Falls and fractures 2 years after acute stroke: the North Dublin Population Stroke Study.

BACKGROUND: Stroke patients are at increased risk of falls and fractures. The aim of this study was to determine the rate, predictors and consequences of falls within 2 years after stroke in a prospective population-based study in North Dublin, Ireland. DESIGN: Prospective population-based cohort study. SUBJECTS: 567 adults aged >18 years from the North Dublin Population Stroke Study. METHODS: Participants were enrolled from an Irish urban population of 294,592 individuals, according to recommended criteria. Patients were followed for 2 years. Outcome measures included death, modified Rankin Scale (mRS), fall and fracture rate. RESULTS: At 2 years, 23.5% (124/522) had fallen at least once since their stroke, 14.2% (74/522) had 2 or more falls and 5.4% (28/522) had a fracture. Of 332 survivors at 2 years, 107 (32.2%) had fallen, of whom 60.7% (65/107) had 2 or more falls and 23.4% (25/107) had fractured. In a multivariable model controlling for age and gender, independent risk factors for falling within the first 2 years of stroke included use of alpha-blocker medications for treatment of hypertension (P = 0.02). When mobility measured at Day 90 was included in the model, patients who were mobility impaired (mRS 2-3) were at the highest risk of falling within 2 years of stroke [odds ratio (OR) 2.30, P = 0.003] and those functionally dependent (mRS 4-5) displayed intermediate risk (OR 2.02, P = 0.03) when compared with independently mobile patients. CONCLUSION: Greater attention to falls risk, fall prevention strategies and bone health in the stroke population are required.

Germination efficiency of clinical Clostridium difficile spores and correlation with ribotype, disease severity and therapy failure.

Spore germination is an important part of the pathogenesis of Clostridium difficile infection (CDI). Spores are resistant to antibiotics, including those therapeutically administered for CDI and strains with a high germination rate are significantly more likely to be implicated in recurrent CDI. The role of germination efficiency in cases of refractory CDI where first-line therapy fails remains unclear. We investigated spore germination efficiencies of clinical C. difficile isolates by measuring drop in OD600 and colony forming efficiency. Ribotype 027 isolates exhibited significantly higher germination efficiencies in the presence of 0.1 % (w/v) sodium taurocholate (51.66 ± 8.75 %; 95 % confidence interval (CI) 47.37-55.95 %) than ribotype 106 (41.91 ± 8.35 %; 95 % CI 37.82-46 %) (P<0.05) and ribotype 078 (42.07 ± 8.57 %, 95 % CI 37.22-46.92 %) (P<0.05). Spore outgrowth rates were comparable between the ribotype groups but the exponential phase occurred approximately 4 h later in the absence of sodium taurocholate. Spore germination efficiencies for isolates implicated in severe CDI were significantly higher (49.68 ± 10.00 %, 95 % CI 47.06-52.30 %) than non-severe CDI (40.92 ± 9.29 %, 95 % CI 37.48-44.36 %); P<0.01. Germination efficiencies were also significantly higher in recurrent CDI or when metronidazole therapy failed than when therapy was successful [(49.00 ± 10.49 %, 95 % CI 46.25-51.75 %) versus (41.42 ± 9.43 %, 95 % CI 37.93-44.91 %); P<0.01]. This study suggests an important link between C. difficile spore germination, CDI pathogenesis and response to treatment; however, further work is warranted before the complex interplay between germination dynamics and CDI outcome can be fully understood.

Stroke recurrence within the time window recommended for carotid endarterectomy.

OBJECTIVE: In the North Dublin Population Stroke Study, we investigated the risk of recurrent stroke within the 14-day time window recommended for endarterectomy. METHODS: In a population-based prospective cohort study, all ischemic stroke patients were identified over 1 year and categorized into those with (CS-positive) and without (CS-negative) ipsilateral carotid stenosis (CS) (≥50% lumen narrowing). Nonprocedural stroke recurrence was determined at 72 hours and 7 and 14 days. RESULTS: Of 365 ischemic stroke patients with carotid imaging, 51 were excluded due to posterior circulation or nonlateralizing stroke, ipsilateral carotid occlusion, or intracranial stenosis, leaving 314 included for analysis (36 CS-positive and 278 CS-negative). Recurrent stroke occurred in 5.6% (2/36) CS-positive and 0.4% (1/278) CS-negative patients by 72 hours of symptom onset (p =0.003), 5.6% (2/36) CS-positive and 0.7% (2/278) CS-negative patients (p =0.01) by 7 days, and in 8.3% (3/36) CS-positive and 1.8% (5/278) CS-negative patients by 14 days (p =0.02). On multivariable Cox regression analysis, CS was the only independent predictor of recurrence at 72 hours (adjusted hazard ratio [HR] 36.1, 95% confidence interval [CI] 1.6-837.5, p =0.03), and 7 days (HR 9.1, 1.1-79.2, p =0.05), with a trend at 14 days (HR 4.6, 0.9-22.8, p =0.06). CONCLUSIONS: Although only a minority of patients with symptomatic CS had a recurrent stroke within 14 days, early recurrent stroke risk was high, particularly within the first 72 hours. Earlier carotid revascularization or improved acute medical treatment may reduce recurrence in this high-risk group.

An investigation of the subtype diversity of clinical isolates of Irish Clostridium difficile ribotypes 027 and 078 by repetitive-extragenic palindromic PCR.

A repetitive-extragenic palindromic PCR (rep-PCR) subtyping method (DiversiLab) in conjunction with ribotyping, toxinotyping and antimicrobial-susceptibility testing was used to detect subtypes within Clostridium difficile ribotypes 027 and 078. Clinical isolates of ribotypes 027 (toxinotype III) (n = 30) and 078 (toxinotype V) (n = 23) were provided by health-care facilities across the Republic of Ireland over 2 months in 2006 and 1 month in 2009. Ribotype 027 isolates were significantly more related to each other (9 different subtype profiles) when compared to ribotype 078 isolates (14 different profiles) (P = 0.001; cut-off >90 % similarity). Almost half of ribotype 078 isolates (45.5 %) showed no relationship to each other. The clonality of ribotype 027 isolates suggests effective adaptation to the human niche, whereas the considerable genetic diversity within ribotype 078 isolates suggests that they may have originated from a variety of sources. Subtyping correlated well with antimicrobial susceptibility, in particular clindamycin susceptibility for ribotype 027, but diverse antimicrobial-susceptibility profiles were seen in ribotype 078 isolates, even within a single health-care facility. Between 2006 and 2009, a change in the predominant subtype of ribotype 027 was seen, with the recent clone representing half of all ribotype 027 isolates studied. This strain exhibited 89 % similarity to a rep-PCR profile of the North American NAP-1 strain.

Medical, social and societal issues in infants with abusive head trauma.

Abusive head trauma (AHT) is the leading cause of death from traumatic brain injury in under 2 year olds. AHT presents with acute encephalopathy, subdural hemorrhages and retinal hemorrhages occurring in the context of an inappropriate or inconsistent history. We retrospectively analyzed, over a 10 year period, admissions and transfers to our hospital with suspected AHT to assess patterns of presentation, presenting symptoms, investigations, subsequent confirmation, social work input and both neurological and social outcomes. We analyzed all suspected AHT infants and children looking for the time of presentation, presenting symptoms, caregivers concerns prior to presentation, a family profile including stressors, investigations (in particular neuroradiology and ophthalmology assessments), treatment in hospital, length of stay in hospital, social work involvement, subsequent discharge, neurological outcome and subsequent social work follow up. Data was collected from the hospital HIPE system, RIS (radiology reports system) and records from the social work department from a period October 1998 to January 2009 inclusive. Of 22 patients with confirmed AHT, ages seizures and irritability followed by vomiting, poor feeding, a bulging fontanelle and lethargy. The father was the sole minder in 5 cases. There was a delayed history in 4 cases. One had multiple visits to his GP. All cases had subdural hemorrhages proven by either CT or MRI scans and retinal hemorrhages diagnosed by ophthalmology. One infant presented with a torn frenulum. Four had suspicious bruising. All had normal coagulation profiles, skeletal surveys and extensive metabolic tests. Hospital stays ranged from 1 to 124 days (the median was 28 days and mean 33 days). Ten (45%) infants required ventilatory support. Sixteen infants had social work involvement within 4 days of admission (7 of these were interviewed immediately). Outcomes after case conferences were that 6 returned home with parents, 9 were placed in foster care. Four parents (18%) admitted to shakng their infants. There was 1 death. Thirteen (60%) were normal on follow up. Two had ADHD. Two had language delay. Two had motor delay. One criminal prosecution has ensued as yet Children with suspected AHT should undergo appropriate investigations which should include brain imaging, ophthalmic examination, skeletal survey and blood investigations. Early social work assessment is a priority as part of the multidisciplinary approach. A prospective national study of AHT is required.

Isolation and characterisation of toxin A-negative, toxin B-positive Clostridium difficile in Dublin, Ireland.

Clostridium difficile is a major cause of infectious diarrhoea in hospitalised patients. Most pathogenic C. difficile strains produce two toxins, A and B; however, clinically relevant toxin A-negative, toxin B-positive (A- B+) strains of C. difficile that cause diarrhoea and colitis in humans have been isolated worldwide. The aims of this study were to isolate and characterise A- B+ strains from two university hospitals in Dublin, Ireland. Samples positive for C. difficile were identified daily by review of ELISA results and were cultured on selective media. Following culture, toxin-specific immunoassays, IMR-90 cytotoxicity assays and PCR were used to analyse consecutive C. difficile isolates from 93 patients. Using a toxin A-specific ELISA, 52 samples produced detectable toxin. All isolates were positive using a toxin A/B ELISA. Similarly, all isolates were positive with the cytoxicity assay, although variant cytopathic effects were observed in 41 cases. PCR amplification of the toxin A and toxin B genes revealed that 41 of the previous A- B+ strains had a c. 1.7-kb deletion in the 3'-end of the tcdA gene. Restriction enzyme analysis of these amplicons revealed the loss of polymorphic restriction sites. These 41 A- B+ isolates were designated toxinotype VIII by comparison with C. difficile strain 1470. PCR ribotyping revealed that all A- B+ isolates belonged to PCR-ribotype 017. A- B+ C. difficile isolates accounted for 44% of the isolates examined in this study, and appeared to be isolated more frequently in Dublin, Ireland, than reported rates for other countries.

Clostridium difficile.

Clostridium difficile is a major cause of antibiotic-associated diarrhea and colitis. The incidence of infection with this organism is increasing in hospitals worldwide, consequent to the widespread use of broad-spectrum antibiotics. Pathogenic strains of C. difficile produce two protein exotoxins, toxin A and toxin B, that cause colonic mucosal injury and inflammation. Many patients who are colonized are asymptomatic, and recent evidence indicates that diarrhea and colitis occur in those individuals who lack a protective antitoxin immune response. In patients who do develop symptoms, the spectrum of C. difficile disease ranges from mild diarrhea to fulminant pseudomembranous colitis. Prevention of nosocomial C. difficile infection involves judicious use of antibiotics and multidisciplinary infection control measures to reduce environmental contamination and patient cross-infection. Ultimately, active or passive immunization against C. difficile may be an effective means of controlling the growing problem of nosocomial C. difficile diarrhea and colitis.

Association between antibody response to toxin A and protection against recurrent Clostridium difficile diarrhoea.

BACKGROUND: We have reported that symptom-free carriers of Clostridium difficile have a systemic anamnestic immune response to toxin A. The aim of this study was to determine whether an acquired immune response to toxin A, during an episode of C. difficile diarrhoea, influences risk of recurrence. METHODS: We prospectively studied 63 patients with nosocomial C. difficile diarrhoea. Serial serum IgA, IgG, and IgM concentrations against C. difficile toxin A, toxin B, or non-toxin antigens were measured by ELISA. Individuals were followed for 60 days. FINDINGS: 19 patients died (30%). Of the 44 who survived, 22 had recurrent C. difficile diarrhoea. Patients with a single episode of C. difficile diarrhoea (n=22) had higher concentrations of serum IgM against toxin A on day 3 of their first episode of diarrhoea than those with recurrent diarrhoea (n=22, p=0.004). On day 12, serum IgG values against toxin A were higher in patients who had a single episode of diarrhoea (n=7) than in those who subsequently had recurrent diarrhoea (n=9, p=0.009). The odds ratio for recurrence associated with a low concentration of serum IgG against toxin A, measured 12 days after onset of C. difficile diarrhoea, was 48.0 (95% CI 3.5-663). INTERPRETATION: A serum antibody response to toxin A, during an initial episode of C. difficile diarrhoea, is associated with protection against recurrence.

Asymptomatic carriage of Clostridium difficile and serum levels of IgG antibody against toxin A.

BACKGROUND: Clostridium difficile infection can result in asymptomatic carriage, mild diarrhea, or fulminant pseudomembranous colitis. We studied whether antibody responses to C. difficile toxins affect the risks of colonization, diarrhea, and asymptomatic carriage. METHODS: We prospectively studied C. difficile infections in hospitalized patients who were receiving antibiotics. Serial stool samples were tested for C. difficile colonization by cytotoxin assay and culture. Serum antibody (IgA, IgG, and IgM) levels and fecal antibody (IgA and IgG) levels against C. difficile toxin A, toxin B, and nontoxin antigens were measured by an enzyme-linked immunosorbent assay (ELISA). RESULTS: Of 271 patients, 37 (14 percent) were colonized with C. difficile at the time of admission, 18 of whom were asymptomatic carriers. An additional 47 patients (17 percent) became infected in the hospital, 19 of whom remained asymptomatic. The baseline antibody levels were similar in the patients who later became colonized and those who did not. After colonization, those who became asymptomatic carriers had significantly greater increases in serum levels of IgG antibody against toxin A than did the patients in whom C. difficile diarrhea developed (P<0.001). The adjusted odds ratio for diarrhea was 48.0 (95 percent confidence interval, 3.4 to 678) among patients with colonization who had a serum level of IgG antibody against toxin A of 3.00 ELISA units or less, as compared with patients with colonization who had a level of more than 3.00 ELISA units. CONCLUSIONS: We find no evidence of immune protection against colonization by C. difficile. However, after colonization there is an association between a systemic anamnestic response to toxin A, as evidenced by increased serum levels of IgG antibody against toxin A, and asymptomatic carriage of C. difficile.

Neutrophilia and congestive heart failure after acute myocardial infarction.

BACKGROUND: Inflammation associated with acute myocardial infarction (AMI) is frequently marked by a peripheral leukocytosis and relative neutrophilia. Whether this process may contribute to the development of postinfarction congestive heart failure (CHF) is not established. The objective of this study was to examine the association between hospital admission peripheral total leukocyte count and the neutrophil percentage and the subsequent development of CHF in patients with AMI. The study was designed as a retrospective cohort study in the setting of a tertiary referral hospital. Participants included 185 patients discharged with a diagnosis of AMI between May 1 and Sept 30, 1996. METHODS AND RESULTS: Outcome measures included clinical episodes of CHF with confirmatory chest roentgenogram findings and/or echocardiographic evidence of contractile dysfunction. Multivariable logistic regression analyses were performed to examine the relation between the total leukocyte count, neutrophil percentage, and the development of CHF in the first 4 days after AMI while controlling for baseline characteristics and early therapeutic interventions. Thirty-one percent of the cohort had a leukocyte count >11.0 x10(9)/L on admission to the hospital; 65% had a neutrophil percentage >65%, and 61% had a lymphocyte percentage 65%) compared with 45% of those in whom CHF did not develop. Multivariable analysis revealed a highly significant association between relative neutrophilia and the subsequent development of CHF (odds ratio 14.3; 95% confidence interval 5.2 to 39.3). CONCLUSIONS: Relative neutrophilia on admission to the hospital in patients with AMI is significantly associated with the early development of CHF. This association may help in the identification of individuals at high risk who might benefit from more aggressive interventions to prevent or reduce the risk of CHF.

Factors associated with prolonged symptoms and severe disease due to Clostridium difficile.

OBJECTIVE: toxigenic Clostridium difficile is responsible for a spectrum of disease severity ranging from mild diarrhoea to fulminant colitis. This study attempts to determine the proportion of patients in each category of severity and evaluate the risk factors for a more prolonged and complicated course. DESIGN: prospective cohort study. SETTING: university teaching hospital. SUBJECTS: all patients with symptomatic C. difficile infection during 4 months of an outbreak (January-April 1995); n=73; median age 74 years (range 17-91). MEASUREMENTS: incidence of C. difficile-associated disease (CDAD); severity of disease; percentage of patients in each category of severity; risk factors for severe disease/prolonged symptoms (univariate and multivariable analyses). RESULTS: the incidence of CDAD was 0.93%. Of the cases identified, 18 (24.7%) had mild, self-limiting disease; 26 (35.6%) had moderately severe disease; 23 (31.5%) had prolonged symptoms and six (8.2%) had a complicated course. Although CDAD was more common in older patients (P < 0.001), increasing age was not a risk factor for severity. Significant risk factors for severe CDAD included low Barthel and abbreviated mental test scores (P < 0.01, P < 0.001 respectively) and recent endoscopy (P=0.03). Logistic regression analysis revealed the following independent predictors of severe CDAD: endoscopy [odds ratios (OR) 4.0, P=0.03] and cognitive impairment (OR 11.0, P < 0.01). A trend towards significance was noted for nasogastric tube insertion (OR 3.1, P=0.08). Complications of infection included dehydration, malnutrition and faecal incontinence (which was statistically significantly associated with more severe disease; P < 0.01). CONCLUSION: risk factors for severity of CDAD include functional disability, cognitive impairment, and recent endoscopy. Anticipation of severe CDAD may limit morbidity and mortality.

Is age a negative prognostic indicator in HIV infection or AIDS?

To better understand disease progression in older persons with human immunodeficiency virus (HIV infection or acquired immunodeficiency syndrome (AIDS), we studied patients aged 50 years and older hospitalized with a diagnosis of HIV infection or AIDS between January 1985 and October 1995. Data collected included demographics, opportunistic infections, comorbid disease, neurologic dysfunction, and antiretroviral therapy. A total of 86 patients with a mean age of 54.3 years was identified. Pneumocystis carinii pneumonia was the most frequent opportunistic infection (43%). Hypertension was the most common previous medical condition (38%). Other comorbid disease was present in less than 15% of the subjects. Fifty-seven patients (66%) had neurologic impairment, with 30 requiring treatment for delirium. In these 30, 23 (77%) had anemia, infection, or both. The median length of survival following the diagnosis of AIDS was 18.5 months, for HIV it was 48 months. The median survival following the diagnosis of AIDS in patients who received antiretroviral therapy was 22 months compared with 11 months for those who did not receive antiretroviral therapy (p < 0.0004). Multivariable analysis found that antiretroviral therapy was the only independent predictor of survival after the diagnosis of AIDS. In contrast to previous studies, the present findings suggest that older age may not necessarily be associated with more rapid disease progression and reduced survival times in persons with HIV infection or AIDS. In those patients with delirium, many may have readily treatable conditions (anemia and/or infection). The absence of significant comorbid disease and the access to antiretroviral therapy may be in part responsible for the longer survival times obtained in this cohort compared to that reported previously.

Community-acquired Clostridium difficile infection.

Clostridium difficile-associated disease (CDAD) is primarily a nosocomial condition. Community-acquired disease has been reported but the incidence is felt to be low and the rate of disease resulting in hospitalization is reported as negligible. We recently experienced a 6-month outbreak of CDAD (January to June 1995): 139 patients were involved and four deaths were attributable to pseudomembranous colitis. Early in the outbreak period we were aware that many new admissions presented with C. difficile cytotoxin B positive diarrhoea: in some cases this was the sole reason for hospitalization. This observation forms the basis of this report.

Familial craniosynostosis, anal anomalies, and porokeratosis: CAP syndrome.

We report on the occurrence of coronal craniosynostosis, anal anomalies, and porokeratosis in two male sibs. A third male sib was phenotypically normal as were the parents. The occurrence of these three clinical features has, to our knowledge, not been reported before. Cutaneous or anal anomalies or both have been reported in a number of syndromes associated with craniosynostosis, including Crouzon, Pfeiffer, Apert, and Beare-Stevenson syndromes. These syndromes are associated with mutations in the fibroblast growth factor receptor genes FGFR1, FGFR2, and FGFR3. They are inherited in an autosomal dominant fashion. In contrast, the cases we report do not carry any of the common FGFR mutations and the pedigree suggests autosomal or X linked recessive inheritance.

Simultaneous outbreaks of two strains of toxigenic Clostridium difficile in a general hospital.

We report an outbreak of Clostridium difficile-associated disease (CDAD) in a large Dublin hospital. From January to June 1995, inclusive, 139 patients were affected; the mean age of cases was 68.8 +/- 19 years. Clinical information is available for 73 cases identified during the first four months of the outbreak. The majority of patients presented with abrupt onset of watery diarrhoea; however, 19.2% presented with an unexplained pyrexia following a course of antimicrobial therapy and 5.5% presented with a surgical acute abdomen. Twenty patients (27.4%) experienced relapsing disease and seven (9.6%) patients died. Seventy-six percent of cases received a cephalosporin prior to the onset of disease, the highest relative risks occurring with third-generation agents; however, 9.6% of patients affected had not been exposed to antimicrobial therapy in the preceding eight weeks. Pyrolysis mass spectrometry identified two clusters of isolates, representing two strains of C. difficile. There was marked spatial clustering of these strains, with each confined to a separate area of the hospital. Infection control measures and an antibiotic policy were introduced. Throughout the outbreak period the use of the most frequently used cephalosporin in the hospital increased; this was accompanied paradoxically by a reduction in the number of new cases of CDAD.

Timing of surgery for fulminating pseudomembranous colitis.

BACKGROUND: With increasing antibiotic usage Clostridium difficile colitis is becoming more common. Surgery for fulminating C. difficile colitis, however, is rare because of the effectiveness of specific anticlostridial chemotherapy. Surgical outcome in five patients with fulminating C. difficile colitis involved in a recent outbreak of this disease is reported. METHODS: Five of 138 patients developed fulminating C. difficile colitis unresponsive to medical therapy. All patients had antibiotics in the preceding period. Indications for operation in those who underwent surgery were systemic toxicity with a pyrexia, marked leukocytosis and abdominal signs leading to progressive organ failure, despite appropriate anticlostridial antibiotic therapy. RESULTS: At operation all patients had a markedly oedematous colon with normal serosa but with acute mucosal colitis. All underwent subtotal abdominal colectomy and ileostomy. Progressive organ failure persisted in four, leading to death, giving a mortality rate of four in five in the operated group in comparison with 3.8 per cent (five of 133 patients) in those treated medically. CONCLUSIONS: These results indicate that this increasingly common disease frequently leads to a fatal outcome in patients requiring surgery and implies that earlier surgical consultation may be necessary to improve survival in patients with fulminating C. difficile colitis unresponsive to antibiotic therapy.

Prospects for a vaccine for Clostridium difficile.

Clostridium difficile diarrhoea and colitis is a new disease that is attributable to broad spectrum antibiotic therapy. During the past 2 decades C. difficile has become one of the most common nosocomial pathogens in the developed world. As changing demographics create an increasingly elderly population and the use of broad spectrum antimicrobials continues to expand, C. difficile is likely to become increasingly problematic. Disease caused by this organism is caused by the inflammatory actions of its 2 toxins, A and B, on the intestinal mucosa. Human antibody responses to these toxins are common in the general population and in patients with C. difficile-associated disease. There is substantial, albeit inconclusive, evidence to indicate that antitoxin antibodies provide protection against severe, prolonged or recurrent C. difficile diarrhoea. Immunity induced by oral or parenteral passive administration of antibody is protective in animal models of C. difficile infection. In humans, intravenous passive immunisation with pooled human immunoglobulin has been successful in the treatment of recurrent and severe C. difficile colitis. Human trials of oral passive immunotherapy with bovine immunoglobulin therapy are in progress. Formalin-inactivated culture filtrate from toxigenic C. difficile, as well as purified and inactivated toxins, have been used to successfully immunise animals. Similar preparations are under investigation as possible human vaccines. Antibiotic therapy is effective in treating most individual patients with C. difficile diarrhoea, but has proven ineffective in reducing the overall incidence of nosocomial infection. Active immunisation is probably the most promising approach to long term control of this difficult iatrogenic disease.