High water vs. ad libitum water intake for autosomal dominant polycystic kidney disease: a randomized controlled feasibility trial.

BACKGROUND: Vasopressin stimulates cyst growth in autosomal dominant polycystic kidney disease (ADPKD) and is a key therapeutic target. Evaluation of high water intake as an alternative to pharmacological vasopressin blockade is supported by patients. However feasibility, safety and adherence-promoting strategies required to deliver this remain unknown. AIMS: Assess the feasibility of a definitive randomized high water intake trial in ADPKD. METHODS: In this prospective open-label randomized trial, adult ADPKD patients with eGFR ≥ 20 ml/min/1.73 m2 were randomized to prescribed high water (HW) intake targeting urine osmolality (UOsm) ≤270 mOsm/kg, or ad libitum (AW) intake (UOsm >300 mOsm/kg). Self-management strategies including home-monitoring of urine-specific gravity (USG) were employed to promote adherence. RESULTS: We enrolled 42 participants, baseline median eGFR (HW 68.4 [interquartile range (IQR) 35.9-107.2] vs. AW 75.8 [IQR 59.0-111.0 ml/min/1.73 m2, P = 0.22) and UOsm (HW 353 [IQR 190-438] vs. AW 350 [IQR 240-452] mOsm/kg, P = 0.71) were similar between groups. After 8 weeks, 67% in the HW vs. 24% in AW group achieved UOsm ≤270 mOsm/kg, P = 0.001. HW group achieved lower UOsm (194 [IQR 190-438] vs. 379 [IQR 235-503] mOsm/kg, P = 0.01) and higher urine volumes (3155 [IQR 2270-4295] vs. 1920 [IQR 1670-2960] ml/day, P = 0.02). Two cases of hyponatraemia occurred in HW group. No acute GFR effects were detected. In total 79% (519/672) of USG were submitted and 90% (468/519) were within target. Overall, 17% withdrew during the study. CONCLUSION: DRINK demonstrated successful recruitment and adherence leading to separation between treatment arms in primary outcomes. These findings suggest a definitive trial assessing the impact of high water on kidney disease progression in ADPKD is feasible.

Establishing the feasibility of a community and primary health care intervention to raise awareness of symptoms of Type 1 Diabetes-The Early Detection of Type 1 Diabetes in Youth (EDDY) study.

AIMS: To design, develop, and evaluate the feasibility of delivering a multi-component community based intervention to parents and primary health care professionals to raise awareness of the symptoms of Type 1 diabetes (T1D) in childhood in 3 adjoining borough counties of South Wales. MATERIALS AND METHODS: Parent and primary health care advisory groups were established to design the intervention. Qualitative interviews with stakeholders and parents assessed the acceptability, feasibility and any potential impact of the intervention. RESULTS: The parent component of the intervention developed was a re-useable shopping bag with the 4 main symptoms of T1D illustrated on the side, based on the road traffic system of red warning triangles and an octagon "stop" sign stating "Seek Medical Help". Accompanying the bag was an A5 leaflet giving further information. Both were overwrapped with clear plastic and delivered to 98% (323/329) schools, equating to 101 371 children. The primary health care professional component was a dual glucose/ketone meter, single use lancets, stickers, the A5 parent leaflet displayed as a poster and an educational visit from a Community Diabetes Liaison Nurse. 87% (73/84) of GP practices received the intervention, 100% received the materials. The intervention was delivered within Cardiff, the Vale of Glamorgan and Bridgend. Qualitative analyses suggest that the intervention raised awareness and had some impact. CONCLUSION: This study showed that it is feasible and acceptable to design, develop and deliver a community based intervention to raise awareness of T1D. There is some suggestion of impact but a definitive evaluation of effectiveness is still required.

Ask Me! self-reported features of adolescents experiencing neglect or emotional maltreatment: a rapid systematic review.

BACKGROUND: Neglect is often overlooked in adolescence, due in part to assumptions about autonomy and misinterpretation of behaviors being part of normal adolescent development. Emotional maltreatment (abuse or neglect) has a damaging effect throughout the lifespan, but is rarely recognized amongst adolescents. Our review aims to identify features that adolescents experiencing neglect and/ or emotional maltreatment report. METHOD: A rapid review methodology searched 8 databases (1990-2014), supplemented by hand searching journals, and references, identifying 2,568 abstracts. Two independent reviews were undertaken of 279 articles, by trained reviewers, using standardised critical appraisal. Eligible studies: primary studies of children aged 13-17 years, with substantiated neglect and/ or emotional maltreatment, containing self-reported features. RESULTS: 19 publications from 13 studies were included, demonstrating associations between both neglect and emotional maltreatment with internalising features (9 studies) including depression, post traumatic symptomatology and anxiety; emotional maltreatment was associated with suicidal ideation, while neglect was not (1 study); neglect was associated with alcohol related problems (3 studies), substance misuse (2 studies), delinquency for boys (1 study), teenage pregnancy (1 study), and general victimization for girls (1 study), while emotionally maltreated girls reported more externalising symptoms (1 study). Dating violence victimization was associated with neglect and emotional maltreatment (2 studies), while emotional abuse of boys, but not neglect, was associated with dating violence perpetration (1 study), and neither neglect nor emotional maltreatment had an association with low self-esteem (2 studies). Neither neglect nor emotional maltreatment had an effect on school performance (1 study), but neglected boys showed greater school engagement than neglected girls (1 study). CONCLUSIONS: If asked, neglected or emotionally maltreated adolescents describe significant difficulties with their mental health, social relationships, and alcohol or substance misuse. Practitioners working with youths who exhibit these features should recognize the detrimental impact of maltreatment at this developmental stage, and identify whether maltreatment is a contributory factor that should be addressed.

A systematic review of the emotional, behavioural and cognitive features exhibited by school-aged children experiencing neglect or emotional abuse.

BACKGROUND: Interventions to minimize the long-term consequences of neglect or emotional abuse rely on prompt identification of these children. This systematic review of world literature (1947-2012) identifies features that children aged 5-14 years experiencing neglect or emotional abuse, as opposed to physical or sexual abuse, may exhibit. METHODS: Searching 18 databases, utilizing over 100 keywords, supplemented by hand searching, 13,210 articles were identified and 111 underwent full critical appraisal by two independent trained reviewers. RESULTS: The 30 included studies highlighted behavioural features (15 studies), externalizing features being the most prominent (8/9 studies) and internalizing features noted in 4/6 studies. Four studies identified attention deficit hyperactivity disorder (ADHD) associated features: impulsivity, inattention or hyperactivity. Child difficulties in initiating or developing friendships were noted in seven studies. Of 13 studies addressing emotional well-being, three highlighted low self-esteem, with a perception of external control (1), or depression (6) including suicidality (1). A negative internal working model of the mother increased the likelihood of depression (1). In assessing cognition or academic performance, lower general intelligence (3/4) and reduced literacy and numeracy (2) were reported, but no observable effect on memory (3). CONCLUSIONS: School-aged children presenting with poor academic performance, ADHD symptomatology or abnormal behaviours warrant assessment of neglect or emotional abuse as a potential underlying cause.

How women receiving adjuvant chemotherapy for breast cancer cope with their treatment: a risk management perspective.

Retrospective interviews were undertaken with 12 women who had received an 18-week course of adjuvant chemotherapy for positive node breast cancer 1 year previously, and who had not experienced cancer recurrence. The nonstandardized interviews covered women's preconceptions about adjuvant chemotherapy, their information needs, and the impact of treatment. The qualitative data analysis drew upon the theoretical ideas of patient career, trajectory projection and qualitative risk analysis. Some women regarded adjuvant chemotherapy as no more than an 'insurance policy'. This perception may have arisen because doctors, attempting to minimize patient anxiety, did not discuss the high risk of disease recurrence which they faced. Other women equated adjuvant with curative chemotherapy, and anticipated hair loss or almost certain death. The women tried to cope with the physical and mental suffering associated with adjuvant chemotherapy through normalizing strategies, such as keeping a brave face, maintaining previous patterns of life, looking for humour and restructuring time. However, the rapid alterations in physical and mental state resulting from cycles of adjuvant chemotherapy resulted in a 'rollercoaster' experience for women which made normalization more difficult. Health professionals caring for women who must cope with uncertain future trajectories need to manage a risk communication dilemma. A strategy of fully informing women about the risks they face may cause anxiety or depression, and even impede recovery, given the evidence for psychological influences on health outcomes. But, if women do not understand the medical thinking on which their treatment is based, their misconceptions may be equally damaging.

Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse.

Iron is essential for many cellular functions; consequently, disturbances of iron homeostasis, leading to either iron deficiency or iron overload, can have significant clinical consequences. Despite the clinical prevalence of these disorders, the mechanism by which dietary iron is absorbed into the body is poorly understood. We have identified a key component in intestinal iron transport by study of the sex-linked anaemia (sla) mouse, which has a block in intestinal iron transport. Mice carrying the sla mutation develop moderate to severe microcytic hypochromic anaemia. Although these mice take up iron from the intestinal lumen into mature epithelial cells normally, the subsequent exit of iron into the circulation is diminished. As a result, iron accumulates in enterocytes and is lost during turnover of the intestinal epithelium. Biochemical studies have failed to identify the underlying difference between sla and normal mice, therefore, we used a genetic approach to identify the gene mutant in sla mice. We describe here a novel gene, Heph, encoding a transmembrane-bound ceruloplasmin homologue that is mutant in the sla mouse and highly expressed in intestine. We suggest that the hephaestin protein is a multicopper ferroxidase necessary for iron egress from intestinal enterocytes into the circulation and that it is an important link between copper and iron metabolism in mammals.

Evidence for altered hepatic matrix degradation in genetic haemochromatosis.

BACKGROUND: Altered matrix degradation contributes to fibrosis in some liver diseases but the role of matrix degradation in fibrogenesis associated with genetic haemochromatosis has not previously been addressed. AIMS: To measure serum concentrations of tissue inhibitor of metalloproteinase 1 (TIMP-1) and matrix metalloproteinases (MMP), MMP-1, MMP-2, and MMP-3 in patients with haemochromatosis and control subjects. PATIENTS: Forty patients with haemochromatosis and 19 healthy control subjects. Ten of the 40 patients were studied before and after venesection therapy. METHODS: Serum levels of TIMP-1, MMP-1, MMP-2, and MMP-3 were measured by enzyme immunoassay and correlated to hepatic iron concentration and degree of histological fibrosis. RESULTS: Serum TIMP-1 was increased in patients with haemochromatosis compared with controls (163 (30) versus 123 (28) ng/ml, p < 0.0002). Mean serum TIMP-1 concentration of patients with haemochromatosis without fibrosis was significantly higher than in controls (153 (16) versus 123 (28) ng/ml, p = 0.03). Serum TIMP-1 concentration correlated with both hepatic iron concentration and hepatic iron index (r = 0.42, p < 0.01; r = 0.42, p < 0.01). Serum MMP-2 concentrations correlated with increasing degree of fibrosis in patients with haemochromatosis (r = 0.38, p = 0.01). The mean MMP-1: TIMP-1, MMP-2:TIMP-1 and age/sex matched MMP-3:TIMP-1 ratios were significantly lower in patients with haemochromatosis than controls (0.11 (0.06) versus 0.2 (0.14), p = 0.02; 3.32 (0.9) versus 3.91 (0.81), p = 0.05; and 0.26 (0.12) versus 0.47 (0.27), p = 0.007, respectively). Following venesection, MMP-2 and MMP-3 concentrations increased by 11% (p = 0.03) and 19% (p = 0.03), respectively. CONCLUSIONS: This study provides the first evidence of an alteration in matrix degradation in haemochromatosis that may be a contributing factor to hepatic fibrogenesis in this disease.

Mapping the gene for sex-linked anemia: an inherited defect of intestinal iron absorption in the mouse.

The sex-linked anemic (sla) mouse carries an anemia that results from an inherited defect of intestinal iron absorption and provides an ideal model with which to investigate this poorly understood yet clinically important process. We have precisely mapped the sla locus within the central region of the X chromosome in relation to a panel of microsatellite markers. Analysis of over 500 progeny from an intraspecific intercross and a smaller intraspecific backcross segregating sla established the following locus order in the sla region: DXMit45-sla- (DXMit16, DXMit96)-DXMit41-DXMit169-DXMit170- DXMit148-(DXMit18, DXMit171)-DXMit84-DXMit64. The two microsatellites DXMit16 and DXMit96 are located 0.60 +/- 0.35cM from sla and form the telomeric limit of the sla region. The mapping of the sla locus is an important first step to identifying the gene itself.

Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis.

BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) is a chronic liver disease that occasionally progresses to cirrhosis but usually has a benign course. The aim of this study was to investigate the role of the hemochromatosis mutation Cys282Tyr in development of the mild hepatic iron overload found in some patients with NASH and its association with hepatic damage in these patients. METHODS: Fifty-one patients with NASH were studied. The presence of the Cys282Tyr mutation was tested in all patients, and the data were analyzed with respect to the histological grade of steatosis, inflammation, Perls' staining, hepatic iron concentration (HIC), and serum iron indices. RESULTS: Thirty-one percent of patients with NASH were either homozygous or heterozygous for the Cys282Tyr mutation. This mutation was significantly associated with Perls' stain grade (P < 0.005), HIC (P < 0.005), and transferrin saturation percentage (P < 0.005) but not with serum ferritin levels. Linear regression analysis showed that increased hepatic iron (Perls' stain or HIC) had the greatest association with the severity of fibrosis (P < 0.0001). CONCLUSIONS: The Cys282Tyr mutation is responsible for most of the mild iron overload found in NASH and thus has a significant association with hepatic damage in these patients. Heterozygosity for the hemochromatosis gene mutation therefore cannot always be considered benign.

Care of the dying: an ethical and historical perspective.

OBJECTIVE: To provide a historical perspective, from ancient Greece to the middle of the 20th century, on ethical issues and principles commonly associated with medical care for the dying in Western civilization. SOURCES: Writings of noted philosophers, historians, ethicists, and physicians, as well as published legal and ethical guidelines. INFORMATION EXTRACTION: The sources used highlight the origins of various ethical principles associated with care of the dying. They also identify the opinions of prominent individuals throughout the history of medical ethics. SUMMARY: Devotion to medical beneficence, concern for the quality of life, and respect for the sanctity of life are all expressed in the earliest medical and philosophical writings of ancient Greece. With regard to care of the dying, these considerations led to a wide acceptance of avoiding or terminating treatment in hopeless cases. They also led to active debate regarding medicine's role in hastening the dying process. The rise of Christianity during the Middle Ages markedly suppressed such debate by strongly reinforcing the principle of sanctity of life. Later, the optimism of the enlightenment added the hope of prolonging life. Finally, modern advances in medical science have made that hope a reality of complex ethical dimensions. CONCLUSIONS: Ethical debates regarding appropriate care for the dying are as old as medicine itself. Although beneficent concerns have characterized the medical community in almost every period of history, tensions have repeatedly arisen as diverse religious and philosophical ideologies have produced varying standards to define such beneficence. In the Christian world, the sanctity of life was often extolled as the paramount standard. For the ancient Greeks and Romans, and again in many post-Renaissance philosophies, quality of life considerations assumed equal or greater importance. Modern life-prolonging technologies heighten the debate by allowing these two standards to dramatically conflict, particularly in the critical care setting.

Early expression of hereditary deep pectoral myopathy in turkeys due to forced wing exercise.

In a deep pectoral myopathy selected (DPMS) line, forced wing exercise (FWE) at 20 weeks of age resulted in the same level of expressed deep pectoral myopathy (DPM) as seen in unexercised DPMS turkey by 72 weeks of age. The FWE at 15 and 17 weeks of age in DPMS line females increased the incidence of DPM to 30 and 50% compared to 5% in unexercised controls. There is an apparent developmental age X exercise relationship in the expression of DPM. In varieties, lines, and crosses without a history of DPM, FWE does not induce the myopathy. Additional evidence confirms the modifier effect in the polygenic DPM defect. Body weight and breast width measurements in genetically susceptible turkeys were not closely or consistently associated with expression of the myopathy. The results suggest FWE of turkeys at 20 weeks of age or later as a method for detecting genetic carriers at prebreeding ages.

Activation of lysosomal acid phosphatase of eosinophil leukocytes.

Acid phosphatase (AP) within the specific granules of eosinophils is held in a latent, inactive form prior to degranulation. Eosinophils responded to membrane stimuli with activation of AP throughout the granules of the cell, prior to degranulation. Activation occurred within the time required for fixation of the cells by glutaraldehyde. Whereas resting normal eosinophils demonstrated AP activity in 7.8 +/- 1.2 per cent of the granules, cells stimulated with opsonized staphylococci demonstrated activity in 78.9 +/- 5.0 per cent of the granules, and the amount of lead phosphate reactant deposited per active granule was considerably more intense in the stimulated than in the unstimulated cells. A similar stimulation of AP activity in eosinophils occurred with exposure to the surface-active agent phorbol myristate acetate or the calcium ionophore A23187. Activation was not altered by 5 microgram. per ml. of cytochalasin B or 4 x 10(-6) M colchicine. These aspects of the response closely parallel the stimulation of oxidative metabolism of eosinophils; however, the two were separable. Eosinophils obtained from a patient with chronic granulomatous disease, although unable to activate the normal oxidative metabolic burst, demonstrated a normal activation of AP.

Double-blind study of thioridazine and haloperidol in geriatric patients with a psychosis associated with organic brain syndrome.

Forty geriatric patients from the psychiatric ward of a state hospital were enrolled in a 12 week double-blind comparative study of the concentrate forms of thioridazine and haloperidol. The objective of the study was to assess the efficacy and safety of these drugs in the treatment of psychosis associated with organic brain syndrome in the elderly. Two types of patients comprised the population, those who had been hospitalized most of their adult lives and those who had not entered the hospital until late in life. Although both drugs produced significant improvement in these patients' symptoms, the improvement with thioridazine tended to be greater than that with haloperidol in most ratings. A plateau effect was seen with haloperidol in contrast to a steady improvement seen with thioridazine. The safety of both drugs was confirmed. Geriatric patients who display both psychotic and OBS symptomatology were found to respond quite well to both drugs, regardless of their previous psychiatric history, but a somewhat more dramatic response was seen with thioridazine.

Acanthocephalan parasitism in the Western Bluebird (Sialia mexicana).

Acanthocephalan parasites of the species Plagiorhynchus (Prosthorhynchus) formosus Van Cleave, 1918, were recovered from the intestinal tracts of two male and two female wild Western Bluebirds (Sialia mexicana). Parasitism by P. formosus was considered to be a contributory cause of death of these breeding adult bluebirds. This is the first reported recovery of acanthocephalan parasites from Western Bluebirds.

Cytologic characteristics of adenoid cystic carcinoma of the cervix uteri.

Cytologic characteristics of three cases of adenoid cystic carcinoma of the cervix uteri are reviewed. The clusters of malignant cells tend to form large acini and mimic the pattern seen in histologic sections. The resemblance to cells of adenocarcinoma of the endometrium is noted. When the acinar pattern is recognized in cervical smears, adenoid cystic carcinoma of the cervix may be suspected.

Agar-screew specimen carrier for bulk processing of biopsy material for electron microscopy.

A specimen carrier for processing large numbers of biopsy materials for epoxy embedding and electron microscopy is described. Commercially available 18-mesh stainless steel or 16-mesh aluminum wire screening is used. The screening is cut into 1 x 3-inch strips. One corner is snipped off for orientation purposes. Four drops of warm 4% agar is placed on a prewarmed standard microscopic glass slide. A thin agar support film is formed on the bottom side of the horizontally held wire screen by lightly running it against the agar. Tissue blocks trimmed to 1 mm-3 are blotted on filter paper and placed in a prearranged order on the top surface of the support film. A thin top coating of agar is applied on the specimen by touching it with the tip of a pasteur pipette containing warm 4% agar. The agar-screen unit with the mounted specimens is stabilized in 4% buffered formalin and rinsed with Sorenson's phosphate buffer, pH 7.4, with 6.8% sucrose. It is then processed as a unit through routine osmium tetroxide postfixation, alcohol dehydration, and Epon 812 filtration. The tissue blocks are plucked off the agar support film with fine-tipped tweezers and embedded in individual capsules. No difficulty in thin sectioning was encountered and examination of the sections under the electron microscope showed good infiltration by the epoxy resin.