disease after neo-adjuvant chemotherapy (NEC) for women with locally advanced and inflammatory breast cancer (LABC) is critical for planning surgery. The study's purpose was to prospectively determine the optimal method (clinical examination (CE), mammogram (MG), and magnetic resonance imaging (MRI)) for assessing residual disease after NEC for women with LABC. METHODS: Women with LABC who received NEC and surgery were enrolled. Patient demographics, tumor size as measured by CE, MG, and MRI both before and after NEC, and final pathologic size of tumor were collected. Response to NEC was calculated using RECIST criteria. Paired t-tests and the Pearson correlation were used to compare tumor size on CE, MG, MRI, and final pathology. RESULTS: Forty-eight women with 50 LABC were recruited. Mean pre-NEC tumor size was 8.2, 5.1, and 6.2 cm on CE, MG, and MRI. Mean post-NEC tumor size was 2.4, 4.3, 3.9, and 3.6 cm on CE, MG, MRI, and final pathology. The Pearson correlation co-efficient between post-NEC measurements and pathology was 0.63 (CE), 0.15 (MG), and 0.49 (MRI). CONCLUSION: We found that there was limited correlation between the extent of residual disease after NEC for patients with LABC as assessed by CE, MG, and MRI as compared to final pathology.

Adults with late diagnosed PKU and severe challenging behaviour: a randomised placebo-controlled trial of a phenylalanine-restricted diet.

BACKGROUND: Although early diagnosis and treatment in phenylketonuria (PKU) leads to excellent outcomes, a population of adults born before the introduction of newborn screening exists. They can have severe intellectual disabilities and behavioural problems, and are often dependent on full-time carers. Anecdotal evidence suggests that a diet that lowers blood phenylalanine concentration can have significant benefits upon behaviour. METHODS: A prospective double-blind randomised placebo-controlled crossover trial of phenylalanine-restricted diet was performed in a group of 34 adults (aged 21-61 years, median 49) with late diagnosed PKU with severe challenging behaviour. RESULTS: Only 17 completed the 60 week study: seven withdrew before the end of the baseline period; five withdrew during the first diet period; five withdrew during the second diet period (after moving into placebo phase). The mean (SD) blood phenylalanine was 1570 (222) micromol/l during baseline, 553(158) mumol/l during the active phase and 1444 (255) micromol/l during the placebo phase. In the 22 participants exposed to both active and placebo phases, no differences were demonstrated in behaviour assessed by the Aberrant Behavior Checklist and Vineland Adaptive Behavior Scales, behaviour diaries or on video analysis of direct observations. However, 76% of carers' comments were scored as positive during the active phase, compared with 54% during the placebo phase (chi(2) = 38.06, p<0.001). CONCLUSIONS: There are significant challenges in studying people with intellectual disabilities and considerable difficulties in instituting phenylalanine-restricted diet in this population. However, if attempted, there are potential benefits to quality of life for the individuals with PKU and their carers.

Prevalence of overt metastases in locally advanced breast cancer.

AIMS: Locally advanced breast cancer (LABC) represents a wide spectrum of clinical presentations and poses significant clinical challenges for both patients and their physicians. Before starting neoadjuvant therapy, most patients undergo staging investigations, including a radioisotope bone scan, liver ultrasound and chest X-ray as per our provincial guidelines. The aim of this study was to document the prevalence of metastatic disease using standard baseline radiological staging in patients with LABC. MATERIALS AND METHODS: A retrospective chart review was carried out for LABC patients at two large Canadian centres between 2003 and 2006. Data on tumour characteristics and baseline staging tests were collected. Information on any confirmatory imaging (bone X-ray, computed tomography, magnetic resonance imaging, positron emission tomography) undertaken due to the presence of suspicious baseline tests or due to worrying symptoms was also obtained. The prevalence of metastatic disease after each baseline imaging technique was analysed, as was the frequency of discordance between baseline staging tests and confirmatory imaging where applicable. RESULTS: In total, 144 patients with LABC were assessed. After initial staging investigations, 15 patients (10.4%) were diagnosed as having overt metastatic disease. Confirmatory imaging was carried out on 19 patients (13.2%); five (3.5%) for unexplained symptoms and 14 (9.7%) due to equivocal baseline imaging. These additional investigations isolated a further four subjects with metastatic disease, bringing the overall prevalence of overt metastases to 13.2%. CONCLUSIONS: Given that the rate of systemic relapse in patients with LABC is very high, current baseline staging investigations probably underestimate the true incidence of metastases. This study has shown that further confirmatory imaging can be helpful, especially in symptomatic patients, as it seems that negative baseline tests in these patients can be falsely reassuring. Accurate staging of patients with LABC has many advantages and, therefore, further research is needed to define the role of newer imaging modalities.

Transfer of follow-up care to family physicians for early-stage breast cancer.

AIMS: As a result of the rising prevalence of breast cancer and improved adjuvant treatment strategies, oncologists are faced with an ever-increasing workload of providing long-term follow-up care for early-stage breast cancer patients. In order to cope with these growing demands, innovative follow-up strategies are urgently required. MATERIALS AND METHODS: To explore if patient transfer back to the family physician for follow-up was a potential option, a prospective programme of planned discharge was established for all patients who had completed adjuvant chemo/radiotherapy or had started adjuvant endocrine therapy. Patient and family physician information packages were also provided. RESULTS: Between April and August 2005, of the 193 patients assessed for transfer back to the family physician for follow-up care, transfer was possible in 43%. Fifty-seven per cent (or 110 patients) were unsuitable for transfer back to the family physician. The reasons cited among those deemed unsuitable for transfer were as follows: clinical trial enrollment (50.9%), ongoing endocrine treatment (31.8%), new symptoms (6.3%), and patient refusal (0.9%). In both discharged and non-discharged groups, patients were also frequently being followed by other oncologists (surgical and/or radiation). CONCLUSION: Transfer of care back to family physicians for follow-up may offer a strategy to control workload volumes, and thus enable oncologists to focus their efforts on newly diagnosed and advanced-stage patients with more complex patient care needs.

Obesity is associated with altered metabolic and reproductive activity in the mare: effects of metformin on insulin sensitivity and reproductive cyclicity.

In mares, obesity is associated with continuous reproductive activity during the non-breeding season. To investigate the effect of obesity and associated alterations in metabolic parameters on the oestrous cycle, two related studies were conducted. In Experiment 1, obese (body condition score > 7) mares were fed ad libitum or were moderately feed restricted during the late summer and autumn months. Feed restriction did not alter the proportion of mares entering seasonal anoestrus. However, obese mares exhibited a significantly longer duration of the oestrous cycle, significant increases in circulating concentrations of leptin and insulin, and decreased insulin sensitivity and concentrations of thyroxine compared with feed-restricted mares throughout the experiment. Experiment 2 was designed to investigate the effects of administration of the insulin-sensitising drug metformin hydrochloride on insulin sensitivity and the characteristics of the oestrous cycle in obese mares. In a dose-response trial, metformin increased insulin sensitivity after 30 days following administration of 3 g day(-1), but not 6 or 9 g day(-1), compared with controls receiving vehicle only. However, there were no differences in insulin sensitivity or oestrous cycle characteristics between control and metformin-treated groups when the 3 g day(-1) dose was tested for a longer period of 2 months. These results demonstrate that obesity is associated with aberrations in the oestrous cycle and perturbations in several markers of metabolic status. The results also indicate that metformin is not an effective long-term monotherapy for increasing insulin sensitivity in horses at the doses tested. Additional studies are needed to examine possible effects of increasing insulin sensitivity on reproductive activity in obese mares.

Chronic disabling disease--impact on outcomes and costs in emergency medical admissions.

BACKGROUND: Chronic disabling disease is present in nearly 90% of emergency medical admissions. We have examined its impact on outcomes and costs in one institution, using a database of episodes collected prospectively over 12 years. METHODS: All emergency admissions (66,933 episodes; 36,271 patients) to St James' Hospital over a 12-year period (2002-13) were evaluated in relation to 30-day in-hospital mortality, length of stay (LOS) and hospital costs. Predictor variables (identified univariately) were entered into a multi-variable logistic regression model to predict 30-day in-hospital mortality. The data were also modelled as count data (absolute LOS, total cost) using zero-truncated Poisson regression. RESULTS: Acute illness severity was the best independent predictor of mortality; chronic disabling disease was an independent predictor (P < 0.001) for patients with 4+ disabling conditions. Age, adjusted for other predictors, was only independently predictive of mortality for patient 85+ years. Chronic disabling disease was an independent predictor of LOS increasing linearly with incidence rate ratios of 1.35 (95% CI: 1.29, 1.42), 1.59 (95% CI: 1.51, 1.66), 1.73 (95% CI: 1.65, 1.83) and 1.74 (95% CI: 1.65, 1.84) for those with 1, 2, 3 or 4+ disabling conditions, respectively. Age, as a predictor of LOS was strongly correlated with the presence of disabling disease. Chronic disabling disease independently predicted costs non-linearly; those with 2 or more disabling conditions had particularly high total hospital costs. CONCLUSION: Chronic disabling disease is an independent predictor of hospital LOS and costs in unselected emergency admissions; adjusted for illness severity, it is only a mortality predictor for those with multiple disabling conditions.

Importance of short luteal phases in the endocrine mechanism controlling initiation of estrous cycles in anestrous ewes.

A transient increase in serum progesterone concentrations (to 1 ng/ml for 1-2 days) is observed in the majority of ewes before the first estrous cycle of the breeding season. To determine whether such a brief antecedent rise in progesterone ensures initiation of a full-length cycle by the next LH surge, synthetic GnRH was administered for 3 days to 24 anestrous ewes in a pulsatile fashion designed to mimic the pattern of LH secretion during the preovulatory period of the breeding season. Six ewes received no further treatment, and 6 ewes were treated sc with Silastic implants containing progesterone for 3 days before injecting GnRH. The remaining 12 ewes were treated with additional injections of GnRH every 4 h for the next 5 days. Four of these ewes received a second increase in GnRH pulse frequency, every 2 h and hourly on the subsequent 2 days. An LH surge was stimulated by each regimen of increasing GnRH pulse frequency in all ewes; progesterone pretreatment had no effect on its time of onset, duration, or amplitude. The LH surges induced full-length luteal phases in 10 of 10 ewes when preceded by either an exogenous (n = 6) or an endogenous (n = 4) progesterone increment, but in only 8 of 18 ewes not pretreated with progesterone. These results indicate that a transient increase in progesterone ensures that an ensuing LH surge will initiate an estrous cycle and suggest that progesterone may play an important role in the endocrine mechanisms governing transitions from acyclic to cyclic states.

Phenotype of AD-HSP due to mutations in the SPAST gene: comparison with AD-HSP without mutations.

BACKGROUND: "Pure" autosomal dominant hereditary spastic paraparesis (AD-HSP) is clinically and genetically heterogeneous. There are at least seven genetic loci with varying ages at onset and disability. The SPAST gene at the SPG4 locus on chromosome 2p is the major disease gene for AD-HSP. OBJECTIVES: To investigate whether there are distinct clinical features among families with AD-HSP due to SPAST mutations compared with families excluded from SPG4. METHODS: Nineteen families with "pure" AD-HSP were identified, and the clinical features of family members were compared using a standard protocol. With use of genetic studies, the families were divided into two groups for comparison: those with mutations in SPAST, the "mutation-positive" group, and those excluded from SPG4 on the basis of linkage studies, the "SPG4-excluded" group. RESULTS: Twenty-nine individuals from four families had mutations in SPAST, whereas 22 individuals from three families comprised the SPG4-excluded group; in 11 families, the pattern of linkage was unknown. In the one remaining family, no mutations were found despite strong linkage to SPG4. Different mutations were identified in the four SPAST pedigrees, but the clinical picture was similar in each. Comparison of the mutation-positive group with the SPG4-excluded group revealed an older age at onset (p = 0.03), more disability (p = 0.001), more rapidly progressive paraparesis (p = 0.044), and more cognitive impairment (p = 0.024) among affected individuals with SPAST mutations, not confounded by disease duration. CONCLUSION: Despite different mutations, SPAST families have a similar phenotype that can be distinguished from other genetic groups.

Age-related cognitive decline in hereditary spastic paraparesis linked to chromosome 2p.

OBJECTIVES: To investigate whether cognitive decline is part of the phenotype of SPG4-linked hereditary spastic paraparesis (HSP) and to determine whether cognitive changes are present in haplotype carriers before the onset of paraparesis. BACKGROUND: The major locus for "pure" autosomal dominant HSP is the SPG4 locus on chromosome 2p. Cognitive impairment linked to this locus has been described in two families. METHODS: The authors identified 19 families with "pure" autosomal dominant HSP. Five had linkage to the SPG4 locus (maximum lod score for D2S2374: 5.99 at zero recombination in four smaller families and 3.86 at zero recombination in the largest family). Haplotype construction identified a disease haplotype for all families; 41 individuals carried this haplotype (30 affected by HSP, 11 unaffected). All haplotype carriers and 41 matched controls underwent Cambridge Cognitive (CAMCOG) examination. Nonparametric significance tests were used comparing total and subset scores. RESULTS: Haplotype carriers affected by HSP had lower total CAMCOG scores than control subjects (85.86/107 versus 96.2/107; p < 0.0005). The subsets of orientation, memory, language expression, and comprehension were also significantly lower. Ten individuals had scores < or =80/107, indicating mild dementia. Unaffected haplotype carriers had mean total CAMCOG scores lower than control subjects (91.82/107 versus 98. 09/107; p = 0.016). In both groups cognitive decline was age-dependent and scores diverged from control subjects from age 40. All SPG4-linked families showed the effect. CONCLUSION: Mild, age-related cognitive impairment is a feature common to these families. It illustrates variable phenotypic expression at this locus and may be the first manifestation of the disease gene in individuals as yet unaffected by paraparesis.