Heterozygous mutations in the PALB2 hereditary breast cancer predisposition gene impact on the three-dimensional nuclear organization of patient-derived cell lines.

PALB2/FANCN is a BRCA1- and BRCA2-interacting Fanconi Anemia (FA) protein crucial for key BRCA2 genome caretaker functions. Heterozygous germline mutations in PALB2 predispose to breast cancer and biallelic mutations cause FA. FA proteins play a critical role in the telomere maintenance pathway, with telomeric shortening observed in FA cells. Less is known about telomere maintenance in the heterozygous state. Here, we investigate the roles of PALB2 heterozygous mutations in genomic instability, an important carcinogenesis precursor. Patient-derived lymphoblastoid (LCL) and fibroblast (FCL) cell lines with monoallelic truncating PALB2 mutations were investigated using a combination of molecular imaging techniques including centromeric FISH, telomeric Q-FISH and spectral karyotyping (SKY). Mitomycin C and Cisplatin sensitivity was assayed via cellular metabolism of WST-1. The PALB2 c.229delT FCL showed increases in telomere counts associated with increased mean intensity compared with two wild-type FCLs generated from first-degree relatives (P =1.04E-10 and P =9.68E-15) and it showed evidence of chromosomal rearrangements. Significant differences in centromere distribution were observed in one of three PALB2 heterozygous FCLs analyzed when compared with PALB2 wild-type, BRCA1 and BRCA2 heterozygous FCLs. No significant consistently increased sensitivity to Mitomycin C or Cisplatin was observed in LCLs. Our results are suggestive of an altered centromere distribution profile and a telomere instability phenotype. Together, these may indicate critical nuclear organization defects associated with the predisposition to transformation and early stage development of PALB2-related cancers.

A comparison of patient and family caregiver prospective control over lung cancer.

AIM: This paper is a report of our secondary analysis of patient and family caregiver prospective control in lung cancer. BACKGROUND: Control beliefs underlie self-care in sickness and health. Self-care often involves 'shared' activities between the afflicted individual and caregiving family and friends. However, depending on how control is perceived, conflicts can occur in decision-making thus jeopardizing optimal self-care. We need to comprehend how control beliefs compare between patients and caregivers and how their control beliefs are linked with dealing with serious illness. METHODS: Based on questionnaire data collected in our larger study between September 2005 and February 2009, we conducted exploratory comparative analyses of 304 patients' and caregivers' control beliefs in managing lung cancer. Eight 5-point response items captured prospective control. Exploratory factor analysis with promax rotation was conducted to compare dyadic perceptions on the dimensionality of prospective control. We also conducted exploratory correlations between control beliefs and smoking cessation, attributional reactions, caregiver helping and symptom reports. RESULTS: Principal component analysis identified the same factors for patients and caregivers: factor 1, Fate control and factor 2, Team control. Patient and caregiver 'Fate' and 'Team' control sub-scales were respectively associated with hope, caregiver helping and patient smoking cessation. CONCLUSION: Clinicians need to support, adapt or develop a philosophy of cancer care that is inclusive of partnerships, drawing on beliefs of patients and caregivers that controlling lung cancer is a team effort which in turn is tentatively linked to patient smoking cessation, positive emotions and caregiver helping.

Characterizing the HIV epidemic in the prairie provinces.

BACKGROUND: The numbers and demographics of HIV-positive patients in care between 2003 and 2007 in the prairie provinces were examined. METHODS: Estimates of HIV-positive patients presenting to care between 2003 and 2007 were obtained from four clinic registries in Manitoba, Saskatchewan and southern Alberta. Detailed data were collected from clinical records of new patients in 2007. RESULTS: By the end of December 2007, 2263 HIV-positive persons were in care in Manitoba, Saskatchewan and southern Alberta. Males and females accounted for 1674 (74.0%) and 589 of the cases, respectively. Overall, there was a 12% increase per year in new HIV cases to care between 2003 and 2007 (P=0.026), with the rate of increase for males being 60% higher than for females over this time period (P=0.002). In 2007, there were 222 new HIV cases to care (37.4% female). Heterosexual contact was the most common HIV risk, but diversity was seen across sites with frequent injection drug use and men who have sex with men risk in Saskatchewan and southern Alberta, respectively. The Aboriginal population remains heavily over-represented, with approximately 36.0% of new cases being Aboriginal. Late presentation was common across all care sites, with 35.1% of cases presenting with CD4 counts of less than 200 cells/mm(3). DISCUSSION: Heterosexual risk is the most common risk reported for HIV acquisition, but injection drug use risk remains significant in Saskatchewan. Aboriginals are over-represented at all sites, and in Saskatchewan accounted for the majority of new cases seen. In contrast to national trends, numbers of new and late diagnoses are increasing in the praire provinces, and this has significant treatment implications and potential public health consequences. Further efforts need to be made to facilitate earlier testing and linkage to care. BACKGROUND: The numbers and demographics of HIV-positive patients in care between 2003 and 2007 in the prairie provinces were examined. METHODS: Estimates of HIV-positive patients presenting to care between 2003 and 2007 were obtained from four clinic registries in Manitoba, Saskatchewan and southern Alberta. Detailed data were collected from clinical records of new patients in 2007. RESULTS: By the end of December 2007, 2263 HIV-positive persons were in care in Manitoba, Saskatchewan and southern Alberta. Males and females accounted for 1674 (74.0%) and 589 of the cases, respectively. Overall, there was a 12% increase per year in new HIV cases to care between 2003 and 2007 (P=0.026), with the rate of increase for males being 60% higher than for females over this time period (P=0.002). In 2007, there were 222 new HIV cases to care (37.4% female). Heterosexual contact was the most common HIV risk, but diversity was seen across sites with frequent injection drug use and men who have sex with men risk in Saskatchewan and southern Alberta, respectively. The Aboriginal population remains heavily over-represented, with approximately 36.0% of new cases being Aboriginal. Late presentation was common across all care sites, with 35.1% of cases presenting with CD4 counts of less than 200 cells/mm3. DISCUSSION: Heterosexual risk is the most common risk reported for HIV acquisition, but injection drug use risk remains significant in Saskatchewan. Aboriginals are over-represented at all sites, and in Saskatchewan accounted for the majority of new cases seen. In contrast to national trends, numbers of new and late diagnoses are increasing in the praire provinces, and this has significant treatment implications and potential public health consequences. Further efforts need to be made to facilitate earlier testing and linkage to care.

HISTORIQUE: Les chercheurs ont examiné le nombre et la démographie des patients positifs au VIH soignés entre 2003 et 2007 dans les provinces des Prairies. MÉTHODOLOGIE: Les chercheurs ont pu évaluer le nombre de patients positifs au VIH qui ont consulté pour la première fois entre 2003 et 2007 d'après quatre registres cliniques du Manitoba, de la Saskatchewan et du sud de l'Alberta. Ils ont également recueilli les données détaillées des dossiers cliniques de nouveaux patients en 2007. RÉSULTATS: À la fin de décembre 2007, 2 263 personnes positives au VIH étaient soignées au Manitoba, en Saskatchewan et dans le sud de l'Alberta. Les hommes et les femmes représentaient 1 674 (74,0 %) et 589 cas, respectivement. Dans l'ensemble, on a constaté une augmentation annuelle de 12 % des nouveaux cas de VIH soignés entre 2003 et 2007 (P=0,026), le taux d'augmentation pour les hommes étant 60 % plus élevé que pour les femmes (P=0,002). En 2007, on a recensé 222 nouveaux cas de VIH soignés (37,4 % de femmes). Le contact hétérosexuel représentait le principal risque de VIH, mais on remarquait une diversité selon les lieux, le risque posé par la consommation fréquente de drogues par injection et par les relations sexuelles entre hommes étant observé en Saskatchewan et au sud de l'Alberta, respectivement. La population autochtone demeure lourdement surreprésentée, puisqu'environ 36,0 % des nouveaux cas étaient d'origine autochtone. Une présentation tardive était fréquente partout, la numération de CD4 étant inférieure à 200 cellules/mm3 à la présentation dans 35,1 % des cas. EXPOSÉ: Les contacts hétérosexuels constituent le principal risque déclaré d'acquisition du VIH, mais la consommation de drogues par injection demeure importante en Saskatchewan. Les Autochtones sont surreprésentés partout, et en Saskatchewan, ils représentent la majorité des nouveaux cas observés. Contrairement aux tendances nationales, le nombre de nouveaux diagnostics et de diagnostics tardifs augmente dans les provinces des Prairies, ce qui a des répercussions thérapeutiques importantes et des conséquences potentielles en matière de santé publique. Il faut faire davantage d'efforts pour favoriser la tenue de tests et des mises en relation plus rapides vers les soins.

Effect of a preventive foot care program on lower extremity complications in diabetic patients with end-stage renal disease.

BACKGROUND: Lower extremity complications are a major cause of morbidity and mortality in patients with end-stage renal disease (ESRD) and diabetes mellitus. Patient education programs may decrease the risk of diabetic foot complications. METHODS: A preventive program was instituted, consisting of regular assessments by a foot care nurse with expertise in foot care and wound management and patient education about foot care practices and footwear selection. Medical records were reviewed and patients were examined. A comparison was made with data about patients from a previous study done from this institution prior to development of the foot care program. RESULTS: Diabetic subjects more frequently had weakness of the left tibialis anterior, left tibialis posterior, and left peroneal muscles than non-diabetic subjects. A smaller percentage of diabetic subjects had sensory neuropathy compared with the previous study from 5years earlier, but a greater percentage of diabetic subjects had absent pedal pulses in the current study. The frequency of inadequate or poor quality footwear was less in the current study compared with the previous study. CONCLUSIONS: The current data suggest that a foot care program consisting of nursing assessments and patient education may be associated with a decrease in frequency of neuropathy and improved footwear adequacy in diabetic patients with ESRD.

A prospective population-based study of triggers of symptomatic flares in IBD.

OBJECTIVES: We aimed to determine whether any of the nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, infections, and stress trigger symptomatic flares of inflammatory bowel diseases (IBDs). METHODS: Participants drawn from a population-based IBD research registry were surveyed every 3 months for 1 year. They simultaneously tracked the use of NSAIDs, antibiotics, infections, major life events, mood, and perceived stress. Social networks, childhood socioeconomic status, and smoking were assessed at baseline. Disease flare was identified using the Manitoba Inflammatory Bowel Disease Index, a validated disease activity index. Across any two consecutive survey periods, participants were categorized as having a flare (inactive/active), having no flare (inactive/inactive), or remaining active (active/active). Potential triggers were evaluated for the first 3-month period to determine predictive rather than concurrent relationships. Data from only one pair of 3-month periods from an individual were analyzed. RESULTS: A total of 704 participants completed the baseline survey; 552 (78.3%) returned all 5 surveys. In all, 174 participants who had a flare were compared with 209 who had no flare. Perceived stress, negative affect (mood), and major life events were the only trigger variables significantly associated with flares. There were no differences between those who flared and those who did not, in the use of NSAIDs, antibiotics, or in the presence of infections. Multivariate logistic regression analyses indicated that only high-perceived stress (adjusted odds ratio=2.40 (1.35, 4.26)) was associated with an increased risk of flare. CONCLUSIONS: This study adds to the growing evidence that psychological factors contribute to IBD symptom flares. There was no support for differential rates of use of NSAIDS, antibiotics, or for the occurrence of (non-enteric) infections related to IBD flares.

Etiology and determinants of sexually transmitted infections in Karnataka state, south India.

BACKGROUND: Syndromic case management remains the cornerstone for STI (sexually transmitted infection) treatment in many countries. We undertook this study to better understand the etiology of STIs in adults in south India and to inform STI management guidelines. METHODS: Adult males and females presenting with genital complaints were recruited from clinics in Karnataka state, south India. A questionnaire was administered, physical examination performed, and blood collected for herpes simplex virus-type 2 (HSV-2) and syphilis serology. Men with urethral discharge (UD) and women with vaginal discharge were tested for Neisseria gonorrhoeae (NG), Chlamydia trachomatis (CT) and Trichomonas vaginalis (TV). Vaginal swabs were also tested for bacterial vaginosis and yeast infection. Participants with genital ulcers were tested for Treponema pallidum (TP), Haemophilus ducreyi (HD), and HSV-2. human immunodeficiency virus (HIV) testing was offered to all individuals. RESULTS: There were 401 male and 412 female participants, and rates of HIV infection were high (men, 17%; women, 15%). HSV-2 was significantly associated with HIV in men and women. Among men with the complaint of UD, NG was identified in 35%, CT in 10.5%, and TV in 8.5%. Very little NG or CT was detected among women with vaginal discharge. However, bacterial vaginosis was identified in approximately 40% of women, with significant amounts of TV and Candida also detected. HSV-2 was the most commonly identified pathogen among participants with genital ulcer disease, and the clinical distinction of herpetic versus nonherpetic lesions was not helpful. CONCLUSIONS: Current STI management guidelines should be reevaluated in south India. Consideration should be given to treating all persons with GUD for both HSV-2 and syphilis, and to adding initial treatment for TV for men with UD in areas of high background prevalence of HSV-2 and TV, respectively. This population is at high risk for HIV, and should be counseled and tested appropriately.

Risk factors for infectious spondylodiscitis in patients receiving hemodialysis.

A retrospective case-control and cohort analysis of hemodialysis patients was done to identify risk factors for spondylodiscitis. These risk factors included bacteremia, receipt of blood products, invasive procedures, and establishment of vascular access. The death rate was greater for case subjects than for control subjects (odds ratio, 2.7).

Flow cytometric quantification of bacteria in vaginal swab samples self-collected by adolescents attending a gynecology clinic.

Bacterial vaginosis (BV) is an important risk factor in reproductive health outcomes, such as pre-term birth and sexually transmitted infections including HIV. However, its etiology, diagnosis and treatment remain poorly defined. We evaluated flow cytometry as a tool to quantify total bacterial cells in vaginal specimens self-collected longitudinally by adolescents. BV was diagnosed by Gram-stain (criteria of Hay and Ison). Average flow cytometric counts of bacterial cell-units (BCU) was log(10) 8.04 per gram sample and was found to correlate with sample weight (p<0.0001). BV was frequently observed in this group, with 22 of 32 participants (69%) diagnosed with BV for at least one timepoint. Surprisingly, increased BCU was associated with normal Hay-Ison score (p=0.0003), even when adjusting for sample weight (p=0.02). Since presence and quantity of Lactobacillus defines normal vaginal microbiology (ie. absence of BV), this result indicates a possible bias towards dominance of Lactobacillus cells in measurements of "total" BCU. Increased BCU per gram was associated in multivariate analysis with longer self-reported time since last menstruation (p=0.004) and last sexual intercourse (p=0.007). Sperm was detected in 3 samples provided by those reporting sexual intercourse in the previous 24 h. Light-scattering profiles of bacteria and vaginal cells in samples collected over time from an individual were often identical and distinct from other individuals. To our knowledge, this is the first description of flow cytometry for analysis of commensal bacteria in vaginal specimens. Further development may help to illuminate the complex dynamics of vaginal microbial communities underlying BV.

Gestational diabetes in Manitoba during a twenty-year period.

PURPOSE: This retrospective cohort study was designed to examine the prevalence and risk factors of gestational diabetes mellitus (GDM) in Manitoba. METHODS: A total of 324,605 deliveries by 165,969 women were reported to Manitoba Health in the years 1985-2004. Data on maternal ages, delivery dates, GDM, self-declared First Nation (FN) status, rural or urban residence and previous GDM were collected for the study. Data were analyzed using multivariate logistic regression models. RESULTS: The prevalence of GDM during the 20-year period was 2.9%, which was 2.3% in 1985-1989 and 3.7% in 1999-2004 (P < 0.01). The trend of increase in the prevalence of GDM continued after major modifications on the screening and diagnostic criteria for GDM in 1998. The prevalence of GDM in FN women was 3-times greater than that in non-FN women. Higher prevalence of GDM was detected in FN pregnant women living in rural areas compared to those in urban areas (P < 0.01), which was opposite for non-FN pregnant women living in rural and urban areas. The prevalence of GDM in pregnant women > or =35 yr was 2.3-fold higher than that in those < 35 yr (P < 0.01). The recurrent rate of GDM was 44.4%. Adjusted odds ratios of GDM for FN status, advanced age, a history of GDM and rural living were 2.2, 2.4, 25.1 and 0.8, respectively. CONCLUSIONS: The prevalence of GDM is increased in Manitoba. FN status, advanced age and a history of GDM, but not rural living, are independent predictors for GDM.

Impact of diabetes on maternal-fetal outcomes in Manitoba: Relationship with ethnic and environmental factors.

PURPOSE: To examine the impact of gestational diabetes mellitus (GDM) on maternal-fetal outcomes in Manitoba. METHODS: The rates of macrosomia, stillbirth, cesarean section (C/S) and shoulder dystocia (S/D) in 324,605 births in Manitoba during 1985-2004, and their relationships with diabetes and demographical factors were analyzed. RESULTS: The incidence of macrosomia, stillbirth, C/S and S/D were 15.3%, 0.57%, 16.0%, and 1.2%, respectively. The rates of macrosomia were elevated in mothers with GDM, type 2 DM (T2DM), rural living, First Nations (FN) status, or >or=35 years of age. Increased rates of stillbirth were associated with women with T2DM, FN status or >or=35 years, but not those with GDM. C/S and S/D were increased in women with GDM or T2DM. FN status in combination with GDM increased the risk of S/D. CONCLUSIONS: GDM, T2DM, advanced maternal age, FN status or rural living affected pregnancy outcomes in Manitoba.

Multidisciplinary treatment of diabetic foot ulcers in Canadian Aboriginal and non-Aboriginal people.

BACKGROUND: Diabetic foot ulcers are a major cause of morbidity and mortality. This study evaluated the clinical outcomes in Canadian non-Aboriginal and Aboriginal diabetic patients with foot ulcers managed at a multidisciplinary, tertiary care diabetic foot clinic. METHODS: A retrospective review of medical records was done for 325 patients receiving care during a 2-year period. All patients were followed at least 1 year after the initial visit. RESULTS: There were 224 (69%) non-Aboriginal and 101 (31%) Aboriginal patients with 697 foot ulcers. At the initial office visit, 204 (63%) patients had lesions in Wagner grades 2-4. At the most recent evaluation (average, 79+/-73 weeks after initial clinic visit), 190 (58%) patients were rated as having a good outcome (either healed or healing), but a poor outcome (static, progression, amputation, or death) was noted in 135 (42%) patients. At the most recent evaluation, the majority of the 697 ulcers that were noted at the initial or subsequent clinic visits were healed. Aboriginal patients had a shorter average time from initial clinic visit to major lower extremity amputation (Aboriginal, 50+/-64 weeks; non-Aboriginal, 62+/-56 weeks; P<0.01). Residence in a rural or reserve community also correlated with shorter average time from initial clinic visit to major lower extremity amputation (rural or reserve, 45+/-56 weeks; urban, 66+/-61 weeks; P<0.002). When controlled for non-urban residence, Aboriginal ethnicity was not associated with poorer clinical outcome. Earlier major lower extremity amputation was significantly associated with non-urban residence, Aboriginal ethnicity, and arterial insufficiency. Poor clinical outcome was significantly associated with being referred with a lesion present, age greater than 60 years, prior lower extremity amputation or revascularization, arterial insufficiency, more than one lesion on initial presentation, longer duration of type 2 diabetes, and a higher initial Wagner grade for the most advanced lesion. CONCLUSIONS: A multidisciplinary diabetic foot clinic may be successful in treating diabetic foot ulcers in Aboriginal and non-Aboriginal people. However, the frequency of poor outcome is high, consistent with the high prevalence of associated significant risk factors in this population.

Is obesity associated with an increased risk for airway hyperresponsiveness and development of asthma?

: We investigated the association between airway hyperresponsiveness (AHR) and obesity in adults referred for confirmation of asthma diagnosis. Data were analyzed for obesity class I (body mass index [BMI] 30-34.9 kg/m2), class II (BMI >/= 35-39.9 kg/m2), and class III (BMI >/= 40 kg/m2). Of 861 subjects, 401 demonstrated AHR; the mean dose of methacholine was 4.16 +/- 2.55 mg/mL. A significant association between obesity and AHR was evident for all subjects: the odds ratio was 1.37 (95% CI 1.02-1.82; p = .0317). One unit of increased BMI (1 kg/m2) was associated with a 3.1% increase in AHR risk (95% CI 1.01-1.05, p < .005). The odds ratio increased from 1.86 (95% CI 1.27-1.76; p = .0012) for class I to 2.61 (95% CI 1.48-4.60; p = .0006) for class III. Obesity was found to be associated with AHR and appears to be a risk factor for asthma.

Antimicrobial treatment in diabetic women with asymptomatic bacteriuria.

BACKGROUND: Asymptomatic bacteriuria is common among women with diabetes, and the treatment of such infections has been recommended to prevent complications related to symptomatic urinary tract infection. METHODS: We enrolled women (>16 years of age) with diabetes, bacteriuria (> or =105 colony-forming units of an organism per milliliter in cultures of two consecutive urine specimens), and no urinary symptoms; 50 were randomly assigned to receive placebo and 55 to receive antimicrobial therapy. For the first six weeks, which included the initial course of treatment, the study was placebo-controlled and double-blind. Subsequently, the women were screened for bacteriuria every three months for up to three years; antimicrobial therapy was provided to women in the antimicrobial-therapy group who had asymptomatic bacteriuria. RESULTS: Four weeks after the end of the initial course of therapy, 78 percent of placebo recipients had bacteriuria, as compared with 20 percent of women who received antimicrobial agents (P<0.001). During a mean follow-up of 27 months, 20 of 50 women in the placebo group (40 percent) and 23 of 55 women in the antimicrobial-therapy group (42 percent) had at least one episode of symptomatic urinary tract infection. The time to a first symptomatic episode was similar in the placebo group and the antimicrobial-therapy group (P=0.67 by the log-rank test), as were the (+/-SD) rates of any symptomatic urinary tract infection (1.10+/-0.17 and 0.93+/-0.14 per 1000 days of follow-up, respectively; relative risk, 1.19; 95 percent confidence interval, 0.28 to 1.81), pyelonephritis (0.28+/-0.08 and 0.13+/-0.05 per 1000 days of follow-up; relative risk, 2.13; 95 percent confidence interval, 0.81 to 5.62), and hospitalization for urinary tract infection (0.10+/-0.36 and 0.06+/-0.22 per 1000 days of follow-up; relative risk, 1.93; 95 percent confidence interval, 0.47 to 7.89). The women in the antimicrobial-therapy group had almost five times as many days of antibiotic use for urinary tract infection as did the women in the placebo group (158.2+/-1.7 vs. 33.7+/-0.91 per 1000 days of follow-up; relative risk, 0.21; 95 percent confidence interval, 0.20 to 0.22). CONCLUSIONS: Treatment of asymptomatic bacteriuria in women with diabetes does not appear to reduce complications. Diabetes itself should not be an indication for screening for or treatment of asymptomatic bacteriuria.

Use of diagnostic tests for presumed lower respiratory tract infection in long-term care facilities.

OBJECTIVES: To describe the current use of diagnostic tests for management of presumed lower respiratory tract infection in selected long-term care facilities (LTCFs) in Canada and to correlate test use with facility and resident characteristics. DESIGN: Prospective, 12-month multicenter cohort study. SETTING: A convenience sample of 21 LTCFs in Canada. PARTICIPANTS: LTCF residents prescribed antimicrobial therapy for presumed lower respiratory tract infection. MEASUREMENTS: Data collection included facility characteristics, patient demographics, level of care, comorbidities, clinical presentations, diagnostic testing, and outcomes. Diagnostic test use was correlated with facility access and resident and episode characteristics. RESULTS: Forty-two percent of 1,702 episodes had chest radiography obtained, 28.5% had pulse oximetry, 23.8% had peripheral leukocyte count, and 3.3% had sputum culture. On-site access correlated with obtaining chest radiography (odds ratio (OR)=4.4; 95% confidence interval (CI)=3.2-6.0) and oximetry (OR=30.3; 95% CI=16.4-55.8). Analyses stratified according to facility found that greater test use was associated with greater premorbid functional impairment and more-severe presentations. Advance directives, time to stabilization, and mortality did not correlate with test use. In multivariate analysis, significant variability between facilities for chest radiography and oximetry remained after incorporating differences in access to diagnostic testing and other facility or resident variables. CONCLUSION: The use of diagnostic tests in the management of presumed lower respiratory tract infection in these Canadian LTCFs is highly variable. Access to diagnostic tests and severity of presentations correlate with test use but do not fully explain the variability in use in institutions.

Diarrheal disease among HIV-infected adults in Karnataka, India: evaluation of risk factors and etiology.

The objectives of this study were to evaluate characteristics associated with diarrhea, the effect of trimethoprim-sulfamethoxazole (TMP/SMX) prophylaxis on diarrhea, the response to treatment with ciprofloxacin and tinidazole (Cipro-TZ), and presence of enteric pathogens. Adults infected with human immunodeficiency virus with and without diarrhea served as cases and controls, respectively. Participants provided a medical history and underwent a physical examination. Blood was collected for CD4 cell counts and stool for culture. Cases were treated with Cipro-TZ. Factors associated with a risk of diarrhea included crowded living and no toilet (all P < 0.05). Protective variables (P < 0.05) included a CD4 count greater than 200 cells/mm(3) and TMP/SMX prophylaxis. Cases were more likely to have a pathogen identified (P = 0.05). Eighty-six percent of the cases responded to treatment. Important risk factors for diarrhea were identified. Protection by TMP/SMX reinforces the importance of prophylaxis. These data suggest that treatment with an antibiotic and anti-parasitic medication may be effective.

Cyclin D expression in chronic lymphocytic leukemia.

Although the majority of circulating leukemic cells in chronic lymphocytic leukemia (CLL) are in G0/early G1, recent studies have shown that these cells have undergone multiple cell divisions. In this study, we have determined whether there are abnormalities in cell cycle control in CLL by examining the three cyclin D isoforms in 43 patients and correlating the findings with clinical features. Cyclin D mRNA was measured by a sensitive RNase protection assay and the order of expression in CLL cells was D3 > D2 > D1. The mean cyclin D1 and D3 mRNA levels were 4 to 6-fold higher in CLL cells than in normal peripheral blood B cells. In contrast, the levels of cyclin D2 mRNA were similar in CLL and normal B cells. Expression of the cyclin D isoforms was two- to four-fold greater in normal T cells than B cells, and the order of expression for both cell types was D2 > D3 > D1. The relative overexpressions of cyclins D1 and D3 in CLL were unrelated to gene amplification, as assessed by Southern blotting, but structural changes in the genes were seen in four patients. Both cyclin D1 and D3 mRNA levels correlated positively with lymphocyte doubling time (LDT) and inversely with Rai stage and duration of disease. In addition, a significant correlation was observed between cyclin D mRNA levels and survival, with patients having high levels of cyclin D1, and to a lesser extent cyclin D3, mRNA having the best survival. Thus, cyclin D1 and D3 are relatively overexpressed in CLL cells and patients with higher levels have low stage disease, long LDT and prolonged survival. Further studies should evaluate the predictive value of cyclin D measurements in comparison to other prognostic markers in CLL.

Evaluation of education in palliative care: determining the effects on nurses' knowledge and attitudes.

Our study was an evaluation of a pilot course in palliative nursing care designed to improve practising nurses' knowledge regarding cancer pain management and attitudes toward care of the dying patient. The course involved 12 weeks (36 hours) of systematic classroom instruction for registered nurses, and a one-day observational experience on a designated palliative care unit. A total of 16 nurses participated in the study. A repeated measures design was used to evaluate the effectiveness of the course. Attitudes toward care of the dying patient and his/her family were also evaluated. Results showed that nurses' attitudes improved significantly from Time 1 (first day of course) to Time 2 (last day of course) (p=0.0007), and that this improvement was maintained at Time 3 (three months later) (p=0.064). The observational experience on a palliative care unit held in conjunction with the course was reported to be helpful to students in consolidating theoretical instruction.

Phenotypic diversity within a Pseudomonas aeruginosa population infecting an adult with cystic fibrosis.

Chronic airway infections caused by Pseudomonas aeruginosa contribute to the progression of pulmonary disease in individuals with cystic fibrosis (CF). In the setting of CF, within-patient adaptation of a P. aeruginosa strain generates phenotypic diversity that can complicate microbiological analysis of patient samples. We investigated within- and between- sample diversity of 34 phenotypes among 235 P. aeruginosa isolates cultured from sputum samples collected from a single CF patient over the span of one year, and assessed colony morphology as a screening tool for predicting phenotypes, including antimicrobial susceptibilities. We identified 15 distinct colony morphotypes that varied significantly in abundance both within and between sputum samples. Substantial within sample phenotypic heterogeneity was also noted in other phenotypes, with morphotypes being unreliable predictors of antimicrobial susceptibility and other phenotypes. Emergence of isolates with reduced susceptibility to ß-lactams was observed during periods of clinical therapy with aztreonam. Our findings confirm that the P. aeruginosa population in chronic CF lung infections is highly dynamic, and that intra-sample phenotypic diversity is underestimated if only one or few colonies are analyzed per sample.

Effect of large volume infusion on left ventricular volumes, performance and contractility parameters in normal volunteers.

OBJECTIVE: Characterize the normal human cardiovascular response to large volume infusion of normal saline. DESIGN: Prospective, interventional trial. SETTING: ICU procedure room. PARTICIPANTS: Healthy male volunteers ( n=32). INTERVENTIONS. Volumetric echocardiography during 4-L saline infusion (3 L over 3 h followed by 1 L over 2 h). MEASUREMENTS AND RESULTS: Following 3-L saline infusion, stroke volume and cardiac output increased approximately 10% without a significant change in heart rate or blood pressure. A decrease in end-systolic volume contributed to the increase in stroke volume to an extent similar to that provided by the increase in end-diastolic volume. All contractility indices except end-systolic wall stress/end-systolic volume index were increased at 3 h post-initiation of saline infusion. Stroke volume but not cardiac output remained elevated at 5 h with persistence of ventricular volume responses; only ejection fraction was significantly elevated among the contractility indices. Afterload measures including total peripheral resistance and end-systolic wall stress were significantly decreased after 3-L infusion but were unchanged compared to baseline following infusion of an additional 1 L over 2 h. Modeled blood viscosity studies demonstrate that changes in apparent contractility after 3-L saline infusion can be explained solely by viscosity reduction associated with hypervolemic hemodilution. CONCLUSION: The initial increase in stroke volume associated with high volume saline infusion in normal volunteers is associated with increases of most load-dependent and ostensibly load-independent parameters of left ventricular contractility. This phenomenon is unlikely to represent a true increase in contractility and appears to be caused by reduced afterload as a consequence of decreased blood viscosity. This decrease in blood viscosity may complicate analysis of some previous in vivo studies examining the effect of volume loading on cardiac function using low-viscosity solutions.

Type 2 diabetes mellitus in children: prenatal and early infancy risk factors among native canadians.

BACKGROUND: Type 2 diabetes mellitus is increasingly being observed among children and youth, including the Native population of Canada. Only one study has investigated prenatal and early infancy risk factors for the disease. METHODS: A case-control study was conducted; 46 patients younger than 18 years were recruited from the only clinical center for the treatment of diabetes serving the province of Manitoba, and 92 age- and sex-matched controls were recruited from a pediatric ambulatory clinic serving a large Native population in Winnipeg, Manitoba. Information on exposure to prenatal and early infancy risk factors was obtained through questionnaires administered by a Native nurse-interviewer. RESULTS: Multiple logistic regression modeling identified preexisting diabetes (odds ratio [OR], 14.4; 95% confidence interval [CI], 2.86-72.5), gestational diabetes (OR, 4.40; 95% CI, 1.38-14.1), and breastfeeding longer than 12 months (OR, 0.24; 95% CI, 0.13-0.99) as significant independent predictors of diabetic status. Other factors, such as low (<2500 g) and high (>4000 g) birth weight and maternal obesity, were also associated with diabetes in our population, but the elevated risks were not statistically significant. CONCLUSION: Breastfeeding reduces the risk of type 2 diabetes among Native Canadian children and should be promoted as a potential intervention to control the disease.