Panitumumab-induced pulmonary toxicity.

Mutations in EGFR have been implicated in the pathogenesis of various types of cancer, and therefore antibody therapy directed against the epidermal growth factor receptor (egfr) is increasingly being used in the management of various cancers. Currently, anti-egfr antibodies are used mainly in the management of cancers of the head and neck and metastatic colorectal cancers. Because of this increasing use, we would like to inform the oncology community in North America of a rare, but life-threatening, toxicity associated with anti-egfr antibody therapy. Although cases in white and Japanese men have been documented, we present the first known North American report of panitumumab-induced pulmonary toxicity in a white woman.

Mechanical dissipation via image potential states on a topological insulator surface.

Joule energy loss due to resistive heating is omnipresent in today's electronic devices whereas quantum-mechanical dissipation is largely unexplored. Here, we experimentally observe a suppression of the Joule dissipation in Bi2Te3 due to topologically protected surface states. Instead, a different type of dissipation mechanism is observed by pendulum atomic force microscopy, which is related to single-electron tunnelling resonances into image potential states that are slightly above the Bi2Te3 surface. The application of a magnetic field leads to the breakdown of the topological protection of the surface states and restores the expected Joule dissipation process. Nanomechanical energy dissipation experienced by the cantilever of the pendulum atomic force microscope provides a rich source of information on the dissipative nature of the quantum-tunnelling phenomena on the topological insulator surface, with implications for coupling a mechanical oscillator to the generic quantum material.

Noncontact Atomic Force Microscope Dissipation Reveals a Central Peak of SrTiO_{3} Structural Phase Transition.

The critical fluctuations at second order structural transitions in a bulk crystal may affect the dissipation of mechanical probes even if completely external to the crystal surface. Here, we show that noncontact force microscope dissipation bears clear evidence of the antiferrodistortive phase transition of SrTiO_{3}, known for a long time to exhibit a unique, extremely narrow neutron scattering "central peak." The noncontact geometry suggests a central peak linear response coupling connected with strain. The detailed temperature dependence reveals for the first time the intrinsic central peak width of order 80 kHz, 2 orders of magnitude below the established neutron upper bound.

Low temperature ultrahigh vacuum noncontact atomic force microscope in the pendulum geometry.

A noncontact atomic force microscope (nc-AFM) operating in magnetic fields up to ±7 T and liquid helium temperatures is presented in this article. In many common AFM experiments the cantilever is mounted parallel to the sample surface, while in our system the cantilever is assembled perpendicular to it; the so called pendulum mode of AFM operation. In this mode measurements employing very soft and, therefore, ultrasensitive cantilevers can be performed. The ultrahigh vacuum conditions allow to prepare and transfer cantilevers and samples in a requested manner avoiding surface contamination. We demonstrate the possibility of nc-AFM and Kelvin force probe microscopy imaging in the pendulum mode. Ultrasensitive experiments on small spin ensembles are presented as well.

Extracellular calcium-sensing receptor is expressed in rat hepatocytes. coupling to intracellular calcium mobilization and stimulation of bile flow.

Liver cells respond to changes in Ca(2+)(o). The hepatic functions affected include bile secretion, metabolic activity, liver regeneration, and the response to xenobiotics. In the present study, we demonstrate the presence, in the liver, of the extracellular calcium-sensing receptor (CASR), described previously in the parathyroid and thyroid glands and kidney. CASR mRNA was specifically expressed in hepatocytes and was absent in nonparenchymal liver cells (stellate, endothelial, and Kupffer cells). Western blot analysis using a specific CASR antibody showed staining in both whole liver and hepatocyte extracts. Immunohistochemistry and in situ hybridization of rat liver sections showed expression of CASR protein and mRNA by a subset of hepatocytes. The known agonists of the CASR, gadolinium (Gd(3+); 0.5-3.0 mm) and spermine (1.25-20 mm), in the absence of Ca(2+)(o), elicited dose-related increases in Ca(2+)(i) in isolated rat hepatocytes loaded with Fura-2/acetoxymethyl ester. There was a greatly attenuated response to a second challenge with either agonist. The response was also abrogated when inositol 1,4,5-trisphosphate (IP(3))-sensitive calcium pools had been depleted by pretreatment with either thapsigargin or phenylephrine, an alpha(1)-adrenergic receptor agonist known to mobilize Ca(2+)(i) from IP(3)-sensitive pools. Addition of the deschloro-phenylalkylamine compound, NPS R-467, but not the S enantiomer, NPS S-467, increased the sensitivity of the Ca(2+)(i) mobilization response to 1.25 mm spermine. Bile flow ceased after Ca(2+)(o) withdrawal, and its recovery was enhanced by spermine in isolated perfused liver preparations. The CASR agonists Ca(2+) and Gd(3+) increased bile flow, and the response to a submaximal Ca(2+) concentration was enhanced by NPS R-467 but not the S compound. Thus, the data indicate that rat hepatocytes harbor a CASR capable of mobilizing Ca(2+)(i) from IP(3)-sensitive stores and that activation of the CASR stimulates bile flow.

Histomorphometric evidence for increased bone turnover without change in cortical thickness or porosity after 2 years of cyclical hPTH(1-34) therapy in women with severe osteoporosis.

Parathyroid hormone (PTH) increases trabecular but may decrease cortical bone mass during treatment of postmenopausal osteoporosis. In a 2-year trial, PTH, with or without sequential calcitonin (CT), was given to 29 osteoporotic women (mean age 67 +/- 7 years), in 3-month cycles [28 days hPTH(1-34), 50 microg/day, +/-42 days CT, 75 units/day, 20 days "free"]. Over 2 years, lumbar spine bone mineral density measurements increased an average of 10%. Paired iliac crest biopsies were obtained 28 days and 2 years after starting the trial. The addition of CT made no difference to changes seen with cyclical PTH alone. Thus, the histomorphometric analyses for all 29 treated patients were compared with a separate group of biopsies from untreated osteoporotic control patients (n = 15). No significant increments in total bone volume or trabecular architecture were seen over 2 years of cyclical PTH treatment, although the light microscopic appearance of bone was normal. At the level of the bone remodeling unit, a twofold increase in total trabecular erosion surface over the control measurements was observed within the first 28 days of PTH treatment (10 +/- 5 vs. 5 +/- 3% trabecular surface, p < 0.01), which was sustained over 2 years. Trabecular bone formation rates (surface referent) were 11 +/- 7 microm(3)/microm(2)/year in control patients and threefold higher in treated patients both acutely (31 +/- 31 microm(3)/microm(2)/year, p < 0.01) and after 2 years (33 +/- 43 microm(3)/microm(2)/year, p < 0. 05). The activation frequency of trabecular remodeling was threefold higher than controls through 2 years of treatment (p < 0.05). The mean wall thickness of completed osteons after 2 years of treatment was significantly larger than controls (28 +/- 7 vs. 22 +/- 5 microm, p < 0.01), suggesting a positive remodeling balance, as well as the histomorphometric evidence of increased bone turnover and the increased resorption surfaces. Over 2 years of cyclical PTH therapy, cortical thickness remained significantly higher than controls (680 +/- 202 vs 552 +/- 218 microm, p < 0.05), without significant changes in cortical porosity. Thus, the histomorphometric changes during cyclical PTH therapy in patients with severe osteoporosis are consistent with increased trabecular bone turnover and a positive remodeling balance, with no evidence for detrimental changes in cortical bone.

Nuclear localization of the type 1 PTH/PTHrP receptor in rat tissues.

The localization of PTH/PTH-related peptide (PTHrP) receptor (PTHR) has traditionally been performed by autoradiography. Specific polyclonal antibodies to peptides unique to the PTHR are now available, which allow a more precise localization of the receptor in cells and tissues. We optimized the IHC procedure for the rat PTHR using 5-microm sections of paraffin-embedded rat kidney, liver, small intestine, uterus, and ovary. Adjacent sections were analyzed for the presence of PTHR mRNA (by in situ hybridization) and PTHrP peptide. A typical pattern of staining for both receptor protein and mRNA was observed in kidney in cells lining the proximal tubules and collecting ducts. In uterus and gut, the receptor and its mRNA are present in smooth muscle layers (PTHrP target) and in glandular cuboidal cells and surface columnar epithelium. This suggests that PTH, or more likely PTHrP, plays a role in surface/secretory epithelia that is as yet undefined. In the ovary, PTHR was readily detectable in the thecal layer of large antral follicles and oocytes, and was present in the cytoplasm and/or nucleus of granulosa cells, regions that also contained receptor transcripts. PTHR protein and mRNA were found in the liver in large hepatocytes radiating outward from central veins. Immunoreactive cells were also present around the periphery of the liver but not within two or three cell layers of the surface. Clear nuclear localization of the receptor protein was present in liver cells in addition to the expected cytoplasmic/peripheral staining. PTHR immunoreactivity was present in the nucleus of some cells in every tissue examined. RT-PCR confirmed the presence of PTHR transcripts in these same tissues. Examination of the hindlimbs of PTHR gene-ablated mice showed no reaction to this antibody, whereas hindlimbs from their wild-type littermates stained positively. The results emphasize that the PTHR is highly expressed in diverse tissues and, in addition, show that the receptor protein itself can be localized to the cell nucleus. Nuclear localization of the receptor suggests that there is a role for PTH and/or PTHrP in the regulation of nuclear events, either on the physical environment (nucleoskeleton) or directly on gene expression.

Nuclear localization of the type 1 parathyroid hormone/parathyroid hormone-related peptide receptor in MC3T3-E1 cells: association with serum-induced cell proliferation.

We have recently demonstrated that the receptor for parathyroid hormone (PTH) and PTH-related peptide (PTHrP), PTHR, can be localized to the nucleus of cells within the liver, kidney, uterus, gut, and ovary of the rat. We set out to determine the localization of the PTHR in cultured osteoblast-like cells. MC3T3-E1, ROS 17/2.8, UMR106, and SaOS-2 cells were cultured in alpha-modified eagle medium containing 15% fetal calf serum under standard conditions. Untreated cells were grown on glass coverslips to 75-95% confluence and fixed in 1% paraformaldehyde. For experiments designed to examine cells synchronized by serum starvation, cells were grown on glass coverslips, starved of serum for 46 h, and then fixed at 2-h intervals for a total of 26 h after the addition of serum to the medium. Parallel sets of cells were pulsed with [3H]thymidine to track the DNA duplication interval. The PTHR was localized by immunocytochemistry using a primary antibody raised against a portion of the N-terminal extracellular domain of the PTHR. The results presented herein indicate that the PTHR attains a nuclear localization in each cell line examined. In UMR106 cells, PTHR immunoreactivity was restricted to the nucleolus. After cell synchronization, MC3T3-E1 cells double approximately 24 h after the addition of serum. Immunocytochemistry for the PTHR in these cells showed that the receptor staining is initially diffuse for the first 6 h, then becomes more perinuclear in distribution by 12-16 h. Nuclear localization of the receptor is achieved approximately 16-20 h after the addition of serum and remains there throughout the mitotic phase. Intense staining of mitotic and postmitotic cells was observed. No change in cell proliferation kinetics was observed in MC3T3-E1 cells cultured in the presence of 25 nM PTH(1-34). These data suggest an important role for the PTHR in the nucleus of MC3T3-E1 cells at the time of DNA synthesis and mitosis.

Enhanced osteoblast development after continuous infusion of hPTH(1-84) in the rat.

Rats and humans respond to intermittent treatment with parathyroid hormone (PTH) with increased bone density and cancellous bone volume. In the rat, osteoblast expression of insulin-like growth factor-I (IGF-I) is elevated by intermittent PTH. We examined the effect of continuous infusion of rhPTH(1-84), a bone catabolic regime, on the IGF system in rat pelvis. Female Sprague-Dawley rats (12 weeks, 250 g) were randomly assigned to receive 0, 0.1, 1, or 5 microg/100 g body weight (b.w.) rhPTH(1-84) (0, 0.106, 1.06, or 5.305 nmol/kg) in vehicle (1% normal rat serum in saline) delivered by subcutaneous Alzet minipump. After 7 days, blood was taken for serum chemistry and pelvises were processed for immunocytochemistry. Sections of pelvis from rats continuously infused with 0.1 or 1 microg/100 g b.w. rhPTH(1-84) for 7 days did not differ significantly from those of the vehicle-treated controls. However, continuous infusion of 5 microg/100 g b.w. rhPTH(1-84) resulted in a dramatic increase in cellular development, with trabeculae surrounded by many layers of large, plump osteoblasts. All pelvis osteoblasts expressed osteocalcin, but only those from rats that received 0, 0.1, or 1 microg/100 g b.w. rhPTH(1-84) showed positive staining for IGF-I. The extra-abundant osteoblasts from rats that received 5 microg/100 g b.w. rhPTH(1-84) did not stain for IGF-I. However, although all osteoblasts stained positively for IGF binding proteins (IGFBPs)-3, -4, and -5, staining for these IGFBPs increased as the dose of rhPTH(1-84) (and osteoblast number) increased. These results suggest that continuous infusion of PTH has a direct effect on osteoblast development (either recruitment or proliferation), decreases the expression of IGF-I, and enhances the expression of IGFBPs in pelvis, factors which may interact to bring about negative bone balance.

Surgical treatment for carcinoma of the gallbladder.

Carcinoma of the gallbladder has always been associated with dismal prognosis. In this study we present single institution experience in surgical treatment for gallbladder cancer obtained during last five years. Even with recent improvement in diagnostic imaging modalities gallbladder malignancies are still diagnosed too late. The choice of operative procedure for a treatment of gallbladder carcinoma still remained the open question. Carcinoma of the gallbladder is not very common disease in Europe, but some how more common in Poland. According to the National Register, based on a study from 1991, 1863 cases of death from the gallbladder carcinomas were registered [13]. At the same time 2015 new cancer cases were diagnosed and registered. These gave us a crude rate of new cases in 1991 as follows: 2.7/100,000 man and 7.7/100,000 female. Those were even higher for some voivodeships in 1988, for example: Lódz (M = 3.95/100,000, F = 10.58/100,000) and Warsaw (M = 3.15/100,000, F = 7.59/100,000). Carcinoma of the gallbladder has always been associated with dismal prognosis. This was essentially the result of the slow and asymptomatic growth of the neoplasm that infiltrates the surrounding structures, such as the portal vein, hepatic artery and liver parenchyma, making a curative surgical treatment almost impossible. So there is a general impression that no progress has been made during last 20 years in the treatment for carcinoma of the gallbladder [2, 7, 9, 12]. However, in last years, we have observed improvements in diagnostic, surgical and intensive care techniques that allowed to offer a wider range of surgical and non-surgical options to our patients [1, 3, 4, 6, 8].(ABSTRACT TRUNCATED AT 250 WORDS)

[Bilateral amputations after multiple vascular operations in patients with advanced ischemia of the lower extremities]. / Obustronne amputacje po mnogich operacjach naczyniowych u chorych z zaawansowanym niedokrwieniem konczyn dolnych.

In 62 patients 72 repeated multiple operations on the arteries of lower extremities were carried out. In 7 cases both lower extremities had to be amputated at mid-femoral level. The time from the first vascular operations to the amputation of the other extremity ranged from 6 months and 16 days to 8 years and 30 days (mean 5 years).

Age-related increase of cuticle permeability in the nematode Caenorhabditis briggsae.

The external cuticular surface of nematodes, which resembles cellular membranes in certain ways, appears to deteriorate with age. For example, when the permeabilities to radioactive water of young and old nematodes were compared, and the data were corrected for the different surface: volume ratios, the older nematodes were significantly more permeable. In both living and dead nematodes, the same rates of water exchange were observed, indicating that the major route of exchange was probably by passive diffusion through the cuticle rather than by active processes such as swallowing or excreting water.

Biogenic amines in the Caenorhabditis briggsae.

Dopamine, epinephrine, norepinephrine and serotonin were demonstrated from homogenates of Caenrohabditis briggsae by two-dimensional thin layer chromotography and the identification confirmed by gas liquid chromtography. In Vitro studies with 14C precursors of these biogenic amines demonstrate the ability of C. briggsae to synthesize each compound. The results provide required preliminary data for studying the neurophysiology of aging utilizing the nematode as a model.

Fine structure of the esophagus of Pratylenchus penetrans.

The fine structure of the esophagus of Pratylenchus penetrans is described. The gland lobe is syncytial and contains two types of nuclei: three large nuclei with little chromatin, and more numerous smaller nuclei with large amounts of chromatin. Some of the smaller nuclei are associated only with glandular tissue, whereas others are part of nerve ceils within the esophagus. Clusters of free ribosomes, rough endoplasmic reticulum, and numerous mitochondria occur in the lobe region where the secretory granules are formed. No Golgi bodies were observed. On the basis of these observations, possible differences in the mechanism of secretory granule formation between plant-parasitic nematodes are discussed. Several other minor differences between the fine structure of other plant-parasitic nematodes previously examined and that of P. penetrans are also noted.

Studies on ageing in Turbatrix aceti.

Morphologic and physiologic changes which occur during senescence in the free-living nematode Turbatrix aceti are described. With age areas of the interchordal hypodermis containing nerve elements thickened, electron-dense aggregates formed within the pseudocoelom and age pigment granules accumulated within the intestinal epithelium. Specific gravity did not change with age. Old nematodes which had reproduced showed increased osmotic fragility, but this change was not observed in virgin females. The parameters characterizing senescence in T. aceti are compared with those of Caenorhabditis briggsae, another nematode being used as a model to study biological ageing.