Circulating interleukin-6 is associated with disease progression,but not cachexia in pancreatic cancer

Background

Cachexia is a wasting syndrome characterized by involuntary loss of >5% body weight due to depletion of adipose and skeletal muscle mass. In cancer, the pro-inflammatory cytokine interleukin-6 (IL-6) is considered a mediator of cachexia and a potential biomarker, but the relationship between IL-6, weight loss, and cancer stage is unknown. In this study we sought to evaluate IL-6 as a biomarker of cancer cachexia while accounting for disease progression.

Transient neonatal hypothyroidism alters plasma and testicular sex steroid concentration in puberal rats

The stimulatory and inhibitory effects on testicular steroidogenesis of transient neonatal hypothyroidism from day 1 postpartum through different postnatal developmental events on testis at puberal age (60 days old) were studied in vivo. Hypothyroidism was induced in neonates by feeding the lactating mother or directly with 0.05% methimazole (MMI) through drinking water from the day of parturition to 10, 15, 30, 40 and 60 days, and were killed at day 60 postpartum. Plasma and testicular interstitial fluid (TIF) progesterone, testosterone, dihydrotestosterone (DHT) and estradiol concentrations were assessed. Testis weight and volume significantly increased in rats subjected to 10 and 15 days of hypothyroidism, decreased in rats subjected to 30, 40 and 60 days of hypothyroidism. A consistent increase in Leydig cell number was seen in puberal rats subjected to transient neonatal hypothyroidism but decreased in 60 days hypothyroid rats. Peritubular myoid cell number was consistently decreased in all experimental rats. Leydig cell diameter decreased consistently in all experimental groups. Persistent hypothyroidism (60 days hypothyroid) consistently decreased both plasma and TIF sex steroids. In transient hypothyroid rats, progesterone concentration decreased in both plasma and TIF. Transient hypothyroidism from birth to day 10 postnatal age maintained normal titre of plasma testosterone, whereas a significant increase in TIF testosterone concentration was evident when compared with controls. All other groups of rats subjected to transient neonatal hypothyroidism had consistently low titres of plasma and TIF testosterone. Plasma DHT concentrations in rats subjected to transient neonatal hypothyroidism remained unaltered. However, TIF DHT increased in 10 days     

Ultrafast folding of alpha3D: a de novo designed three-helix bundle protein

Here, we describe the folding/unfolding kinetics of alpha3D, a small designed three-helix bundle. Both IR temperature jump and ultrafast fluorescence mixing methods reveal a single-exponential process consistent with a minimal folding time of 3.2 +/- 1.2 micros (at approximately 50 degrees C), indicating that a protein can fold on the 1- to 5-micros time scale. Furthermore, the single-exponential nature of the relaxation indicates that the prefactor for transition state (TS)-folding models is probably >or=1 (micros)-1 for a protein of this size and topology. Molecular dynamics simulations and IR spectroscopy provide a molecular rationale for the rapid, single-exponential folding of this protein. alpha3D shows a significant bias toward local helical structure in the thermally denatured state. The molecular dynamics-simulated TS ensemble is highly heterogeneous and dynamic, allowing access to the TS via multiple pathways.     

Cholecystokinin-stimulated peak lipase concentration in duodenal drainage fluid: a new pancreatic function test

OBJECTIVE: Hormonal stimulation with secretin or cholecystokinin (CCK) is the most sensitive means of assessing pancreatic function. Secretin is not available, and current CCK tests are cumbersome, requiring dual tube intubation and marker perfusion techniques. The aim of this study was to test the efficacy of a new CCK-stimulated pancreatic function test measuring peak lipase concentration. METHODS: A Dreiling gastroduodenal tube was inserted to the ligament of Treitz, and fluid was collected on ice for 80 min in four 20-min aliquots. CCK was infused i.v. at a constant rate of 40 ng/kg/h. Gastric aspirations were discarded. Duodenal aspirates were analyzed for volume and enzyme concentration with a clinical laboratory autoanalyzer. RESULTS: Nineteen healthy volunteers and 18 chronic pancreatitis patients were studied. Lipase concentration and secretory volume showed a peak response by 40 min of stimulation, whereas amylase response was variable. The mean peak lipase concentrations (+/-SEM) for normal volunteers and mild, moderate, and advanced chronic pancreatitis patients were 16.9+/-1.9, 7.9+/-1.7, 3.7+/-1.2, and 2.1+/-0.6 x 10 5 IU/L, respectively. Lower peak lipase concentrations were significantly associated with more advanced chronic pancreatitis (p < 0.001). The receiver operating characteristic curve area for all chronic pancreatitis patients was 0.944 (95% CI = 0.825-0.985). A peak lipase concentration of 780,000 IU/L provided a sensitivity and specificity of 0.833 and 0.867, respectively. This CCK test was well tolerated and without complications. CONCLUSIONS: Lipase concentration in duodenal fluid increases nearly 3-fold from baseline after CCK stimulation in healthy volunteers but is markedly reduced in patients with chronic pancreatic disease. Peak lipase concentration is a significant predictor of chronic pancreatitis and correlates with severity of pancreatic disease. Aspiration of duodenal drainage fluid with a Dreiling tube and analysis with a laboratory autoanalyzer are less cumbersome than marker perfusion and back titration techniques. Measurement of enzyme concentration instead of output could lead to the development of an endoscopic or through-the-scope screening method for assessing patients with suspected chronic pancreatitis or chronic abdominal pain.     

Real-time stability measurement system for postural control

A method for assessing balance, which was sensitive to changes in the postural control system is presented. This paper describes the implementation of a force-sensing platform, with force sensing resistors as the sensing element. The platform is capable of measuring destabilized postural perturbations in dynamic and static postural conditions. Besides providing real-time qualitative assessment, the platform quantifies the postural control of the subjects. This is done by evaluating the weighted center of applied pressure distribution over time. The objective of this research was to establish the feasibility of using the force-sensing platform to test and gauge the postural control of individuals. Tests were conducted in Eye Open and Eye Close states on Flat Ground (static condition) and the balance trainer (dynamic condition). It was observed that the designed platform was able to gauge the sway experienced by the body when subject’s states and conditions changed.     

The intrinsic conformational propensities of the 20 naturally occurring amino acids and reflection of these propensities in proteins

Here, we compare the distributions of main chain (Φ,Ψ) angles (i.e., Ramachandran maps) of the 20 naturally occurring amino acids in three contexts: (i) molecular dynamics (MD) simulations of Gly-Gly-X-Gly-Gly pentapeptides in water at 298 K with exhaustive sampling, where X = the amino acid in question; (ii) 188 independent protein simulations in water at 298 K from our Dynameomics Project; and (iii) static crystal and NMR structures from the Protein Data Bank. The GGXGG peptide series is often used as a model of the unstructured denatured state of proteins. The sampling in the peptide MD simulations is neither random nor uniform. Instead, individual amino acids show preferences for particular conformations, but the peptide is dynamic, and interconversion between conformers is facile. For a given amino acid, the (Φ,Ψ) distributions in the protein simulations and the Protein Data Bank are very similar and often distinct from those in the peptide simulations. Comparison between the peptide and protein simulations shows that packing constraints, solvation, and the tendency for particular amino acids to be used for specific structural motifs can overwhelm the “intrinsic propensities” of amino acids for particular (Φ,Ψ) conformations. We also compare our helical propensities with experimental consensus values using the host–guest method, which appear to be determined largely by context and not necessarily the intrinsic conformational propensities of the guest residues. These simulations represent an improved coil library free from contextual effects to better model intrinsic conformational propensities and provide a detailed view of conformations making up the “random coil” state.     

Health economics of cardiovascular disease: Defining the research agenda

Background

When allocating limited resources, public and private sector leaders in health policy consider both the health and economic value of new measures for cardiovascular disease (CVD) prevention. The ability to develop and prioritize policy measures is hindered by important gaps in health economics data.

Methods and Results

The Policy Research Implementation Group (PRIG) of the National Forum for Heart Disease and Stroke Prevention convened a symposium to develop priorities for research on the economics of CVD primary prevention and elimination of CVD disparities. Suggested top opportunities include expanded CVD surveillance, advances in evaluation and economic modeling of primary prevention, and use of behavioral economics to identify new prevention strategies. Enhanced policy, funding, and leadership support are vital to realizing this research agenda.

Conclusions

Targeted research on the health and economic value of CVD prevention, especially to eliminate CVD disparities, would bolster the justification for increased investment in cardiovascular health.     

Injury induced neointima formation and its inhibition by retrovirus-mediated transfer of nitride oxide synthase gene in an in-vitro human saphenous vein culture model

Human saphenous veins were cultured to characterize neointima formation and feasibility of gene transfer to inhibit the intimal proliferative response to injury. Mechanical injury was introduced by abrading the luminal surface of the vein patch with a sterile cotton bud. Both injured and non-injured vein patches were cultured and transduced with retroviral vectors carrying marker or therapeutic genes. After a 14-day culture, the thickness of the intimal layer of non-injured vein patches reached 90+/-28 microm at the edge and 61+/-22 microm at the center (n=29) from the original 22+/-12 microm at harvest (n=6, P=0.02). Mechanical injury to the intimal surface prior to culture resulted in an exaggerated proliferative response. The intimal thickness of injured vein patches increased from 3.4+/-1 microm right after injury to 128+/-23 microm (n=12, P<0.001) at the edge after 14-day culture. Genes were transduced efficiently into a luminal layer of cultured veins using a pseudotyped murine leukemia viral vector. Transduction of gene encoding nitric oxide synthase resulted in reduction of neointima formation to 33+/-7 microm (n=12) at the edge after 14-day culture compared to 90 microm (P<0.01) seen in untransduced non-injured vein patches. Marker gene transduction did not alter intimal proliferative response or its immunohistochemical profile. The data suggest that cultured vein can be used as a model for studying the effects of injury to blood vessels and to evaluate the effects of candidate therapeutic genes.     

Binding of α-Bungarotoxin to Acetylcholine Receptors In Mammalian Muscle

Experiments were performed to determine the specificity of [(125)I]alpha-bungarotoxin binding to skeletal muscle. In adult rat diaphragm, [(125)I]alpha-bungarotoxin was found to bind almost exclusively to those regions of the muscle that contain endplates and are known to be sensitive to acetylcholine. In contrast, chronically denervated adult muscle and muscle from neonatal rats, both of which are sensitive along their entire lengths, bound substantial amounts of toxin in all regions. Toxin binding to all muscles was inhibited by d-tubocurarine and by carbamylcholine, but not by atropine. The bound [(125)I]toxin was solubilized by homogenization of the tissue in 1% Triton X-100 and was recovered as a single band, distinct from free toxin, after zone sedimentation. Treatment of the solubilized, toxin-bound complex with 2-mercaptoethanol and sodium dodecyl sulfate resulted in the recovery of free toxin. A toxin-bound complex was also obtained when toxin was incubated directly with extracts of muscle endplate regions prepared by homogenization in Triton X-100. No such complex was observed with extracts prepared from muscle lacking endplates. These results are consistent with the interpretation that alpha-bungarotoxin binds specifically to the acetylcholine receptor of mammalian skeletal muscle.     

Elevated serum parathyroid hormone concentration in eucalcemic patients after parathyroidectomy for primary hyperparathyroidism and its relationship to vitamin D profile

Elevation of serum parathyroid hormone (PTH) level in eucalcemic patients after parathyroidectomy for primary hyperparathyroidism has been described in up to 40% of patients, but little is known about its etiology or clinical significance. To better understand the cause of this phenomenon, we studied 49 patients without renal dysfunction or osteomalacia who underwent parathyroidectomy for primary hyperparathyroidism. Patients were categorized into 2 groups based on their serum PTH and calcium levels after parathyroidectomy: (1) elevated PTH with eucalcemia (n = 21), (2) normal PTH with eucalcemia (n = 28). Elevation of serum PTH with eucalcemia after parathyroidectomy occurred in 43% of patients. Patients in group 1 had significantly higher preoperative and postoperative mean serum PTH levels and significantly lower postoperative serum levels of 1,25(OH)(2)D(3), 1,25(OH)(2)D(3)/25(OH)D(3) ratio, and 1,25(OH)(2)D(3)/PTH ratio compared with patients in group 2. Serum PTH in group 1 patients normalized as early as 3 months, but remained elevated in some patients for more than 4 years, and was not associated with development of recurrent hypercalcemia. Normalization of serum PTH in group 1 patients was associated with significant increase in 1,25(OH)(2)D(3) and 1,25(OH)(2)D(3)/PTH ratio. Our data suggest that elevation of serum PTH in eucalcemic patients after parathyroidectomy is a frequently reversible state of resistance of the kidneys to PTH-mediated 1-alpha hydroxylation of 25(OH)D(3) and does not signify subsequent recurrence of hyperparathyroidism.