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Biomedical subjects

J Welsch

Publications and source records attributed to J Welsch.

12 recordsLinked to original sources
PubMed2006

Growth hormone response in low-dose apomorphine test correlates with nigrostriatal dopamine transporter binding in patients with Parkinson's disease.

Challenge with low-dose apomorphine causes a rise in growth hormone (GH) in patients with Parkinson's disease (PD). We studied 18 patients with early PD, who showed an increase of GH in the low-dose apomorphine test, by means of [(123)I] FP-CIT-SPECT. The mean specific dopamine transporter binding of the 18 patients was 1.50 +/- 0.56 in the striatum, 1.20 +/- 0.59 in the putamen, and 1.76 +/- 0.59 in the caudate nucleus. The increase of GH (1.05 +/- 1.01 ng/ml at baseline to 9.46 +/- 6.36 ng/ml 45 min after apomorphine injection; p < 0.001) was significant. There was a significant negative correlation of the increase of GH with the mean specific dopamine transporter binding in all three regions (r between -0.490 and -0.587; p between 0.04 and 0.01). Challenge with low-dose apomorphine may therefore be used as an indirect tool to measure the extent of nigrostriatal neurodegeneration in early PD.

Adult↗
PubMed2001

Phosphodiesterase type 4 inhibitor suppresses expression of anti-apoptotic members of the Bcl-2 family in B-CLL cells and induces caspase-dependent apoptosis.

B cell chronic lymphocytic leukemia (B-CLL) is an incurable clonal disease which shows initial responsiveness to a number of chemotherapeutic drugs. However, in most patients the disease becomes resistant to treatment. Rolipram, a specific inhibitor of phosphodiesterase (PDE) type 4, the PDE predominantly expressed in B-CLL cells, has been shown to induce cAMP-dependent apoptosis in these cells. In the present study, we demonstrate that the extent of rolipram-induced apoptosis is similar to fludarabine-induced apoptosis in vitro. The combination of rolipram and fludarabine results in an enhancement in the number of apoptotic cells compared to apoptosis induced by either agent alone. Second, rolipram suppresses the expression of anti-apoptotic members of the Bcl-2 family and induces the pro-apoptotic protein Bax, thereby shifting the balance between pro- and anti-apoptotic members of the Bcl-2 family towards a pro-apoptotic direction. Finally rolipram-induced apoptosis is caspase-dependent. PDE 4 inhibitors are currently under investigation for chronic obstructive pulmonary disease and asthma in phase III clinical trials showing promising results with tolerable side-effects. In conclusion, by inducing apoptosis, by enhancing apoptosis induced by fludarabine, by suppressing Bcl-2, Bcl-X and by inducing Bax expression, PDE 4 inhibitors may add a new therapeutic option for patients with B-CLL.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2000

Mammalian pituitary growth hormone: applications of free flow electrophoresis.

We have used free flow electrophoresis (FFE) technology to study the electrophoretic behavior of growth hormone (GH) molecules, GH secretory granules and GH cell subpopulations contained in pituitary glands of humans and rodents. GH activities in different electrophoresis fractions were measured by immunoassay or bioassay, viz., measurement of chondrocyte proliferation in the tibial growth plate of the hypophysectomized rat. Using FFE we discovered a peptide in human post mortem pituitary tissue and cryopoor human plasma that is active in the tibial line bioassay, is inactive in a GH immunoassay, and is neither GH nor a GH fragment. This peptide, called tibial peptide, has high anodal mobility and is readily separable from GH by FFE. Its molecular mass is approximately 5 kD. It is particularly rich in glycine. A partial amino acid sequence (residues 9-25) in the middle region of the peptide shows that 9 of the 16 residues are nonpolar. On the basis of results from other FFE experiments, using either GH-containing secretory granules or GH-producing cells, we believe that the peptide is stored within the secretion granule of a subpopulation of GH cells. On the basis of recent information elucidating the role of C peptide contained in the insulin storage granule of the pancreatic cell, we propose that the tibial peptide serves a similar role in the GH cell. Thus, not only may tibial peptide aid in proper alignment of disulfide bonds between GH monomers in the secretory granule, but, like the C peptide, it also appears to have biologic activity in its own right.

Amino Acid Sequence↗
PubMed1997

Inhibition of Fas-induced apoptotic cell death by osmotic cell shrinkage.

Apoptosis is an active physiological mechanism permitting the elimination of cells by triggering an intracellular signalling cascade. Here, we tested whether osmotic alterations of cell volume interfere with apoptotic cell death in Jurkat T-lymphocytes. Apoptotic cell death of Jurkat cells was elicited by activation of the Fas receptor which results in sphingomyelinase stimulation, release of ceramide, activation of Ras, Rac-proteins and formation of O2. Osmotic cell shrinkage inhibited apoptotic cell death induced by the Fas receptor in Jurkat T-lymphocytes. Osmotic cell shrinkage did not interfere with Fas induced activation of the acidic sphingomyelinase or activation of Ras but impaired the formation of O2 suggesting an important function of cell volume in the synthesis of reactive oxygen intermediates upon Fas receptor ligation.

Apoptosis↗
PubMed1996

Fas-induced programmed cell death is mediated by a Ras-regulated O2- synthesis.

Fas induces apoptosis in lymphocytes via a poorly defined intracellular signalling cascade. Previously, we have demonstrated the involvement and significance of a signalling cascade from the Fas receptor via sphingomyelinases and ceramide to Ras in Fas-induced apoptosis. Here we demonstrate rapid and transient synthesis of reactive oxygen intermediates (ROI) via activation of Ras after Fas. Genetic inhibition of Ras by transfection of transdominant inhibitory N17Ras blocked Fas-mediated ROI synthesis and programmed cell death. Likewise, the antioxidants N-acetyl-cysteine and N-t-butyl-phenylnitrone abolished Fas-induced cell death, pointing to an important role for Ras-triggered ROI synthesis in Fas-mediated programmed cell death.

Acetylcysteine↗
PubMed1989

Vascular congestion in ischemic renal failure: the role of cell swelling.

Experiments were performed on rats to examine the cause of the vascular congestion that accompanies renal ischemia, and the potential role of cell swelling in its generation. Renal function and gross morphology were examined after reflow, whereas tissue morphometry was performed both before and after reflow in kidneys. Small doses of mannitol applied into the renal artery just before ischemia greatly reduced the incidence of vascular congestion and the depression of renal function. During ischemia the outwardly directed swelling of the proximal tubule depleted the interstitial and vascular space of the cortex and outer medullary outer stripe and the inwardly directed swelling of the thick ascending limb occluded the lumen. Mannitol reduced cell swelling, lessened the depletion of the interstitial and vascular space and eliminated the occlusion of the thick ascending limb. It is proposed that the loss of interstitial and vascular fluid during ischemia is the cause of the vascular congestion, which, in turn, is responsible for the poor perfusion and impaired renal function seen after ischemia.

Acute Kidney Injury↗
PubMed1987

The contribution of vascular obstruction to the functional defect that follows renal ischemia.

Experiments were performed on rats subjected to renal ischemia and various treatment procedures to determine the origin and functional consequences of vascular obstruction. To this end, its occurrence and severity was assessed qualitatively and quantitatively in the outer medulla, where it is particularly prominent. The incidence of medullary hyperemia was not influenced by inhibiting thrombocyte aggregation with 5 or 70 mg/kg of acetyl salicylic acid or preventing fibrin deposition with 100 IE/kg of heparin before ischemia, and these substances produced no improvement renal function. The incidence and degree of hyperemia, however, could be substantially reduced or completely eliminated by acutely raising blood pressure after ischemia or by decreasing the number of circulating erythrocytes before ischemia. These procedures were effective in raising filtration rate and tubular reabsorption from 20% to 60% of normal, in restoring renal blood flow and vascular resistance to completely normal, and in diminishing epithelial damage both three and 18 hours after ischemia. The following conclusions are drawn: first, vascular obstruction, which is not lessened by inhibiting thrombus formation but is easily reversed or prevented by raising perfusion pressure or decreasing hematocrit, is probably caused by erythrocyte aggregation during ischemia. Second, vascular obstruction, which appears to raise renal vascular resistance and lower blood flow and filtration rate, cannot be limited to the medulla but must also be present in the cortex. Finally, reversing or preventing vascular obstruction can fully restore renal perfusion, partially restore glomerular and tubular function, greatly reduce tubular necrosis and thus prevent renal failure.

Animals↗
PubMed1984

Role of the medullary perfusion defect in the pathogenesis of ischemic renal failure.

Experiments were performed on rats to investigate the significance of the medullary hyperemia known to follow renal ischemia. To this end, its frequency was determined, its severity was quantified, and its relation to renal function was examined early (1 to 3 hr) and later (18 hr) after 45 min of warm ischemia. All kidneys were found to have a hyperemic outer medulla early after ischemia, which was shown to develop during the period of ischemia itself, but which was found to be highly variable in its severity. The degree of hyperemia was assessed both subjectively by grading and by histometric determinations of inner stripe capillary volume. One to hours after ischemia, the severity of medullary hyperemia was reflected in all indices of renal function, the least congested kidneys showing the best function. Eighteen hours after ischemia, the degree of medullary hyperemia was reflected in all indices of renal function, except urine flow rate; the non-congested kidneys showed functional recovery and the still-congested kidneys showed worsening function. Glomerular blood flow, known to be preferentially reduced in deep nephrons 1 to 3 hr after ischemia, had normalized 18 hr after ischemia in the non-congested kidneys but was still severely and unevenly depressed in the congested kidneys. It is concluded that congestion of the outer medulla is a key event in ischemic renal failure, its occurrence is coincidental with the reduction in deep nephron perfusion and urinary concentrating power in the early and maintenance phase and its disappearance heralds the restoration of deep nephron perfusion and urinary concentrating ability in the recovery phase.

Acute Kidney Injury↗
PubMed1983

Disparity between surface and deep nephron function early after renal ischemia.

Experiments were performed using a variety of methods to assess the functional status of different nephron populations following 45 min of renal ischemia in the rat. Micropuncture techniques revealed that SNGFR and reabsorption in the surface nephrons are only modestly reduced after ischemia, whereas kidney GFR and reabsorption are more severely affected. Determinations of bolus velocity with the Hanssen technique or of glomerular blood flow with the microsphere method confirmed that both were highest in the surface nephrons, lower in the middle nephrons and lowest of all in the juxtamedullary nephrons after ischemia. It is concluded that surface nephron function is well-maintained following ischemia and that it is the functional deficiency of the deeper nephrons that is predominantly responsible for the impairment in whole kidney function. Although the pathogenic mechanism is not yet clear, neither tubular obstruction nor tubular leakage in the deeper nephrons seems to be involved. The present findings suggest that micropuncture of the surface nephrons is a technique of questionable validity for studying this type of acute renal failure, they explain the inability of the kidney to concentrate the final urine, and they predict a more pronounced deficiency in medullary than in outer cortical blood flow.

Acute Kidney Injury↗
PubMed1981

The early phase of experimental acute renal failure. VI. The influence of furosemide.

Experiments were performed to determine whether furosemide, given in doses high enough to induce a strong diuresis and to inhibit the mechanism of tubuloglomerular feedback, offers any protection from acute renal failure induced by a nephrotoxin or ischaemia. Microperfusion of the loop of Henle revealed that a tubular furosemide concentration of 5 x 10(-5) mol x 1(-1) was necessary to fully inhibit the tubuloglomerular feedback response to a raised sodium chloride concentration at the macula densa. The infusion of furosemide systemically to achieve such concentrations in the tubule resulted in an improvement in renal function when given before or after the nephrotoxin but was without effect when given before or after ischaemia. Measurements of furosemide concentrations in the urine, however, confirmed that sufficient amounts were applied to inhibit the feedback mechanism. It is concluded from this and similar studies that furosemide is only beneficial in models of acute renal failure with an obstructive or nephrotoxic pathogenesis, in which it acts by flushing out the noxious material and not by inhibiting the mechanism of tubuloglomerular feedback.

Acute Kidney Injury↗
PubMed1979

The early phase of experimental acute renal failure. V. The influence of suppressing the renin-angiotensin system.

Experiments were conducted to determine whether suppression of the renin-angiotensin-system and inhibition of the tubuloglomerular feedback response offer protection from acute renal failure, as found in chronically-salt loaded animals. The juxtaglomerular renin activity and tubuloglomerular feedback response were inhibited acutely, by saline expansion, or chronically, by DOCA-treatment with saline drinking fluid or salt diet, by high salt diet alone, or by inducing two-kidney Goldblatt hypertension. The chronic pretreatment procedures depressed juxtaglomerular renin to 16, 7, 13 and 4% of control, respectively, inhibited the feedback response to 53, 37, 56, and 38% of control, respectively, but conferred no benefit in the first hours following a nephrotoxin or ischaemia. In contrast, the acute treatment procedure reduced juxtaglomerular renin activity to only 56% and lowered the feedback response to only 71%, but improved renal function after the nephrotoxin, although not after ischaemia. It is concluded that since severe restrictions of renin activity and tubuloglomerular feedback are not protective, neither is primarily involved in generating the functional restrictions early in acute renal failure. The restoration of renal function by saline expansion accompanied only a modest depression of these two systems and suggests that the beneficial effect may result more from volume expansion or diuresis than from suppression of renal renin or inhibition of tubuloglomerular feedback.

Acute Kidney Injury↗