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Biomedical subjects

P Klein

Publications and source records attributed to P Klein.

At least 37 records · Page 2Linked to original sources
PubMed2001

Water-soluble poly-(L-glutamic acid)-Gly-camptothecin conjugates enhance camptothecin stability and efficacy in vivo.

The therapeutic efficacy of 20(s)-camptothecin (CPT) is limited in humans by the instability of the active lactone form due to preferential binding of the carboxylate to serum albumin and by difficulty in formulation. Formation of an ester bond with an amino acid via the hydroxyl group at carbon 20 of CPT stabilizes the lactone. Linking CPT to a high molecular weight (MW) anionic polymer enhances solubility and improves distribution to the tumor through enhanced permeability and retention (EPR effect). Poly-(L-glutamic acid) (PG) is an anionic homo-polymer that can theoretically bind one molecule of a drug via the gamma carboxylic acid of each monomeric subunit. It has been used to make a water-soluble PG-paclitaxel conjugate currently in Phase II clinical trials that contains 37% paclitaxel by weight and is administered in a 10 min infusion without pre-medication. We evaluated the anti-tumor activity of PG conjugates of CPT after a single intraperitoneal injection using subcutaneous murine B-16 melanoma tumor growth as an indicator. Interposition of a glycine (gly) linker allowed CPT loading up to 50% w/w on the polymer. Increasing the PG MW from 33 to 49 kDa enhanced the efficacy without altering the maximum tolerated dose (MTD). In athymic mice bearing ectopic human colon or lung tumors, efficacy was enhanced compared to free camptothecin. Thus, as with paclitaxel, conjugation of CPT to PG enhanced pharmaceutical properties and preclinical efficacy.

Animals↗
PubMed2001

Three-dimensional kinematics of the lumbar spine during treadmill walking at different speeds.

The lumbar spine is of primary importance in gait and its development is influenced by the upright posture adopted in human locomotion. However, little is known about the kinematic behavior of the lumbar spine during walking. The aim of this study was to examine (1) lumbar spine kinematics during walking, (2) the effect of walking velocity on lumbar motion patterns and (3) the coupling characteristics of rotation and bending. In 22 volunteers aged 15-57 years, the three-dimensional displacements of T12 to the sacrum were sampled during elementary movements of the trunk and during walking on a treadmill at four walking velocities. A three-dimensional electrogoniometer (CA 6000 Spine Motion Analyzer) sampling at 100 Hz was used. We analyzed maximal primary and coupled motion ranges (ROM) and velocities in each plane. Lumbar ROM during walking did not exceed 40% of maximal active ROM. Transverse plane ROM and frontal and transverse velocities increased with walking velocity. Coupling of rotation and bending during walking was individually variable and dependent on walking velocity. Moreover, the smoothness of the bending-rotation path varied with walking velocity. A simplified envelope of lumbar coupling characteristics during walking is presented, and the existence of an individually variable walking speed that is characterized by a more harmonic lumbar contribution is hypothesized.

Adult↗
PubMed2001

Premature ovarian failure in women with epilepsy.

PURPOSE: Women with epilepsy (WWE) have an increased risk for several reproductive endocrine disorders that may affect their fertility. The incidence of premature ovarian failure (POF) in women with epilepsy has not been systematically studied. This study examined the incidence of POF in women with epilepsy. METHODS: Fifty consecutively evaluated cognitively normal women with epilepsy, aged 38-64 years, whose seizures began before age 41 years, were interviewed for symptoms of perimenopause and menopause. Endocrine studies, performed in women aged 45 years or younger at the time of evaluation, included serum follicle-stimulating hormone (FSH; done on menstrual cycle day 3 in menstruating women), inhibin A levels when FSH was normal, thyroid-stimulating hormone (TSH), prolactin, and, in menstruating women, menstrual cycle day 20 serum progesterone level. Nonsurgical premature menopause was defined as secondary amenorrhea of >12 months' duration with FSH levels of >14 International Units (IU) in women younger than 42 years. Premature perimenopause was defined by the presence of one or more of the following: somatic perimenopausal symptoms; change in previously regular menstrual cycles without evidence of other reproductive endocrine disturbance; and FSH level of >14 IU or inhibin A level of <7 pg/ml. Similarly aged neurologically normal women seen in the menopause and sleep clinics served as control subjects. Statistical analysis included Fisher's exact test, Kruskal-Wallis test, t test, and multivariate logistic regression analysis with significance set at p < 0.05. RESULTS: Seven (14%) of 50 women with epilepsy had nonsurgical premature perimenopause (six of seven) or menopause (one of seven), compared with three of 82 control (p=0.042). Five of 41 women with localization-related epilepsy (LRE) had POF compared with two of nine women with primary generalized epilepsy (PGE; p=0.595). Mean age of POF was 39.6 years (range, 37-42 years). Seizure duration, age at seizure onset, seizure severity and lateralization, smoking history, age of menarche, body mass index and incidence of depression was not statistically different between women with and without POF. There was no statistically significant association between POF and antiepileptic drugs (AEDs). Women with POF were more likely to have had catamenial exacerbation of their seizures than were women without POF (p=0.02). CONCLUSIONS: Women with epilepsy have an increased risk for developing POF. This finding should be considered in counseling women with epilepsy on family planning.

Adult↗
PubMed2001

[Anastomotic protection with a transanal tube after rectum resection and total mesorectal excision].

Between October 1998 and December 1999 50 patients with a primary cancer of the rectum were treated by sphincter saving anterior resection of the rectum and total mesorectal excision. Eight patients were given a neoadjuvant combined radio-chemotherapy. The anastomoses were performed in the triple-stapling technique with a Premium Plus CEEA stapling device (Fa. Tyco Health Care, Tönisvorst, Germany) or with a Proximate ILS curved stapling device (Fa. Ethicon Endo Surgery, Norderstedt, Germany). The anastomoses were situated in 7 cm or in lower distance from the anal skin. In all patients with complete anastomotic tissue rings the anastomoses were protected with the transanal tube. The integrity of the anastomosis (n = 48) was checked for completeness in the 2nd and 12th postoperative week. The patients were sigmoidoscoped and the anastomoses were controlled by transanal ultrasonography. During the hospital stay 2 patients (4.2 %) with a clinically evident anastomotic leakage were detected. 3 patients (6.2 %) with an asymptomatic anastomotic leakage were detected by computertomography. The anastomoses of 27 patients (56.2 %) were clinically and by ultrasonographical examination intact. In these patients a postoperative radiogram was not indicated. Relaparotomy was necessary in one patient for bleeding, in two patients for anastomotic leaks and in three patients for ileus (12.5 %). Because of low anastomotic leakage rate and low morbidity we find the transanal tube to be at least equivalent to conventional colostoma for anastomotic protection.

Adult↗
PubMed2001

Immunoglobulin E and eosinophilic cationic protein in segmental lavage fluid of the small and large bowel identify patients with food allergy.

OBJECTIVE: Members of the general population often assume that they suffer from food allergy, but the true prevalence is low. Testing for the diagnosis of food-related hypersensitivity entails laborious procedures, including GI endoscopy. Our objective was to develop an endoscopic screening approach for food allergy. METHODS: Endoscopically guided segmental lavage was performed in 11 patients with GI allergy and in 20 controls during lower GI endoscopy of the terminal ileum, the coecum, and the rectosigmoid. Eosinophilic cationic protein (ECP) and protein were measured in native lavage fluid, and immunoglobulin E (IgE) was also measured after a 10-fold lavage concentration. RESULTS: IgE/protein in lavage fluid from the coecum (0.055 +/- 0.068 U/mg vs 0.003 +/- 0.012 U/mg; p = 0.001) and the rectosigmoid (0.134 +/- 0.170 U/mg vs 0.019 +/- 0.042 U/mg; p < 0.05) was significantly elevated in patients with GI allergy. ECP/protein was significantly elevated at the terminal ileum (22.95 +/- 37.67 microg/mg vs 7.09 +/- 7.68 microg/mg; p < 0.05) and the rectosigmoid (23.66 +/- 19.43 microg/mg vs 11.97 +/- 16.39 microg/mg; p < 0.05). The combined use of GI lavage IgE and ECP as a diagnostic test for food allergy resulted in a sensitivity of 91% and a specificity of 80%. CONCLUSIONS: In endoscopically guided segmental lavage fluid, IgE and ECP/protein are increased in patients with food allergy. These measurements seem to offer an attractive diagnostic tool and may serve as a screening method.

Adult↗
PubMed2001

Endocytosed SP-A and surfactant lipids are sorted to different organelles in rat type II pneumocytes.

Intracellular transport of endocytosed surfactant protein A (SP-A) and lipid was investigated in isolated rat type II cells. After internalization, SP-A and lipid are taken up via the coated-pit pathway and reside in a common compartment, positive for the early endosomal marker EEA1 but negative for the lamellar body marker 3C9. SP-A then recycles rapidly to the cell surface via Rab4-associated recycling vesicles. Internalized lipid is transported toward a Rab7-, CD63-, 3C9-positive compartment, i.e., lamellar bodies. Inhibition of calmodulin led to inhibition of uptake and transport out of the EEA1-positive endosome and thus of resecretion of both components. Inhibition of intravesicular acidification (bafilomycin A1) led to decreased uptake of both surfactant components. It inhibited transport out of early endosomes for lipid only, not for SP-A. We conclude that in type II cells, endocytosed SP-A and lipid are transported toward a common early endosomal compartment. Thereafter, both components dissociate. SP-A is rapidly recycled to the cell surface and does not enter classic lamellar bodies. Lipid is transported toward lamellar bodies.

Adenosine Triphosphate↗
PubMed2001

Validation of a simple method for assessing sodium intake in dialysis patients.

It has been reported that sodium intake can be estimated in dialysis patients by the increment in the body sodium pool from the end of a dialysis session to the beginning of the following one. To verify the reliability of this method we compared the sodium intake, estimated by the interdialytic changes in plasma sodium concentration (C) and body water volume (V), to sodium removal during three consecutive sessions. For this purpose we investigated 9 nondiabetic patients, 5 females and 4 males, under chronic hemofiltration treatment. Sodium intake was estimated by the formula (C(pre) V(pre)) - (C(post) V(post)) using a flame photometer and electrical bioimpedance to determine the plasma sodium concentration and total body water, respectively. Sodium removal was calculated by the difference between sodium loss into the ultrafiltrate and sodium gain with the reinfusion fluid. The mean values of sodium intake calculated during the three intervals corresponded with the sodium losses measured during the three hemofiltration sessions in each patient (338+/-55 vs. 329+/-67 mEq; r = 0.92, p<0.0001). A direct relationship was also observed between sodium intake and both interdialytic body weight increase (r = 0.89, p< 0.0001) and fluid loss during the sessions (r = 0.88, p<0.0001). This data demonstrates that sodium intake can be properly estimated by the interdialytic changes in body water and plasma sodium concentrations. They also suggest that fluid intake may be influenced by sodium consumption and that sodium intake monitoring could be useful for the control of excessive interdialytic fluid gain.

Aged↗
PubMed2001

The rescue by phage display of human Fabs to gp120 HIV-1 glycoprotein using EBV transformed lymphocytes.

Human hybridomas secreting monoclonal antibodies in a stable manner are difficult to develop. The main difficulties are the restricted techniques for B-cell immortalization, the low number of sensitized B cells in peripheral blood, and the impossibility, for ethical reasons, to immunize humans with most antigens. Phage display has proved to be a powerful method for the generation of recombinant antibody fragments. This technology relies on the construction of recombinant Fab or scFv libraries and their display on phage M13. In order to rescue unstable B-cell clones secreting human antibodies we set up a method for the selection by phage display of human IgG fragments from Epstein-Barr virus (EBV)-transformed clones and applied it to the selection by phage display of Fabs directed against HIV-1 gp120, using a seropositive blood sample. The approach combines B-cell transformation by EBV of peripheral blood lymphocytes from a seropositive donor, preselection of specific IgG anti-gp120 producing clones, and the construction of a targeted human antibody library. In this library the percentage of heavy and light chain coding sequences expressed in Escherichia coli, amplified by a set of specific 5' primers for different antibody germ lines, was similar to that observed with the original untransformed B-cell sample. One round of panning was sufficient for the rescue of three Fabs specific for HIV-1 gp120 protein, which proves the efficiency of this technique.

Amino Acid Sequence↗
PubMed2001

Immunocytochemical observations on the organ distribution of exogenous monomeric and dimerized lysozyme.

Using commercial anti-lysozyme antibodies and anti-dimerized lysozyme rabbit serum produced by us we demonstrated by immunohistochemistry, in some organs of rats, the expression of exogenous egg white lysozyme preparations beside the native lysozyme. After oral administration, the egg white lysozyme was detected in intestinal epithelium, proximal and distal tubules of some nephrons, pulmonary alveolar walls and hepatocytes in the 3rd zone of liver acini, whereas native lysozyme was strongly expressed in intestinal and pulmonary macrophages in both the experimental and control animals. However, expression of the dimerized lysozyme released from the intraperitoneally implanted mini-osmotic pumps and detected using specific antisera was evident only on erythrocytes in intestinal blood vessels. It is concluded that the lysozyme preparations administered per os or parenterally are resorbed to blood circulation and distributed among various organs in an active form and maintaining their antigenic specificity. It may speak for their direct anti-inflammatory and immunomodulatory effects in respiratory, urinary, digestive and other systems.

Animals↗
PubMed2000

Pharmacological inhibition of phosphatidylcholine biosynthesis is associated with induction of phosphatidylinositol accumulation and cytolysis of neoplastic cell lines.

De novo production of phosphatidic acid (PA) in tumor cells is required for phospholipid biosynthesis and growth of tumor cells. In addition, PA production by phospholipase D has been cited among the effects of certain oncogenes and growth factors. In this report, it has been demonstrated that enhanced phospholipid metabolism through PA in tumor cells can be exploited pharmacologically for development of anticancer agents, such as CT-2584, a cancer chemotherapeutic drug candidate currently in Phase II clinical trials. By inhibiting CTP:choline-phosphate cytidylyltransferase (CT), CT-2584 caused de novo phospholipid biosynthesis via PA to be shunted away from phosphatidylcholine (PC) and into phosphatidylinositol (PI), the latter of which was doubled in a variety of CT-2584-treated tumor cell lines. In contrast, cytotoxic concentrations of cisplatin did not induce accumulation of PI, indicating that PI elevation by CT-2584 was not a general consequence of chemotherapy-induced cell death. Consistent with this mechanism of action, propranolol, an inhibitor of PA phosphohydrolase and phosphatidylcholine biosynthesis, was also cytotoxic to tumor cell lines, induced PI accumulation, and potentiated the activity of CT-2584 in cytotoxicity assays. As expected from biophysical properties of anionic phospholipids on cellular membranes, CT-2584 cytotoxicity was associated with disruption and swelling of endoplasmic reticulum and mitochondria. We conclude that CT-2584 effects a novel mechanism of cytotoxicity to cancer cells, involving a specific modulation of phospholipid metabolism.

Adrenergic beta-Antagonists↗
PubMed2000

Hypoglycemic sensorimotor polyneuropathy associated with insulinoma.

Hypoglycemia-induced peripheral neuropathy due to insulinoma is unusual and, as far as we know, has previously been reported in only 34 patients. In this case report, we describe the clinical features, electrophysiological features, and pathological findings in a 37-year-old patient with polyneuropathy from repeated hypoglycemic episodes over a 9-year period that related to an insulinoma. The literature is discussed. The reported case is of special interest because the peripheral neuropathy led to the correct diagnosis.

Adult↗
PubMed2000

[Intraoperative electromyographic recurrent laryngeal nerve identification as a routine measure].

In recent years, two methods of intraoperative monitoring of the laryngeal nerve have mostly been used: evoked electromyographic responses via endscopically applied needle electrodes inserted into the adducting laryngeal muscles, and non-invasive electrodes like special tubes with integrated electrodes or separately insertable electrodes like the postcricoid electrode or disposable electrodes attached to the tube, as used in this study. The incidence of recurrent nerve paresis or paralysis during the IRM period was 1/174 nerves (0.6%). The advantage of the IRM is the quick and certain identification of the nerve; intraoperative monitoring cannot replace a proper surgical technique. We conclude that the IRM, using a laryngeal surface electrode attached to the tube, is a safe and reliable method.

Adult↗
PubMed2000

Vascular organization in the mesorectum: angiography of rectal resection specimens.

The technical advances in rectal cancer surgery are known as the total mesorectal excision. The resection in an anatomically defined plane under direct vision and with sharp dissection distinguishes it conventional rectal surgery. The result must be a complete mesorectum without deep gouges. We performed specimen angiography to confirm completeness of the removed mesorectum. Thirteen total mesorectal excision specimens were examined by angiography after continence-preserving resection of rectal carcinoma. In 11 of the 13 cases the vascular supply was exclusively via the superior rectal artery. In two cases with hypoplastic left terminating branches of the superior rectal artery there was additional perfusion via a caudally ascending vessel or via smaller vessels connected laterally. In all specimens both arterial supply and venous outflow were located within the mesorectal fascial sheath. There was no radio-opaque substance leaking from the mesorectal surface in the case of a complete mesorectal specimen. Tiny vascular branches running laterally occurred in 7 of the 13 cases. We found no larger vascular connections branching off in the lateral direction. The rectal blood supply comes almost exclusively through the superior rectal vessels. Thus the fascia covering the mesorectum forms, as far as rectal vascularization is concerned, a closed compartment. The mesorectal vessels are enclosed in the fibrous avascular mesorectal fascia. They run close above the fascia. In the case of an incomplete mesorectal excision the specimen angiography shows a stain leaking from the mesorectal fascia. Our method can be used to confirm the completeness of the removed mesorectum.

Aged↗
PubMed2000

D3 lymph node dissection in gastric cancer: evaluation of postoperative mortality and complications.

Since November 1995 we have been performing a D3 lymph node dissection in patients undergoing an operation for gastric cancer with a curative intent. The aim of the present study was to evaluate whether this procedure results in an increased postoperative mortality or complication rate in a Western population. Between November 1995 and August 1997 the postoperative courses of 76 patients were retrospectively assessed (45.3 lymph nodes per patient, lymph node ratio: 0.16). The patient outcome was compared with data from a historic control group of patients (n = 383) in whom the newly established D2 dissection was studied in our department. Regarding the demographic, clinical, and tumor-pathologic data, and the choice of resection and reconstructive procedures, the two groups differed only slightly. The postoperative mortality of 1% was lower (vs 6.8%) while the overall complication rate of 34% (vs 32.1%) was identical. In particular, no anastomotic leakage (vs 9.4%) and fewer nonsurgical complications (17.1% vs 27.9%) occurred. The reoperation rate was 1% vs 9.7%. However, in 6% of the patients drainage tubes had to be inserted under computed tomographic guidance. The average hospital stay remained unchanged (21.9 vs 20.7 days). A D3 dissection was shown to be feasible while demonstrating no disadvantages in the patients when compared with the D2 procedure.

Adenocarcinoma↗