A Unifying Framework for Understanding Biological Structures and Functions Across Levels of Biological Organization.

The relationship between structure and function is a major constituent of the rules of life. Structures and functions occur across all levels of biological organization. Current efforts to integrate conceptual frameworks and approaches to address new and old questions promise to allow a more holistic and robust understanding of how different biological functions are achieved across levels of biological organization. Here, we provide unifying and generalizable definitions of both structure and function that can be applied across all levels of biological organization. However, we find differences in the nature of structures at the organismal level and below as compared to above the level of the organism. We term these intrinsic and emergent structures, respectively. Intrinsic structures are directly under selection, contributing to the overall performance (fitness) of the individual organism. Emergent structures involve interactions among aggregations of organisms and are not directly under selection. Given this distinction, we argue that while the functions of many intrinsic structures remain unknown, functions of emergent structures are the result of the aggregate of processes of individual organisms. We then provide a detailed and unified framework of the structure-function relationship for intrinsic structures to explore how their unknown functions can be defined. We provide examples of how these scalable definitions applied to intrinsic structures provide a framework to address questions on structure-function relationships that can be approached simultaneously from all subdisciplines of biology. We propose that this will produce a more holistic and robust understanding of how different biological functions are achieved across levels of biological organization.

Highly efficient and sensitive patient-specific quality assurance for spot-scanned proton therapy.

The purpose of this work was to develop an end-to-end patient-specific quality assurance (QA) technique for spot-scanned proton therapy that is more sensitive and efficient than traditional approaches. The patient-specific methodology relies on independently verifying the accuracy of the delivered proton fluence and the dose calculation in the heterogeneous patient volume. A Monte Carlo dose calculation engine, which was developed in-house, recalculates a planned dose distribution on the patient CT data set to verify the dose distribution represented by the treatment planning system. The plan is then delivered in a pre-treatment setting and logs of spot position and dose monitors, which are integrated into the treatment nozzle, are recorded. A computational routine compares the delivery log to the DICOM spot map used by the Monte Carlo calculation to ensure that the delivered parameters at the machine match the calculated plan. Measurements of dose planes using independent detector arrays, which historically are the standard approach to patient-specific QA, are not performed for every patient. The nozzle-integrated detectors are rigorously validated using independent detectors in regular QA intervals. The measured data are compared to the expected delivery patterns. The dose monitor reading deviations are reported in a histogram, while the spot position discrepancies are plotted vs. spot number to facilitate independent analysis of both random and systematic deviations. Action thresholds are linked to accuracy of the commissioned delivery system. Even when plan delivery is acceptable, the Monte Carlo second check system has identified dose calculation issues which would not have been illuminated using traditional, phantom-based measurement techniques. The efficiency and sensitivity of our patient-specific QA program has been improved by implementing a procedure which independently verifies patient dose calculation accuracy and plan delivery fidelity. Such an approach to QA requires holistic integration and maintenance of patient-specific and patient-independent QA.

Effect of eicosapentaenoic acid and docosahexaenoic acid supplementation on C-peptide preservation in pregnant women with type-1 diabetes: randomized placebo controlled clinical trial.

BACKGROUND/OBJECTIVES: Type-1 diabetes mellitus (T1DM) is caused by autoimmune insulitis. There are evidences that pregnancy and n-3 fatty acids exhibit suppressive effect on human inflammatory system. SUBJECTS/METHODS: Ninety pregnant women with T1DM were included in the prospective randomized placebo controlled clinical trial. Forty-seven of them were put on standard diabetic diet enriched with EPA and DHA twice a day (EPA 120 mg and DHA 616 mg; Study group) and 43 pregnant diabetic women were on standard diabetic diet with placebo (Control group). Duration of T1DM in all participants was between 5 to 30 years. Blood samples were analyzed from all pregnant women for fasting C-peptide (FC-peptide), fasting plasma glucose (FPG) and HbA1c in each trimester throughout pregnancy and after delivery. Umbilical vein blood was analyzed for fetal C-peptide level, glucose concentration and insulin resistance. RESULTS: In the Study group FC-peptide concentration raised from 59.6±103.9 pmol/l in first trimester, to 67.7±101.3 pmol/l in the second trimester and to 95.1±152.7 pmol/l in the third trimester. Comparing the FC-peptide values during first and third trimester a statistically significant increase in third trimester was found (P<0.001). In the Control group FC-peptide concentration ranged from 41.7±91.6 pmol/l in the first trimester to 41.2±70.9 mmol/l in the second trimester while in the third trimester it reached 52.4±95.3 pmol/l. Comparing the FC-peptide values during first and third trimester the statistical difference was not significant. CONCLUSION: Combining of LC n-3 PUFAs and pregnancy yields immunological tolerance and stimulates the production of endogenous insulin in women with T1DM.

An innovative care model coordinated by a physical therapist and nurse practitioner for osteoarthritis of the hip and knee in specialist care: a prospective study.

The subject of the study is to investigate whether health-related quality of life (HRQoL), pain and function of patients with hip or knee osteoarthritis (OA) improves after a specialist care intervention coordinated by a physical therapist and a nurse practitioner (NP) and to assess satisfaction with this care at 12 weeks. This observational study included all consecutive patients with hip or knee OA referred to an outpatient orthopaedics clinic. The intervention consisted of a single, standardized visit (assessment and individually tailored management advice, to be executed in primary care) and a telephone follow-up, coordinated by a physical therapist and a NP, in cooperation with an orthopaedic surgeon. Assessments at baseline and 10 weeks thereafter included the short form-36 (SF-36), EuroQol 5D (EQ-5D), hip or knee disability and osteoarthritis outcome score (HOOS or KOOS), the intermittent and constant osteoarthritis pain questionnaire (ICOAP) for hip or knee and a multidimensional satisfaction questionnaire (23 items; 4 point scale). Eighty-seven patients (57 female), mean age 68 years (SD 10.9) were included, with follow-up data available in 63 patients (72 %). Statistically significant improvements were seen regarding the SF-36 physical summary component score, the EQ-5D, the ICOAP scores for hip and knee, the HOOS subscale sports and the KOOS subscales pain, symptoms and activities of daily living. The proportions of patients reporting to be satisfied ranged from 79 to 98 % per item. In patients with hip and knee OA pain, function and HRQoL improved significantly after a single-visit multidisciplinary OA management intervention in specialist care, with high patient satisfaction.

Dios y el cerebro. Una perspectiva judía / No disponible

La religiosidad es sobre todo, una capacidad experimental. Como tal no puede existir sin un sustrato biológico, sin circuitos neuronales cuya activación evoca experiencias religiosas. La investigación de la naturaleza de estos circuitos ha producido ya algunos resultados. ¿Se reduce de este modo la religiosidad a un fenómeno de determinación puramente psicológica? Rotundamente no. La religiosidad no está anclada en los circuitos cerebrales. No se encontrarán sus raíces en un nivel psicológico. Las funciones del cerebro son un intermediario; un intermediario entre las necesidades religiosidades y la satisfacción experimental. En otras palabras, el homo sapiens ha desarrollado una base física que hace posible el desarrollo de la religiosidad. Concluyo que la investigación neuroteológica no respalda la perspectiva atea. La susceptibilidad religiosa no puede ser vista como un sofisticado complejo de quimeras. Al contrario, los datos neuroteológicos respalda la visión teísta: la religiosidad es un componente normal y valioso de la psique humana. Tiene una firme fijación biológica, que es, en parte, intrísecamente genética(AU)

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Small bowel obstruction due to a persistent omphalomesenteric duct.

We report a case of a Meckel diverticulum connected with the umbilicus through a fibrotic cord causing small bowel obstruction. On admission, the patient presented with an acute abdomen. A plain upright radiography of the abdomen, an ultrasonography of the abdomen, and an enema with gastrografin were performed, showing a small bowel obstruction at the level of the pre-terminal ileum, without revealing the cause. Urgent surgery followed, showing a persistent omphalomesenteric duct connected to the abdominal wall through a fibrotic cord, with a secondary volvulus of the small bowel. The remnant was resected and the volvulus reduced. The post-operative course was uneventful. Because of the serious complications and even possible mortality due to ischemic disease of the affected small bowel the possibility of a complicated persistent omphalomesenteric duct should be kept in mind, even if the preoperative work-up does not reveal a Meckel diverticulum.

Effect of dietary coenzyme Q and fatty acids on the antioxidant status of rat tissues.

Wistar rats were fed with different diets with or without supplement coenzyme Q(10) (CoQ(10)) and with oil of different sources (sunflower or virgin olive oil) for six or twelve months. Ubiquinone contents (CoQ(9) and CoQ(10)) were quantified in homogenates of livers and brains from rats fed with the four diets. In the brain, younger rats showed a 3-fold higher amount of ubiquinone than older ones for all diets. In the liver, however, CoQ(10) supplementation increased the amount of CoQ(9) and CoQ(10) in both total homogenates and plasma membranes. Rats fed with sunflower oil as fat source showed higher amounts of ubiquinone content than those fed with olive oil, in total liver homogenates, but the total ubiquinone content in plasma membranes was similar with both fat sources. Older rats showed a higher amount of ubiquinone after diets supplemented with CoQ(10). Two ubiquinone-dependent antioxidant enzyme activities were measured. NADH-ferricyanide reductase activity in hepatocyte plasma membranes was unaltered by ubiquinone accumulation, but this activity increased slightly with age. Both cytosolic and membrane-bound dicumarol-sensitive NAD(P)H:(quinone acceptor) oxidoreductase (DT-diaphorase, EC 1.6.99.2) activities were decreased by diets supplemented with CoQ(10). Animals fed with olive oil presented lower DT-diaphorase activity than those fed with sunflower oil, suggesting that the CoQ(10) antioxidant protection is strengthened by olive oil as fat source.

GDNF protects against aluminum-induced apoptosis in rabbits by upregulating Bcl-2 and Bcl-XL and inhibiting mitochondrial Bax translocation.

Direct (intracisternal) injection of aluminum complexes into rabbit brain results in a number of similarities with the neuropathological and biochemical changes observed in Alzheimer's disease and provides the opportunity to assess early events in neurodegeneration. This mode of administration induces cytochrome c release from mitochondria, a decrease in Bcl-2 in both mitochondria and endoplasmic reticulum, Bax translocation into mitochondria, activation of caspase-3, and DNA fragmentation. Coadministration of glial cell neuronal-derived factor (GDNF) inhibits these Bcl-2 and Bax changes, upregulates Bcl-XL, and abolishes the caspase-3 activity. Furthermore, treatment with GDNF dramatically inhibits apoptosis, as assessed by the TUNEL technique for detecting DNA damage. Treatment with GDNF may represent a therapeutic strategy to reverse the neuronal death associated with Alzheimer's disease and may exert its effect on apoptosis-regulatory proteins.

Comparison of three forms of bowel preparations for screening flexible sigmoidoscopy.

Our initial attempts at implementing a high-volume clinic were impeded by the quality of colon preparation. While two Fleet enema preparations were generally easy to administer and well tolerated, the results were frequently poor. Current studies are limited and opinions vary regarding the most effective bowel preparation. The purpose of this study was to compare three forms of bowel preparation for screening flexible sigmoidoscopy. All patients scheduled for screening flexible sigmoidoscopy were given one of three colon preparations: two Fleet enemas; magnesium citrate orally the evening before, clear liquid diet and two Dulcolax suppositories the day of the exam; or magnesium citrate orally the evening before, clear liquid the day of the exam, and two Fleet enemas 1 hour before the procedure. Examinations were performed using a video flexible sigmoidoscopy by specialty trained gastroenterologists. Physicians were asked to rate the preparations as excellent, good, fair, or poor according to explicit criteria, and to document depth of insertion. Results showed that the magnesium citrate and Fleet enema preparation was excellent for 70% of patients, allowing for greater depth of insertion. Need for repeat examination due to poor preparation was infrequent with this group and patient tolerance of the preparation was acceptable.

Adjuvant intraportal chemotherapy for Dukes B2 and C colorectal cancer also receiving systemic treatment: results of a multicenter randomized trial. Groupe Régional d'Etude du Cancer Colo-Rectal (Belgium).

In a randomized trial, the authors evaluated the possible adjuvant activity of intraportal chemotherapy (with 5-fluorouracil 500 mg/m2/day in continuous infusion for 7 days and mitomycin C 10 mg/m2 at day 7) administered after surgery to half of the patients who underwent a full resection for Dukes B2 or C colorectal cancer. The procedure appeared manageable and safe. Two hundred and sixty patients were initially randomized, among whom 173 were finally considered as fully evaluable after having completed six courses of systemic chemotherapy. The reasons for withdrawal were basically tumoral ones and patients or doctors compliance. After a median follow-up of 4.5 years, no difference could be observed in the patients evolution assessed as relapses or deaths rate, or as relapse-free (at 5 years: 68% in the portal treatment group versus 70% in the control group) or overall survival (at 5 years: 76 versus 74%). The frequency of hepatic metastases (21 versus 18%) was also similar in both groups.

Erythropoietin, folic acid deficiency and hyperhomocysteinemia: is there a possible relationship in chronically hemodialyzed patients?

AIMS: To examine the possible relationships between recombinant human erythropoietin (rhEPO) therapy, serum folic acid and homocysteine levels in a cohort of stable, chronically hemodialyzed patients. MATERIAL AND METHODS: The study was cross-sectional in its first phase and consisted of 3 groups of subjects (group 1:6 healthy controls; group 2:7 dialyzed patients not receiving rhEPO; group 3: 14 patients on rhEPO therapy). Hematological and biochemical parameters were taken after an overnight fast in all subjects. The second phase of the study was prospective, and included 8 dialyzed patients, and investigated the effects of a 6-month period of folic acid supplementation (10 mg, 3 times a week) on the same parameters examined in the first phase of the study. RESULTS: In the first part of the study hemoglobin levels were near-normal, or normal, in all patients. No differences in hemoglobin or hematocrit values were observed in the 3 groups. 80% of all hemodialyzed patients had low serum folic acid levels, irrespective of whether they were receiving rhEPO. Serum erythropoietin level was elevated in group 3 (23.3+/-10.4 mIU/ml). In group 2, serum erythropoietin level was not different from that of the healthy controls (13.5+/-11.2 vs. 8.0+/-5.4 mIU/ml, p = n.s.). Total serum homocysteine levels were elevated in all dialyzed patients (group 2: 24.7+/-9.2 micromol/l; group 3: 31.6+/-14.4 micromol/l), with a significant difference seen when comparing controls and those dialyzed patients on rhEPO therapy (8.7+/-2.2 vs. 31.6+/-14.4 micromol/l; p<0.05). Significant correlations (ANOVA) were observed between serum erythropoietin and folic acid levels (r = -0.382; p = 0.049), and between folic acid and homocysteine levels (r = -0.560; p = 0.002). In the second part of the study folic acid supplementation led to a highly significant reduction in homocysteine levels (20.9+/-4.9 vs. 11.9+/-2.5 micromol/l; p<0.0005). Two of 3 patients receiving rhEPO therapy, had rhEPO discontinued after commencing folic acid, as hemoglobin levels remained adequate, even without rhEPO. CONCLUSIONS: In hemodialyzed patients, the presence of a near-normal hemoglobin level, irrespective of rhEPO therapy, implies efficient erythropoiesis. Without adequate folic acid reserves, folic acid deficiency may develop in these patients and this will aggravate already high homocysteine levels. Therefore, folic acid supplementation is warranted in hemodialyzed patients, especially in those patients with hemoglobin levels approaching normal. This treatment is safe and effective in reducing homocysteine levels, especially when given in high doses for prolonged periods of time.

Importance of 5-fluorouracil dose-intensity in a double randomised trial on adjuvant portal and systemic chemotherapy for Dukes B2 and C colorectal cancer.

366 patients fully resected from a Dukes B2 or C colorectal cancer were randomised to receive 6 courses of systemic chemotherapy comprising either 5-fluorouracil (5 FU) alone (arm A: 450 mg/m2/day-5/21 days) or combined folinic acid (FOL) and 5 FU (arm B: respectively 200 mg/m2 racemic form or 100 mg/m2-l-form and 370 mg/m2/day-5/21 days). 173 patients had also been initially randomised to receive one course of intraportal chemotherapy just after surgery or no portal treatment. Oral levamisole (150 mg/day; 3 days every other week) was given to all patients for one year. A significantly higher incidence of leuco-granulocytopenia was observed in the arm A (5 FU alone) inducing more frequent dose delays and adaptations as well as levamisole's withdrawal. Then dose-intensities and dose-intensity products were lower in this arm but the dose intensity expressed in mg/m2/week remained higher (631 +/- 107 vs 557 +/- 99; p < 0.001). The median follow-up in the study was 4.5 years. Relapse free (RFS) and overall survivals (OAS) were prolonged in the 5 FU alone group peculiarly in those patients who had not been randomised for portal treatment. Curves diverged progressively with longer follows-up (at 8 years; RFS in arm A: 67-71% vs 59-53% in arm B; OAS in arm A: 72-74% vs 56-46% in arm B). Patients suffering from a colon or a Dukes C cancer benefited the most from the treatment with 5 FU alone. The results are discussed in the light of other recent adjuvant trials. Well dosed 5 FU over a short period of time without folinic acid may be a valuable and inexpensive adjuvant treatment for colorectal cancer. Levamisole may no longer be recommended in this setting.

Calcium balance during pulse alfacalcidol therapy for secondary hyperparathyroidism in CAPD patients treated with 1.0 and 1.25 mmol/L dialysate calcium.

Hypercalcemia frequently occurs in continuous ambulatory peritoneal dialysis (CAPD) patients treated with calcium carbonate and vitamin D metabolites. To reduce the incidence of this complication, it has been proposed to use dialysate solutions with a low calcium concentration. However, there is concern that these solutions may lead to a negative calcium balance. We measured calcium balance in 13 CAPD patients with secondary hyperparathyroidism who were treated with calcium carbonate and alfacalcidol, 2 microg twice weekly, while using 1.0- (1.0 group) and 1.25-mmol/L (1.25 group) dialysate calcium solutions. Calcium absorption was measured after the administration of Ca47. Results for the 1.0 (n = 6) and 1.25 (n = 7) groups included fractional calcium absorptions of 0.14 (range, 0.09 to 0.27) and 0.08 (range, 0.03 to 0.40; P = not significant [NS]) and calcium absorptions of 380 +/- 92 and 331 +/- 83 mg/d (P = NS). Dialysate calcium losses were 93 +/- 20 and 91 +/- 26 mg/d, and total calcium losses (dialysate and urine) were 106 +/- 16 and 108 +/- 40 mg/d (P = NS). Calcium balance was positive in all patients (274 +/- 92 and 223 +/- 65 mg/d; P = NS). These data suggest that the use of 1.0- and 1.25-mmol/L calcium solutions in conjunction with calcium carbonate and pulse alfacalcidol therapy is associated with a positive calcium balance in CAPD patients.

Integrating primary care and methadone maintenance treatment: implementation issues.

Linking primary medical care with methadone maintenance treatment brings critical services to drug users, many with HIV/AIDS, tuberculosis and other illnesses. However, a variety of important philosophical, ethical, and systems issues may impede the process of implementing a "linked" service delivery model. Conflicting paradigms, such as the traditional "doctor-patient" relationship with its emphasis on continuity of care and the substance abuse treatment model of limit-setting and behavioral consequences, create tension in the treatment system. This article describes these tensions and uses clinical vignettes to demonstrate how to address these implementation issues. In conclusion, solutions are proposed for successfully integrating services for medically ill substance abusers.