bluuebunny/crossref_metadata_2025 huggingface dataset:
Independent ingestion and microstructure of feeding patterns in infant rats lacking CCK-1 receptors
Authors: Blumberg S. , Haba D. , Schroeder M. , Smith G. P. , Weller A.
Published: August 2005

Otsuka Long-Evans Tokushima fatty (OLETF) rats are a strain of Long-Evans Tokushima Otsuka (LETO) rats that do not express CCK-1 receptors, developing in adulthood, hyperphagia, obesity, and non-insulin-dependent diabetes mellitus (NIDDM). We examined weight gain and meal patterns during a 30-min independent ingestion test on postnatal days 2–4 and again on days 9–11 in OLETF and LETO rat pups. OLETF pups were significantly heavier compared with their LETO controls at both ages, and they consumed significantly more of the sweet milk diet. The difference in intake can be attributed to a significant increase in meal size and duration. Number of clusters and bursts of licking within a meal were greater in OLETF rat pups, with no difference between strains in burst and cluster size. Interlick interval (ILI) was not significantly different between OLETF and LETO pups. This measure decreased on days 9–11 compared with days 2–4 in both strains. Latency to start feeding was significantly shorter on days 2–4 in OLETF vs. LETO pups, but this difference disappeared at the second test at the older age. Two- to four-day-old OLETF pups consumed a larger volume of milk during the first minute of feeding, and their initial lick rate and decay of lick rate were significantly larger compared with their LETO controls. Lack of CCK-1 receptors, or other OLETF-related abnormalities, therefore, resulted in a satiation deficit, leading to increased meal size, hyperphagia, and increased weight gain as early as 2–4 postnatal days.
In Vivo Clearance of Human Protein S in a Mouse Model
Authors: Denis Cécile V. , Roberts Sarah J. , Hackeng Tilman M. , Lenting Peter J.
Published: August 2005

Objective—

To explore the effect of the Heerlen polymorphism and C4b-binding protein (C4BP) on protein S catabolism in vitro and in vivo.

Methods and Results—

Radiolabeled protein S was efficiently bound and intracellularly degraded by THP-1 macrophages, and both processes were strongly reduced in the presence of the protein S-carrier protein C4BP. To test whether C4BP displays a similar protective effect in vivo, survival experiments were performed in mice. In the absence of C4BP, radiolabeled human protein S disappeared in a biphasic manner (mean residence time [MRT] 2 hours). However, the presence of C4BP resulted in a 4-fold prolonged survival of protein S (MRT 8 hours;
P
<0.0001). We also applied this experimental model to recombinant protein S-Heerlen, a naturally occurring variant that contains a Ser460Pro substitution. These clearance experiments revealed a strongly decreased survival of recombinant protein S-S460P (MRT 0.6 hours;
P
=0.021), which could be compensated partially by C4BP (MRT 1.4 hours;
P
=0.012 compared with protein S-S460P).

Conclusion—

Protein S-S460P has a reduced survival in vivo, which may explain the low levels of free protein S in individuals carrying this polymorphism. Furthermore, C4BP prevents premature clearance of protein S and uses this ability to compensate the increased clearance of protein S-S460P.
Cell-Signaling Evidence for Adenosine Stimulation of Coronary Smooth Muscle Proliferation via the A
1
Adenosine Receptor
Authors: Shen Jianzhong , Halenda Stephen P. , Sturek Michael , Wilden Peter A.
Published: August 2005

For decades, it has been thought that adenosine is exclusively antimitogenic on vascular smooth muscles via the A
2
-type adenosine receptor. Recently, we have demonstrated that adenosine stimulates proliferation of porcine coronary artery smooth muscle cells (CASMC) through the A
1
adenosine receptor. However, the cell-signaling mechanisms underlying A
1
receptor–mediated CASMC proliferation in response to adenosine have not been defined. Here, we show that in cultured CASMC, adenosine stimulates phosphorylation of extracellular signal–regulated kinase (ERK), Jun N-terminal kinase (JNK), and AKT in a concentration- and time-dependent manner. This effect is fully mimicked by NECA (nonselective agonist), largely mimicked by CCPA (A
1
-selective agonist), weakly mimicked by 2-Cl-IB-MECA (A
3
-selective agonist), but not by CGS21680 (A
2A
-selective agonist), indicating that adenosine signals strongly via the A
1
receptor to these mitogenic signaling pathways. This interpretation is supported by the finding that adenosine- and CCPA-induced phosphorylation of ERK, JNK, and AKT are inhibited by pertussis toxin (inactivator of Gi proteins) and by DPCPX (A
1
-selective antagonist), but not by SCH58261, MRS1706, and VUF5574 (A
2A
-, A
2B
-, and A
3
-selective antagonists, respectively). In addition, adenosine- and CCPA-induced phosphorylation of ERK, JNK, and AKT is inhibited, respectively, by U0126, PD98059 (mitogen-activated protein kinase kinase inhibitors), SP600125 (JNK kinase inhibitor), and wortmannin (phosphatidylinositol 3-kinase inhibitor). Furthermore, these kinase inhibitors abolish or diminish adenosine- and CCPA-induced increases in the rate of cellular DNA synthesis, bromodeoxyuridine incorporation, protein synthesis, and cell number. We conclude that adenosine activates the ERK, JNK, and phosphatidylinositol 3-kinase/AKT pathways primarily through the A
1
receptor, leading to CASMC mitogenesis.
Crosstalk of β-Adrenergic Receptor Subtypes Through G
i
Blunts β-Adrenergic Stimulation of L-Type Ca
2+
Channels in Canine Heart Failure
Authors: He Jia-Qiang , Balijepalli Ravi C. , Haworth Robert A. , Kamp Timothy J.
Published: August 2005

The mechanisms underlying the blunted contractile response to β-adrenergic receptor (β-AR) stimulation in heart failure (HF) are incompletely understood, especially with regard to β-AR subtype–specific regulation of L-type Ca
2+
channels. We evaluated the impact of HF induced by pacing tachycardia on β-AR regulation of L-type Ca
2+
channels in a canine model. To evaluate changes in the relative subcellular distribution of β-AR subtypes, left ventricular membranes enriched in surface sarcolemma and T-tubular sarcolemma were prepared. Radioligand binding using [
125
I]cyanopindolol revealed that HF resulted in a comparable decrease in the density of β
1
-ARs in both surface and T-tubule sarcolemma (55±4%, n=7,
P
<0.001; and 45±10%, n=7,
P
<0.01, respectively), but no significant change in β
2
-AR density was observed. Whole-cell patch clamp studies demonstrated a markedly blunted increase in
I
Ca,L
in response to saturating concentrations of the nonselective β-AR agonist isoproterenol (0.1 μmol/L) in failing myocytes compared with control (129±20%, n=11, versus 332±35%, n=7;
P
<0.001). Experiments testing β
1
-AR– and β
2
-AR–selective stimulation showed that the major component of the blunted response to nonselective β-AR stimulation in HF was caused by β
2
-AR activation, resulting in a pertussis toxin–sensitive, G
i
-mediated inhibition of the β
1
-AR–induced increase in
I
Ca,L
. In conclusion, canine HF results in the following: (1) a uniform reduction in β
1
-AR density in surface and T-tubule membrane fractions without a change in β
2
-AR density; and (2) the emergence of distinct G
i
-coupling to β
2
-ARs resulting in accentuated antagonism of β
1
-AR–mediated stimulation of
I
Ca,L
. These results have implications for optimizing the use of β-AR drugs in HF.
Calpain-Mediated Impairment of Na
+
/K
+
–ATPase Activity During Early Reperfusion Contributes to Cell Death After Myocardial Ischemia
Authors: Inserte Javier , Garcia-Dorado David , Hernando Victor , Soler-Soler Jordi
Published: August 2005

Na
+
overload and secondary Ca
2+
influx via Na
+
/Ca
2+
exchanger are key mechanisms in cardiomyocyte contracture and necrosis during reperfusion. Impaired Na
+
/K
+
–ATPase activity contributes to Na
+
overload, but the mechanism has not been established. Because Na
+
/K
+
–ATPase is connected to the cytoskeleton protein fodrin through ankyrin, which are substrates of calpains, we tested the hypothesis that calpain mediates Na
+
/K
+
–ATPase impairment in reperfused cardiomyocytes. In isolated rat hearts reperfused for 5 minutes after 60 minutes of ischemia, Na
+
/K
+
–ATPase activity was reduced by 80%, in parallel with loss of α-fodrin and ankyrin-B and detachment of α
1
and α
2
subunits of Na
+
/K
+
–ATPase from the membrane–cytoskeleton complex. Calpain inhibition with MDL-7943 during reperfusion prevented the loss of these proteins, increased Na
+
/K
+
–ATPase activity, attenuated lactate dehydrogenase release, and improved contractile recovery, and these beneficial effects of MDL-7943 were reverted by ouabain. The impairment of Na
+
/K
+
–ATPase was not a mere consequence of cell death because it was not altered in hearts in which contracture and cell death had been prevented by contractile blockade with 2,3-butanedione monoxime. In these hearts, concomitant calpain inhibition preserved Na
+
/K
+
–ATPase content and function and attenuated cell death occurring on withdrawal of 2,3-butanedione monoxime. In vitro assay showed no detectable degradation of Na
+
/K
+
–ATPase subunits after 10 minutes of incubation with activated calpain. Thus, we conclude that calpain activation contributes to the impairment of Na
+
/K
+
–ATPase during early reperfusion and that this effect is mainly mediated by degradation of the anchorage of Na
+
/K
+
–ATPase to the membrane cytoskeleton.
Impairment of Diazoxide-Induced Formation of Reactive Oxygen Species and Loss of Cardioprotection in Connexin 43 Deficient Mice
Authors: Heinzel Frank R. , Luo Yukun , Li Xiaokui , Boengler Kerstin , Buechert Astrid , García-Dorado David , Di Lisa Fabio , Schulz Rainer , Heusch Gerd
Published: August 2005

Protection by ischemic preconditioning is lost in cardiomyocytes and hearts of heterozygous connexin 43 deficient (Cx43
+/−
) mice. Because connexin 43 (Cx43) is localized in cardiomyocyte mitochondria and mitochondrial Cx43 content is increased with ischemic preconditioning, we now tried to identify a functional defect at the level of the mitochondria in Cx43
+/−
mice by use of diazoxide and menadione. Diazoxide stimulates the mitochondrial formation of reactive oxygen species (ROS) and menadione generates superoxide at multiple intracellular sites; both substances elicit cardioprotection through increased ROS formation. ROS formation in response to the potassium ionophore valinomycin was also measured for comparison. Menadione (2 μmol/L) and valinomycin (10 nmol/L) induced similar ROS formation in wild-type (WT) and Cx43
+/−
cardiomyocytes. In contrast, diazoxide (200 μmol/L) increased ROS formation by 43±10% versus vehicle in WT, but only by 18±4% in Cx43
+/−
cardiomyoctes (
P
<0.05). Two hour–simulated ischemia and oxygenated, hypo-osmolar reperfusion reduced viability as compared with normoxia (WT: 7±1% versus 39±2%, Cx43
+/−
: 8±1% versus 40±3%,
P
<0.01). Although menadione protected WT and Cx43
+/−
cardiomyocytes, diazoxide increased viability (17±2%,
P
<0.01) in WT, but not in Cx43
+/−
(9±1%). Menadione (37 μg/kg i.v.) before 30 minutes coronary occlusion and 2 hour reperfusion reduced infarct size in WT and Cx43
+/−
mice (24±4% versus 24±5%). In contrast, diazoxide (5 mg/kg i.v.) reduced infarct size in WT (35±4% versus 55±3% of area at risk,
P
<0.01), but not in Cx43
+/−
mice (56±2% versus 54±3%). Cardiomyocytes of Cx43
+/−
mice have a specific functional deficit in ROS formation in response to diazoxide and accordingly less protection.
Oral Small Peptides Render HDL Antiinflammatory in Mice and Monkeys and Reduce Atherosclerosis in ApoE Null Mice
Authors: Navab Mohamad , Anantharamaiah G.M. , Reddy Srinivasa T. , Hama Susan , Hough Greg , Frank Joy S. , Grijalva Victor R. , Ganesh Vannakambadi K. , Mishra Vinod K. , Palgunachari Mayakonda N. , Fogelman Alan M.
Published: August 2005

A peptide containing only 4 amino acid residues (KRES) that is too small to form an amphipathic helix, reduced lipoprotein lipid hydroperoxides (LOOH), increased paraoxonase activity, increased plasma HDL-cholesterol levels, rendered HDL antiinflammatory, and reduced atherosclerosis in apoE null mice. KRES was orally effective when synthesized from either L or D-amino acids suggesting that peptide-protein interactions were not required. Remarkably, changing the order of 2 amino acids (from KRES to KERS) resulted in the loss of all biologic activity. Solubility in ethyl acetate and interaction with lipids, as determined by differential scanning calorimetry, indicated significant differences between KRES and KERS. Negative stain electron microscopy showed that KRES formed organized peptide-lipid structures whereas KERS did not. Another tetrapeptide FREL shared many of the physical-chemical properties of KRES and was biologically active in mice and monkeys when synthesized from either L- or D-amino acids. After oral administration KRES and FREL were found associated with HDL whereas KERS was not. We conclude that the ability of peptides to interact with lipids, remove LOOH and activate antioxidant enzymes associated with HDL determines their antiinflammatory and antiatherogenic properties regardless of their ability to form amphipathic helixes.
Reduced Wall Compliance Suppresses Akt-Dependent Apoptosis Protection Stimulated by Pulse Perfusion
Authors: Li Manxiang , Chiou Kuan-Rau , Bugayenko Artem , Irani Kaikobad , Kass David A.
Published: August 2005

Reduced arterial compliance and increased pulse pressure are common and major risk factors for cardiovascular disease. Here, we reveal a novel mechanism whereby loss of wall distensibility blunts endothelial cell protection to oxidant stress–induced apoptosis. Bovine aortic endothelial cells cultured in compliant or stiff silastic tubes were pulse perfused by arterial pressure/flow waveforms generated by a servo-pump. Pulse perfusion induced time-dependent Akt activation peaking >6-fold after 2 hours in compliant tubes and a similar time course but half the magnitude in stiff tubes. This was accompanied by quantitatively similar disparities in phosphoinositide-3 kinase activation and in Akt-stimulated suppressors of apoptosis: glycogen synthase kinase-3β, forkhead, and Bad. Cells perfused in compliant tubes had twice the protection against H
2
O
2
-stimulated apoptosis than those in stiffer tubes. This protection was lost by pretreatment with an Akt inhibitor and restored in cells transfected with myristoylated Akt yet perfused in stiff tubes. Shear and stretch Akt signaling coupled to different upstream pathways as inhibition of vascular endothelial growth factor receptor 2 (VEGF2R) or disruption of caveolae blocked steady and pulse flow–mediated activation, yet did not suppress phosphorylated Akt induced by pulse perfusion in compliant tubes (concomitant stretch). Unlike Akt, reactive oxygen species, activated nuclear factor κB, and suppression of H
2
O
2
-stimulated c-Jun-N-terminal kinase activity were similar in pulse-perfused compliant and stiff tubes. Thus, cyclic endothelial cell stretch by pulse perfusion enhances Akt-dependent antiapoptosis above that induced by steady or phasic shear stress and, unlike the latter, signals via a VEGF2R/caveolae-independent pathway. Enhancing this stretch pathway may prove useful for improving endothelial function in stiff arteries.
Antiplatelet Agents in Secondary Prevention of Stroke
Authors: Norris John W.
Published: August 2005

Background and Purpose—

Antiplatelet agents are widely used in the secondary prevention of stroke and other vascular events. The purpose of this review is to give a perspective of the factors involved in clinical practice for selecting antiplatelet drugs appropriate to the patient population.

Summary of Review—

Aspirin remains the most popular drug, because it is modestly effective (≈25% risk reduction); however, it has undesirable side effects that are sometimes serious. The nonaspirin compounds are marginally more effective but are much more expensive and subject to commercial pressures from industry. A completely new look at these compounds is necessary, rather than spending more precious resources on “drug wars” that are expensive in time and money.

Conclusion—

A “polypill” has been previously proposed, and possibly a combination of drugs targeted at the major vascular risk factors that is given to patients within 24 hours of initial stroke symptoms and to clearly defined patient populations may prove a solution.
Baroreflex Sensitivity Is Impaired in Bilateral Carotid Atherosclerosis
Authors: Nasr Nathalie , Pavy-Le Traon Anne , Larrue Vincent
Published: August 2005

Background and Purpose—

The arterial baroreflex is an important determinant of the short-term regulation of blood pressure and cardiovascular variability. The purpose of our study was to determine whether baroreflex sensitivity (BRS) and heart rate (HR) variability are altered in patients with carotid atherosclerosis (CA) and to assess the impact of characteristics of CA on BRS.

Methods—

BRS and HR variability were prospectively evaluated in 75 consecutive patients undergoing carotid duplex examination in our neurosonology unit. Resting BRS was measured with the sequence method. HR variability was evaluated using spectral analysis.

Results—

BRS was significantly reduced in patients with bilateral CA compared with patients without CA (
P
=0.015) and patients with unilateral CA (
P
=0.045). BRS was unaltered in patients with unilateral CA compared with patients with no CA. BRS was already reduced in mild (stenosis <50%), bilateral CA and was not further impaired in more severe CA. The association of BRS impairment with bilateral CA remained significant after adjustment for age, hypertension, and a history of stroke or transient ischemic attack. The study of HR variability demonstrated a reduction in the power of high-frequency band in patients with bilateral CA compared with patients with unilateral CA or without CA (
P
=0.015).

Conclusion—

Bilateral CA is associated with an impairment of BRS and a shift of the sympathovagal balance toward a relative decrease of the parasympathetic component of HR variability. These changes are already present in mild, bilateral CA.
The Bioequivalence of Telithromycin Administered Orally as Crushed Tablets Versus Tablets Swallowed Whole
Authors: Lippert Christina , Gbenado Seth , Qiu Chunfu , Lavin Bruce , Kovacs Steven J.
Published: August 2005

This open‐label, randomized, crossover study was conducted to demonstrate bioequivalence for telithromycin administered as crushed or whole tablets. Single 800‐mg telithromycin doses (2 × 400‐mg tablets) were administered as crushed tablets mixed in 240 mL nutritional supplement drink followed by 120 mL water or as whole tablets swallowed with 240 mL water. Plasma telithromycin concentrations were measured by liquid chromatography/mass spectrometry; pharmacokinetic parameters were determined using noncompartmental methods. Average bioequivalence criteria were applied. Thirty‐two subjects received telithromycin by both methods. The 90% confidence intervals for the geometric mean ratios of maximum plasma concentration and area under the plasma concentration‐time curve to 24 hours were within the 0.80 to 1.25 range. Median tmax was 3.00 hours for both treatments. Both methods of administration were well tolerated. Crushing telithromycin tablets and administering them with a nutritional supplement drink is bioequivalent to ingesting whole tablets and could be a viable method of administration for patients unable to swallow tablets whole.
Concomitant Tacrolimus and Micafungin Pharmacokinetics in Healthy Volunteers
Authors: Hebert Mary F. , Blough David K. , Townsend Robert W. , Allison Mark , Buell Donald , Keirns James , Bekersky Ihor
Published: August 2005

Tacrolimus is an approved immunosuppressive agent and a known substrate for CYP3A. Micafungin is an echinocandin antifungal agent and a mild inhibitor of CYP3A metabolism in vitro. The objectives of this study were to evaluate the pharmacokinetics of tacrolimus (5 mg oral) and micafungin (100 mg intravenous) alone and with concomitant administration (n = 26). Tacrolimus area under the concentration‐time curve was 298 ± 135 μg•h/L when tacrolimus was administered alone, 305 ± 129 μg•h/L (P = .8; confidence interval 89%, 118%) when tacrolimus was given with single‐dose micafungin, and 282 ± 138 μg•h/L (P = .4; confidence interval 82%, 107%) when tacrolimus was given with steady‐state micafungin. Despite the mild inhibition of CYP3A in vitro by micafungin, there does not appear to be a drug interaction with tacrolimus and micafungin either with single‐dose or steady‐state micafungin administration.
Acute and Chronic Effects of Vinpocetine on Cerebral Hemodynamics and Neuropsychological Performance in Multi‐infarct Patients
Authors: Kemény Vendel , Molnár Sándor , Andrejkovics Mónika , Makai Attila , Csiba László
Published: August 2005

A double‐blind, prospective, randomized, placebo‐controlled clinical trial was carried out to test the acute and long‐term hemodynamical and beneficial cognitive effects of the vasoactive agent vinpocetine on patients suffering from multiple cerebral infarcts by means of functional transcranial Doppler examinations and by neuropsychological tests. Twenty‐six patients (17 men, 9 women) with multiple cerebral infarctions, aged between 50 and 83 years (mean age ± SD = 63.4 ± 9.39 years) were examined, 14 of whom received vinpocetine and 12 placebo. The functional transcranial Doppler included breath‐holding tests, finger movement, word fluency, and picture‐discrimination tasks. Twenty‐five patients were assessed by neuropsychological battery. No serious side effect was found in the vinpocetine group. The flow velocities were significantly lower in the acute phase after breath holding in the vinpocetine group than in the placebo group. Three months later, the vinpocetine patients did not show any significant worsening in digit span backward test, while the placebo group did. No other significant differences in the neuropsychological test could be detected between the treatment and the placebo groups. Longer lasting and higher dosage of vinpocetine therapy is suggested to prove its potential effect.
Contrasting Challenges of Insulin Pump Therapy in a Toddler and Adolescent With Type 1 Diabetes
Authors: Doyle Elizabeth A. , Steffen Amy T. , Tamborlane William V.
Published: August 2005

Purpose

To describe the challenges and outcomes of continuous subcutaneous insulin infusion (CSII) pump therapy in a toddler and adolescent with type 1 diabetes. Insight into patient-family aspects motivating pump use is provided.

Methods

Two cases treated at the Pediatric Diabetes Clinic at Yale University.

Results

Upon parental request, CSII was initiated to improve glycemic control in a 4-year-old boy (case 1) with unpredictable food intake. During 68 months of CSII therapy, hemoglobin A1C levels averaged 6.3% ± 0.6%. Severe hypoglycemic episodes ceased 36 months ago, and occasional postprandial hyperglycemia during early school years was corrected with school nurses’ reminders about premeal insulin bolus doses. Currently 9.5 years old, he independently manages all his insulin injections with parental assistance only to change the catheter site. Case 2 is a girl who was nearly 12 years of age when diagnosed with type 1 diabetes. Initially managed with daily injections, hypoglycemic episodes were interfering with her physically active lifestyle. At age 13 years, she elected CSII therapy, and glycemic control improved. Temporarily erratic in the immediate period pre- and postmenarche, metabolic control has since stabilized. At 15 years old, she successfully manages her diabetes independently.

Conclusions

To optimize glycemic control, CSII can be initiated and used effectively, both in children of all ages and in adolescents with type 1 diabetes. CSII may be ideal therapy for toddlers, with no apparent lower age boundary for initiating CSII; however, the parenting challenges and requirements for supportive education differ between toddlers and adolescents. When disease and pump management are appropriately individualized, CSII therapy can help children with diabetes achieve and sustain glycemic control. Lifestyle flexibility, quality-of-life improvement, and independence can thus begin early in childhood and be maintained throughout young adulthood.
Culturally Competent Diabetes Education
Authors: Anderson-Loftin Wanda , Barnett Steve , Bunn Peggy , Sullivan Patra , Hussey James , Tavakoli Abbas
Published: August 2005

Purpose

The purpose of this study was to test effects of a culturally competent, dietary self-management intervention on physiological outcomes and dietary behaviors for African Americans with type 2 diabetes.

Methods

A longitudinal experimental study was conducted in rural South Carolina with a sample of 97 adult African Americans with type 2 diabetes who were randomly assigned to either usual care or the intervention. The intervention consisted of 4 weekly classes in low-fat dietary strategies, 5 monthly peer-professional group discussions, and weekly telephone follow-up. The culturally competent approach reflected the ethnic beliefs, values, customs, food preferences, language, learning methods, and health care practices of southern African Americans.

Results

Body mass index and dietary fat behaviors were significantly lowered in the experimental group. At 6 months, weight decreased 1.8 kg (4 lb) for the experimental group and increased 1.9 kg (4.2 lb) for the control group, a net difference of 3.7 kg (8.2 lb). The experimental group reduced high-fat dietary habits to moderate while high-fat dietary habits of the control group remained essentially unchanged. A trend in reduction of A1C and lipids was observed.

Conclusions

Results suggest the effectiveness of a culturally competent dietary self-management intervention in improving health outcomes for southern African Americans, especially those at risk due to high-fat diets and body mass index ≥ 35 kg/mm2. Given the burgeoning problem of obesity in South Carolina and the nation, the time has come to focus on aggressive weight management. Diabetes educators are in pivotal positions to assume leadership in achieving this goal for vulnerable, rural populations.
Clinical Inertia Contributes to Poor Diabetes Control in a Primary Care Setting
Authors: Ziemer David C. , Miller Christopher D. , Rhee Mary K. , Doyle Joyce P. , Watkins Clyde , Cook Curtiss B. , Gallina Daniel L. , El-Kebbi Imad M. , Barnes Catherine S. , Dunbar Virginia G. , Branch William T. , Phillips Lawrence S.
Published: August 2005

Purpose

The purpose of this study was to determine whether “clinical inertia”—inadequate intensification of therapy by the provider—could contribute to high A1C levels in patients with type 2 diabetes managed in a primary care site.

Methods

In a prospective observational study, management was compared in the Medical Clinic, a primary care site supervised by general internal medicine faculty, and the Diabetes Clinic, a specialty site supervised by endocrinologists. These municipal hospital clinics serve a common population that is largely African American, poor, and uninsured.

Results

Four hundred thirty-eight African American patients in the Medical Clinic and 2157 in the Diabetes Clinic were similar in average age, diabetes duration, body mass index, and gender, but A1C averaged 8.6% in the Medical Clinic versus 7.7% in the Diabetes Clinic (P < .0001). Use of pharmacotherapy was less intensive in the Medical Clinic (less use of insulin), and when patients had elevated glucose levels during clinic visits, therapy was less than half as likely to be advanced in the Medical Clinic compared to the Diabetes Clinic (P < .0001). Intensification rates were lower in the Medical Clinic regardless of type of therapy (P < .0001), and intensification of therapy was independently associated with improvement in A1C (P < .001).

Conclusions

Medical Clinic patients had worse glycemic control, were less likely to be treated with insulin, and were less likely to have their therapy intensified if glucose levels were elevated. To improve diabetes management and glycemic control nationwide, physicians in training and generalists must learn to overcome clinical inertia, to intensify therapy when appropriate, and to use insulin when clinically indicated.
Longitudinal Study on the Relationship Between Symptomatology of Dementia and Levels of Subjective Burden and Depression Among Family Caregivers in Memory Clinic Patients
Authors: Berger Gabriele , Bernhardt Tanja , Weimer Erik , Peters Juergen , Kratzsch Tilman , Frolich Lutz
Published: August 2005

The objective was to evaluate the course and severity of dementia-related symptoms and their relationship to caregivers’ subjective burden and depression over time. Forty-five patients with dementia and their caregivers were followed over a period of 2 years. Patients’ cognition, function, and behavioral/psychological symptoms were assessed by the Mini Mental State Examination, Syndrome Kurz Test, Geriatric Depression Screening scale, Instrumental Activities of Daily Living Scale, Physical Self Maintenance Scale, Behavioral Abnormalities in Alzheimer’s Disease Rating Scale, and Nurses Observation Scale for Geriatric Patients. Caregivers’ depression and subjective burden were evaluated by the Geriatric Depression Screening scale or Beck Depression Inventory and the Caregiver Burden Interview. Global dementia severity, functional impairment, and behavioral disturbances increased significantly over the 2-year observation period. Caregivers’ burden remained stable, and severe depression decreased over time. There were significant associations between burden and dementia-related symptoms. For deficits in activities of daily living as well as behavioral disturbances, these associations became stronger over time. It was concluded that stage of dementia, functional deficits, and behavioral disturbances are important factors when evaluating the relationship between patients’ symptoms and caregivers’ well-being.
The Performance of the Clock Drawing Test in Elderly Medical Inpatients: Does It Have Utility in the Identification of Delirium?
Authors: Adamis Dimitrios , Morrison Catriona , Treloar Adrian , Macdonald Alastair J. D. , Martin Finbarr C.
Published: August 2005

The Clock Drawing Test is an often-used test for the detection of cognitive impairment, but the few studies that have evaluated its utility in delirium have produced rather inconsistent results. In a longitudinal study of delirium in elderly medical inpatients, we have investigated the relationships between the Clock Drawing Test, the presence and severity of delirium, and cognitive impairment. Using mixed linear model analysis we found that cognitive impairment was the major factor associated with low Clock Drawing Test scores ( P < .0001): neither the presence nor the severity of delirium had additional significant effect on the Clock Drawing Test. Thus, we conclude that although the Clock Drawing Test is a good detector of cognitive impairment, it is not a suitable tool for detection of delirium in elderly medical inpatients.
Delusion of Theft and Phantom Intruder Delusion in Demented Elderly Patients in Japan
Authors: Terada Seishi , Ishizu Hideki , Fujisawa Yoshikatsu , Yokota Osamu , Kugo Aki , Nakashima Hanae , Tanaka Yuji , Ishihara Takeshi , Nakashima Tadao , Nakashima Yoshihiko , Sasaki Ken , Kuroda Shigetoshi
Published: August 2005

Delusion of theft and phantom intruder delusion are among the most frequent delusions in dementia. The purpose of this study was to clarify the clinical characteristics of patients with these symptoms. The authors conducted a questionnaire survey; items included age, gender, dementia diagnosis, cognitive function, and activities of daily living. Other clinical characteristics were evaluated using the quality of life questionnaire for dementia. A total of 217 patients with dementia were rated. Frequencies of delusion of theft were as follows: frequent, 7%; sometimes, 11%; rare, 16%; and none, 66%. Frequencies of phantom intruder delusion were as follows: frequent, 4%; sometimes, 10%; rare, 9%; and none, 77%. Comparison between positive and negative groups with these symptoms revealed that positive groups had higher scores in 2 of 6 domains of the quality of life questionnaire for dementia, namely, negative affect and actions, and restlessness. The positive group with delusion of theft had higher scores in cognitive function and activities of daily living than did the negative group. These results suggest that negative affect and action and restlessness might be related to delusion of theft or phantom intruder delusion and that delusion of theft frequently occurs in the early stage of dementia.
Cognitive Predictors of Dementia in Parkinson’s Disease: A Community-Based, 4-Year Longitudinal Study
Authors: Janvin Carmen Cristea , Aarsland Dag , Larsen Jan Petter
Published: August 2005

Although mild cognitive impairment and dementia are common and have important clinical consequences for patients with Parkinson’s disease (PD) and their caregivers, it is still unclear whether cognitive symptoms may predict the development of dementia in PD patients. The objective of this study was to determine whether cognitive deficits in nondemented PD patients predicted the development of dementia 4 years later. A total of 76 nondemented PD patients from an epidemiological study of PD in the county of Rogaland, Norway, were assessed at baseline and 4 years later with neurological, psychiatric, and neuropsychological evaluations. Twenty-five (42%) new cases of dementia were diagnosed after 4 years. Time to complete the third card of the Stroop test was the only variable that was independently associated with dementia. The authors concluded that poor performance on a test sensitive to executive dysfunction predicted later development of dementia in PD patients. This finding may have important clinical implications as a marker of subsequent development of dementia.
Inappropriate Sexual Behaviors in Dementia
Authors: Black Benjamin , Muralee Sunanda , Tampi Rajesh R.
Published: August 2005

Dementias are the most common type of neurodegenerative disorder. Behavioral disturbances are seen in more than 80% of patients suffering from these disorders. Although sexually inappropriate behaviors are not as common as some of the other behaviors seen in dementia, they can cause immense distress to all those who are affected. There are no randomized trials for the treatment of these behaviors, but the available data suggest efficacy for some commonly used treatment modalities. In this review, we systematically discuss various aspects of these behaviors and available treatments.
Profiling Local-Level Outcomes of Environmental Decentralizations: The Case of Cameroon’s Forests in the Congo Basin
Authors: René Oyono Phil
Published: August 2005

Since the mid-1990s, Cameroon has launched a process of decentralization of the management of its forests. Among other innovations, this decentralization process has transferred powers over forests and financial benefits accruing from their exploitation to local communities. This article explores and profiles such local-level outcomes. It shows that the experiment has not yet brought up expected positive results and very often generates internal conflicts, a new social stratification and the marginalization of traditional authorities. Second, the article argues that decentralized management is not producing positive economic results, as there is no significant economic change in the case study villages. Third, it demonstrates that the experiment is leading to negative environmental results, such as the degradation of many community forests in the forested Cameroon. The author recommends that policy makers, researchers, nongovernmental organizations, and the local communities design a monitoring framework for decentralized management.
Politicizing Indiscriminate Terror: Imagining an Inclusive Framework for the Anti-Landmines Movement
Authors: Berhe Asmeret Asefaw
Published: August 2005

Landmines are indiscriminate weapons of mass terror that detrimentally affect human beings, the ecological system they live in, the regional economy, and political stability. Despite the extensive nature of the impacts, the landmine crisis is almost exclusively advocated on the basis of human rights principles. A comprehensive framework that considers environmental degradation as a principal aftermath of the global landmine crisis is critically missing from the broader matrix of variables around which the anti-landmine movement converges. This article discusses the current humanitarian framework of the International Campaign to Ban Landmines; its shortcomings to address the interconnected impacts of landmines on the environment; and attempts to describe what an inclusive, environmentally sensitive framework would have to incorporate to address the overall landmine impacts effectively.
A Review of the Mechanisms Implicated in the Pathogenesis of the Diabetic Foot
Authors: Dinh Thanh L. , Veves Aristidis
Published: August 2005

The developmental pathway toward diabetic foot ulceration is best described as multifactorial. A critical triad of neuropathy, minor foot trauma, and foot deformity has been identified in greater than 63% of foot ulcers. In addition to these risk factors, increased peak plantar pressures, autonomic and motor neuropathy, limited joint mobility, and impaired wound healing contribute to the formation of diabetic foot ulcers. It is essential to understand the pathogenesis of foot ulcers so that appropriate treatments may be developed.
Infection in the Neuroischemic Foot
Authors: Edmonds Michael
Published: August 2005

Infection in the neuroischemic foot can lead to cellulitis, which often progresses to necrosis as a result of septic vasculitis. Therefore, it is important to diagnose infection early. However, the signs and symptoms of infection are diminished in the neuroischemic foot. Microbiological investigation is essential. Severe infection needs intravenous antibiotic therapy and urgent assessment of the need for surgical drainage and debridement. Infected neuroischemic feet need vascular assessment and intervention where appropriate. It is important to maintain strict metabolic control and optimize cardiovascular function. Recent modern approaches based on multi-disciplinary clinics have resulted in improved results in the management of infection in the ischemic diabetic foot.
Donor origin of multipotent adult progenitor cells in radiation chimeras
Authors: Reyes Morayma , Li Sheng , Foraker Jessica , Kimura En , Chamberlain Jeffrey S.
Published: August 2005

Multipotent adult progenitor cells (MAPCs) are bone marrow-derived stem cells that have extensive in vitro expansion capacity and can differentiate in vivo and in vitro into tissue cells of all 3 germinal layers: ectoderm, mesoderm, and endoderm. The origin of MAPCs within bone marrow is unknown. MAPCs are believed to be derived from the bone marrow stroma compartment as they are isolated within the adherent cell component. Numerous studies of bone marrow chimeras in the human and the mouse point to a host origin of bone marrow stromal cells. Mesenchymal stem cells (MSCs), which coexist with stromal cells, have also been proven to be of host origin after allogeneic bone marrow transplantation in numerous studies. We report here that following syngeneic bone marrow transplants into lethally irradiated C57BL6 mice, MAPCs are of donor origin.
Molecular identification of PAL-E, a widely used endothelial-cell marker
Authors: Niemelä Harri , Elima Kati , Henttinen Tiina , Irjala Heikki , Salmi Marko , Jalkanen Sirpa
Published: August 2005

The pathologische anatomie Leiden-endothelium (PAL-E) antibody has been used for almost 20 years as a specific marker for vascular endothelial cells. Due to the fact that this antibody works only in very limited applications, the molecular identity of PAL-E has remained unknown. In this work, we demonstrate by double stainings, cross-immunoprecipitations, and transfectants that the PAL-E antigen is identical with a protein designated PV-1 (plasmalemmal vesicle 1) or FELS (fenestrated endothelial-linked structure protein) and is not vimentin, as reported earlier. As the expression of this molecule is by no means restricted to fenestrated endothelium, we suggest the use of the name PLVAP for this protein. Molecular identification of PLVAP should help in the production of new tools for the identification of vascular as opposed to lymphatic endothelium and to elucidate the function of this protein.
p21-activated kinase (Pak) regulates NADPH oxidase activation in human neutrophils
Authors: Martyn Kendra D. , Kim Moon-Ju , Quinn Mark T. , Dinauer Mary C. , Knaus Ulla G.
Published: August 2005

The phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase plays an instrumental role in host defense and contributes to microbicial killing by releasing highly reactive oxygen species. This multicomponent enzyme is composed of membrane and cytosolic components that assemble in the plasma membrane or phagolysosome. While the guanosine S′-triphosphatase (GTPase) Rac2 has been shown to be a critical regulator of NADPH oxidase activity and assembly, the role of its effector, p21-activated kinase (Pak), in oxidase function has not been well defined. Using HIV-1 Tat-mediated protein transduction of Pak inhibitory domain, we show here that Pak activity is indeed required for efficient superoxide generation in intact neutrophils. Furthermore, we show that Pak translocates to the plasma membrane upon N-formyl-methionyl-leucyl-phenylalanine (fMLF) stimulation and colocalizes with translocated p47phox and with p22phox, a subunit of flavocytochrome b558. Although activated Pak phosphorylated several essential serine residues in the C-terminus of p47phox, direct binding to p47phox was not observed. In contrast, active Pak bound directly to p22phox, suggesting flavocytochrome b was the oxidase-associated membrane target of this kinase and this association may facilitate further phosphorylation of p47phox in the assembling NADPH oxidase complex.
Constitutive NF-κB and NFAT activation in aggressive B-cell lymphomas synergistically activates the CD154 gene and maintains lymphoma cell survival
Authors: Pham Lan V. , Tamayo Archito T. , Yoshimura Linda C. , Lin-Lee Yen-Chiu , Ford Richard J.
Published: August 2005

Abnormalities in B-lymphocyte CD40 ligand (CD154) expression have been described for a number of immunologic diseases, including B-cell lymphomas. Although functional analysis of the CD154 gene and protein has been extensive, little is known about the mechanisms controlling CD154 expression in activated T cells, and even less is known for normal and malignant B cells. In this study we describe the transcriptional mechanism controlling CD154 expression in large B-cell lymphoma (LBCL). We show that the nuclear factor of activated T cells (NFAT) transcription factor is also constitutively activated in LBCL. We demonstrate that the constitutively active NFATc1 and c-rel members of the NFAT and nuclear factor–κB (NF-κB) families of transcription factors, respectively, directly interact with each other, bind to the CD154 promoter, and synergistically activate CD154 gene transcription. Down-regulation of NFATc1 or c-rel with small interfering RNA (siRNA) or chemical inhibitors inhibits CD154 gene transcription and lymphoma cell growth. These findings suggest that targeting NF-κB and NFAT, by inhibiting the expression of these transcription factors, or interdicting their interaction may provide a therapeutic rationale for patients with non-Hodgkin lymphoma of B-cell origin, and possibly other disorders that display dysregulated CD154 expression.
Inhibition of dynamin-dependent endocytosis increases shedding of the amyloid precursor protein ectodomain and reduces generation of amyloid β protein
Authors: Carey Robyn M , Balcz Brigitte A , Lopez-Coviella Ignacio , Slack Barbara E
Published: August 2005

Background

The amyloid precursor protein (APP) is transported via the secretory pathway to the cell surface, where it may be cleaved within its ectodomain by α-secretase, or internalized within clathrin-coated vesicles. An alternative proteolytic pathway occurs within the endocytic compartment, where the sequential action of β- and γ-secretases generates the amyloid β protein (Aβ). In this study, we investigated the effects of modulators of endocytosis on APP processing.

Results

Human embryonic kidney cells were transfected with a dominant negative mutant of dynamin I, an important mediator of clathrin-dependent endocytosis, and APP proteolysis was analyzed. Overexpression of the mutant dynamin (dyn I K44A) resulted in increased shedding of the APP ectodomain (sAPPα), accumulation of the C-terminal α-secretase product C83, and a reduction in the release of Aβ. Levels of mature APP on the cell surface were increased in cells expressing dyn I K44A, and internalization of surface-immunolabeled APP, assessed by fluorescence microscopy, was inhibited. Dynamin is a substrate for protein kinase C (PKC), and it was hypothesized that activators of PKC, which are known to stimulate α-secretase-mediated cleavage of APP, might exert their effects by inhibiting dynamin-dependent endocytosis. However, the internalization of surface-biotinylated APP was unaffected by treatment of cells with phorbol 12-myristate 13-acetate in the presence of the α-secretase inhibitor TAPI-1.

Conclusion

The results indicate that APP is internalized by a dynamin-dependent process, and suggest that alterations in the activity of proteins that mediate endocytosis might lead to significant changes in Aβ production.
No significant role for beta tubulin mutations and mismatch repair defects in ovarian cancer resistance to paclitaxel/cisplatin
Authors: Mesquita Bárbara , Veiga Isabel , Pereira Deolinda , Tavares Ana , Pinto Isabel M , Pinto Carla , Teixeira Manuel R , Castedo Sérgio
Published: August 2005

Background

The mechanisms of chemoresistance in ovarian cancer patients remain largely to be elucidated. Paclitaxel/cisplatin combination is the standard chemotherapeutic treatment for this disease, although some patients do not respond to therapy. Our goals were to investigate whether TUBB mutations and mismatch repair defects underlie paclitaxel and cisplatin resistance.

Methods

Thirty-four patients with primary ovarian carcinomas (26 serous and eight clear cell carcinomas) treated with paclitaxel/cisplatin were analysed. TUBB exon 4 was analysed by nested PCR after a first round PCR using intronic primers. Microsatellite analysis was performed with the quasimonomorphic markers BAT 26 and BAT 34.

Results

Twenty-two of the 34 ovarian cancers (64.7%) presented residual tumour after surgery, seven of which (7/22; 31.8%) were shown to be chemoresistant (five serous and two clear cell tumours). Sequence analysis did not find any mutation in TUBB exon 4. Microsatellite instability was not detected in any of the ovarian carcinomas.

Conclusion

We conclude that TUBB exon 4 mutations and mismatch repair defects do not play a significant role in paclitaxel/cisplatin resistance.
Mitral supravalvular ring: a case report
Authors: Serra Walter , Testa Paola , Ardissino Diego
Published: August 2005

Supravalvular mitral stenosis is a rare condition characterized by an abnormal ridge, with one or two orifices, covering and obstructing the mitral valve. Preoperative diagnosis is difficult with transtoracic echo (TTE), angiography and magnetic resonance imaging (MRI).

In this case, a 36-year-old male, was admitted to our Heart department: He experienced progressive dyspnea on effort and at rest.

Diagnosis was made by transesophageal echocardiography which showed, on apical 4-chamber section, an anulare structure attached since a membrane to the atrial wall anterior mitral valve leaflet and just proximal to the posterior mitral leaflet.

Pre-operative identification of the supravalvular mitral ring is the target for obtaining good surgical results. Cineangiography and MRI both failed in reaching this objective, whereas, transesophageal echocardiography is the best method to identify this congenital heart disease.

Using TEE the identification is not only possible but also easier.