A rare cause of dilated bile duct incidentally detected on imaging.
Adenomas involving the extrahepatic bile ducts are rare benign tumours of the biliary tract. Given the asymptomatic nature of these tumours and the natural progression of biliary adenoma to carcinoma including cholangiocarcinoma, early detection is challenging. We present a case of an octogenarian woman with a remote history of gallstones who initially presented to the gastroenterology office for an incidental finding of biliary dilation, and whose subsequent imagings and biopsy suggested common bile adenoma. However, the patient was deemed a poor surgical candidate for pancreaticoduodenectomy, and unfortunately represented 5 months later with findings suggesting cholangiocarcinoma. This case provides a unique opportunity to study the natural progression of biliary adenoma to cholangiocarcinoma.


A clinicopathological study of mediastinal masses operated in a tertiary care hospital in Eastern India in 3 years with special reference to thymoma.
The mediastinum is the central portion of the thoracic cavity, limited by pleural cavities laterally, thoracic inlet superiorly, and the diaphragm inferiorly. Housing numerous organs, it is a veritable Pandora's box, within which various lesions may develop. This study was conducted to assess the epidemiologic profile, clinicoradiological features, cytological, and histopathological findings in patients presenting with mediastinal masses in a tertiary care hospital over a period of 3 years. This is a retrospective study of cases presenting with mediastinal masses attending the Cardiothoracic Surgery Department of Medical College, Kolkata between May 2011 and April 2014. Detailed history, physical, and radiological findings were noted. Fine needle aspiration cytology (FNAC) was performed when feasible. Following surgery, histopathological, and immunohistochemical (IHC) examinations of the specimens were undertaken. Of the 22 cases included in our study, ten were anterior, seven middle, and five posterior mediastinal masses. Fifteen cases were male and seven were female. Thymic pathology was detected in seven cases, lymphoma in five, extragonadal germ cell tumor (GCT) in three, schwannoma and pericardial cyst in two cases each and neurofibroma, ganglioneuroma, and retrosternal thyroid in one case each. The age group of the patients for each diagnostic category was found to be of significance. FNAC was done in 15 cases. IHC was required for classification of lymphoma cases (CD45, CD15, CD30, CD20, CD3, Tdt, CD34, and Ki-67). This study reflects the incidence of different mediastinal masses in West Bengal with their clinicopathologic correlation.


Perspectives on hepatitis B infections and the efficacy of vaccination (hepatitis B and pneumococci) in dialysis patients.
Hepatitis B is a well known problem in dialysis units. We therefore examined the historical frequency of hepatitis B carriers in our unit, our vaccination program to hepatitis B virus (HBV), the response to hepatitis B vaccine, the IgG subclass response of anti-HBs and the response and IgG subclass response to pneumococcal vaccination (another vaccine) in dialysis patients. From 1970 and onwards 23 HBV carriers were found, but no new cases of hepatitis B occurred during the study period, i.e. from 1980 and onwards. Only one of the carriers was alive by the end of 2001. In four patients liver disease (in one of them liver cirrhosis) may have been a concomitant cause of death. The antibody response to hepatitis B vaccine was significantly lower in patients than in staff. In four patients a fourth injection was cancelled due to transplantation and bad health, while such data were lacking in 8 cases. In anti-HBs positive patients and controls a significant difference in the response of healthy adults was observed in anti-HBs IgG1 (p < 0.001) vs all other IgG subclasses. Dialysis patients had low levels, or negative findings, in all cases, with IgG1 as the highest proportion found (3/11 patients). An antibody response to pneumococcal vaccination was registered in 25 out of 29 dialysis patients (in all 86%). The IgG-subclass vaccination response to pneumococci in 28 dialysis patients was mainly IgG2 and IgG1 but also occurred in IgG3 and IgG4. Prevaccination antibody levels of the controls were higher in IgG1 and IgG2 (p < 0.01) (n = 21) than in dialysis patients (n = 28). Hepatitis B is nowadays a rare, but still dangerous disease in nephrology units. Dialysis patients have a reduced response to hepatitis B vaccine and vaccination schedules should be started early as some patients otherwise may not receive a fourth injection. The adequate antibody response to pneumococcal vaccination mainly due to IgG2 and IgG1 antibodies indicates that the antigen involved is important in vaccination responses in dialysis patients.


Management of Kaposi's sarcoma in resource-limited settings in the era of HAART.
The introduction of highly active antiretroviral therapy (HAART) has changed the natural history of AIDS-associated Kaposi's sarcoma (KS). Although the use of HAART remains limited in low-resource settings, there are global initiatives to make these drugs available to several millions of HIV-infected persons. While there are multiple reports of KS regression during HAART with or without chemotherapy, there is little documentation on KS management in resource-limited settings. In this paper we review current KS treatments available worldwide and discuss the implications of the increased access to antiretrovirals for KS treatment strategies in resource-limited settings.


Altered myocellular and abdominal fat partitioning predict disturbance in insulin action in HIV protease inhibitor-related lipodystrophy.
HIV protease inhibitor-related lipodystrophy is characterized by peripheral fat loss, hyperlipidemia, and insulin resistance. Increased availability of lipid to muscle may be one of the mechanisms that induce insulin resistance. Regional fat, intramyocellular lipid (by (1)H-magnetic resonance spectroscopy), serum lipids, and insulin-stimulated glucose disposal (by hyperinsulinemic-euglycemic clamp) were quantified in 10 men who had HIV-1 infection with moderate to severe lipodystrophy and a control group of 10 nonlipodystrophic men who had HIV-1 infection and were naïve to protease inhibitors to examine the effects of lipodystrophy on glucose and lipid metabolism. Lipodystrophic subjects showed lower insulin-stimulated glucose disposal than control subjects (P = 0.001) and had increased serum triglycerides (P = 0.03), less limb fat (P = 0.02), increased visceral fat as a proportion of total abdominal fat (P = 0.003), and increased intramyocellular lipid (1.90 +/- 0.15 vs. 1.23 +/- 0.16% of water resonance peak area; P = 0.007). In both groups combined, visceral fat related strongly to intramyocellular lipid (r = 0.83, P < 0.0001) and intramyocellular lipid related negatively to insulin-stimulated glucose disposal (r = -0.71, P = 0.0005). Fasting serum cholesterol and triglycerides related positively to intramyocellular lipid and visceral fat in lipodystrophic subjects only. The data indicate that lipodystrophy is associated with increased lipid content in muscle accompanying impaired insulin action. The results do not establish causation but emphasize the interrelationships among visceral fat, myocyte lipid, and insulin action.


Induction of protective immunity against larval Onchocerca volvulus in a mouse model.
BALB/cBYJ mice were immunized against larval Onchocerca volvulus by subcutaneous injection of normal, irradiated, or freeze-thaw-killed Onchocerca sp. larvae. The mice received challenge infections of O. volvulus third-stage larva (L3) contained in diffusion chambers implanted subcutaneously. At two-weeks postinfection, the diffusion chambers were removed and larval survival was assessed. When mice were immunized a single time with 35-krad-irradiated or normal O. volvulus L3, there was a significant reduction in the survival of challenge parasites. However, there was little or no reduction in challenge worm survival when mice were immunized a single time with freeze-thaw-killed O. volvulus L3 or fourth-stage larva (L4), or irradiated O. lienalis L3. When a second dose of freeze-thaw killed O. volvulus L3 or irradiated O. lienalis L3 was administered, there was a significant reduction in parasite survival in immunized mice. Immunization with O. volvulus L4 or a combination of L3 and L4 failed to confer protection. These results demonstrate that mice can be immunized against larval O. volvulus and that diffusion chambers are an efficient method for studying protective immunity to this parasite in a mouse model.


Comparison of protein intake per eating occasion, food sources of protein and general characteristics between community-dwelling older adults with a low and high protein intake.
Adequate protein intake is required to maintain muscle health in old age, but a low protein intake is very common in older adults. There is little insight in the general and dietary profile of older adults with a low protein intake. Therefore, this study aimed to compare community-dwelling older adults with a low and a high protein intake with regard to protein intake per eating occasion, food sources of protein and general participant characteristics. Data were used from 727 Dutch community-dwelling older adults aged ≥70 years. Protein intake at meal and snack moments was measured with two non-consecutive dietary record assisted 24-h recalls. Low protein intake was defined as below the Recommended Dietary Allowance of 0.8 g protein per kg adjusted body weight per day (g/kg aBW/d). Differences in protein and food intakes between those with a low and a high protein intake were assessed with the Mann-Whitney U test and Chi-square test. Eating occasions were compared with regard to differences between the low and high protein intake group by using MANOVA. Characteristics of older adults with low protein intake were selected by using a multiple logistic backward elimination procedure. Low protein intake was present in 15% of the participants. At all eating occasions, median protein intake was lower in the low compared to the high protein intake group (breakfast, 7.8 vs. 10.8 g; lunch, 12.6 vs. 24.3 g; dinner, 21.8 vs. 31.1 g; snack moments, 6.7 vs. 9.7 g; P < 0.001), and was also consistently lower relative to energy intake. The contribution of animal protein to total protein intake was lower among the low protein intake group. Both groups obtained most protein from dairy, meat and cereals, but meat contributed less (21.5 vs. 28.2%) and cereals more (21.9 vs. 19.6%) among the low than the high protein intake group (all P < 0.01). Differences in protein intake, percentage of energy from protein and contribution of animal to total protein intake between the groups were largest at lunch compared to the other eating occasions. Out of a long list of variables, low protein intake was only associated with following a diet, being obese vs. normal-weight and drinking alcohol on none vs. some but <5 days/week (P < 0.05). At all eating occasions, Dutch community-dwelling older adults with a protein intake <0.8 g/kg aBW/d ate less protein (also relative to their energy intake) and a lower proportion of animal protein compared to those with a high protein intake. These differences were largest at lunch. Major food sources of protein - in both groups - were dairy, meat and cereals. We could only identify following a diet, being obese and not drinking alcohol as general characteristics of older adults with a low protein intake.


A rat model of radiation injury in the mandibular area.
Radiation technology focuses on delivering the radiation as precisely as possible to the tumor, nonetheless both acute and long-term damage to surrounding normal tissue may develop. Injuries to the surrounding normal tissue after radiotherapy of head and neck cancer are difficult to manage. An animal model is needed to elucidate good treatment modalities. The aim of this study was to establish a rat model where a certain radiation dose gives reproducible tissue reactions in the mandibular area corresponding to injuries obtained in humans. The left mandible of male Sprague Dawley rats was irradiated by external radiotherapy (single fraction 15 Gy, total dose 75 Gy) every second week five times. Endpoint was six weeks after last radiation treatment, and the test group was compared to non-irradiated controls. Morphological alterations of the soft tissues, bone and tooth formation, as well as alterations of salivation, vascularity and collagen content were assessed. An unpaired, non-parametric Mann-Whitney test was used to compare the statistical differences between the groups. Analysis of the soft tissues and mandible within the radiation field revealed severe unilateral alopecia and dermatitis of the skin, extensive inflammation of the submandibular gland with loss of serous secretory cells, hyperkeratinization and dense connective fiber bundles of the gingival tissue, and disturbed tooth development with necrosis of the pulp. Production of saliva and the vascularity of the soft tissues were significantly reduced. Furthermore, the collagen fibril diameter was larger and the collagen network denser compared to non-irradiated control rats. We have established an animal model of radiation injury demonstrating physiological and histological changes corresponding to human radiation injuries, which can be used for future therapeutic evaluations.


A Study on Strategic Planning and Procurement of Medicals in Uganda's Regional Referral Hospitals.
This study was an analysis of the effect of strategic planning on procurement of medicals in Uganda's regional referral hospitals (RRH's). Medicals were defined as essential medicines, medical devices and medical equipment. The Ministry of Health (MOH) has been carrying out strategic planning for the last 15 years via the Health Sector Strategic Plans. Their assumption was that strategic planning would translate to strategic procurement and consequently, availability of medicals in the RRH's. However, despite the existence of these plans, there have been many complaints about expired drugs and shortages in RRH's. For this purpose, a third variable was important because it served the role of mediation. A questionnaire was used to obtain information on perceptions of 206 respondents who were selected using simple random sampling. 8 key informant interviews were held, 2 in each RRH. 4 Focus Group Discussions were held, 1 for each RRH, and between 5 and 8 staff took part as discussants for approximately three hours. The findings suggested that strategic planning was affected by funding to approximately 34% while the relationship between funding and procurement was 35%. The direct relationship between strategic planning and procurement was 18%. However when the total causal effect was computed it turned out that strategic planning and the related variable of funding contributed 77% to procurement of medicals under the current hierarchical model where MOH is charged with development of strategic plans for the entire health sector. Since even with this contribution there were complaints, the study proposed a new model called CALF which according to a simulation, if adopted by MOH, strategic planning would contribute 87% to effectiveness in procurement of medicals.


Sodium caprate enables the blood pressure-lowering effect of Ile-Pro-Pro and Leu-Lys-Pro in spontaneously hypertensive rats by indirectly overcoming PepT1 inhibition.
The tripeptides, Ile-Pro-Pro (IPP) and Leu-Lys-Pro (LKP), inhibit angiotensin-converting enzyme (ACE) resulting in lowered blood pressure. Our hypothesis was that the medium chain fatty acid permeation enhancer, sodium caprate (C10), may prevent the decrease in permeability of the tripeptides when PepT1 is inhibited by glycyl-sarcosine (Gly-Sar), a situation that may occur in the presence of food hydrolysates. Using Caco-2 monolayers and isolated rat jejunal tissue, the apparent permeability coefficients (Papp) of [3H]-IPP and [3H]-LKP were assessed in the presence of Gly-Sar with and without C10. Gly-Sar decreased the Papp of both tripeptides across monolayers and isolated jejunal tissue, but C10 restored it. C10 likely increased the paracellular permeability of the tripeptides, as indicated by immunofluorescence changes in tight junction proteins in Caco-2 monolayers accompanied by a concentration-dependent decrease in transepithelial electrical resistance (TEER). [3H]-IPP and [3H]-LKP were orally-gavaged to normal rats with Gly-Sar, C10, or with a mixture. Plasma levels of both peptides were reduced by Gly-Sar to less than half that of the levels detected in its absence, but were restored when C10 was co-administered. In spontaneously hypertensive rats (SHRs), unlabelled IPP and LKP lowered blood pressure when delivered either by i.v. or oral routes. Oral gavage of Gly-Sar reduced the hypotensive action of peptides in SHRs, but the effect was restored in the presence of C10. In conclusion, there was a reduction in the hypotensive effects of IPP and LKP in SHRs when intestinal PepT1 was inhibited by Gly-Sar, but C10 may circumvent this by enhancing paracellular permeability.


Capturing postoperative pain responses in critically ill infants aged 0 to 9 months.
The purpose of this study was to describe physiologic and behavioral pain behaviors in postoperative critically ill infants. A secondary aim was to identify how these pain responses vary over time. This observational study was conducted in the pediatric intensive care unit at two tertiary referral hospitals. Using ethological methods of observation, video recordings of postoperative infants were viewed to depict different situations of pain and no pain and were then coded using a reliable checklist. A total of 803 recorded segments were generated from recordings of five critically ill infants aged between 0 and 9 months who had undergone major surgery. There was an 82% agreement between the two coders. Multivariate analyses showed that physiologic responses differed only when adjusted for time. Significant decreases in systolic and diastolic arterial pressure (p < .001 and p = .036, respectively) were associated with postoperative pain exacerbated by painful procedures on day 2. On day 3, however, heart rate, arterial pressure (systolic, diastolic, and mean), and central venous pressure significantly increased (p < .05) in response to postoperative pain. Indicators included vertical stretch of the mouth, hand twitching, and jerky leg movements for postoperative pain and increase in respiratory distress, frown, eyes tightly closed, angular stretch of the mouth, silent or weak cry, jerky head movements, fist, pulling knees up, and spreading feet for postoperative pain exacerbated by painful stimuli. Findings support the ability to capture different intensities of postoperative pain in critically ill infants beyond neonatal age. These pain indicators can be used for the development of a pain assessment tool for this group of infants.


Barrett's esophagus: review of diagnosis and treatment.
Barrett's esophagus (BE) is an acquired condition characterized by replacement of stratified squamous epithelium by a cancer predisposing metaplastic columnar epithelium. Endoscopy with systemic biopsy protocols plays a vital role in diagnosis. Technological advancements in dysplasia detection improves outcomes in surveillance and treatment of patients with BE and dysplasia. These advances in endoscopic technology radically changed the treatment for dysplastic BE and early cancer from being surgical to organ-sparing endoscopic therapy. A multimodal treatment approach combining endoscopic resection of visible and/or raised lesions with ablation techniques for flat BE mucosa, followed by long-term surveillance improves the outcomes of BE. Safe and effective endoscopic treatment can be either tissue acquiring as in endoscopic mucosal resection and endoscopic submucosal dissection or tissue ablative as with photodynamic therapy, radiofrequency ablation and cryotherapy. Debatable issues such as durability of response, recognition and management of sub-squamous BE and optimal management strategy in patients with low-grade dysplasia and non-dysplastic BE need to be studied further. Development of safer wide field resection techniques, which would effectively remove all BE and obviate the need for long-term surveillance, is another research goal. Shared decision making between the patient and physician is important while considering treatment for dysplasia in BE.


Optimizing in vitro culture conditions leads to a significantly shorter production time of human dermo-epidermal skin substitutes.
Autologous dermo-epidermal skin substitutes (DESS) generated in vitro represent a promising therapeutic means to treat full-thickness skin defects in clinical practice. A serious drawback with regard to acute patients is the relatively long production time of 3-4 weeks. With this experimental study we aimed to decrease the production time of DESS without compromising their quality. Two in vitro steps of DESS construction were varied: the pre-cultivation time of fibroblasts in hydrogels (1, 3, and 6 days), and the culture time of keratinocytes (3, 6, and 12 days) before transplantation of DESS on nude rats. Additionally, the impact of the air-liquid interface culture during 3 days before transplantation was investigated. 3 weeks after transplantation, the macroscopic appearance was evaluated and histological sections were produced to analyze structure and thickness of epidermis and dermis, the stratification of the epidermis, and the presence of a basal lamina. Optimal DESS formation was obtained with a fibroblast pre-cultivation time of 6 days. The minimal culture time of keratinocytes on hydrogels was also 6 days. The air-liquid interface culture did not improve graft quality. By optimizing our in vitro culture conditions, it was possible to very substantially reduce the production time for DESS from 21 to 12 days. However, pre-cultivation of fibroblasts in the dermal equivalent and proliferation of keratinocytes before transplantation remain crucial for an equilibrated maturation of the epidermis and cannot be completely skipped.


Coronavirus Disease 2019, Superinfections, and Antimicrobial Development: What Can We Expect?
Coronavirus disease 2019 (COVID-19) arose at a time of great concern about antimicrobial resistance (AMR). No studies have specifically assessed COVID-19-associated superinfections or AMR. Based on limited data from case series, it is reasonable to anticipate that an appreciable minority of patients with severe COVID-19 will develop superinfections, most commonly pneumonia due to nosocomial bacteria and Aspergillus. Microbiology and AMR patterns are likely to reflect institutional ecology. Broad-spectrum antimicrobial use is likely to be widespread among hospitalized patients, both as directed and empiric therapy. Stewardship will have a crucial role in limiting unnecessary antimicrobial use and AMR. Congressional COVID-19 relief bills are considering antimicrobial reimbursement reforms and antimicrobial subscription models, but it is unclear if these will be included in final legislation. Prospective studies on COVID-19 superinfections are needed, data from which can inform rational antimicrobial treatment and stewardship strategies, and models for market reform and sustainable drug development.


The acute effects of dietary carbohydrate reduction on postprandial responses of non-esterified fatty acids and triglycerides: a randomized trial.
Postprandial non-esterified fatty acid (NEFA) and triglyceride (TG) responses are increased in subjects with type 2 diabetes mellitus (T2DM) and may impair insulin action and increase risk of cardiovascular disease and death. Dietary carbohydrate reduction has been suggested as non-pharmacological therapy for T2DM, but the acute effects on NEFA and TG during subsequent meals remain to be investigated. Postprandial NEFA and TG responses were assessed in subjects with T2DM by comparing a carbohydrate-reduced high-protein (CRHP) diet with a conventional diabetes (CD) diet in an open-label, randomized, cross-over study. Each diet was consumed on two consecutive days, separated by a wash-out period. The iso-caloric CRHP/CD diets contained 31/54 E% from carbohydrate, 29/16 E% energy from protein and 40/30 E% from fat, respectively. Sixteen subjects with well-controlled T2DM (median HbA1c 47 mmol/mol, (37-67 mmol/mol) and BMI 30 ± 4.4 kg/m2) participated in the study. NEFA and TG were evaluated following breakfast and lunch. NEFA net area under curve (AUC) was increased by 97 ± 38 μmol/Lx270 min (p = 0.024) after breakfast but reduced by 141 ± 33 μmol/Lx180 min (p < 0.001) after lunch on the CRHP compared with CD diet. Likewise, TG net AUC was increased by 80 ± 28 μmol/Lx270 min (p = 0.012) after breakfast but reduced by 320 ± 60 μmol/Lx180 min (p < 0.001) after lunch on the CRHP compared with CD diet. In well-controlled T2DM a modest reduction of dietary carbohydrate with a corresponding increase in protein and fat acutely reduced postprandial serum NEFA suppression and increased serum TG responses after a breakfast meal but had the opposite effect after a lunch meal. The mechanism behind this second-meal phenomenon of CRHP diet on important risk factors for aggravating T2DM and cardiovascular disease awaits further investigation. The study was registered at clinicaltrials.gov ID: NCT02472951. https://clinicaltrials.gov/ct2/show/NCT02472951 . Registered June 16, 2015.


Immobilization of copper flotation waste using red mud and clinoptilolite.
The flash smelting process has been used in the copper industry for a number of years and has replaced most of the reverberatory applications, known as conventional copper smelting processes. Copper smelters produce large amounts of copper slag or copper flotation waste and the dumping of these quantities of copper slag causes economic, environmental and space problems. The aim of this study was to perform a laboratory investigation to assess the feasibility of immobilizing the heavy metals contained in copper flotation waste. For this purpose, samples of copper flotation waste were immobilized with relatively small proportions of red mud and large proportions of clinoptilolite. The results of laboratory leaching demonstrate that addition of red mud and clinoptilolite to the copper flotation waste drastically reduced the heavy metal content in the effluent and the red mud performed better than clinoptilolite. This study also compared the leaching behaviour of metals in copper flotation waste by short-time extraction tests such as the toxicity characteristic leaching procedure (TCLP), deionized water (DI) and field leach test (FLT). The results of leach tests showed that the results of the FLT and DI methods were close and generally lower than those of the TCLP methods.


[New strategy in type 2 diabetes tested in clinical trials. Glucagon-like peptide 1 (GLP-1) affects basic caused of the disease].
A novel therapy for type 2 diabetes is based on the gut hormone, glucagon-like peptide-1 (GLP-1). GLP-1 is released from the gut during a meal intake and stimulates insulin secretion. The hormone also inhibits glucagon secretion, delays gastric emptying and induces satiety. It has been shown to reduce circulating glucose both under fasting conditions and after meal intake in subjects with type 2 diabetes. A problem in developing this novel therapy is that GLP-1 is rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4), which results in a short half-life of the hormone requiring continuous infusion. Two strategies have been developed to circumvent this drawback. One strategy is the use of DPP-4 resistant GLP-1 receptor agonists (exenatide and liraglutide) and another strategy is to inhibit DPP-4 activity (LAF237). Both these strategies have been successful in clinical studies.


Alkali and alkaline earth metal salts of tetrazolone: structurally interesting and excellently thermostable.
Tetrazolone (5-oxotetrazole) was synthesized by a moderate strategy through three steps (addition, cyclization and catalytic hydrogenation) avoiding the unstable intermediate diazonium, as reported during the previous preparation. Alkali and alkaline earth metal salts with lithium (1), sodium (2), potassium (3), rubidium (4) caesium (5), magnesium (6), calcium (7), strontium (8) and barium (9) were prepared and fully characterized using elemental analysis, IR and NMR spectroscopy, DSC and TG analysis. All metal salts were characterized via single-crystal X-ray diffraction. They crystallize in common space groups with high densities ranging from 1.479 (1) to 3.060 g cm-3 (5). Furthermore, the crystal structures of 7, 8 and 9 reveal interesting porous energetic coordination polymers with strong hydrogen bond interactions. All new salts have good thermal stabilities with decomposition temperature between 215.0 °C (4) and 328.2 °C (7), significantly higher than that of the reported nitrogen-rich salt neutral tetrazolone. The sensitivities towards impact and friction were tested using standard methods, and all the tetrazolone-based compounds investigated can be classified into insensitive. The flame test of these metal salts supports their potential use as perchlorate-free pyrotechnics or eco-friendly insensitive energetic materials.


[Appraisal of the Millennium Development Goals by means of a review of the scientific literature in 2008].
The Millennium Development Goals (MDGs) are now at the midterm of their target period, as 2015 is the date scheduled by the United Nations Organisation (UN) for their attainment. The purpose of this article is to review the current situation of the MDGs worldwide and to analyse the barriers which are preventing them from being attained in each of the MDG areas, as well as to assess a number of the indicators evaluated. In order to do so, a review has been made of the scientific literature published on the MDGs in the principal health sciences and social sciences databases, as well as the most significant reports on the issue drawn up by the United Nations. The scientific studies on the 8 MDGs and their 18 Targets make it possible to undertake a critical analysis of the situation in which each of these Goals are found at the present time, identifying the determinants that are preventing the attainment of the Goals and the actions considered necessary in order to achieve progress. Although there have been improvements in some of the goals on a world level, the research carried out to date reveals barriers to the attainment of the MDGs, as well as the insufficient weight of the developing countries in the economic and political decision-making processes, together with the incoherence between the economic policies and the social and health policies. Furthermore, Sub-Saharan Africa constitutes the most disadvantaged region, which means that it will not attain the majority of the MDGs. Spain and the developed countries, in addition to contributing resources, can also contribute to the MDGs by means of the identification and eradication of the barriers preventing attainment. This involves promoting international economic relations under conditions of social justice, by supporting a greater decision-making power for developing countries and denouncing actions that increase social inequalities and the impoverishment of the population.


Clinical features of isolated noncompaction of the ventricular myocardium: long-term clinical course, hemodynamic properties, and genetic background.
A nationwide survey was conducted to clarify the clinical features of isolated noncompaction of the ventricular myocardium (INVM) in Japanese children in comparison with features previously described in patients with INVM. Isolated noncompaction of the ventricular myocardium is a rare disorder characterized by an excessively prominent trabecular meshwork. It is accompanied by depressed ventricular function, systemic embolism and ventricular arrhythmia. A questionnaire specifically designed for this study was sent to 150 hospitals in Japan where a pediatric cardiology division exists. Twenty-seven patients were diagnosed by two-dimensional echocardiography, their ages ranging from one week to 15 years at presentation, with follow-up lasting as long as 17 years. The gross anatomical appearance and the extension of noncompacted myocardium predominantly at the apex observed on two-dimensional echocardiograms were similar to observations reported previously. Dissimilarities included a greater number of asymptomatic patients at initial presentation, a longer clinical course with gradually depressed left ventricular function, no systemic embolism, and rare ventricular tachycardia in the Japanese children. Cardiac catheterization disclosed normal left ventricular end-diastolic volume and increased left ventricular end-diastolic pressure in most cases, consistent with restrictive hemodynamics. A higher incidence of Wolff-Parkinson-White syndrome was found in the children, whereas left bundle branch block was rarer than reported in adults. Familial recurrence was high (44%) and included many women. In Japanese children, INVM can be found by screening examinations at asymptomatic stage, and it might have a longer dinical course with gradually depressed left ventricular function and restrictive hemodynamics. The pattern of familial recurrence we observed implies that INVM is a distinctive clinical entity with a heterogeneous genetic background.


Public health department accreditation: setting the research agenda.
Health department accreditation is one of the most important initiatives in the field of public health today. The Public Health Accreditation Board (PHAB) is establishing a voluntary accreditation system for more than 3000 state, tribal, territorial, and local health departments using domains, standards, and measures with which to evaluate public health department performance. In addition, public health department accreditation has a focus on continuous quality improvement to enhance capacity and performance of health departments in order to advance the health of the population. In the accreditation effort, a practice-based research agenda is essential to build the scientific base and advance public health department accreditation as well as health department effectiveness. This paper provides an overview of public health accreditation and identifies the research questions raised by this accreditation initiative, including how the research agenda will contribute to better understanding of processes underlying the delivery of services by public health departments and how voluntary accreditation may help improve performance of public health departments.


Identification of phosphocaveolin-1 as a novel protein tyrosine phosphatase 1B substrate.
Protein tyrosine phosphatase 1B (PTP1B) is implicated in a number of signaling pathways including those mediated by insulin, epidermal growth factor (EGF), and the Src family kinases. The scaffolding protein caveolin-1 is also a participant in these pathways and is specifically phosphorylated on tyrosine 14, when these pathways are activated. Here, we provide evidence that PTP1B can efficiently catalyze the removal of the phosphoryl group from phosphocaveolin-1. Overexpression of PTP1B decreases tyrosine 14 phosphorylation in caveolin-1, while expression of the substrate-trapping mutant PTP1B/D181A causes the accumulation of phosphocaveolin-1 and prevents its dephosphorylation by endogenous PTPs. We further demonstrate that PTP1B physically associates with caveolin-1. Finally, we show that inhibition of PTP1B activity with a potent and specific small molecule PTP1B inhibitor blocks the PTP1B-catalyzed caveolin-1 dephosphorylation both in vitro and in vivo. Taken together, the results strongly suggest that caveolin-1 is a specific substrate for PTP1B. Identification of caveolin-1 as a PTP1B substrate represents an important new step in further understanding the signaling pathways regulated by PTP1B.


Factors affecting graft and patient survival after live donor kidney transplantation in the UK.
The outcome after living donor renal transplantation is superior to that for deceased donor transplantation, but the results are not uniformly successful. The factors responsible for the variable outcome after living donor transplantation have not been well defined. UK Transplant Registry data were analyzed to determine the outcomes of 3142 first adult kidney transplants from living donors (71% genetically related and 29% unrelated) performed between 2000 and 2007 inclusive. Kaplan-Meier survival estimates were determined, and factors that might be associated with graft and patient survival were analyzed using Cox proportional hazards regression modeling. Patient survival at 5 years was better for recipients of grafts from related than unrelated donors (97% vs. 93%, P=0.0002), but conversely graft survival was better in recipients of genetically unrelated grafts (93% vs. 89%, P=0.06). After adjustment for the factors found to influence graft and patient survival, these differences were no longer apparent. In contrast to the expectations, the degree of human leukocyte antigen-A, -B, and -DR mismatch did not influence graft survival. Increasing donor age (but not recipient age), recipient diabetes, and grafts from adult offspring were independently associated with poorer patient survival in the first 3 years after transplantation. Poorer graft survival was independently associated with donor age older than 59 years, and female recipients. Advanced donor age, but not human leukocyte antigen mismatch, is associated with poorer outcome after live donor kidney transplantation. However, the results of live donor transplantation remain superior to deceased donor kidney transplantation.


Potential refugia in Taiwan revealed by the phylogeographical study of Castanopsis carlesii Hayata (Fagaceae).
In this study, we examined spatial patterns of chloroplast DNA (cpDNA) variation in a total of 30 populations of Castanopsis carlesii Hayata (Fagaceae), a subtropical and temperate tree species, including 201 individuals sampled throughout Taiwan. By sequencing two cpDNA fragments using universal primers (the trnL intron and the trnV-trnM intergenic spacer), we found a total of 1663 bp and 21 polymorphic sites. These gave rise to a total of 28 cpDNA haplotypes. The level of differentiation among the populations studied was relatively high (GST = 0.723). Two ancestral haplotypes are widely distributed. The Central Mountain Ridge (CMR) of Taiwan represents an insurmountable barrier to the east-west gene flow of C. carlesii. Among the populations studied, three separated populations, at Lienhuachih, Fushan and Lichia, have high nucleotide diversity. Estimates of NST-GST for populations on both sides of the CMR indicate that no phylogeographical structure exists. According to the genealogical tree, number of rare haplotype and population genetic divergence, this study suggests that two potential refugia existed during the last glaciation: the first refugium was located in a region to the north of Hsuehshan Range (HR) and west of the CMR; the second refugium was located in south, especially southeastern Taiwan. In fact, the second refugium happens to be the same as that reported for Quercus glauca. A 'star-like' genealogy is characteristic when all haplotypes rapidly coalesce and is a general outcome of population expansion. The neutrality test and mismatch distribution also suggest demographic expansion recovering from a bottleneck.


Depression, Alcoholics Anonymous Involvement, and Daily Drinking Among Patients with co-occurring Conditions: A Longitudinal Parallel Growth Mixture Model.
Patients with cooccurring mental health and substance use disorders often find it difficult to sustain long-term recovery. One predictor of recovery may be how depression symptoms and Alcoholics Anonymous (AA) involvement influence alcohol consumption during and after inpatient psychiatric treatment. This study utilized a parallel growth mixture model to characterize the course of alcohol use, depression, and AA involvement in patients with cooccurring diagnoses. Participants were adults with cooccurring disorders (n = 406) receiving inpatient psychiatric care as part of a telephone monitoring clinical trial. Participants were assessed at intake, 3-, 9-, and 15-month follow-up. A 3-class solution was the most parsimonious based upon fit indices and clinical relevance of the classes. The classes identified were high AA involvement with normative depression (27%), high stable depression with uneven AA involvement (11%), and low AA involvement with normative depression (62%). Both the low and high AA classes reduced their drinking across time and were drinking at less than half their baseline levels at all follow-ups. The high stable depression class reported an uneven pattern of AA involvement and drank at higher daily frequencies across the study timeline. Depression symptoms and alcohol use decreased substantially from intake to 3 months and then stabilized for 90% of patients with cooccurring disorders following inpatient psychiatric treatment. These findings can inform future clinical interventions among patients with cooccurring mental health and substance use disorders. Specifically, patients with more severe symptoms of depression may benefit from increased AA involvement, whereas patients with less severe symptoms of depression may not.


Electron transfer-induced dynamics of oxygen molecules on the TiO2(110) surface.
Diffusion of oxygen molecules on transition metal oxide surfaces plays a vital role for the understanding of catalysis and photocatalysis on these materials. By means of time-resolved scanning tunneling microscopy, we provide evidence for a charge transfer-induced diffusion mechanism for O2 molecules adsorbed on a rutile TiO2(110) surface. The O2 hopping rate depended on the number of surface donors (oxygen vacancies), which determines the density of conduction band electrons. These results may have implications for the understanding of oxidation processes on metal oxides in general.


Effects of 28 days of resistance exercise while consuming commercially available pre- and post-workout supplements, NO-Shotgun® and NO-Synthesize® on body composition, muscle strength and mass, markers of protein synthesis, and clinical safety markers in males.
The effects of 28 days of heavy resistance training while ingesting the pre- and post-workout supplements, NO-Shotgun® and NO-Synthesize® were determined on body composition, muscle strength and mass, markers of protein synthesis, and clinical safety markers. Nineteen non-resistance-trained males participated in a resistance training program 4 times/week for 28 days while either ingesting 27 g/day of carbohydrate (CARB) or NO-Shotgun® 30 min pre-exercise and 27 g/day of carbohydrate or NO- Synthesize® 30 min post-exercise (NOSS). Data were analyzed with separate 2 × 2 ANOVA (p < 0.05). Total body mass was increased in both groups (p = 0.001), but not different between groups. Fat mass was unchanged with CARB, but NOSS decreased fat mass (p = 0.026). Both groups increased fat-free mass (p = 0.001); however, the increases were greater with NOSS (p = 0.023). NOSS underwent greater increases in upper-body (p = 0.023) and lower-body (p = 0.035) strength than CARB. Myofibrillar protein significantly increased in both groups (p = 0.041), with NOSS being greater than CARB (p = 0.049). All of the MHC isoforms were significantly increased in both groups; however, NOSS was greater than CARB for MHC 1 (p = 0.013) and MHC 2A (p = 0.046). All of the myogenic regulatory factors were significantly increased in both groups; however, NOSS was greater than CARB for Myo-D (p = 0.038) and MRF-4 (p = 0.001). For the whole blood and serum clinical chemistry markers, all variables remained within normal clinical ranges. Heavy resistance training for 28 days, with NO-Shotgun® and NO-Synthesize® ingested before and after exercise, respectively, significantly improved body composition and increased muscle mass and performance without abnormally impacting any of the clinical chemistry markers.


In vitro generation of human cytolytic T-cells specific for peptides derived from the HER-2/neu protooncogene protein.
The development of T-cell therapy for the treatment of human malignancy has been hindered, in large part, by a lack of identifiable tumor antigens. Studies to identify potential T-cell targets in humans have been difficult because of practical problems limiting the use of in vivo immunization and a lack of reproducible in vitro priming methods. Oncogenic proteins are involved in malignant transformation and maintenance of the transformed phenotype and theoretically are potential targets to T-cell therapy. HER-2/neu protein is a protooncogene product overexpressed in a variety of human malignancies and is associated with malignant transformation and aggressive disease in human breast cancer. Previous studies have shown that some patients with breast cancer have existent helper/inducer T-cell immunity to p185HER-2/neu protein and peptides. The current study represents initial attempts to identify candidate cytotoxic T-lymphocyte (CTL) epitopes. Synthetic peptides were constructed identical to HER-2/neu protein segments with amino acid motifs similar to the published motif for HLA-2.1-binding peptides. Four peptides were synthesized and two were shown to be avid binders to HLA-A2.1. Two of the four peptides could be shown to elicit peptide-specific CTL by primary in vitro immunization in a culture system using peripheral blood lymphocytes from a normal individual homozygous for HLA-A2. p185HER-2/neu protooncogene protein contains immunogenic epitopes capable of generating human CD8+ CTL. The identification of candidate CTL epitopes will allow studies to determine whether some cancer patients have existent CTL immunity to HER-2/neu protein. The demonstrated ability to generate human peptide-specific CTL in vitro allows screening of other oncogenic proteins to identify candidate T-cell epitopes potentially useful for future immunotherapy studies.


IgM myeloma: a report of four cases.
IgM myeloma is a rare disease, accounting for approximately 0.5% of multiple myelomas (MM). Here we report four cases of IgM multiple myeloma. Two were diagnosed in advanced clinical stages with multiple osteolytic lesions, leading to hypercalcemia in one patient. Bone marrow morphology showed a variable degree of infiltration with mainly mature plasma cells. An immunophenotypic analysis performed in one case showed expression of CD38 and monoclonal cytoplasmatic immunoglobulin. Interphase fluorescence in situ hybridization performed in one case did not reveal any aneuploidies or deletions of the retinoblastoma, P16, or P53 tumor suppressor genes. While one patient with a smoldering IgM myeloma did not need specific therapy, the others received cytotoxic treatment based on standard chemotherapy for MM. The outcomes were one stable disease, one sustained complete remission, and one progressive disease. All four patients were alive 1 year after diagnosis. One died due to progressive disease after 31 months. We conclude that IgM myeloma shares clinical and histological features with other MM rather than with Waldenström's macroglobulinemia, which is most commonly diagnosed in cases with IgM monoclonal gammopathy. Since MM and Waldenström's macroglobulinemia differ in prognosis and treatment strategies, the two disease entities should be distinguished based on clinical criteria, bone marrow morphology, and immunophenotypic analysis.


Neuropsychological support to relatives of patients with severe traumatic brain injury in the sub-acute phase.
Many studies have reported emotional distress in relatives of patients with brain injury, but few studies have investigated neuropsychological interventions for relatives. The present study assessed the amount of neuropsychological support as well as the actual number of sessions with a neuropsychologist during rehabilitation in a sub-acute unit. The study also examined whether the amount of support was related to the condition of the patient or the relative at admission. The sample consisted of 26 patients and their closest relative, and measures included demographic variables as well as characteristics related to the patient: Glasgow Coma Scale, Injury Severity Score, Early Functional Abilities, Functional Independence Measure, Rancho Los Amigos; and to the relative: symptoms of anxiety and depression (SCL-90-R), quality of life (SF-36) and amount and number of sessions of neuropsychological support. On average, the relatives received about 18 units of 15 minutes and had six sessions with a neuropsychologist during hospitalisation. A total of 38% participated in group sessions. Relatives' symptoms of anxiety at admission were associated with the number of sessions as well as the amount of support, indicating that relatives with more symptoms of anxiety received more support during the hospitalisation.


Paperless clinical trials: Myth or reality?
There is an urgent need to expedite the time-to-market for new drugs and to make the approval process simpler. But clinical trials are a complex process and the increased complexity leads to decreased efficiency. Hence, pharmaceutical organizations want to move toward a more technology-driven clinical trial process for recording, analyzing, reporting, archiving, etc., In recent times, the progress has certainly been made in developing paperless systems that improve data capture and management. The adaptation of paperless processes may require major changes to existing procedures. But this is in the best interests of these organizations to remain competitive because a paperless clinical trial would lead to a consistent and streamlined framework. Moreover, all major regulatory authorities also advocate adoption of paperless trial. But challenges still remain toward implementation of paperless clinical trial process.


Accuracy of self-reported waist and hip measurements in 4492 EPIC-Oxford participants.
To assess the accuracy of self-reported waist and hip circumferences and the waist-to-hip ratio (WHR) by comparison with measured waist and hip circumferences and WHR in a sample of middle-aged men and women. Analysis of measured and self-reported waist and hip data from participants in the Oxford cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Oxford). Four thousand four hundred and ninety-two British men and women aged 35-76 years. Spearman's rank correlation coefficients between measured and self-reported waist, hip and WHR were 0.80, 0.74 and 0.44, respectively, for men and 0.83, 0.86 and 0.62 for women. Waist was underestimated, on average, by 3.1 (standard deviation (SD) 5.6) cm in men and 1.9 (SD 5.4) cm in women. The extent of underestimation was greater in participants with larger waists, older participants and women with greater body mass index (BMI). Hip was underestimated by a mean of 1.8 (SD 4.9) cm in men and 1.2 (SD 4.5) cm in women; the extent of underestimation was greater in participants with larger hip circumference and older participants. On average, WHR was underestimated by less than 2% by men and women; the extent of underestimation was greater among those with larger WHR, older people and those with greater BMI. Using self-reported values, the proportion of classification to the correct tertile was over 65% for waist and hip measurements. For WHR this proportion was 50% among men and 60% among women. Self-reported waist and hip measurements in EPIC-Oxford are sufficiently accurate for identifying relationships in epidemiological studies.


Sensitization of lanthanides by nonnatural amino acids.
The sensitization of Eu(III) and Tb(III) by ethylenediaminetetraaceticacid (EDTA)-derivatized tryptophan (Trp), 7-azatryptophan (7AW) and 5-hydroxytryptophan (5HW) has been examined. These Trp analogs were utilized in the present study because they can be incorporated into proteins in place of native Trp residues and because they absorb strongly beyond 305 nm (where Trp absorbance goes to zero), allowing selective excitation of such species in the presence of other Trp-containing proteins. All three indole derivatives were able to sensitize Tb(III) luminescence, with the relative sensitization being in the order Trp > 5HW > 7AW. On the other hand, only the 7AW-EDTA complex was able to sensitize Eu(III) luminescence, likely owing to a better spectral overlap between 7AW emission and Eu(III) absorbance. The sensitized emission of Tb(III) and Eu(II) displayed the expected long emission lifetimes at 545 nm [for Tb(III)] and 617 nm [for Eu(III)], indicating that long-lifetime lanthanide emission could be produced using nonnatural amino-acid donors. Thus, 7AW- and 5HW-sensitized lanthanide emissions should prove to be useful in biophysical studies, such as the use of fluorescence energy transfer to probe biomolecular interactions in vivo.


Shape retrieval using hierarchical total Bregman soft clustering.
In this paper, we consider the family of total Bregman divergences (tBDs) as an efficient and robust "distance" measure to quantify the dissimilarity between shapes. We use the tBD-based ℓ₁-norm center as the representative of a set of shapes, and call it the t-center. First, we briefly present and analyze the properties of the tBDs and t-centers following our previous work in. Then, we prove that for any tBD, there exists a distribution which belongs to the lifted exponential family (lEF) of statistical distributions. Further, we show that finding the maximum a posteriori (MAP) estimate of the parameters of the lifted exponential family distribution is equivalent to minimizing the tBD to find the t-centers. This leads to a new clustering technique, namely, the total Bregman soft clustering algorithm. We evaluate the tBD, t-center, and the soft clustering algorithm on shape retrieval applications. Our shape retrieval framework is composed of three steps: 1) extraction of the shape boundary points, 2) affine alignment of the shapes and use of a Gaussian mixture model (GMM) to represent the aligned boundaries, and 3) comparison of the GMMs using tBD to find the best matches given a query shape. To further speed up the shape retrieval algorithm, we perform hierarchical clustering of the shapes using our total Bregman soft clustering algorithm. This enables us to compare the query with a small subset of shapes which are chosen to be the cluster t-centers. We evaluate our method on various public domain 2D and 3D databases, and demonstrate comparable or better results than state-of-the-art retrieval techniques.


An electrophoretic study on phospholipase A2 isoenzymes in the venoms of Central American crotaline snakes.
The number and isoelectric points of phospholipase A2 isoenzymes were studied in the venoms of 12 Central American crotaline snakes of the genera Bothrops, Crotalus, Lachesis and Agkistrodon. The study was carried out by using a methodology based on electrophoretic separation of venoms, transfer to nitrocellulose and detection of activity of the bands by an indirect hemolytic assay in agarose-erythrocyte-egg yolk gels. All venoms tested had indirect hemolytic activity, although they varied in the number and isoelectric point of their phospholipases A2. Most venoms had predominantly acidic isoenzymes, with the exception of A. bilineatus which had mainly basic isoenzymes and B. schlegelii which had both acidic and basic isoenzymes. Analysis of interindividual variability in B. asper venom demonstrated that two phospholipase A2 isoenzymes are present in some venoms but absent in others. Polyvalent antivenom was effective in neutralizing phospholipase A2 activity of the 12 venoms tested, when venoms and antivenom were incubated in the fluid phase. This work demonstrates a conspicuous interspecific variability in the number and isoelectric points of phospholipases A2 present in Central American crotaline snake venoms.


Associations of physical activity, sedentary time, and cardiorespiratory fitness with heart rate variability in 6- to 9-year-old children: the PANIC study.
To study the associations of physical activity (PA), sedentary time (ST), and cardiorespiratory fitness (CRF) with heart rate variability (HRV) in children. The participants were a population sample of 377 children aged 6-9 years (49% boys). ST, light PA (LPA), moderate PA (MPA), vigorous PA (VPA), and moderate-to-vigorous PA (MVPA), and PA energy expenditure (PAEE) were assessed using a combined heart rate and movement sensor, maximal power output per kilograms of lean body mass as a measure of CRF by maximal cycle ergometer exercise test, and HRV variables (SDNN, RMSSD, LF, and HF) using 5 min resting electrocardiography. Data were analysed by linear regression adjusted for years from peak height velocity. In boys, ST was inversely associated (β = - 0.185 to - 0.146, p ≤ 0.049) and MVPA, VPA, PAEE, and CRF were directly associated (β = 0.147 to 0.320, p ≤ 0.048) with HRV variables. CRF was directly associated with all HRV variables and PAEE was directly associated with RMSSD after mutual adjustment for ST, PAEE, and CRF (β = 0.169 to 0.270, p ≤ 0.046). In girls, ST was inversely associated (β = - 0.382 to - 0.294, p < 0.001) and LPA, MPA, VPA, MVPA, and PAEE were directly associated with HRV variables (β = 0.144 to 0.348, p ≤ 0.049). After mutual adjustment for ST, PAEE, and CRF, only the inverse associations of ST with HRV variables remained statistically significant. Higher ST and lower PA and CRF were associated with poorer cardiac autonomic nervous system function in children. Lower CRF in boys and higher ST in girls were the strongest correlates of poorer cardiac autonomic function.


Long-term consequences of polycystic ovary syndrome on cardiovascular risk.
Most available data suggest that the prevalence of cardiovascular diseases in women with polycystic ovary syndrome (PCOS) is smaller than expected based on risk calculations during fertile years; therefore, more studies are needed on long-term cardiovascular consequences. Evidence is accumulating that postmenopausal women with PCOS have an increased risk of cerebrovascular events and cardiovascular morbidity. These events are partially related to persisting hyperandrogenism but are mostly correlated with excessive body weight (mainly visceral obesity); this suggests that our best long-term strategy is to ensure that women with PCOS are informed about their high risk for metabolic and cardiovascular diseases.


Immunological characterization of a gammadelta T-cell stimulatory ligand on autologous monocytes.
Bovine gammadelta T cells are stimulated to proliferate by autologous monocytes. This is referred to as the autologous mixed leucocyte reaction (AMLR). It has been shown previously that the stimulatory component is constitutively expressed on the monocyte plasma membrane and is a protein or has a protein moiety. Here we showed that gammadelta T-cell responses to the monocytes requires interaction with the T-cell receptor because Fab1 fragments of a monoclonal antibody (mAb) that reacts with the delta chain of the T-cell receptor blocked proliferation in the AMLR. Monocyte molecules involved in stimulation were also characterized further by biochemical and immunological methods. A mAb, named M5, was generated by immunizing mice with bovine monocytes and shown to block the ability of monocytes to stimulate in the AMLR. Treatment of monocytes or monocyte membranes with high salt, chelating agents or phospholipase C did not affect their ability to stimulate gammadelta T-cell proliferation or reactivity with mAb M5 indicating the ability of monocytes to stimulate does not involve peripheral membrane components or a glycosyl-phosphatidylinsositol (GPI)-anchored components. Hence it was concluded that the stimulation occurred as a result of intergral membrane proteins including that recognized by mAb M5. The ligand for mAb M5 was on all bovine monocytes and to a lower level on granulocytes but not on lymphocytes. MAb M5 also reacted with sheep monocytes but not with human monocytes or murine macrophages, in agreement with a previous reports that sheep monocytes but not human or mouse mononuclear phagocytes have the capacity to stimulate bovine gammadelta T cells in in vitro cultures. The level of expression of the M5 ligand was not altered by gamma-irradiation or culture of monocytes with lipopolysaccharide but it was decreased following culture with interferon-gamma-containing cell culture supernatants.


Screening for speech and language delay in preschool children: systematic evidence review for the US Preventive Services Task Force.
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Published in the public domain by the American Academy of Pediatrics. Speech and language development is a useful indicator of a child's overall development and cognitive ability and is related to school success. Identification of children at risk for developmental delay or related problems may lead to intervention services and family assistance at a young age, when the chances for improvement are best. However, optimal methods for screening for speech and language delay have not been identified, and screening is practiced inconsistently in primary care. We sought to evaluate the strengths and limits of evidence about the effectiveness of screening and interventions for speech and language delay in preschool-aged children to determine the balance of benefits and adverse effects of routine screening in primary care for the development of guidelines by the US Preventive Services Task Force. The target population includes all children up to 5 years old without previously known conditions associated with speech and language delay, such as hearing and neurologic impairments. Studies were identified from Medline, PsycINFO, and CINAHL databases (1966 to November 19, 2004), systematic reviews, reference lists, and experts. The evidence review included only English-language, published articles that are available through libraries. Only randomized, controlled trials were considered for examining the effectiveness of interventions. Outcome measures were considered if they were obtained at any time or age after screening and/or intervention as long as the initial assessment occurred while the child was < or =5 years old. Outcomes included speech and language measures and other functional and health outcomes such as social behavior. A total of 745 full-text articles met our eligibility criteria and were reviewed. Data were extracted from each included study, summarized descriptively, and rated for quality by using criteria specific to different study designs developed by the US Preventive Services Task Force. The use of risk factors for selective screening has not been evaluated, and a list of specific risk factors to guide primary care physicians has not been developed or tested. Sixteen studies about potential risk factors for speech and language delay in children enrolled heterogeneous populations, had dissimilar inclusion and exclusion criteria, and measured different risk factors and outcomes. The most consistently reported risk factors included a family history of speech and language delay, male gender, and perinatal factors. Other risk factors reported less consistently included educational levels of the mother and father, childhood illnesses, birth order, and family size. The performance characteristics of evaluation techniques that take < or =10 minutes to administer were described in 24 studies relevant to screening. Studies that were rated good to fair quality reported wide ranges of sensitivity and specificity when compared with reference standards (sensitivity: 17-100%; specificity: 45-100%). Most of the evaluations, however, were not designed for screening purposes, the instruments measured different domains, and the study populations and settings were often outside of primary care. No "gold standard" has been developed and tested for screening, reference standards varied across studies, few studies compared the performance of > or =2 screening techniques in 1 population, and comparisons of a single screening technique across different populations are lacking. Fourteen good- and fair-quality randomized, controlled trials of interventions reported significantly improved speech and language outcomes compared with control groups. Improvement was demonstrated in several domains including articulation, phonology, expressive language, receptive language, lexical acquisition, and syntax among children in all age groups studied and across multiple therapeutic settings. Improvement in other functional outcomes such as socialization skills, self-esteem, and improved play themes were demonstrated in some, but not all, of the 4 studies that measured them. In general, studies of interventions were small and heterogeneous, may be subject to plateau effects, and reported short-term outcomes based on various instruments and measures. As a result, long-term outcomes are not known, interventions could not be compared directly, and generalizability is questionable. Use of risk factors to guide selective screening is not supported by studies. Several aspects of screening have been inadequately studied to determine optimal methods, including which instrument to use, the age at which to screen, and which interval is most useful. Trials of interventions demonstrate improvement in some outcome measures, but conclusions and generalizability are limited. Data are not available addressing other key issues including the effectiveness of screening in primary care settings, role of enhanced surveillance by primary care physicians before referral for diagnostic evaluation, non-speech and language and long-term benefits of interventions, and adverse effects of screening and interventions.


Hypertension Status and Associations with Self-Rated Health and General Practitioner Health Seeking in a Rural Australian Cohort.
Hypertension is the most frequently managed condition by Australian general practitioners (GP). Knowledge of hypertension and blood pressure (BP) values may motivate individuals to seek GP management. Our study aims to determine the associations of knowledge of BP values, BP perception, GP health seeking, and self-rated health (SRH) in a rural population. Two-hundred and seventy-eight (278) residents responded to the health survey on socio-demographic profile, medical history, BP knowledge and perception, SRH, and GP visit frequency. Associations were evaluated using Chi-squared test and multivariate logistic regression. Cohort mean age was 63.6 (12.4) years with 63.3% females. Hypertension (37.8%) was the most common condition. GP visits were made at least once every month (19.1%), every 2⁻6 months (35.6%), >6 months (11.5%), or only when needed (29.5%). Univariate analyses showed age, education, alcohol consumption, comorbidities, hypertension status, and SRH were significantly associated with visit frequency. After adjustments, hypertension status (OR = 3.6, 95% CI [1.7, 7.9]) and poor SRH (OR = 3.1, 95% CI [1.4, 7.0]) were significantly associated with frequent monthly visits. Our cohort demonstrated that having hypertension and poor self-rated health were associated with frequent monthly GP visits. The perception of high blood pressure does not drive seeking additional GP input.


A Multicenter Study to Evaluate Harmonization of Assays for C-Terminal Telopeptides of Type I Collagen (ß-CTX): A Report from the IFCC-IOF Committee for Bone Metabolism (C-BM).
Biochemical bone turnover markers are useful tools to assess bone remodeling. C-terminal telopeptide of type I collagen (ß-CTX) has been recommended as a reference marker for bone resorption in research studies. We describe the results of a multicenter study for routine clinical laboratory assays for ß-CTX in serum and plasma. Four centers (Athens GR, Copenhagen DK, Liege BE and Sheffield UK) collected serum and plasma (EDTA) samples from 796 patients presenting to osteoporosis clinics. Specimens were analyzed in duplicate with each of the available routine clinical laboratory methods according to the manufacturers' instructions. Passing-Bablok regressions, Bland-Altman plots, V-shape evaluation method, and Concordance correlation coefficient for ß-CTX values between serum and plasma specimens and between methods were used to determine the agreement between results. A generalized linear model was employed to identify possible variables that affected the relationship between the methods. Two pools of serum were finally prepared and sent to the four centers to be measured in 5-plicates on 5 consecutive days with the different methods. We identified significant variations between methods and between centers although comparison results were generally more consistent in plasma compared to serum. We developed univariate linear regression equations to predict Roche Elecsys®, IDS-iSYS, or IDS ELISA ß-CTX results from any other assay and a multivariable model including the site of analysis, the age, and weight of the patient. The coefficients of determination (R2) increased from approximately 0.80 in the univariate model to approximately 0.90 in the multivariable one, with the site of analysis being the major contributing factor. Results observed on the pools also suggest that long-term storage could explain the difference observed with the different methods on serum. Our results show large within- and between-assay variation for ß-CTX measurement, particularly in serum. Stability of the analyte could be one of the explanations. More studies should be undertaken to overcome this problem. Until harmonization is achieved, we recommend measuring ß-CTX by the same assay on EDTA plasma, especially for research purposes in large pharmacological trials where samples can be stored for long periods before they are assayed.


Tea polyphenols induce S phase arrest and apoptosis in gallbladder cancer cells.
Gallbladder cancer (GBC) is the most common malignancy in the biliary tract. Without effective treatment, its prognosis is notoriously poor. Tea polyphenols (TPs) have many pharmacological and health benefits, including antioxidant, anti-inflammatory, anti-tumor, anti-thrombotic, antibacterial, and vasodilatory properties. However, the anti-cancer effect of TPs in human gallbladder cancer has not yet been determined. Cell viability and colony formation assay were used to investigate the cell growth. Cell cycle and apoptosis were evaluated by flow cytometry analysis. Western blot assay was used to detect the expression of proteins related to cell cycle and apoptosis. Human tumor xenografts were used to examine the effect of TPs on gallbladder cancer cells in vivo. TPs significantly inhibited cell growth of gallbladder cancer cell lines in a dose- and time-dependent manner. Cell cycle progression in GBC cells was blocked at the S phase by TPs. TPs also induced mitochondrial-related apoptosis in GBC cells by upregulating Bax, cleaved caspase-3, and cleaved PARP expressions and downregulating Bcl-2, cyclin A, and Cdk2 expressions. The effects of TPs on GBC were further proven in vivo in a mouse xenograft model. Our study is the first to report that TPs inhibit GBC cell growth and these compounds may have potential as novel therapeutic agents for treating gallbladder cancer.


Pulmonary embolism: update on diagnosis and management.
Pulmonary embolism (PE) is a potentially life-threatening condition, mandating urgent diagnosis and treatment. The symptoms of PE may be non-specific; diagnosis therefore relies on a clinical assessment and objective diagnostic testing. A clinical decision rule can determine the pre-test probability of PE. If PE is "unlikely", refer for a D-dimer test. If the D-dimer result is normal, PE can be excluded. If D-dimer levels are increased, refer for chest imaging. If PE is "likely", refer for chest imaging. Imaging with computed tomography pulmonary angiogram is accurate and preferred for diagnosing PE, but may detect asymptomatic PE of uncertain clinical significance. Imaging with ventilation-perfusion (VQ) scan is associated with lower radiation exposure than computed tomography pulmonary angiogram, and may be preferred in younger patients and pregnancy. A low probability or high probability VQ scan is helpful for ruling out or confirming PE, respectively; however, an intermediate probability VQ scan requires further investigation. The direct oral anticoagulants have expanded the anticoagulation options for PE. These are the preferred anticoagulant for most patients with PE because they are associated with a lower risk of bleeding, and have the practical advantages of fixed dosage, no need for routine monitoring, and fewer drug interactions compared with vitamin K antagonists. Initial parenteral treatment is required before dabigatran and edoxaban.


A Novel Contrast Stain for the Rapid Diagnosis of Dermatophytoses: A Cross-Sectional Comparative Study of Chicago Sky Blue 6B Stain, Potassium Hydroxide Mount and Culture.
The current upsurge of complicated dermatophytosis in India and other parts of the world has necessitated the development of rapid and accurate diagnostic techniques. Conventional methods such as potassium hydroxide (KOH) mount lack color contrast and require a trained eye, whereas fungal culture is laborious and costly. Chicago sky blue 6B (CSB) a new contrast stain promises to be a reliable and rapid diagnostic method. It contains 1% CSB stain and is used with 10% KOH as clearing agent. The objective of this study is to compare the efficacy of a novel contrast stain (CSB) and KOH mount in the diagnosis of dermatophytoses with culture as the reference method. The infected skin scrapings, nail clippings, and hair specimens from 100 patients, with clinically diagnosed dermatophytoses, were subjected to KOH mount, CSB stain, and culture on Sabouraud's dextrose agar. Using fungal culture as the reference standard, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of CSB stain and KOH mount were determined. An inter-rater reliability analysis was performed using the Cohen's κ statistic to determine agreement amongst the different diagnostic modalities. Of the 100 cases, the CSB stain and KOH mount were positive in 85 (85%) and 70 (70%) cases, respectively. Cultures on Sabouraud's agar yielded growth in 59 (59%) cases. The sensitivity, specificity, PPV, NPV, and accuracy of CSB stain were 98%, 34%, 68%, 93%, and 72%, respectively. The same for KOH mount were 71%, 32%, 60%, 43%, and 55%, respectively. CSB stain is a simple, rapid, sensitive, accurate, and inexpensive office-based method with qualitatively superior demonstration of dermatophytes compared to KOH mount.


Elevated synthesis of an axonally transported protein correlates with axon outgrowth in normal and injured pyramidal tracts.
Axons of the adult mammalian CNS typically fail to regenerate after injury. Among the hypotheses to account for this failure is the proposition that certain axonal proteins necessary for axon growth are expressed in much greater abundance in developing than in mature neurons, and that these proteins are not reinduced after injury to mature axons (Skene and Willard, 1981b). In the present experiments, we have found that hamster pyramidal tract neurons synthesize an acidic, 43K protein that is transported into growing axons during the first 2 weeks of postnatal development, and then declines at least an order of magnitude by the fourth postnatal week. The decline in synthesis of the 43K protein coincides with the cessation of pyramidal tract axon elongation. This protein resembles a "growth-associated protein," GAP-43, which is induced during regeneration of CNS axons in lower vertebrates. The 43K protein in hamster pyramidal tract neurons is not reinduced after axotomy in adult animals, which correlates with the failure of the injured axons to regenerate. Injury to neonatal pyramidal tract axons does not reverse or delay the decline in 43K protein synthesis. This is consistent with previous findings (Kalil and Reh, 1982) that pyramidal tract axons regrow for only a brief period after neonatal injury. Taken together, these results lend support to the hypothesis that synthesis of GAP-43 is important for axon growth in development and regeneration.


B cell positive selection by self antigens and counter-selection of dual B cell receptor cells in the peripheral B cell pools.
The presence of B cells expressing two B cell receptors (BCR), described in BCR-transgenic, gene-targeted and normal mice, may represent an autoimmune hazard. We generated RAG-2-deficient mice bearing two complete rearranged immunoglobulin transgenes. In these mice most mature resting B cells express chains from the two transgenes. We studied selection of these dual receptor B cells in the presence of self antigens. In spite of the reduced surface density of the anti-self receptor, self-reactive B cells are deleted in the presence of membrane-bound self antigens. In contrast, the presence of soluble self antigen positively selects single receptor B cells expressing the self-reactive receptor. At the periphery these positively selected B cells down-regulate surface IgM expression and become unresponsive. A few dual receptor cells, however, escape tolerance induction. We examined the peripheral fate of the dual receptor B cells and showed that they are poorly selected into the activated B cell compartment and show a poor competitive capacity when in presence of populations of single receptor B cells. These results indicate that peripheral selection contributes to the very low frequencies of dual receptor B cells in normal mice and that multiple safeguard mechanisms operate to minimize the autoimmune hazard that allelically included B cells could represent.


RIAM, an Ena/VASP and Profilin ligand, interacts with Rap1-GTP and mediates Rap1-induced adhesion.
The small GTPase Rap1 induces integrin-mediated adhesion and changes in the actin cytoskeleton. The mechanisms that mediate these effects of Rap1 are poorly understood. We have identified RIAM as a Rap1-GTP-interacting adaptor molecule. RIAM defines a family of adaptor molecules that contain a RA-like (Ras association) domain, a PH (pleckstrin homology) domain, and various proline-rich motifs. RIAM also interacts with Profilin and Ena/VASP proteins, molecules that regulate actin dynamics. Overexpression of RIAM induced cell spreading and lamellipodia formation, changes that require actin polymerization. In contrast, RIAM knockdown cells had reduced content of polymerized actin. RIAM overexpression also induced integrin activation and cell adhesion. RIAM knockdown displaced Rap1-GTP from the plasma membrane and abrogated Rap1-induced adhesion. Thus, RIAM links Rap1 to integrin activation and plays a role in regulating actin dynamics.


Fruit and vegetable intake and risk of cancer: a prospective cohort study.
There is probable evidence that some types of fruit and vegetables provide protection against many cancers. We hypothesized that fruit and vegetable intakes are inversely related to the incidence of total cancers among women and men aged >50 y. We performed a prospective study among the cohort of the National Institutes of Health-AARP Diet and Health Study. We merged the MyPyramid Equivalents Database (version 1.0) with food-frequency-questionnaire data to calculate cup equivalents for fruit and vegetables. From 1995 to 2003, we identified 15,792 and 35,071 cancer cases in 195,229 women and 288,109 men, respectively. We used Cox proportional hazards models to estimate multivariate relative risks (RRs) and 95% CIs associated with the highest compared with the lowest quintile (Q) of fruit and vegetable intakes. Fruit intake was not associated with the risk of total cancer among women (RR(Q5 vs Q1) = 0.99; 95% CI: 0.94, 1.05; P trend = 0.059) or men (RR(Q5 vs Q1) = 0.98; 95% CI: 0.95, 1.02; P for trend = 0.17). Vegetable intake was not associated with risk of total cancer among women (RR(Q5 vs Q1) = 1.04; 95% CI: 0.98, 1.09; P for trend = 0.084), but was associated with a significant decrease in risk in men (RR(Q5 vs Q1) = 0.94; 95% CI: 0.91, 0.97; P trend = 0.004). This significant finding among men was no longer evident when we limited the analysis to men who never smoked (RR(Q5 vs Q1) = 0.97; 95% CI: 0.91, 1.04; P for trend = 0.474). Intake of fruit and vegetables was generally unrelated to total cancer incidence in this cohort. Residual confounding by smoking is a likely explanation for the observed inverse association with vegetable intake among men.


Regulatory variation in a TBX5 enhancer leads to isolated congenital heart disease.
Recent studies have identified the genetic underpinnings of a growing number of diseases through targeted exome sequencing. However, this strategy ignores the large component of the genome that does not code for proteins, but is nonetheless biologically functional. To address the possible involvement of regulatory variation in congenital heart diseases (CHDs), we searched for regulatory mutations impacting the activity of TBX5, a dosage-dependent transcription factor with well-defined roles in the heart and limb development that has been associated with the Holt-Oram syndrome (heart-hand syndrome), a condition that affects 1/100 000 newborns. Using a combination of genomics, bioinformatics and mouse genetic engineering, we scanned ∼700 kb of the TBX5 locus in search of cis-regulatory elements. We uncovered three enhancers that collectively recapitulate the endogenous expression pattern of TBX5 in the developing heart. We re-sequenced these enhancer elements in a cohort of non-syndromic patients with isolated atrial and/or ventricular septal defects, the predominant cardiac defects of the Holt-Oram syndrome, and identified a patient with a homozygous mutation in an enhancer ∼90 kb downstream of TBX5. Notably, we demonstrate that this single-base-pair mutation abrogates the ability of the enhancer to drive expression within the heart in vivo using both mouse and zebrafish transgenic models. Given the population-wide frequency of this variant, we estimate that 1/100 000 individuals would be homozygous for this variant, highlighting that a significant number of CHD associated with TBX5 dysfunction might arise from non-coding mutations in TBX5 heart enhancers, effectively decoupling the heart and hand phenotypes of the Holt-Oram syndrome.


Modified sympathetic nerve system activity with overexpression of the voltage-dependent calcium channel beta3 subunit.
N-type voltage-dependent calcium channels (VDCCs) play determining roles in calcium entry at sympathetic nerve terminals and trigger the release of the neurotransmitter norepinephrine. The accessory beta3 subunit of these channels preferentially forms N-type channels with a pore-forming CaV2.2 subunit. To examine its role in sympathetic nerve regulation, we established a beta3-overexpressing transgenic (beta3-Tg) mouse line. In these mice, we analyzed cardiovascular functions such as electrocardiography, blood pressure, echocardiography, and isovolumic contraction of the left ventricle with a Langendorff apparatus. Furthermore, we compared the cardiac function with that of beta3-null and CaV2.2 (alpha1B)-null mice. The beta3-Tg mice showed increased expression of the beta3 subunit, resulting in increased amounts of CaV2.2 in supracervical ganglion (SCG) neurons. The beta3-Tg mice had increased heart rate and enhanced sensitivity to N-type channel-specific blockers in electrocardiography, blood pressure, and echocardiography. In contrast, cardiac atria of the beta3-Tg mice revealed normal contractility to isoproterenol. Furthermore, their cardiac myocytes showed normal calcium channel currents, indicating unchanged calcium influx through VDCCs. Langendorff heart perfusion analysis revealed enhanced sensitivity to electric field stimulation in the beta3-Tg mice, whereas beta3-null and Cav2.2-null showed decreased responsiveness. The plasma epinephrine and norepinephrine levels in the beta3-Tg mice were significantly increased in the basal state, indicating enhanced sympathetic tone. Electrophysiological analysis in SCG neurons of beta3-Tg mice revealed increased calcium channel currents, especially N- and L-type currents. These results identify a determining role for the beta3 subunit in the N-type channel population in SCG and a major role in sympathetic nerve regulation.


Trihalomethane formation potential of filter isolates of electrolyte-extractable soil organic carbon.
Certain organic C moieties of soil origin in drinking source waters of Sacramento-San Joaquin Delta (Delta) can react with chlorine to form trihalomethanes (THMs) during the disinfection process. Isolation and characterization of them and quantitation of their THM formation potential (THMFP) is necessary for developing effective strategies to reduce their influxes in Delta waters and for removing them during drinking water treatment. In this study, organic C from two Delta soils was extracted using deionized H(2)O and four Na- or Ca-based electrolytes of varying electrical conductivity values. Extracts were filtered into particulate, colloidal, fine colloidal, and soluble organic C for quantitation and THMFP determination. Results suggested that <1.5% of soil organic C was electrolyte-extractable. The soluble organic C fraction from both soils dominated in quantity and THMFP. Electrolyte effects were cation dependent. Sodium-based electrolytes at either conductivity level did not significantly decrease extractable organic C (EOC) or THMFP compared with deionized H(2)O. In contrast, Ca-based electrolytes reduced EOC and THMFP by >50% even at 1 dS m(-1). Further increase in Ca concentration did not significantly decrease EOC or THMFP. Most reduction in EOC and THMFP by Ca-based electrolytes occurred with the fractions other than the soluble organic C. Results suggested that under natural soil leaching and runoff conditions, the majority of THMFP is associated with organic C of <0.025 mum in diameter. Further molecular characterization of the fractions with high THMFP may help understand the nature of chlorine-reactive organic C from Delta soils.


Socioeconomic status and non-fatal injuries among Canadian adolescents: variations across SES and injury measures.
While research to date has consistently demonstrated that socioeconomic status (SES) is inversely associated with injury mortality in both children and adults, findings have been less consistent for non-fatal injuries. The literature addressing SES and injury morbidity among adolescents has been particularly inconclusive. To explore potential explanations for these discrepant research findings, this study uniquely compared the relationship across different measures of SES and different causes of injury (recreation versus non-recreation injuries) within a sample of Canadian adolescents. The sample included adolescent participants (aged 12 to 19 years) in the Canadian 1996-1997 cross-sectional National Population Health Survey (n = 6967). Five SES measures (household income, two neighbourhood-level proxy measures, two parental indicators) were examined in relation to three injury outcomes (total, recreation, and non-recreation injuries) using multivariable logistic regression. Among males, a clear relationship with injury was observed only for a parental SES index, which was positively associated with total and recreation injuries (odds ratios for the highest versus lowest SES category of 1.9 for total and 2.5 for recreation injuries). Among females, there was some evidence of a positive relationship between SES and injuries, particularly for a neighbourhood-level education measure with total and recreation injuries (odds ratios of 1.7 for total and 2.0 for recreation injuries). The results suggest that differences related to the measures of SES chosen and the causes of injury under study may both contribute to discrepancies in past research on SES and non-fatal injuries among adolescents. To clarify the potential SES-injury relationship among youth, the findings emphasize a need for a greater understanding of the meaning and relevance of different SES measures for adolescents, and for an exploration of the pathways through which SES may be related to injury risk.


Therapeutic monitoring of amiodarone: pharmacokinetics and evaluation of the relationship between effect and dose/concentration.
Amiodarone is the most effective agent in the therapy of arrhythmias. However, the clinical effect of acute and chronic treatment is unclear and there are differences irrespective of comparable plasma/myocardial amiodarone and its metabolite desethylamiodarone concentations as well. Its unusual pharmacokinetics results in interindividual variation in plasma levels. The association between amiodarone and desethylamiodarone plasma levels and clinical efficacy is difficult to evaluate. This review was carried out to assess whether there is any objective correlation between amiodarone and desethylamiodarone plasma levels and the clinical effect. We summarized the results of relevant studies and clarified the relationship between plasma levels and effect vis á vis the pharmacokinetics and pharmacogenetics of this drug. Certain correlation was seen with oral amiodarone therapy, in others, plasma amiodarone levels were unrelated to therapeutic response and showed no correlation with changes in electrocardiogram or electrophysiological parametres. Several studies show that plasma concentration ranging between 0.5 and 2.5 mg/L appears to be the most effective, others demonstrate no difference between responders and non-responders. One way of interpreting plasma levels is to establish an individual patient´s effective concentration. Therapeutic drug monitoring can contribute to determining optimal concentration.


'Relatives are a resource, but...': registered nurses' views and experiences of relatives of residents in nursing homes.
Registered Nurses (RNs) working in nursing homes in Sweden have obligations towards the residents' relatives, besides the care of residents. Relatives' involvement and satisfaction with the care partly depend on their contacts and communication with the staff. This study aimed to explore and describe RNs' views and experiences of relatives of residents who live in nursing homes. Open interviews were conducted with 19 RNs at three nursing homes. The verbatim-transcribed interviews were subjected to qualitative content analysis. Relatives were seen as a resource (with some restrictions) and nice, although demanding. The RNs saw relatives as part of their work--a part that could be time-consuming and had low priority. Interviewees noticed a difference between young and old relatives, and between female and male relatives. A large proportion of accounts could be related to issues about communication and interpersonal relationships with relatives. Building a trusting relationship with relatives may result in them being involved in residents' care and thus giving the nurses time rather than consuming time.


Effect of self-hypnosis on hay fever symptoms - a randomised controlled intervention study.
Many people suffer from hay fever symptoms. Hypnosis has proved to be a useful adjunct in the treatment of conditions where allergic phenomena have an important role. Randomised parallel group study over an observation period of two consecutive pollen seasons. Outcome data include nasal flow under hypnosis, pollinosis symptoms from diaries and retrospective assessments, restrictions in well-being and use of anti-allergic medication. We investigated 79 patients with a mean age of 34 years (range 19-54 years; 41 males), with moderate to severe allergic rhinitis to grass or birch pollen of at least 2 years duration and mild allergic asthma. The intervention consisted of teaching self-hypnosis during a mean of 2.4 sessions (SD 1.7; range 2-5 sessions) and continuation of standard anti-allergic pharmacological treatment. Of 79 randomised patients, 66 completed one, and 52 completed two seasons. Retrospective VAS scores yielded significant improvements in year 1 in patients who had learned self-hypnosis: pollinosis symptoms -29.2 (VAS score, range 0-100; SD 25.4; p < 0.001), restriction of well-being -26.2 (VAS score, range 0-100; SD 28.7; p < 0.001. In year 2, the control group improved significantly having learned self-hypnosis as well: pollinosis symptoms -24.8 (SD 29.1; p < 0.001), restriction of well-being -23.7 (SD 30.0; p < 0.001). Daily self-reports of subjects who learnt self-hypnosis do not show a significant improvement. The hazard ratio of reaching a critical flow of 70% in nasal provocation tests was 0.333 (95% CI 0.157-0.741) after having learnt and applied self-hypnosis.


Mathematical projection model of visual loss due to fuchs corneal dystrophy.
PURPOSE. To devise a mathematical disease classification model for eyes with primary guttata cornea, on the bases of endothelial loss trajectory and probability of advanced disease. METHODS. A series of 1971 patients (3281 eyes), some with and some without guttata corneas, undergoing specular microscopy were retrospectively reviewed. The eyes were classified into four stages; stage 0, without guttae; 1, guttata cornea without edema; 2, mild Fuchs' corneal dystrophy (FCD); and 3, severe FCD, according to clinical records, and patient age and corneal endothelial cell density (ECD) were plotted. Nonparametric density smoothing was used to create a contour map, and a best-fit curve for ECD loss was calculated. The relation between ECD decrease rate and the stages were evaluated. RESULTS. Endothelial decrease rate in stage 0 was 0.44%/year, which was compatible with that of normal eyes reported in previous studies. Decrease rates of stages 1, 2, and 3 were 0.81%, 2.65%, and 3.08%/ year, respectively. The age-ECD loss curves of 1.40%/year (ECO(1.4)) and 2.00%/year (ECO(2.0)) further divided stage 1 into three subgroups; stage 1a, asymptomatic guttata cornea; 1b, borderline guttata cornea; and 1c, pre-FCD. The ECO(2.0) cutoff line differentiated eyes with FCD from those without edema with a sensitivity and specificity of >90%. Stage 1c eyes were below ECO(2.0) and had a decrease rate as high as FCD. CONCLUSIONS. This mathematical model can be used to predict the prognosis of patients with primary guttata cornea.


The development of a systemic school-based intervention: Marte Meo and coordination meetings.
Antisocial behavior is often persistent, and in addition to causing suffering to children and their families, it also poses considerable costs for society. Children who display externalizing behavior in their early years run a high risk of having severe problems later in life. There is a need for treatment methods that may be used in various settings because these children constitute a group that is hard to reach with conventional treatment methods. In addition, the dropout rate from ordinary treatment is often high. In the present study, a systemic school-based model for early detection and intervention among 4-12-year-old children who displayed externalizing behavior problems was developed and examined in a nonrandomized study in the county of Skaraborg in Sweden. The intervention was collaborative and included a combination of the Marte Meo model and coordination meetings based on systemic theory and practice. Treatment effects in the group who had received the intervention were compared with a group who had received treatment as usual in their ordinary school setting. Assessments were carried out before, and 2 years after, the intervention. For the intervention group (N = 33), there was a significant decrease in the children's reported symptoms in school and in the home. No decrease in externalizing behavior was found in the comparison group (N = 16). There were no dropouts in the intervention group after the intervention had begun. The results are promising; the study demonstrates that it is possible to work effectively with many children who display externalizing behavior problems in a nonclinical setting.


Functional correlates of Doppler flow study of the female urethral vasculature.
To examine the effect of individual patient factors (age, parity, body mass index, menstrual cycle, menopause, hormone replacement therapy, bladder neck position and urethral mobility) on the appearance of Doppler flow in urethral vessels, to investigate the association between the Doppler flow parameters and intrinsic urethral function, storage and voiding, and to explore differences in the urethral vasculature between subjects with and without urodynamic stress incontinence (USI). Over a 4-year period we prospectively performed imaging studies in 355 women, including 244 who denied any lower urinary tract symptoms within the previous 3 months (Group A) and 111 who had had lower urinary tract symptoms (Group B). Studies included morphologic assessment and Doppler flow investigation of the lower urinary tract. Vascular flow velocity and vessel density in the urethral vasculature were measured. For women in Group B, multichannel urodynamic studies were also performed. The urethral vasculature has five main branches of vessels. Their appearance was not affected by the menstrual cycle or menopause except for those of the anterior vaginal vessel and anterior branch of the middle urethral vessel. Other than that of the posterior urethral vessel, in which there was a correlation with parity, the resistance index (RI) was not affected by individual patient factors. However, there was a correlation between the vascular index (VI) and individual factors such as age (r = -0.336, P = 0.002), body mass index (r = -0.287, P = 0.028), menopause (r = -0.402, P < 0.001), and hormone replacement therapy (r = 0.392, P = 0.027). Only the VI and RI of the posterior urethral vessel correlated significantly with the urethral pressure profile. In subjects with lower urinary tract symptoms, the appearance of the urethral vasculature on power Doppler imaging and the corresponding RI and VI values were not correlated with objective evidence of USI. Patient factors may affect specific Doppler flow parameters of the urethral vasculature, which are related to intrinsic resting urethral closure. There is no difference in the appearance of the urethral vasculature in subjects with or without USI.