Molecular Genetics of Lactase Deficiencies

Congenital lactase deficiency (CLD) (MIM 223000) is a rare autosomal recessive gastrointestinal disorder characterized by watery diarrhea in infants fed with breast milk or other lactose-containing formulas. The CLD locus was previously assigned by linkage and linkage disequilibrium analyses on 2q21 in 19 Finnish families. In this study, the molecular background of this disorder is reported. The CLD locus was refined in 32 CLD patients in 24 families by using microsatellite and single nucleotide polymorphism (SNP) haplotypes. Mutation analyses were performed by direct sequencing. We identified 5 distinct mutations in the lactase (LCT) gene, encoding the enzyme that hydrolyzes lactose in the intestinal lumen. These findings facilitate genetic testing of CLD in clinical practice and enable genetic counseling. The present data also provide the basis for detailed characterization of the molecular pathogenesis of this disorder. Adult-type hypolactasia (MIM 223100) (lactase non-persistence, lactose intolerance) is an autosomal recessive gastrointestinal condition that is a result of a decline in the activity of lactase in the intestinal lumen after weaning. Adult-type hypolactasia is considered to be a normal phenomenon among mammals and symptoms are remarkably milder than experienced in CLD. Recently, a variant C/T-13910 was shown to associate with the adult-type hypolactasia trait, locating 13.9 kb upstream of the LCT gene. In this study, the functional significance of the C/T-13910 variant was determined by studying the LCT mRNA levels in intestinal biopsy samples in children and adults with different genotypes. RT-PCR followed by solid-phase minisequencing was applied to determine the relative expression levels of the LCT alleles using an informative SNP located in exon 1. In children, the C-13910 allele was observed to be downregulated after five years of age in parallel with lactase enzyme activity. The expression of the LCT mRNA in the intestinal mucosa in individuals with the T-13910 A-22018 alleles was 11.5 times higher than that found in individuals with the C-13910, G-22018 alleles. These findings suggest that the C/T-13910 associated with adult-type hypolactasia is associated with the transcriptional regulation of the LCT gene. The presence of the T-13910 A-22018 allele also showed significant elevation lactase activity. Galactose, the hydrolysing product of the milk sugar lactose, has been hypothesized to be poisonous to ovarian epithelial cells. Hence, consumption of dairy products and lactase persistence has been proposed to be a risk factor for ovarian carcinoma. To investigate whether lactase persistence is related to the risk of ovarian carcinoma the C/T-13910 genotype was determined in a cohort of 782 women with ovarian carcinoma 1331 individuals serving as controls. Lactase persistence did not associate significantly with the risk for ovarian carcinoma in the Finnish, in the Polish or in the Swedish populations. The findings do not support the hypothesis that lactase persistence increases the risk for ovarian carcinoma.

Frailty: A key indicator to minimize inappropriate medication in older people

Older populations are more likely to have multiple co-morbid diseases that require multiple treatments, which make them a large consumer of medications. As a person grows older, their ability to tolerate medications becomes less due to age-related changes in pharmacokinetics and pharmacodynamics often heading along a path that leads to frailty. Frail older persons often have multiple co-morbidities with signs of impairment in activities of daily living. Prescribing drugs for these vulnerable individuals is difficult and is a potentially unsafe activity. Inappropriate prescribing in older population can be detected using explicit (criterion-based) or implicit (judgment-based) criteria. Unfortunately, most current therapeutic guidelines are applicable only to healthy older adults and cannot be generalized to frail patients. These discrepancies should be addressed either by developing new criteria or by refining the existing tools for frail older people. The first and foremost step is to identify the frail patient in clinical practice by applying clinically validated tools. Once the frail patient has been identified, there is a need for specific measures or criteria to assess appropriateness of therapy that consider such factors as quality of life, functional status and remaining life expectancy and thus modified goals of care.

Construction timbers in Queensland. Book 1 and Book 2: Properties and specifications for satisfactory performance of construction timbers in Queensland. Class 1 and Class 10 buildings (houses, carports, garages, greenhouses and sheds). 2013 edition.

This publication lists the more important wood properties of commercial timbers used for construction in Queensland. It also provides requirements and conditions of use for these timbers to provide appropriate design service life in various construction applications. The correct specification of timber considers a range of timber properties including, but not limited to, stress grade; durability class; moisture content and insect resistance. For the specification of timber sizes and spans, relevant Australian Standards and design manuals should be consulted—e.g. Australian Standard AS 1684 series Residential timber—framed construction parts 2 and 3 (Standards Australia 2006a;b.) Book 1 explains the terms used; with reference to nomenclature; origin and timber properties presented under specific column headings in the schedules (Book 2). It also explains target design life; applications and decay hazard zones; presented in the Book 2 Schedules. Book 2 consists of reference tables; presented as schedules A; B and C: • Schedule A contains commercial mixtures of unidentified timbers and of some Australian and imported softwoods. Index numbers 1–10 • Schedule B contains Australian-grown timber species; including both natural forests and plantations. Index numbers 11–493 • Schedule C contains timbers imported into Australia from overseas. Index numbers 494–606 Each schedule has two parts presenting data in tables. • Part 1: Nomenclature, origin and properties of imported timber species • Part 2: Approved uses for commercial mixtures of imported timber species The recommendations made in this publication assume that good building practice will be carried out.

Contact lens citation metrics: The Spanish connection

To eye care practitioners, citation metrics may seem to be a somewhat esoteric and irrelevant concept, far removed from the realities or real world, day-to-day clinical practice. However, quantitative analysis of the published literature is becoming increasingly important, and a beautiful example of this is presented in this issue of the Journal of Optometry. My former PhD student, Genís Cardona, has teamed up with Joan Sanz to undertake a thorough and telling analysis of current worldwide publishing trends in the contact lens field. When held in the mirror, this work reflects the growing contributions from Spanish researchers to the field...

Oral medication delivery in impaired swallowing: Thickening liquid medications for safe swallowing alters dissolution characteristics

Acetaminophen (paracetamol) is available in a wide range of oral formulations designed to meet the needs of the population across the age-spectrum, but for people with impaired swallowing, i.e. dysphagia, both solid and liquid medications can be difficult to swallow without modification. The effect of a commercial polysaccharide thickener, designed to be added to fluids to promote safe swallowing by dysphagic patients, on rheology and acetaminophen dissolution was tested using crushed immediate-release tablets in water, effervescent tablets in water, elixir and suspension. The inclusion of the thickener, comprised of xanthan gum and maltodextrin, had a considerable impact on dissolution; acetaminophen release from modified medications reached 12-50% in 30 minutes, which did not reflect the pharmacopeia specification for immediate release preparations. Flow curves reflect the high zero-shear viscosity and the apparent yield stress of the thickened products. The weak gel nature, in combination with high G’ values compared to G” (viscoelasticity) and high apparent yield stress, impact drug release. The restriction on drug release from these formulations is not influenced by the theoretical state of the drug (dissolved or dispersed), and the approach typically used in clinical practice (mixing crushed tablets into pre-prepared thickened fluid) cannot be improved by altering the order of incorporation or mixing method.

Assessment of conjunctival goblet cell density using laser scanning confocal microscopy versus impression cytology

Purpose To determine the association between conjunctival goblet cell density (GCD) assessed using in vivo laser scanning confocal microscopy and conjunctival impression cytology in a healthy population. Methods Ninety (90) healthy participants undertook a validated 5-item dry eye questionnaire, non-invasive tear film break-up time measurement, ocular surface fluorescein staining and phenol red thread test. These tests where undertaken to diagnose and exclude participants with dry eye. The nasal bulbar conjunctiva was imaged using laser scanning confocal microscopy (LSCM). Conjunctival impression cytology (CIC) was performed in the same region a few minutes later. Conjunctival goblet cell density was calculated as cells/mm2. Results There was a strong positive correlation of conjunctival GCD between LSCM and CIC (ρ = 0.66). Conjunctival goblet cell density was 475 ± 41 cells/mm2 and 466 ± 51 cells/mm2 measured by LSCM and CIC, respectively. Conclusions The strong association between in vivo and in vitro cellular analysis for measuring conjunctival GCD suggests that the more invasive CIC can be replaced by the less invasive LSCM in research and clinical practice.

Factors influencing hospital readmission and length of stay of Vietnamese patients with type 2 diabetes and cardiac disease

Background: Increased hospital readmission and longer stays in the hospital for patients with type 2 diabetes and cardiac disease can result in higher healthcare costs and heavier individual burden. Thus, knowledge of the characteristics and predictive factors for Vietnamese patients with type 2 diabetes and cardiac disease, at high risk of hospital readmission and longer stays in the hospital, could provide a better understanding on how to develop an effective care plan aimed at improving patient outcomes. However, information about factors influencing hospital readmission and length of stay of patients with type 2 diabetes and cardiac disease in Vietnam is limited. Aim: This study examined factors influencing hospital readmission and length of stay of Vietnamese patients with both type 2 diabetes and cardiac disease. Methods: An exploratory prospective study design was conducted on 209 patients with type 2 diabetes and cardiac disease in Vietnam. Data were collected from patient charts and patients' responses to self-administered questionnaires. Descriptive statistics, bivariate correlation, logistic and multiple regression were used to analyse the data. Results: The hospital readmission rate was 12.0% among patients with both type 2 diabetes and cardiac disease. The average length of stay in the hospital was 9.37 days. Older age (OR= 1.11, p< .05), increased duration of type 2 diabetes (OR= 1.22, p< .05), less engagement in stretching/strengthening exercise behaviours (OR= .93, p< .001) and in communication with physician (OR= .21, p< .001) were significant predictors of 30-dayhospital readmission. Increased number of additional co-morbidities (β= .33, p< .001) was a significant predictor of longer stays in the hospital. High levels of cognitive symptom management (β= .40, p< .001) significantly predicted longer stays in the hospital, indicating that the more patients practiced cognitive symptom management, the longer the stay in hospital. Conclusions: This study provides some evidence of factors influencing hospital readmission and length of stay and argues that this information may have significant implications for clinical practice in order to improve patients' health outcomes. However, the findings of this study related to the targeted hospital only. Additionally, the investigation of environmental factors is recommended for future research as these factors are important components contributing to the research model.

Infrared thermal imaging for automated detection of diabetic foot complications

Background Although thermal imaging can be a valuable technology in the prevention and management of diabetic foot disease, it is not yet widely used in clinical practice. Technological advancement in infrared imaging increases its application range. The aim was to explore the first steps in the applicability of high-resolution infrared thermal imaging for noninvasive automated detection of signs of diabetic foot disease. Methods The plantar foot surfaces of 15 diabetes patients were imaged with an infrared camera (resolution, 1.2 mm/pixel): 5 patients had no visible signs of foot complications, 5 patients had local complications (e.g., abundant callus or neuropathic ulcer), and 5 patients had difuse complications (e.g., Charcot foot, infected ulcer, or critical ischemia). Foot temperature was calculated as mean temperature across pixels for the whole foot and for specified regions of interest (ROIs). Results No diferences in mean temperature >1.5 °C between the ipsilateral and the contralateral foot were found in patients without complications. In patients with local complications, mean temperatures of the ipsilateral and the contralateral foot were similar, but temperature at the ROI was >2 °C higher compared with the corresponding region in the contralateral foot and to the mean of the whole ipsilateral foot. In patients with difuse complications, mean temperature diferences of >3 °C between ipsilateral and contralateral foot were found. Conclusions With an algorithm based on parameters that can be captured and analyzed with a high-resolution infrared camera and a computer, it is possible to detect signs of diabetic foot disease and to discriminate between no, local, or difuse diabetic foot complications. As such, an intelligent telemedicine monitoring system for noninvasive automated detection of signs of diabetic foot disease is one step closer. Future studies are essential to confirm and extend these promising early findings.

The association of chronic kidney disease and dialysis treatment with foot ulceration and major amputation

Objective The objective of this study was to investigate the risk of chronic kidney disease (CKD) stage 4-5 and dialysis treatment on incidence of foot ulceration and major lower extremity amputation in comparison to CKD stage 3. Methods In this retrospective study, all individuals who visited our hospital between 2006 and 2012 because of CKD stages 3 to 5 or dialysis treatment were included. Medical records were reviewed for incidence of foot ulceration and major amputation. The time from CKD 3, CKD 4-5, and dialysis treatment until first foot ulceration and first major lower extremity amputation was calculated and analyzed by Kaplan-Meier curves and multivariate Cox proportional hazards model. Diabetes mellitus, peripheral arterial disease, peripheral neuropathy, and foot deformities were included for potential confounding. Results A total of 669 individuals were included: 539 in CKD 3, 540 in CKD 4-5, and 259 in dialysis treatment (individuals could progress from one group to the next). Unadjusted foot ulcer incidence rates per 1000 patients per year were 12 for CKD 3, 47 for CKD 4-5, and 104 for dialysis (P < .001). In multivariate analyses, the hazard ratio for incidence of foot ulceration was 4.0 (95% confidence interval [CI], 2.6-6.3) in CKD 4-5 and 7.6 (95% CI, 4.8-12.1) in dialysis treatment compared with CKD 3. Hazard ratios for incidence of major amputation were 9.5 (95% CI, 2.1-43.0) and 15 (95% CI, 3.3-71.0), respectively. Conclusions CKD 4-5 and dialysis treatment are independent risk factors for foot ulceration and major amputation compared with CKD 3. Maximum effort is needed in daily clinical practice to prevent foot ulcers and their devastating consequences in all individuals with CKD 4-5 or dialysis treatment.

Statistical analysis of spectral data: A methodology for designing an intelligent monitoring system for the diabetic foot

Early detection of (pre-)signs of ulceration on a diabetic foot is valuable for clinical practice. Hyperspectral imaging is a promising technique for detection and classification of such (pre-)signs. However, the number of the spectral bands should be limited to avoid overfitting, which is critical for pixel classification with hyperspectral image data. The goal was to design a detector/classifier based on spectral imaging (SI) with a small number of optical bandpass filters. The performance and stability of the design were also investigated. The selection of the bandpass filters boils down to a feature selection problem. A dataset was built, containing reflectance spectra of 227 skin spots from 64 patients, measured with a spectrometer. Each skin spot was annotated manually by clinicians as "healthy" or a specific (pre-)sign of ulceration. Statistical analysis on the data set showed the number of required filters is between 3 and 7, depending on additional constraints on the filter set. The stability analysis revealed that shot noise was the most critical factor affecting the classification performance. It indicated that this impact could be avoided in future SI systems with a camera sensor whose saturation level is higher than 106, or by postimage processing.

Evaluation of haemoglobin in blister fluid as an indicator of paediatric burn wound depth

The early and accurate assessment of burns is essential to inform patient treatment regimens; however, this first critical step in clinical practice remains a challenge for specialist burns clinicians worldwide. In this regard, protein biomarkers are a potential adjunct diagnostic tool to assist experienced clinical judgement. Free circulating haemoglobin has previously shown some promise as an indicator of burn depth in a murine animal model. Using blister fluid collected from paediatric burn patients, haemoglobin abundance was measured using semi-quantitative Western blot and immunoassays. Although a trend was observed in which haemoglobin abundance increased with burn wound severity, several patient samples deviated significantly from this trend. Further, it was found that haemoglobin concentration decreased significantly when whole cells, cell debris and fibrinous matrix was removed from the blister fluid by centrifugation; although the relationship to depth was still present. Statistical analyses showed that haemoglobin abundance in the fluid was more strongly related to the time between injury and sample collection and the time taken for spontaneous re-epithelialisation. We hypothesise that prolonged exposure to the blister fluid microenvironment may result in an increased haemoglobin abundance due to erythrocyte lysis, and delayed wound healing

Heparin versus 0.9% sodium chloride intermittent flushing for the prevention of occlusion in long term central venous catheters in infants and children: A systematic review

Background Around the world, guidelines and clinical practice for the prevention of complications associated with central venous catheters (CVC) vary greatly. To prevent occlusion, most institutions recommend the use of heparin when the CVC is not in use. However, there is debate regarding the need for heparin and evidence to suggest normal saline may be as effective. The use of heparin is not without risk, may be unnecessary and is also associated with increased costs. Objectives To assess the clinical effects (benefits and harms) of heparin versus normal saline to prevent occlusion in long-term central venous catheters in infants, children and adolescents. Design A Cochrane systematic review of randomised controlled trials was undertaken. - Data sources: The Cochrane Vascular Group Specialised Register (including MEDLINE, CINAHL, EMBASE and AMED) and the Cochrane Register of Studies were searched. Hand searching of relevant journals and reference lists of retrieved articles was also undertaken. - Review Methods: Data were extracted and appraisal undertaken. We included studies that compared the efficacy of normal saline with heparin to prevent occlusion. We excluded temporary CVCs and peripherally inserted central catheters. Rate ratios per 1000 catheter days were calculated for two outcomes, occlusion of the CVC, and CVC-associated blood stream infection. Results Three trials with a total of 245 participants were included in this review. The three trials directly compared the use of normal saline and heparin. However, between studies, all used different protocols with various concentrations of heparin and frequency of flushes. The quality of the evidence ranged from low to very low. The estimated rate ratio for CVC occlusion per 1000 catheter days between the normal saline and heparin group was 0.75 (95% CI 0.10 to 5.51, two studies, 229 participants, very low quality evidence). The estimated rate ratio for CVC-associated blood stream infection was 1.48 (95% CI 0.24 to 9.37, two studies, 231 participants; low quality evidence). Conclusions It remains unclear whether heparin is necessary for CVC maintenance. More well-designed studies are required to understand this relatively simple, but clinically important question. Ultimately, if this evidence were available, the development of evidenced-based clinical practice guidelines and consistency of practice would be facilitated.

Fatigue self-management behaviors in patients with advanced cancer: A prospective longitudinal survey

Purpose: To explore the fatigue self-management behaviors and factors associated with effectiveness of these behaviors in patients with advanced cancer. Design: Prospective longitudinal interviewer-administered survey. Setting: A tertiary cancer center in Queensland Australia. Sample: One hundred fifty two outpatients with metastatic breast, lung, colorectal and prostate cancer experiencing fatigue (>3/10) were recruited. Main Research Variables: Fatigue self-management behaviors outcomes (perceived effectiveness, self-efficacy and frequency), medical/demographic characteristics (including sites of primary cancer and metastasis, comorbidity, performance status), social support, depressive, anxiety, and other symptoms were assessed. Findings: The participants reported moderate levels of fatigue at baseline (M=5.85, SD 1.44), and maintained moderate levels at 4 weeks and 8 weeks. On average, participants consistently used approximately nine behaviors at each time point. Factors significantly associated with higher levels of perceived effectiveness of fatigue self-management behaviors were higher self-efficacy (p<.001), higher education level (p=.02), and lower levels of depressive symptoms (p=.04). Conclusions: The findings of this study demonstrate that patients with cancer, even with advanced disease, still want and are able to use a number of behaviors to control their fatigue. Self-management interventions that aim to enhance self-efficacy and address any concurrent depressive symptoms have the potential to reduce fatigue severity. Implications for Nursing: Nurses are well positioned to play a key role in supporting patients in their fatigue self-management. Knowledge Translation: This study particularly focused on the perspectives of patients about fatigue self-management, highlighting a number of issues requiring further attention in clinical practice and the potential for future research.

Postmenopausal hot flushes, vascular health and hormone therapy

Vasomotor hot flushes are complained of by approximately 75% of postmenopausal women, but their frequency and severity show great individual variation. Hot flushes have been present in women attending observational studies showing cardiovascular benefit associated with hormone therapy use, whereas they have been absent or very mild in randomized hormone therapy trials showing cardiovascular harm. Therefore, if hot flushes are a factor connected with vascular health, they could perhaps be one explanation for the divergence of cardiovascular data in observational versus randomized studies. For the present study 150 healthy, recently postmenopausal women showing a large variation in hot flushes were studied in regard to cardiovascular health by way of pulse wave analysis, ambulatory blood pressure and several biochemical vascular markers. In addition, the possible impact of hot flushes on outcomes of hormone therapy was studied. This study shows that women with severe hot flushes exhibit a greater vasodilatory reactivity as assessed by pulse wave analysis than do women without vasomotor symptoms. This can be seen as a hot flush-related vascular benefit. Although severe night-time hot flushes seem to be accompanied by transient increases in blood pressure and heart rate, the diurnal blood pressure and heart rate profiles show no significant differences between women without and with mild, moderate or severe hot flushes. The levels of vascular markers, such as lipids, lipoproteins, C-reactive protein and sex hormone-binding globulin show no association with hot flush status. In the 6-month hormone therapy trial the women were classified as having either tolerable or intolerable hot flushes. These groups were treated in a randomized order with transdermal estradiol gel, oral estradiol alone or in combination with medroxyprogesterone acetate, or with placebo. In women with only tolerable hot flushes, oral estradiol leads to a reduced vasodilatory response and increases in 24-hour and daytime blood pressures as compared to women with intolerable hot flushes receiving the same therapy. No such effects were observed with the other treatment regimes or in women with intolerable hot flushes. The responses of vascular biomarkers to hormone therapy are unaffected by hot flush status. In conclusion, hot flush status contributes to cardiovascular health before and during hormone therapy. Severe hot flushes are associated with an increased vasodilatory, and thus, a beneficial vascular status. Oral estradiol leads to vasoconstrictive changes and increases in blood pressure, and thus to possible vascular harm, but only in women whose hot flushes are so mild that they would probably not lead to the initiation of hormone therapy in clinical practice. Healthy, recently postmenopausal women with moderate to severe hot flushes should be given the opportunity to use hormone therapy alleviate hot flushes, and if estrogen is prescribed for indications other than for the control of hot flushes, transdermal route of administration should be favored.

The research capacity and culture of Australian podiatrists

Background Best practice clinical health care is widely recognised to be founded on evidence based practice. Enhancing evidence based practice via the rapid translation of new evidence into every day clinical practice is fundamental to the success of health care and in turn health care professions. There is little known about the collective research capacity and culture of the podiatry profession across Australia. Thus, the aim of this study was to investigate the research capacity and culture of the podiatry profession within Australia and determine if there were any differences between podiatrists working in different health sectors and workplaces. Method All registered podiatrists were eligible to participate in a cross-sectional online survey. The Australian Podiatry Associations disseminated the survey and all podiatrists were encouraged to distribute it to colleagues. The Research Capacity and Culture (RCC) tool was used to collect all research capacity and culture item variables using a 10-point scale (1 = lowest; 10 = highest). Additional demographic, workplace and health sector data variables were also collected. Mann–Whitney-U, Kruskal–Wallis and logistic regression analyses were used to determine any difference between health sectors and workplaces. Word cloud analysis was used for qualitative responses of individual motivators and barriers to research culture. Results There were 232 fully completed surveys (6% of Australian registered podiatrists). Overall respondents reported low success or skills (Median rating < 4) on the majority of individual success or skill items. Podiatrists working in multi-practitioner workplaces reported higher individual success or skills in the majority of items compared with sole practitioners (p < 0.05). Non-clinical and public health sector podiatrists reported significantly higher post-graduate study enrolment or completion, research activity participation, provisions to undertake research and individual success or skill than those working privately. Conclusions This study suggests that podiatrists in Australia report similar low levels of research success or skill to those reported in other allied health professions. The workplace setting and health sector seem to play key roles in self reported research success and skills. This is important knowledge for podiatrists and researchers aiming to translate research evidence into clinical practice.