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Reference 51-56

Reference 51-56

Prof. Sven Kurbel MD, PhD - personal web pages
Dept. of Physiology, Osijek Medical Faculty
J. Huttlera 4, 31000 Osijek, Croatia


51. Simulation model of defective insulin receptors as byproducts of receptor recycling.
Kurbel B, Kurbel S, Kristek Z, Jakić M, Jurić M, Sulava D.
Med Hypotheses. 1997 Aug;49(2):165-70.

Department of Anaesthesiology, University Hospital Dubrava, Zagreb, Croatia.

Our simulation model assumes that the defective insulin-binding receptors in
non-insulin-dependent diabetes (NIDDM) patients result from functional receptor
recycling. The model is a short program written in MS DOS 5.0 Qbasic. MODEL
DESIGN: Receptors with intracellular portions damaged in the process of recycling
are considered defective since they bind insulin but do mediate insulin effects,
or recycle. Their occurrence depends on the average activation rate of functional
receptors. The insulin-binding receptors (defective and functional) are objects
of slow and time-dependent turnover defined by the turnover rate. Recycled
receptors rejoin functional receptors or enter the pool of defective receptors.
The waste in the functional receptors' pool is covered by a limited amount of
newly synthesized receptors. The defective receptors often accumulate in cases of
increased activation of functional receptors. SIMULATION RESULTS: The
insulin-binding receptor quantity is determined, in the model, only by the number
of newly synthesized receptors, reflecting the intensity of insulin stimulation.
Synthesis is increased following variable insulin stimulations and decreased
after sustained, intensive insulin stimulation. The number of functional
receptors inversely reflects the average activation rate of functional receptors
compared with the insulin-binding receptors turnover rate. High activation rates
can diminish the proportion of functional receptors to less than 5% of that of
all insulin-binding receptors. The model predicts that cells bearing only
functional receptors show progressively shortened half-lives of receptors,
reflecting the receptor activation intensity. On the other hand, cells bearing
both defective and functional receptors show stable receptors' half-lives (20-36%
of the defective receptors' half-life). Simulation results suggest that reduced
functional receptor proportions in NIDDM patients might reflect the imbalance
between the activation of functional receptors and the slow catabolism of
defective receptors.

PMID: 9278929  [PubMed - indexed for MEDLINE]

52. Influence of subinhibitory concentrations of ceftazidime, ciprofloxacin and
azithromycin on the morphology and adherence of P-fimbriated escherichia coli.
Vranes J, Zagar Z, Kurbel S.
J Chemother. 1996 Aug;8(4):254-6


Department of Microbiology and Parasitology, University of Zagreb, Medical
School, Croatia.

The influence of subinhibitory concentrations (1/2, 1/4, 1/8, 1/16 and 1/32 x
MIC) of ceftazidime, ciprofloxacin and azithromycin on the morphology and
adherence of 29 wild-type P-fimbriated strains of Escherichia coli was studied.
Bacterial adherence to the Buffalo green monkey (BGM) cell line was tested before
and after treatment with antibiotics and detected by means of an
immunofluorescence staining. Significant dose dependent reduction of bacterial
adherence was observed, which correlated with the alterations in bacterial cell
morphology. After exposure of strains to sub-MICs of antibiotics, normal shapes,
spherical forms and filaments were noted. The greatest filamentation and the
greatest loss of adherence ability occurred at 1/2 x MIC of ceftazidime.
Treatment with sub-MICs of ciprofloxacin resulted in shorter filaments, while
filamentation did not occur after bacterial exposure to sub-MICs of azithromycin.
Azithromycin was least damaging to the adherence ability of E. coli and at a
concentration of 1/2 x MIC caused globoid cell formation.

PMID: 8873829  [PubMed - indexed for MEDLINE]

53. Computer simulation of factors involved in the down-regulation of hormonal
Kurbel S, Kurbel B, Dicić M, Ugraji V.
Med Hypotheses. 1996 Mar;46(3):173-9.

Department of Oncology, Osijek Clinical Hospital.

Down-regulation of hormonal effects is in the presented simulation related to the
number of functional receptors and quantity of available hormonal stimulation.
The former is in the model substituted with the quantity of stimulation able to
produce a full down-regulation (Hs100) of target cells. The halftime (t1/2) of
the hormonal effect recovery means the interval before the second hormonal
stimulation can elicit half of the initial hormonal effect. Recovered hormonal
effects are calculated after periods of two, three, four and five t1/2. The
interval among hormonal stimulations varied from 1/2 to 5/2 of t1/2. Shorter than
t1/2 intervals showed profound down-regulation even at weak hormonal stimulations
(> 20% of Hs100). Stable levels of hormonal effects after frequent hormonal
stimulations are found only in cases of very weak stimulations (< 10% of Hs100).
Intervals equalling t1/2 among weak stimulations (< 20% Hs100) produced stable
hormonal effects. Further prolongation among repeated stimulations improved
stability of hormonal effects and even strong stimulations (> 60% of Hs100) were
followed with only temporary profound down-regulation. Hormone-binding receptors
unable to activate target cells are in the model described as defective.
Probability for the target cell to be stimulated is in the model defined as P.
Relative quantity of hormonal stimulation per target cell needed to achieve
certain P is calculated for cells bearing different proportions of defective
receptors. Activation following weak hormone stimulations is highly probable (>
90%) for cells bearing less than 30% of defective receptors. With the proportion
of defective receptors over 60%, the activation probability after weak hormone
stimulations is reduced (< 66%). Down-regulation can be considered as a modulator
of hormonal effects. In prediabetic patients, intense stimulation of pancreatic
insulin secretion by frequent or increased ingestion of carbohydrates might lead
to sustained hyperinsulinemia. A substantial portion of the target tissue would
become down-regulated with increased number of defective insulin receptors. Poor
glucose utilization in the down-regulated tissue with resultant hyperglycemia
would further stimulate insulin secretion until failure. Reduced tissue
transportability of large hormone molecules, such as hGH, or proinsulin, can make
their effects more pronounced in the perivascular space. Circulating hormone
binding proteins or the basal membrane thickening in small vessels can further
decrease the hormonal effects on more remote cells. Physical activity in IDDM
patients increases insulin effect. Possible explanation is that increased muscle
perfusion is making more insulin available to the less down-regulated skeletal
muscle cells.

PMID: 8676750  [PubMed - indexed for MEDLINE]

54. Mechanisms of prion diseases described as long-lasting disorders of the
blood-brain barrier system.
Kurbel S, Kurbel B.
Med Hypotheses. 1995 Dec;45(6):543-4.

Department of Oncology, Osijek Clinical Hospital, Croatia.

Prison diseases can be described as disorders wherein circulating prion molecules
of external origin intervene with the normal synthesis of similar molecules in
the central nervous system. The hypothesis is that the endogenous prion-like
molecules denote the blood-brain barrier discontinuity. In the case of barrier
discontinuity, small numbers of hypothetical signal molecules enter circulation
and attach to the receptor sites in the neighbouring blood vessels. The specific
receptors of the cells in the blood vessels stimulated by endogenous prion-like
molecules might initiate the repairing processes of the blood-brain barrier. In
prion diseases, prion molecules from external sources are similar to endogenous
prion-like molecules or to the hypothetical signal molecules described here.
Large numbers of prion molecules enter circulation and initiate repairing
processes in large brain areas causing the tissue damage. This damage leads to
new barrier discontinuities that would provoke pathological process even when the
exogenous prion molecules are no longer present in the circulation.

PMID: 8771048  [PubMed - indexed for MEDLINE]

55. The role of gastric mast cells, enterochromaffin-like cells and parietal cells in
the regulation of acid secretion.
Kurbel S, Kurbel B.
Med Hypotheses. 1995 Dec;45(6):539-42.

Department of Oncology, Osijek Clinical Hospital, Croatia.

The idea presented here is that, in gastric mucosa, two independent regulatory
systems use the same transmitter: histamine molecules. The IgE/mast cell system
is dispersed throughout the body, while the other regulates the gastric acid
secretion. IgE molecules in gastric mucosa are attached to the mast cells. Mast
cells release histamine molecules after the antigen has been recognized by IgE.
These molecules normally act on vascular H1 receptors to promote extravasation
and chemotaxy. Gastrin molecules are released from antral G cells to stimulate
gastric acid secretion. Their influence on parietal cells is indirectly augmented
by gastrin governed release of histamine molecules from enterochromaffin-like
cells. These histamine molecules normally act on H2 receptors of parietal cells
to promote gastric acid secretion. Chronic infection of gastric mucosa (i.e. with
Helicobacter pylori), autoimmune disorders or repetitive mucosal exposure to the
same antigen, can develop chronic inflammation of gastric mucosa. Gastric acid
secretion is diminished with secondary hypergastrinemia and increased release of
histamine from enterochromaffin-like cells in an attempt to stimulate the few
remaining parietal cells. Hypothetically, increased concentrations of released
histamine in gastric mucosa might activate the vascular H1 receptors with
extravasation and aggravated inflammation. This can further decrease the number
of active parietal cells, reduce gastric acid secretion and potentiate
hypergastrinemia. In this hypothetical setting, H1 blockers might reduce the
damage by abolishing the vascular reactions. The prolonged antigen load on
gastric mucosa can promote production of specific IgE antibodies. Further
exposures to the same antigen degranulate sensitized mucosal mast cells.
Liberated histamine can produce extravasation through the vascular H1 receptor
and, hypothetically, local hyperacidity through the parietal cell H2 receptors.
The result would be hyperacidity and hypogastrinemia with possible ulcer disease.
Some individuals are more predisposed to IgE production or have increased numbers
of mast cells that might explain why only some people develop ulcer disease after
H. pylori infection.

PMID: 8771047  [PubMed - indexed for MEDLINE]

56. [Myelography, CT scan, electromyography and neurologic examination in the
diagnosis of herniated lumbar disk].
[Article in Croatian]
Kristek B, Dicić M, Vranković D, Kurbel S.
Lijec Vjesn. 1995 May-Jun;117(5-6):133-8.

Odjel za radiodijagnostiku, Klinicka bolnica Osijek.

The research was carried out at the Clinical Hospital Osijek during a three-year
period. Sixty-nine patients (34 men and 35 women) with the diagnosis of lumbar
slipped disc who underwent surgery were followed up. The main inclusion criterion
was the surgical finding of hernia. The aim of the study was to obtain a clearer
insight into the values of the myelography and CT scan by observing a
sufficiently large number of patients with surgically verified hernia of lumbar
disc. The characteristics of neurological and EMG findings were surveyed, as
well. Thirty-one patients were at the age of 40-49 years and 21 were at 30-39
years of age. Only 5 hernias were at the level L3L4, 28 at the level L4L5, and 46
at the level L5S1. Sensitivity, specificity and overall accuracy of the observed
parameters were estimated for 41 leftwards and 30 rightwards located hernias.
Myelographic finding, regardless of the observed level of slipped disc, showed
excellent sensitivity, specificity and accuracy of diagnosis. CT finding was
slightly less sensitive at the level L4L5, it was 0.93, and specific at the level
L5S1, amounting to 0.90. Its accuracy was not substantially lower than that of
myelography. The pathological EMG was 0.88 sensitive, 0.83 specific and 0.84
accurate. The accuracy was excellent at the level L3L4, it was 0.96, but only
very good at the level L5S1, amounting to 0.76. A t-test of linked pairs was used
to compare surgical reports and diagnostic findings. There was a great similarity
between a CT finding and surgical one in all three levels (t-values 1.00, 0.21
and 0.36). Myeolography was more congruent with the surgical finding in the
middle level (t-values 1.65, 0.93 and 1.52). An EMG finding was significantly
different from that found by surgery (t-values 1.71, 1.76 and 2.71). The
existence of Las?gue's sign for the diagnosis of hernia was 0.93 sensitive, 0.07
specific (remarkably low) and 0.36 accurate. It was particularly inaccurate at
the level L3L4, moderately accurate at the level L4L5, and rather accurate at the
lowest level L5S1. The weakened Achilles tendon reflex was less sensitive than
Las?gue's sign, amounting to 0.80. Its specificity was 0.19 and accuracy 0.40.
The highest accuracy was in hernias of the lower two levels L4L5 and L5S1. The
existence of weakened sense was 0.91 sensitive, specificity was remarkably low,
amounting to 0.08, and accuracy was 0.36. It was most inaccurate at the level
L3L4 and slightly better at the levels L4L5 and L5S1. Disturbance of leg
movements showed sensitivity of only 0.60, but specificity was 0.39 and accuracy
0.46. It was most precise at the level L4L5. Neurological symptoms and signs were
insufficiently sensitive and specific for the diagnosis of lumbar disc hernia. On
the basis of these parameters, the level of hernia could not be exactly

PMID: 8600326  [PubMed - indexed for MEDLINE]