Prof. Sven Kurbel MD, PhD – personal web pages
Dept. of Physiology, Osijek Medical Faculty
J. Huttlera 4, 31000 Osijek, Croatia
e-mail: sven@jware.hr
21. Duplex sonography of arteriovenous fistula in chronic hemodialysis patients.
Misević T, Brkljacić B, Zibar L, Jakić M, Kurbel S, Radić R, Misević S.
Coll Antropol. 2006 Sep;30(3):535-41.
Department of Radiology, University Hospital Osijek, Osijek, Croatia.
misevic.tonci@kbo.hr
Duplex sonography was used to assess functional features of arteriovenous fistula
(AVF) for hemodialysis (HD). Internal diameter (ID), resistance index (RI) and
blood flow (BF) velocity in feeding artery and in vein ofAVF, and venous BF
volume were analyzed with purpose to determine the normal values. Presumed normal
BF velocities are those of clinically well functioning shunts, allowing BF
through HD lines of minimally 250 ml/min. Study included 66 nondiabetic
HDpatients (30 women, 36 men), mean age 52-13 years, treated by HD for median 61
(4-252) months. Measurements in 47patients with clinically well functioning AVF
were as followed: mean arterial ID 5.2 +/- 1.4 mm, median arterial RI 0.3
(0.3-0.9), median arterial BF velocity 1.5 (0.6-3.6) m/s, mean venous ID 7.6 +/-
2.2 mm, median venous RI 0.3 (0.3-0.9), mean venous BF velocity 1.6 +/- 0.7 m/s,
and median venous BF volume 530 (120-1890) ml/min. Patients with poor functioning
AVF had significantly less arterial ID, higher arterial RI, less venous ID, less
venous BF velocity and volume. Duplex sonography findings obtained for clinically
estimated well functioning shunt should be considered as normal Doppler values.
Blood vessels’ morphologic features depend upon age, and older patients have more
pronounced changes.
PMID: 17058520 [PubMed – indexed for MEDLINE]
22. Resorption of gas trapped in body cavities: comparison of alveolar and pleural
space with inner ear and paranasal sinuses.
Ivezić Z, Kurbel S, Skrinjarić-Cincar S, Radić R.
Adv Physiol Educ. 2006 Mar;30(1):30-2.
Osijek Medical Faculty, University of Osijek, Osijek, Croatia.
This paper describes our attempt to devise a short text aimed at improving
students’ understanding of gas resorption in body cavities. Students are expected
to understand the mechanisms behind paranasal sinusitis, otitis media, closed
pneumothorax, and atelectasis of collapsed lung tissue, all used as examples. On
the basis of the interpretation that during pneumothorax resorption, gas diffuses
down pressure gradients into the blood, students are encouraged to calculate
tables of pressure gradients for the above-mentioned pathological conditions.
After answering a few questions, students need to analyze and eventually accept
the following conclusion: in cases of air trapping in collapsible body cavities,
all gases will be fully reabsorbed without pain. Air trapping in bone cavities
leads only to partial reabsorption of gases and results in subatmospheric
intracavity pressure. Partial vacuum causes painful mucosal edema and free fluid
secretion.
PMID: 16481606 [PubMed – indexed for MEDLINE]
23. Are HER1/EGFR interactions with ligand free HER2 related to the effects of
HER1-targeted drugs?
Kurbel S.
Med Hypotheses. 2006;67(6):1355-7. Epub 2006 Aug 4.
Osijek Clinical Hospital, Department of Oncology, J Huttlera 4, 31000 Osijek,
Croatia. sven@jware.hr
This paper is aimed to describe consequences of possible dimerization modes
between ligand binding HER1 and ligand free HER2 receptors on cellular membrane.
Cells without HER2/neu need high exposure to HER1 ligands for growth stimulation
since formation of HER1-ligand:HER1-ligand homodimers depends on the number of
both HER1 and ligand molecules and an “all or none” threshold under which cell
growth is not stimulated can be expected. Cells with HER2/neu molecules on their
surface can react to moderate or even low HER1 ligand exposure through formation
of HER2:HER1-ligand dimers, making them more sensitive to growth stimulation by
EGF or other ligands without the “all or none” threshold in cell growth
stimulation. Formation of some HER2:HER2 homodimers can provide the basal cell
growth stimulation despite available ligands to HER1. In tumors, high expression
of HER2 can lead to many HER2:HER2 homodimers and increased cell growth that
contributes to a poor prognosis. Here presented concept is that some 75 millions
of years ago, introduction of HER2/neu with increased sensitivity to low EGFR
ligand exposure, might be the cause of increased variability of HER1 expression
on normal cells and of the basal EGF secretion from the uninjured tissue.
Spontaneous formation of HER2:HER2 homodimers in cells with HER2/neu expression
might have substituted the low ligand exposure from uninjured tissue and thus
slowly reduce importance of basal secretions of EGFR ligands. Reported
variability in HER1 tumor expression and response to HER1-targeted agents, a wide
range of EGF concentration in healthy women breasts fluid and the skin rash/tumor
response relation to HER1-targeted drugs are discussed as possible examples of
individual differences in tissue dependency on HER1 interactions with ligands in
normal and cancer tissue.
PMID: 16890381 [PubMed – indexed for MEDLINE]
24. Intestinal gases and flatulence: possible causes of occurrence.
Kurbel S, Kurbel B, Vcev A.
Med Hypotheses. 2006;67(2):235-9. Epub 2006 Mar 29.
Department of Physiology, Osijek Medical Faculty, J. Huttlera 4, 31000 Osijek,
Croatia. sven@jware.hr
All gases entrapped in closed body cavities are destined to be partially or
completely absorbed. Intestinal gases often accumulate and cause flatulence. This
paper proposes a simple concept of intestinal gas occurrence based on our
knowledge on gas resorption in other body cavities. Compliance of intestinal and
abdominal walls makes pressure in the liquid chyme bubbles near 760 mmHg.
Intestinal gases are from three sources. Air can be swallowed, CO2 come from the
gastric acid neutralisation and from intestinal bacterial colonies that also
produce hydrogen and methane. In continuously mixed liquid chyme, the total
pressure of blood gases is similar or lower than in the venous blood (<or=706),
well below the bubble forming pressure (>or=760 mmHg). Some local production of
bacterial gases with partial pressure of more than 90 mmHg is required, so the
resulting small bowel bubbles would contain less than 20% of bacterial gases. If
peristaltic mixing of chyme is prevented by an obstacle, local pressures of
bacterial gases build up, form bubbles that fuse and finally make X-ray visible
aeroliquid levels. Bacterial gases make almost 3/4 of the flatulence. Formation
of bubbles destined to become flatulence might depend on altered rheological
condition of the large bowel content, with local abundant production of bacterial
gases near bacterial colonies. Gases are unable to diffuse rapidly through the
dense liquid content and local accumulation allows formation of bubbles mainly of
bacterial gases. Their pressure can be higher 760 mmHg, since they are stretching
the thick content. Poor diffusion of gases keeps them almost free of blood gases
and their entrance makes them bigger. As the content moves along the colon, the
content is becoming more solid and gases are becoming entrapped in large bubbles.
Some blood and bacterial gases are absorbed and exhaled, but the remaining
quantity has no other escape except flatulence. Flatulence rich in bacterial
gases might be the price for the large bowel water reabsorption. It seems that
beside the peroral use of antibiotics active in the colon, little can be done to
reduce flatulence.
PMID: 16574342 [PubMed – indexed for MEDLINE]
25. Preservation of HER2/neu gene during evolution: possible physiological role and
survival advantages.
Kurbel S, Dmitrović B, Golcić G, Dovhanj J.
Med Hypotheses. 2006;66(5):1039-40. Epub 2006 Jan 30.
PMID: 16446054 [PubMed – indexed for MEDLINE]
26. Breast or colon cancer patients with more than one tumor: Are tumor and adjacent
normal tissue sharing same mutations?
Kurbel S, Kovacić D, Misević T, Kovacić B.
Med Hypotheses. 2006;66(3):676-7. Epub 2005 Dec 2.
PMID: 16326026 [PubMed – indexed for MEDLINE]
27. Mutations that modulate receptor-hormone congruency as a cause of the primate GH
receptor species specificity.
Kurbel S, Gulam D, Kovacić D, Mihaljević I, Faj D.
Theory Biosci. 2005 Apr;123(4):435-40. doi: 10.1016/j.thbio.2004.10.004.
Department of Physiology, Osijek Medical Faculty, Osijek Clinical Hospital,
Huttlera 4, 31000, Osijek, Croatia, sven@jware.hr.
Peptide hormones depend on reliable recognition by their receptors. Any mutation
that compromises recognition of hormone and receptor molecules is dangerous, the
carrier animal would not procreate and the mutation would be lost. Although, most
of the hormones from one mammalian species are active when injected into another,
the incompatibility of human GH receptor toward nonprimate GHs is a notable
exception. It is reported that the coevolution of GH and GHR in primates includes
two crucial steps (Mol. Biol. Evol. 18 (2001) 945). The first was mutation of GH
His–>Asp at position 171 that happened before the split of Old world and New
world monkeys. The second event was Leu–>Arg change at position 43 in the GH
receptor molecule that happened in the ancestor of Old world monkeys. The
proposed model is based on the possibility that certain mutations can modify the
surface of one of interacting molecules to form a confined empty space, a niche
in the otherwise congruent hormone/receptor interface. Altoough affinity between
molecules is probably slightly reduced, recognition and function are not
compromised in this special case. Further mutations of hormone and receptor
molecules are allowed under the condition that they remain confined to the niche
space. Mutations that do not compromise hormone function can be passed to
offsprings. If the consequent mutation of one molecule change its shape to fill
the niche space, further mutations without function loss will become less
probable. Without the niche space, the phase of fast evolution is closed and both
genes become conserved. In this setting, accumulated mutations before the niche
closing mutation are the cause of species specificity. To become a dominant
variety, carrier animals must possess survival advantage in comparison to the
carriers of other less advantageous mutations.
PMID: 18202875 [PubMed]
28. Association of skin rash and tumor response to HER1/EGFR inhibition: does HER1
stimulated tumor growth depend on circulatory instead of paracrine ligands?
Kurbel S, Faj D.
Med Hypotheses. 2005;64(6):1244-5.
PMID: 15823732 [PubMed – indexed for MEDLINE]
29. Selective reduction of estrogen receptor (ER) positive breast cancer occurrence
by estrogen receptor modulators supports etiological distinction between ER
positive and ER negative breast cancers.
Kurbel S.
Med Hypotheses. 2005;64(6):1182-7.
Department of Physiology, Osijek Medical Faculty, J. Huttlera 4, 31000 Osijek,
Croatia. sven@jware.hr
Reports that selective estrogen receptor modulators (SERMs) reduce occurrence of
only estrogen receptor (ER) positive tumors strongly support the etiological
distinction between ER positive and ER negative breast cancers. Based on these
evidences three concepts are described: Concept I. The occurrence of ER negative
tumor cells might be a consequence of the clonal selection among tumor cells.
This would lead to mosaicism in the ER expression. If ER negative cells become
the most prevalent clone, the patient will be diagnosed to have an ER negative
breast cancer. Since all cancers start as ER positive, SERMs should equally
prevent occurrence of ER positive and ER negative breast cancers, but this
prediction is evidently wrong. Concept II. Mammary ducts normally contain ER
positive and ER negative cells, both prone to malignancy. Cancer occurrence in
ductal cells that normally lack ER would be unrelated to estrogen exposure or
SERMs protection. Estrogen and SERMs can influence cancer occurrence only in ER
positive ductal cells. The main drawback is that this concept does not predict
occurrence of mosaicism in ER expression among tumor cells. Unified Concept I and
II. To overcome limitations of described concept a unified concept is presented.
Cancers from ER positive ductal cells start as pure ER positive tumors and those
from ER negative ductal cells as pure ER negative tumors. During the preclinical
phase, in some ER positive tumors, clonal selection introduces ER negative
clones. These tumors become mosaic in the cellular ER expression, some of them
predominantly ER positive other ER negative. Estrogen deprivation, or SERMs can
help mostly to patients with pure ER positive, or mosaic ER positive tumors.
Since the dominant metastatic clone can have different ER status from the primary
breast tumor, both surprising successes and failures of endocrine therapy can be
expected in tumors with mosaic ER expression.
PMID: 15823713 [PubMed – indexed for MEDLINE]
30. Estrogen receptor (ER) in breast cancer tissue of premenopausal patients: are
some ER- findings false due to down-regulation?
Kurbel S, Kovacić D, Kristek J, Sisljagić V, Mihaljević I.
Med Hypotheses. 2005;64(5):1069-70.
PMID: 15780520 [PubMed – indexed for MEDLINE]