bluuebunny/crossref_metadata_2025 huggingface dataset:
Calcium–Sensing Receptor: Regulation of Electrolyte Transport in the Thick Ascending Limb of Henle's Loop
Authors: Desfleurs E. , Wittner M. , Simeone S. , Pajaud S. , Moine G. , Rajerison R. , Di Stefano A.
Published: April 2003

A calcium–sensing receptor (CaR) has functionally been described in the cortical thick ascending limb of Henle's loop (CTAL) of rat and mouse. This G protein–coupled receptor activates phospholipase C and increases the intracellular Ca2+ concentration. We observed that in the mouse CTAL cAMP formation, induced by 10–8 mol/l AVP, was inhibited by more than 90% when the extracellular Ca2+ concentration ([Ca2+]e) was increased from 0.5 to 3 mmol/l. Measurements of transepithelial potential difference (PDte) in rat and mouse CTAL and medullary thick ascending limb (mTAL) segments and of transepithelial ion net fluxes in the mouse CTAL (isotonic perfusion conditions: 150 mmol/l NaCl in the lumen and bath) showed that an increase in the [Ca2+]e had no effect on basal and arginine vasopressin (AVP, 10–10 mol/l)–stimulated transepithelial PDte, NaCl and Mg2+ transport. However, Ca2+ reabsorption was strongly inhibited by increased [Ca2+]e. Addition of AVP reversed this inhibitory effect of increased [Ca2+]e. Under hypotonic perfusion conditions (lumen 50 mmol/l NaCl; bath 150 mmol/l NaCl), a high [Ca2+]e induced a 50% decrease in Mg2+ reabsorption which was restored by AVP. Under these conditions, the effects on Ca2+ transport described above were still observed. In conclusion, activation of the CaR in the mouse TAL has no effect on basal and AVP–stimulated transepithelial NaCl reabsorption despite its large inhibitory effect on cAMP synthesis. The CaR, however, could play a role in the regulation of transepithelial Ca2+ and Mg2+ reabsorption.
Renal Potassium Handling in Aging Rats
Authors: de Araujo Magali , de B. Helou Claudia M. , Seguro Antonio Carlos
Published: April 2003

Aging is often related to electrolyte disorders. This study was designed to evaluate the renal capacity for K+ handling of aging rats submitted to both extreme situations of K+ depletion and K+ loading. Aging rats were submitted to metabolic assessment, measurement of plasma aldosterone and determination of Na+,K+–ATPase and H+,K+–ATPase activity in the inner medullary collecting duct (IMCD). During K+ depletion, aging rats showed low values of urine K+ excretion. After 2 weeks of dietary K+ restriction, the plasma K+ levels of these animals reached 2.9±0.1 mEq/l without acid–base disorders. During K+ loading, aging rats showed a significant increase in urinary K+ excretion, with plasma K+ remaining at normal levels (4.7±0.1 mEq/l). Plasma aldosterone levels were low in control aging rats but K+ intake modulated the levels of this hormone, with K+ depletion reducing it and K+ loading significantly increasing it. Na+,K+–ATPase activity increased only in the initial portion of the IMCD of aging rats after 2 weeks of K+ depletion. In the distal portion of the IMCD, Na+,K+–ATPase activity did not change. H+,K+–ATPase remained unchanged in both the proximal and distal portions of the IMCD of aging rats. During K+ loading, there was no change in Na+,K+–ATPase or H+,K+–ATPase activity in the proximal or distal portions of the IMCD of aging rats. This study suggests that the senescent kidney responded to K+ conservation and excretion under the two extremes of low and high K+ intake.
Long–Term Effect on Blood Pressure of Early Brief Treatment by Different Antihypertensive Agents: A Study in the Prague Hypertensive Rat
Authors: Heller Jiřî , Hellerová Soňa
Published: April 2003

In the Prague hypertensive rat (PHR), a strain of genetic hypertension derived from Wistar, administration of various antihypertensive drugs (AHD) during the developmental phase of hypertension (weeks 5–9 of life) prevents the rise of blood pressure. However, only drugs blocking the renin–angiotensin system (RAS, i.e. AT1–antagonist losartan and ACE inhibitor perindopril) have a long–term effect on blood pressure leading to values of systolic blood pressure (SBP) of 174.5±14.5 and 169.8±15.3 mmHg, respectively, at week 30. At this time, control, untreated PHR have a SBP of 222.0±16.6 mmHg (p<0.01 for both groups); age–matched PNR (Prague normotensive rat, bred in parallel with PHR from the same parent pair) exhibit values as low as 123.3±11.7 mmHg (p<0.01 from all other values). When losartan was administered to another group of PHR not only at weeks 5–9 but once more at weeks of 15–19 of age, the values of their SBP at week 30 were 156.8±12.64 mmHg, i.e., values significantly (p<0.01) different not only from 239.7±17.59 mmHg (value of the untreated PHR group) but also from 174.5±14.5 mmHg (value of PHR to which losartan was administered only once, at weeks 5–9). Thus, twice repeated administration of losartan in young age almost normalizes blood pressure deep into adult age. Proteinuria, a common finding in adult PHR, is also significantly lower in adult age in both groups receiving at weeks 5–9 drugs blocking RAS; the values at week 30 are 4.0±0.26 mg/24 h/rat in the losartan and 3.87±0.27 in the perindopril group, in contrast to 12.8±1.08 (p<0.01 for both groups) in control PHR. In conclusion, early brief administration (weeks 5–9 of life) of RAS–blocking agents to PHR led to long–term antihypertensive and antiproteinuric effects. These effects were significantly intensified by a second brief administration at weeks 15–19.
Enalaprilat Improves the Impaired Left Ventricular Pump Function during Exercise in Hypertensives with Coronary Microangiopathy and with Coronary Artery Disease
Authors: Franz Ingomar-Werner , Tönnesmann Ulrich , Schaupp Stefan , van der Meyden Jochen
Published: April 2003

Background: The pump function during exercise can be disturbed not only in hypertensives with coronary artery disease (CAD), but also in those with a normal angiogram. Methods: In 10 hypertensive patients (group 1; aged 52±4 years, 1 men, 9 women) with ST segment depression during exercise and concomitant angina pectoris but normal coronary angiograms (microangiopathy) and without left ventricular hypertrophy (LVMI <110 g/m2), the left ventricular function at rest and during exercise was studied by cardiac catheterization and compared with 10 hypertensives with CAD (group 2; aged 57.6±4 years, 7 men, 3 women) and 10 hypertensives without ST segment depression (group 3; aged 51.8±5 years, 10 men) before and after intravenous administration of 1.25 mg enalaprilat. Results: The pulmonary capillary wedge pressure (PCWP) was normal at rest and pathologically increased at 60±13 W only in groups 1 and 2 (27.2±3 and 32.2±8 mm Hg, respectively), but not in group 3 (12.2±4 mm Hg; p<0.001). At the identical load level, the PCWP in patients with microangiopathy (group 1) was significantly (p<0.01) reduced after enalaprilat (–21.7%) and even normalized in 5 of 10 patients. This was accompanied by a significant (p>0.01) decrease in ST segment depression (–73.9%) and in the occurrence of angina pectoris, despite the fact that the rate–pressure product as a measure of myocardial oxygen consumption was significantly (p<0.05) increased. Also in patients with CAD enalaprilat had a significant effect on PCWP (p<0.01), ST segment depression (p<0.01), occurrence of angina pectoris (p<0.001), cardiac index (p<0.05), and stroke index (p<0.05) during exercise. In group 3 there were no significant changes in PCWP, cardiac index, and stroke index after enalaprilat either at rest or during exercise. Conclusion: The functional improvement under the action of enalaprilat suggests that the advantages of the drug may be mediated mainly through an increase in myocardial blood flow and that angiotensin II might be involved in the restricted increase in coronary blood flow during dynamic exercise in hypertensives with coronary microangiopathy.
Role of Glomerular Endothelial Damage in Progressive Renal Disease
Authors: Yamanaka Nobuaki , Shimizu Akira
Published: April 2003

Although glomerular lesions are caused by multiple mechanisms, when the lesion is severe, it frequently results in segmental or global sclerosis regardless of etiology, and contributes to progression of renal disease. Initially, glomerular mesangial cell injury was considered to be central to glomerular sclerosis. Recently, glomerular epithelial cell injury has attracted attention as the primary event of the sclerosis. Less attention has been paid to glomerular endothelial cell injury. However, the latter is acquiring increasing interest as to whether endothelial cell injury is also a crucial factor in the cause and progression of glomerular sclerosis. It has been clearly demonstrated that regeneration of impaired glomerular capillary networks plays an important role in the repair process of glomerular lesions. Glomerular endothelial cell injury exerts significant influences on the progression and repair process of glomerular disease. When the glomerular lesion is severe, angiogenesis is prevented due to endothelial cell injury, with subsequent sclerosis taking place in the impaired region. These glomerular endothelial cell injuries inevitably affect mesangial and epithelial cells and presumably modify the progression of renal disease by reciprocally interacting with them.
Macrophage Activation and Programming and Its Role for Macrophage Function in Glomerular Inflammation
Authors: Erwig Lars-Peter , Rees Andrew J.
Published: April 2003

Macrophages have a central role in the control of inflammation because, depending on the local microenvironment, they can develop into cells that cause further injury or facilitate tissue repair. Understanding what signals determine whether macrophages develop into cells that promote injury or facilitate repair is one of the most important issues in inflammatory cell biology, not least because of the opportunities for developing novel therapies. This is highly relevant to glomerulonephritis because of the prominence of the macrophage infiltrate in all types of severe or progressive nephritis, and the present unsatisfactory nature of treatments for these diseases. This review will focuses on how macrophages are activated in vitro and in normal and inflamed glomeruli. The new concept of 'macrophage programming’ is introduced and novel strategies to alter macrophage function within nephritic glomeruli that could be used for the treatment of glomerular inflammation are highlighted.
Interstitial Pathomechanisms Underlying Progressive Tubulointerstitial Damage
Authors: Strutz Frank , Müller Gerhard A.
Published: April 2003

Progressive renal disease poses an increasing problem for the medical community. Though the causes of end–stage renal failure are multiple, the histologic pictures of chronic renal disease are remarkably similar being characterized by interstitial infiltration, fibrosis, tubular atrophy and dilatation. This similarity points to a final common pathway. In addition, renal disease often progresses despite elimination or amelioration of the inciting stimulus. This review deals with the pathomechanisms of progressive renal failure proposing a three–step model of fibrogenesis with an induction phase, a phase of inflammatory, and, lastly, a phase of postinflammatory matrix synthesis. The central role of the tubular epithelial cell as a mediator of interstitial inflammation and its participation in matrix synthesis will be discussed particularly. Finally, a brief overview is listed on new therapeutic approaches to limit the progressive nature of fibrogenesis.
1,25–Dihydroxyvitamin D3 Stimulates Transforming Growth Factor–β1 Synthesis by Mouse Renal Proximal Tubular Cells
Authors: Weinreich T. , Landolt M. , Booy C. , Wüthrich R.P. , Binswanger U.
Published: April 2003

1,25–Dihydroxyvitamin D3 [1,25–(OH)2 D3] is a secosteroid hormone with effects on cell growth, differentiation and immunoregulatory functions in a number of tissues not primarily involved in mineral metabolism. We recently demonstrated growth–regulating effects of 1,25–(OH)2 D3 on human mesangial cells and proximal tubular cells. To investigate whether 1,25–(OH)2 D3 might also affect the synthesis of cytokines and growth factors in proximal tubular cells, we assessed in the present study the expression and secretion of transforming growth factor–β1 (TGF–β1) in a mouse proximal tubular cell line (MCT) in vitro. TGF–β1 synthesis was measured by a monospecific ELISA in culture supernatant. The secreted TGF–β1 was proven to be biologically active by means of a bioassay system (CCL–64 mink lung epithelial cell proliferation assay). TGF–β1 gene expression was assessed by RT–PCR. To analyze whether TGF–β1 expression mediates the 1,25–(OH)2 D3–induced antiproliferative actions in MCT, proliferation studies in the absence or presence of a blocking monoclonal anti TGF–β1–3 antibody were performed. 1,25–(OH)2 D3 (10–11 to 10–7 M) specifically increased the TGF–β1 protein secretion in MCT with a maximum at 10–8 M. No detectable effect was found with 25 D3 at 10 times higher concentrations. A synthetic 20–epi analogue, MC 1288, increased TGF–β1 secretion up to similar amounts at equimolar concentrations as the natural hormone 1,25–(OH)2 D3. Steady–state TGF–β1 mRNA concentration in MCT was transiently increased by 1,25–(OH)2 D3 between 12 and 24 h, returning to control values at 48 h. Blocking TGF–β1 did not reduce or abrogate the antiproliferative effect of 1,25–(OH)2 D3. In conclusion, 1,25–(OH)2 D3 stimulates TGF–β1 expression in renal proximal tubular cells, a growth factor with anti–inflammatory and profibrotic actions which plays an important role in the development and progression of nephrosclerosis.
Short– and Long–Term Effects of Fish Oil on Proteinuria, Morphology and Renal Hemodynamics in the Milan Normotensive Rat Model of Spontaneous Glomerulosclerosis
Authors: Eberhard Oliver K. , Pötschick Harald , Neumann Klaus H. , Kliem Volker , Brunkhorst Reinhard
Published: April 2003

Background/Aims: A diet rich in polyunsaturated Ω3 fatty acids has been shown to modulate the course of several experimental models of renal disease. The short– and long–term effects of an 8% fish oil (FO) chow on proteinuria, renal blood flow and glomerular morphology were evaluated in Milan normotensive rats that spontaneously develop progressive glomerulosclerosis. Methods: Eight rats each were pairfed FO– versus cholesterol–enriched or control diets for either 2 or 32 weeks. 4/48 animals died (2–week trial: 1 rat on the FO and 1 rat on the control diet; 32–week trial: 1 rat on the cholesterol and 1 rat on the control diet) and were excluded from all statistic analyses. Results: After 2 weeks the renal blood flows were higher in the FO animals versus controls (8.75±2.19 vs. 6.87±1.91 ml/min/g, p<0.05), and the prostaglandin E2/thromboxane B2 ratio shifted towards the vasodilatative prostaglandin E2 (1.76±0.18 vs. 0.91±0.19, p<0.05). During the long–term trial proteinuria in the FO animals progressed faster and to a higher level (176.5±32.2 vs. 82.7±36.7 mg/24 h at week 32, p<0.01). After 32 weeks the renal blood flow was significantly lower in th FO group 2.8±1.1 vs. 4.6±1.9 ml/min/g, (p<0.05), and the rats had an accelerated development of nephrosclerosis, with sclerotic lesions in 60.3±6.6% of the glomeruli as compared with 46.5±9.8% in the cholesterol and 39.8±5.9 in the control group (p<0.05). Conclusion: The short–time effects of FO on renal hemodynamics did not alleviate the progress of renal damage in Milan normotensive rats, but the morphologic and functional signs of injury were rather pronounced with FO feeding.
A Th1 Response Is Essential for Induction of Crescentic Glomerulonephritis in Mice
Authors: Schatzmann Ursula , Haas Cordula , Le Hir Michel
Published: April 2003

Crescentic glomerulonephritis can be induced in rodents by injection of heterologous antibodies against the glomerular basement membrane. There is evidence that glomerular inflammation in that model represents a delayed–type hypersensitivity response to the heterologous immunoglobulin, whereas the antibody response is not important. The aim of the present study was to test this hypothesis. Delayed–type hypersensitivity is mediated by T cells with the Th1 phenotype. We compared mice immunized with rabbit immunoglobulin G in complete Freund’s adjuvant or in incomplete Freund’s adjuvant, producing, respectively, Th1– or Th2–biased responses to the antigen. Intravenous injection of rabbit antimouse glomerular basement membrane serum provoked proteinuria, infiltration with T cells and macrophages, as well as profound histological damage in the group treated with complete Freund’s adjuvant. There was no evidence of glomerulonephritis in the group which received incomplete Freund’s adjuvant. Deposits of mouse IgG along the glomerular basement membrane were similar in both groups. Thus, a Th1 response appears to be essential for the induction of glomerulonephritis in this model.
Regulatory Mechanisms of Na/Pi Cotransporter by Glucocorticoid in Renal Proximal Tubule Cells: Involvement of cAMP and PKC
Authors: Han Ho Jae , Kim Dae Hoon , Park Soo Hyun
Published: April 2003

The signaling pathways involved in the regulation of glucocorticoid on Pi uptake were examined in primary cultured rabbit renal proximal tubule cells (PTCs). Dexamethasone (DEX, 10–9 M) inhibited Pi uptake, although aldosterone, a mineralocorticoid, did not affect Pi uptake. Its effect was due to a 23% decrease in the Vmax value. DEX–induced inhibition of Pi uptake was prevented by actinomycin D, cycloheximide, and the glucocorticoid receptor antagonists, progesterone and cortexolone. SQ 22536 (adenylate cyclase inhibitor) and the myristoylated protein kinase A inhibitor amide 14–22 (PKI) did not block the DEX–induced inhibition of Pi uptake. Indeed, DEX did not affect cAMP production. However, neomycin and U 73122 (PLC inhibitors), staurosporine and bisindolylmaleimide I (PKC inhibitors) blocked the DEX–induced inhibition of Pi uptake. In addition, DEX increased the membrane–bound PKC activity from 2.82±0.21 to 4.16±0.34 pmol/mg protein/min. These findings demonstrate that glucocorticoid inhibits Pi uptake and its effect is genomic and receptor–mediated and the activation of the PLC/PKC pathway is involved in its effect on the PTCs.
Acute Regulation of the Betaine/GABA Transporter BGT-1 Expressed in Xenopus Oocytes by Extracellular pH
Authors: Matskevitch Ioulia , Stegen Carola , Wagner Carsten A. , Moschén Ivano , Bindels Renée , van Os Carel , Bröer Stefan , Lang Florian
Published: April 2003

Besides uptake of Na+ and Cl–, mammalian cells counteract osmotic cell shrinkage also by Na+-coupled uptake of osmolytes, e.g., myo-inositol, taurine or betaine. The expression of the corresponding transporters is transcriptionally regulated by the ambient pH and osmolarity and is increased upon cell shrinkage, a process requiring hours. The present study has been performed to disclose rapid regulation by pH of osmolyte transport via BGT-1. Transport of GABA was investigated by using the two-electrode voltage-clamp technique with BGT-1 expressing Xenopus oocytes. GABA was used as a substrate, because of the low oocyte endogenous transport activity. Extracellular acidification to pH 5.5 reversibly decreased and extracellular alkalinization to pH 8.5 increased GABA-induced currents. Kinetic analysis revealed that extracellular alkalinization increases the affinity for Cl– as reflected by a decrease of the apparent Km-value for Cl– from >500 mM to 55.8 ± 4.7 mM upon an increase of the pH from 7.0 to 8.5. The apparent Km- values for Na+ and GABA remained unaltered in the pH range from 6.0 to 8.5. Instead, alkalinization increased the maximal current induced by saturating Na+ and GABA concentrations. The results are compatible with a model of interference of H+ ions with Cl– binding and a pH-dependent reduction of Vmax for Na+ and GABA.
Effect of Bee Venom and Its Melittin on Apical Transporters of Renal Proximal Tubule Cells
Authors: Han Ho Jae , Lee Jang Hern , Park Soo Hyun , Choi Hyun Joo , Yang Il Suk , Mar Woong Chon , Kang Sung Keel , Lee Hye Jung
Published: April 2003

Renal failure by bee venom may be related to a malfunction of renal transporters. However, the effects of bee venom on apical membrane transporters of renal proximal tubular cells are not yet known. The aim of this study was to examine the effects of dried bee venom of Apis mellifera and its melittin on apical transporter activity of primary cultured rabbit kidney proximal tubule cells. Bee venom (1 μg/ml) decreased the cell viability and increased lactate dehydrogenase activity over 30–min treatments. Its effect was blocked by mepacrine or AACOCF3 (10–6 M; phospholipase A2 inhibitors). However, there was no effect on cell viability at a concentration of 0.01 μg/ml of bee venom. Thus, we investigated the effect of bee venom (1 μg/ml) on the activity of renal transporters at 30 min. Bee venom inhibited α–methyl–D–glucopyranoside, Pi, and Na+ uptakes, but increased Ca2+ uptake. These effects of bee venom were blocked by mepacrine or AACOCF3 (10–6 M), and bee venom–induced stimulation of Ca2+ uptake was also blocked by methoxyverapamil and nifedipine (L–type calcium channel blockers). In addition, bee venom increased [3H]–arachidonic acid release by 216 % of that of control. In all experiments, bee venom melittin (0.5 μg/ml) had an identical effect to that of bee venom itself. In conclusion, bee venom inhibited, in part, α–MG, Pi, and Na+ uptakes through its melittin which increased Ca2+ uptake and arachidonic acid release in primary cultured rabbit renal proximal tubule cells.
Noncompliance with Treatment among Psychiatric Patients in Kuwait
Authors: Fido Abdullahi A. , Husseini Abdulrazik M.
Published: April 2003

One hundred and twenty psychiatric patients were discharged for outpatient treatment, of which 55% had prematurely discontinued their medications. Clinically, these patients were characterized as being young, single male individuals with diagnoses of schizophrenia and mania. Previous multiple hospital admissions were strongly associated with noncompliance. Fear of drug dependence, complex treatment regimen and social ‘stigma’ were the main reasons given by the patients for their noncompliance. The need for improved doctor-patient relationship and greater efforts toward public education is emphasized.
Normative Data of Nerve Conduction Studies in the Upper Limb in Kuwait: Are They Different from the Western Data?
Authors: Shehab Dia K.
Published: April 2003

Objective: To establish the normal electrophysiological data for the median, ulnar and radial nerves and to compare our results with the Western data published in the literature. Methods: Nerve conduction studies were performed prospectively in the upper limbs of 50 carefully screened healthy individuals between the ages of 16 and 56 years using standardized technique. Results: The median motor distal latency (DL) was 3.1 (0.3) ms, amplitude 11.01 (2.8) mV, conduction velocity (CV) 56.5 (3.5) m/s. The ulnar motor studies gave DL of 2.4 (0.3) ms, amplitude 9.2 (2.2) mV, CV 60.4 (5.0) m/s. Sensory studies for the median nerve were: DL of 2.3 (0.3) ms, amplitude 63.3 (18.9) µV for men and 79.3 (28.8) µV for women and CV 56.6 (7.6) m/s. For the ulnar nerve (DL) 2.0 (0.23) ms, amplitude 54.5 (18.4) µV for men and 63.9 (16.8) µV for women and CV 51.7 (5.3) m/s. The radial sensory studies were DL 1.95 (0.3) ms, amplitude 18.7 (5.5) µV and CV 52.3 ms. Only gender showed a statistically significant effect on the sensory nerve action potential for the median (p = 0.04) and ulnar nerves (p = 0.07). Conclusion: Normative conduction parameters of commonly tested nerves in the upper limb were established in our EMG lab in Kuwait. The mean motor nerve conduction parameters for the median and ulnar nerves compare favourably with the existing literature data. However, for the sensory nerves, higher value for the nerve action potential amplitude was demonstrated in the study. Gender was shown to have a significant effect on the sensory amplitude of the median and ulnar nerves.
Isolation and Characterization of Coagulase-Negative Methicillin-Resistant Staphylococcus aureus from Patients in an Intensive Care Unit
Authors: Al Obaid Inaam A. , Udo E.E. , Jacob L.E. , Johny M.
Published: April 2003

Objective: To report the isolation and characterization of four coagulase-negative methicillin-resistant Staphylococcus aureus isolated from patients admitted to the ICU of a Kuwait hospital by bacteriological and molecular methods. Methods: The isolates were characterized by cultural characteristics, Gram stain, catalase, coagulase, DNase and biochemical tests and typed by a combination of antibiogram and pulsed-field gel electrophoresis to evaluate their relatedness. Results: These isolates were gram-positive cocci in clusters, catalase, DNase and slide coagulase-positive but tube coagulase-negative. They gave negative results for ornithine decarboxylase and pyrrolidonyl-arylamidase tests, which indicated that these were not Staphylococcus lugdunensis or Staphylococcus schleiferi, and were identified as S. aureus by API Staph. They had identical antibiograms and pulsed-field gel electrophoresis patterns which suggested that they had a common origin. Conclusion: The results highlight the need to complement the coagulase tests with other tests such as DNase and biochemical tests to correctly identify S. aureus. Coagulase-negative S. aureus appears to be an increasing problem that clinical laboratories should be aware of. They are as virulent as those producing coagulase and can colonize, cause infections and spread among patients.
The Epidemiology of Hospital-Referred Head Injury in Northern Norway
Authors: Ingebrigtsen Tor , Mortensen Kim , Romner Bertil
Published: April 2003

This retrospective population-based survey describes the epidemiology of head injury in a defined population in Northern Norway. It includes all 247 patients with head injury referred to the University Hospital of Tromsø, Norway, during 1993. Head injury was defined as physical damage to the brain or skull caused by external force. The annual incidence rate of hospital-referred head injury was 229/100,000 population with a male preponderance of 1.7:1.0. The cause was a fall in 62%, road traffic accident in 21% and assault in 7% of the cases. The observed incidence rate is low despite the use of wide inclusion criteria, probably due to a decrease in road traffic accidents. A further decrease in the number of head injuries in our region may be achieved by preventing falls.
The Effect of Apolipoprotein E ε4 in the Relationships of Smoking and Drinking to Cognitive Function
Authors: Carmelli Dorit , Swan Gary E. , Reed Terry , Schellenberg GerardD. , Christian Joe C.
Published: April 2003

Objectives: To investigate the joint effect of the apolipoprotein E ε4 (APOE ε4), smoking and drinking on cognitive performance in a population-based longitudinal study of elderly men. Design and Setting: The NHLBI Twin Study, a longitudinal cardiovascular study of World War II, white, male veterans. Participants: A total of 589 male participants in the third cardiovascular examination of this panel and aged 59–69 when assessed for cognitive function. Outcome Measures: Cognitive function assessed by the Mini-Mental State Examination, the Digit Symbol Substitution Test, the Benton Visual Retention Test, APOE ε4 allele frequency and cardiovascular disease (CVD) health status. Results: For the sample as a whole, after adjustment for age, education and CVD, smoking was significantly associated with poor cognitive function (odds ratio (OR) = 2.0, 95% confidence interval (CI) 1.2–3.2, in current smokers compared with never smokers), whereas light drinking (one or fewer drinks per day) showed a protective effect (OR = 0.6, 95% CI 0.4–0.9 compared with abstainers). Stratification by APOE ε4 indicated that the protective effect of light drinking was stronger and the harmful effect of smoking was weaker among APOE ε4 carriers than among noncarriers. Conclusions: These data suggest a possible mediating effect of the APOE ε4 allele in the relation of smoking and drinking to cognitive function in the elderly.
A Report on the WHO Working Group on Parkinson’s Disease
Authors: Janca Aleksandar
Published: April 2003

In order to raise awareness of the public health importance of Parkinson’s disease, the World Health Organisation (WHO) has recently established a Working Group on Parkinson’s Disease and included it in the framework of the WHO Global Initiative on Neurology and Public Health. The first meeting of this international expert group produced a set of recommendations covering the following aspects of Parkinson’s disease: epidemiology; organisation of services and treatment; education, training and information, and direct and indirect costs of care. An independent international research project entitled Global Parkinson’s Disease Survey has recently been launched in response to the recommendations of the WHO Working Group on Parkinson’s Disease. This paper summarises the recommendations of this WHO Working Group and outlines objectives, methods and preliminary pilot results of the Global Parkinson’s Disease Survey.
Patterns of Outcome Measurement in Parkinson’s Disease Clinical Trials
Authors: Mitchell Susan L. , Harper Dan W. , Lau Anita , Bhalla Rishi
Published: April 2003

The study examines the pattern of use and clinimetric properties of clinical endpoints used in randomized trials for Parkinson’s disease (PD). Randomized drug trials for PD were identified through a Medline search conducted from January 1966 until August 1998. The endpoints used in these trials were abstracted. Reports examining the clinimetric properties of the disease-specific scales used in these trials were also abstracted. Data regarding the consistency, accuracy, discrimination and feasibility of scales used in at least 10% of trials were determined. One hundred and thirty-seven articles met the inclusion criteria; 70.8% of trials used some clinical scale for PD as an endpoint. The Unified Parkinson’s Disease Rating Scale (UPDRS) was the most commonly used scale (32.8%). Factors independently associated with the use of the UPDRS included: the study location in the US, mean age of subjects over 62.7 years and publication after 1994. The UPDRS was more thoroughly studied and superior in most clinimetric domains compared to scales developed earlier. Few studies included generic health status (2.9%) or cognitive measures (16.8%) as secondary endpoints. There have been definite improvements in the area of disease-specific measurement in PD trials since the introduction of the UPDRS. The results of studies that used instruments with poor or unreported clinimetric properties should be critically interpreted.
Prevalence of Alzheimer’s Disease and Other Dementing Disorders in an Urban Community of Beijing, China
Authors: Wang Wenzhi , Wu Shengping , Cheng Xueming , Dai Hanteng , Ross Kathryn , Du Xiaoli , Yin Wengang
Published: April 2003

A door-to-door two-phase study was used to investigate the prevalence of senile dementia in an urban community of Beijing. In the study population, 5,003 individuals aged 60 years and older (≥65 years, n = 3,728) were screened at home with the Chinese version of the MMSE. Persons who screened positive for dementia, using different cutoff scores based on degree of literacy, were further evaluated using the criteria of DSM-III-R and ICD-10. Among subjects who screened positive in phase I, 134 were diagnosed as having dementia in phase II. The prevalence ratios of dementia were 2.68% in the population aged 60 years and older, and 3.49% in the population aged 65 years and older. The prevalence rates among those aged 65 years and older were 1.85% for Alzheimer’s disease, 1.37% for vascular dementia and 0.27% for other dementia (including mixed dementia). The prevalence of all dementia and AD increased steeply with advancing age and was consistently higher in women, but it was not obviously higher for VaD in women. Alzheimer’s disease was the commonest type of dementia. Our prevalence figures for dementia and AD are similar to those previously reported for China.
Cognitive Test Performance and Presence of Subclinical Cardiovascular Disease in the Cardiovascular Health Study
Authors: Saxton Judith , Ratcliff Graham , Newman Anne , Belle Steven , Fried Linda , Yee John , Kuller Lewis
Published: April 2003

The purpose of the present study was to investigate the relationship between performance on a comprehensive battery of neuropsychological tests and the presence of clinical, subclinical or no cardiovascular disease in an elderly community-dwelling population. The results confirm previous reports of significant associations of age, education and gender with test performance. When performance was examined controlling for these variables, significant associations of disease group were seen with five measures emphasizing speed of performance; Parts A and B of the Trail Making Test, the WAIS-R Digit Symbol and Block Design subtests and category verbal fluency. These results add to the evidence that, in addition to other health implications, cardiovascular disease is related to cognitive functioning in the elderly even at subclinical levels.
Interleukin-1 Stimulates Hypothalamic Inhibitory Amino Acid Neurotransmitter Release
Authors: Feleder Carlos , Refojo Damián , Nacht Silvina , Moguilevsky Jaime A.
Published: April 2003

Interleukin-1 (IL-1), a polypeptide cytokine, has been postulated as a chemical messenger between the immune and the neuroendocrine system. IL-1 receptors and immunopositive neurons have been visualized in the human and rat hypothalamus, suggesting that IL-1 can act as a neurotransmitter within the brain. In the hypothalamus IL-1 and the amino acid neurotransmitters are known to modulate several functions, such as fever, anorexia and the gonadal and adrenal axis. Since the hypothalamic actions of IL-1 on the amino acid neurotransmitter output are unknown, the aim of the present paper was to evaluate the effects of IL-1 on the hypothalamic release of both, the inhibitory taurine, glycine and GABA and the excitatory glutamate, amino acid neurotransmitters. Intact adult male rats were employed. The preoptic/mediobasal hypothalamic area was dissected and superfused with Earle’s balanced salt solution. Superfusate fractions were collected after a 60-min stabilization period. Following 60 min of basal release, IL-1 was added to the superfusion medium over 30 min. GABA, taurine and glycine release were significantly (p < 0.05) increased in the superfusion medium, while glutamate was not modified compared with the control group. These observations show that IL-1 increased GABA, taurine and glycine release. These effects indicate that this cytokine can affect the hypothalamic inhibitory amino acid output, which may help us to understand the mechanism by which IL-1 exerts its effects.
A New View on Immune-Adrenal Interactions: Role for Fas and Fas Ligand?
Authors: Marx Christian , Wolkersdörfer Gernot W. , Bornstein Stefan R.
Published: April 2003

The hypothalamic-pituitary-adrenal axis and the immune system interact in a bidirectional manner providing the basis for the regulation of the immune response due to a pathogenic stimulus. This interplay is commonly believed to be based on the action of hormones or cytokines, respectively. Since it has been detected that adrenocortical cells offer immunological properties such as expression of MHC class II antigens and/or CD95 (Fas antigen) and its ligand, the question has to be raised whether direct intercellular communication between immune cells and ‘immunocompetent’ endocrine cells contributes to the complexity of immunoregulation. Here we discuss the possible reciprocal relevance of physiological and pathological adrenal changes, as well as T-cell-mediated immune response for immune and/or adrenal pathology during disease.
Neural-Immune Interactions – An Evolutionary Perspective
Authors: Clatworthy Andrea L.
Published: April 2003

Efforts to understand how the immune system can influence nervous system function are hampered by the complexity of mammalian nervous and immune systems. The marine mollusc Aplysia californica has recently emerged as a useful model system to investigate cellular mechanisms underlying neural-immune interactions. Aplysia has a relatively simple, well-characterized nervous system that is accessible for intracellular recording. Moreover, it shares with mammals basic cellular defensive responses to non-self or wounded-self, i.e. the accumulation of numerous defense cells (hemocytes) around foreign objects or at injured sites. We have shown that the excitability of a population of nociceptive sensory neurons in Aplysia can be influenced by the presence of hemocytes close to their axons. These sensory neurons also show profound, long-lasting increases in their excitability following axonal injury. Hemocytes are attracted to injured sites on peripheral nerves, and we have developed an in vitro nervous system-hemocyte coculture system to demonstrate that hemocytes can also influence the expression of this injury-induced sensory hyperexcitability. Immunoreactive interleukin-1 (IL-1) and tumor necrosis factor have been identified in Aplysia. Preliminary in vitro studies showing that IL-1 can modulate the expression of injury-induced sensory hyperexcitability raise the interesting possibility that hemocyte-derived cytokine-like factors can modulate sensory neuron functioning. The relevance of this work to more phylogenetically advanced organisms is also discussed.
The Role of Cytokines in the Neuropathology of Stroke and Neurotrauma
Authors: Feuerstein Giora Z. , Wang Xinkang , Barone Frank C.
Published: April 2003

Accumulating evidence during the last decade has shown that the CNS can mount a well-defined inflammatory reaction to a variety of insults including trauma, ischemia, transplantation, viral infections as well as neurodegeneration. Many aspects of this centrally derived inflammatory response parallel to some extent the nature of such a reaction in the periphery. Through the recent application of molecular genetic techniques including PCR, utilization of cDNA probes in conjuncture with the availability of highly specific antibodies, new concepts are rapidly emerging as to the molecular mechanisms associated with the development of brain injury. In particular, the importance of cytokines, especially TNFα and IL-1β, is emphasized in the propagation and maintenance of a CNS inflammatory response. This review summarizes evidence in support of a case for ischemia and trauma eliciting an inflammatory condition in the injured brain. The inflammatory condition consists of cells (neutrophils early after the onset of brain injury and subsequently monocyte infiltration) and mediators (cytokines, chemokines and adhesion molecules). It is clear that de novo up-regulation of pro-inflammatory cytokines, chemokines and endothelial-leukocyte adhesion molecules in the brain occurs soon following focal ischemia and trauma and at a time when the tissue injury is evolving. The significance of the inflammatory response and its contribution to brain injury are now becoming better understood. Evidence has emerged in support of the role of cytokines in driving the inflammatory response and that this process is causally related to the degree of brain injury. Evidence reviewed includes: (1) the capacity of specific cytokines to exacerbate brain damage; (2) the capacity of specific cytokine blockade to reduce ischemic brain damage; (3) depletion of circulating neutrophils reduces ischemic brain injury, and (4) antagonists of the endothelial-leukocyte adhesion interactions (e.g. anti-ICAM-1) reduce ischemic brain injury. Targeting the cytokines that drive the brain inflammatory response to injury provides opportunities to intervene with novel therapeutics in stroke and neurotrauma.
Hypothalamic Control of FSH and LH by FSH-RF, LHRH, Cytokines, Leptin and Nitric Oxide
Authors: McCann Samuel M. , Kimura Mayumi , Walczewska Anna , Karanth Sharada , Rettori Valeria , Yu Wen H.
Published: April 2003

Gonadotropin secretion by the pituitary gland is under the control of luteinizing hormone-releasing hormone (LHRH) and the putative follicle-stimulating hormone-releasing factor (FSHRF). Lamprey III LHRH is a potent FSHRF in the rat and appears to be resident in the FSH controlling area of the rat hypothalamus. It is an analog of mammalian LHRH and may be the long-sought FSHRF. Gonadal steroids feedback at hypothalamic and pituitary levels to either inhibit or stimulate the release of LH and FSH, which is also affected by inhibin and activin secreted by the gonads. Important control is exercised by acetylcholine, norepinephrine (NE), dopamine, serotonin, melatonin and glutamic acid (GA). Furthermore, LH and FSH also act at the hypothalamic level to alter secretion of gonadotropins. More recently, growth factors have been shown to have an important role. Many peptides act to inhibit or increase release of LH, and the sign of their action is often reversed by estrogen. A number of cytokines act at the hypothalamic level to suppress acutely the release of LH but not FSH. NE, GA and oxytocin stimulate LHRH release by activation of neural nitric oxide synthase (nNOS). The pathway is as follows: oxytocin and/or GA activate NE neurons in the medial basal hypothalamus (MBH) that activate NOergic neurons by α1 receptors. The NO released diffuses into LHRH terminals and induces LHRH release by activation of guanylate cyclase (GC) and cyclooxygenase. NO not only controls release of LHRH bound for the pituitary, but also that which induces mating by actions in the brain stem. An exciting recent development has been the discovery of the adipocyte hormone, leptin, a cytokine related to tumor necrosis factor-α (TNF-α). In the male rat, leptin exhibits a high potency to stimulate FSH and LH release from hemipituitaries incubated in vitro, and increases the release of LHRH from MBH explants by stimulating the release of NO. LHRH and leptin release LH by activation of NOS in the gonadotropes. The NO released activates GC that releases cyclic GMP which induces LH release. Leptin induces LH release in conscious, ovariectomized estrogen-primed female rats, presumably by stimulating LHRH release. At the effective dose of estrogen to activate LH release, FSH release is inhibited. Leptin may play an important role in induction of puberty and control of LHRH release in the adult as well.
Rapid Progesterone Actions on Thymulin-Secreting Epithelial Cells Cultured from Rat Thymus
Authors: Head Gail M. , Downing James E.G. , Brucker Cosima , Mentlein Rolf , Kendall Marion D.
Published: April 2003

Many soluble factors of neural, endocrine, paracrine and autocrine origin are present in the thymus and modulate its function. Long-term effects of sex steroids have been documented for thymocytes and cells of the thymic microenvironment. In this report we examine rapid actions of progesterone upon aspects of epithelial cell physiology. Progesterone (0.1–10 µM) was applied to cultured thymulin-secreting thymic epithelial cells (TS-TEC) and changes in transmembrane potential, transmembrane current, intracellular calcium levels and thymulin secretion were assessed. Rapid changes in electrophysiology and intracellular calcium provide evidence for a membrane-bound progesterone receptor in these cells, in addition to classical cytoplasmic receptors. Application of progesterone to TS-TEC caused electrophysiological changes in 56% of cells (n = 40), activating an inward current (–24 ± 9 pA at 1 µM, n = 7, p < 0.02) and dose-dependent depolarization (7.1 ± 1.8 mV at 1 µM, n = 19, p < 0.01). Intracellular calcium levels, monitored by the ratiometric fluorescent calcium indicator fura-2, increased within seconds of progesterone (1 µM) application. Progesterone (1 µM) increased thymulin levels in supernatant, as measured by ELISA, above the levels in the preapplication period (142 ± 16% of the preapplication period, n = 3, p < 0.02). This effect was reduced in the presence of cobalt chloride which blocks voltage-dependent calcium channels. In addition, TS-TEC in culture were immunoreactive to antibody AG7. This antibody was raised to a membrane-bound antigen involved in calcium influx subsequent to progesterone binding in sperm. Thus we suggest that progesterone acts upon many aspects of TS-TEC physiology through both cytoplasmic and membrane-bound receptors.
Effect of Transmitters and Co-Transmitters of the Sympathetic Nervous System on Interleukin-6 Synthesis in Thymic Epithelial Cells
Authors: von Patay Birte , Kurz Bodo , Mentlein Rolf
Published: April 2003

In the thymus, sympathetic nerves run in septa in close connection to subcapsular/perivascular thymic epithelial cells (TEC). Since TEC are supposed to create a microenvironment of cytokines necessary for the development of thymocytes to T cells, we investigated the influence of sympathetic transmitters and co-transmitters on interleukin-6 (IL-6) synthesis in cultivated rat TEC that express markers of perivascular/subcapsular TEC. Noradrenaline and ATP stimulated IL-6 production in the culture supernatants 14- and 23-fold over basal values after 24 h. Co-stimulation with noradrenaline and ATP yielded an additive effect. Synthesis of IL-6 was concentration-dependent upon ATP and appeared to be mediated by P2 purinoceptors. During 24 h stimulation with 1 mM ATP, two thirds of the ligand was degraded mainly to ADP, production of AMP and adenosine was minor or negligible. Thus, in TEC, transmitters and co-transmitters of the sympathetic nervous system have a co-stimulatory effect on synthesis of IL-6 that is an important factor for thymocyte differentiation and proliferation.
Metabolic, Neuroendocrine and Immune Functions in Basal Conditions and during the Acute-Phase Response to Endotoxic Shock in Undernourished Rats
Authors: Giovambattista Andrés , Chisari Andrea N. , Corró Lucrecia , Gaillard Rolf C. , Spinedi Eduardo
Published: April 2003

Chronic malnutrition is one of the most important causes of several metabolic, immune and neuroendocrine dysfunctions. The aim of the present study was to determine the influence of chronic food restriction on basal neuroendocrine, immune and adipocyte functions and during the acute-phase response to endotoxic shock in female rats. The effect of refeeding of undernourished rats on the above-mentioned functions was also investigated. For these purposes, plasma total protein, glucose, triglycerides, ACTH, corticosterone, tumor necrosis factor-α (TNF) and leptin (LEP) levels were determined in basal condition and 2 h after endotoxin (LPS; 180 µg/kg body weight, i.p.) administration in 3 different groups: (1) well-nourished (WN) controls; (2) undernourished (UN) rats as a consequence of chronic food restriction, and (3) UN rats re-fed to restoration of their body weights in the WN rat range. The results indicate that UN rats, in comparison with WN controls, developed an arrest in body weight gain as well as in basal hypoglycemia, hypotriglyceridemia, hypoleptinemia, hypercorticosteronemia and enhanced adrenal glucocorticoid content; however, no changes in basal total protein, ACTH and TNF plasma levels and in anterior pituitary ACTH concentrations were found. When endotoxic shock was induced, the LPS-induced hypoglycemia developed in WN rats was abolished in UN animals, and both ACTH and TNF plasma concentrations after endotoxin, albeit significantly (p < 0.05) higher than the respective basal values, were significantly (p < 0.05) lower in UN than in WN control rats. Despite the high basal plasma corticosterone concentration in UN vs. WN rats, the LPS-induced glucocorticoid release was similar in WN and UN rats. Additionally, LPS treatment did not modify basal plasma LEP levels, regardless of the group. Interestingly, UN rats fed ad libitum for 15 days restored their body weight to WN rat range values, and the various metabolic dysfunctions seen in UN rats in both basal and post-LPS conditions were fully normalized. Our results clearly indicate that chronic undernutrition not only affects, as earlier described, reproductive function but also metabolic, neuroendocrine, immune and adipocyte functions, and that the effects induced by undernutrition can be fully reversed after recovery of normal body weight. The present study strongly supports the involvement of the metabolic status in the effectiveness of the defense mechanisms developed in patients in inflammatory stress conditions.