Influence of pelvic volume on surgical outcome after low anterior resection for rectal cancer.

BACKGROUND: Low anterior resection (LAR) for rectal cancer is a potentially challenging operation due to limited space in the pelvis. CT pelvimetry allows to quantify pelvic space, so that its relationship with outcome after LAR may be assessed. Studies investigating this, however, yielded conflicting results. We hypothesized that a small pelvis is associated with a higher rate of incomplete mesorectal excision, anastomotic leakages, and increased rate of urinary dysfunction in patients operated for rectal cancer. METHODS: In a single-center retrospective analysis, we studied 74 patients that underwent LAR for rectal cancer with primary anastomosis. Thin-layered multi-slice CT datasets were used for slice by slice depiction of the inner pelvic surface, and the inner pelvic volume was automatically compounded. The primary outcome was quality of total mesorectal excision (TME; Mercury grading); secondary outcomes were anastomotic leakage and urinary dysfunction with regard to pelvic dimensions. Univariate analyses and multiple logistic regression analyses were performed for the primary and the secondary outcomes. RESULTS: Shorter obstetric conjugate diameters were associated with a higher probability of a worse TME quality (110.8 ± 10.2 vs. 105.0 ± 8.6 mm; OR 0.85; 95% CI 0.73-0.99; p = 0.038). Short interspinous distance showed a trend towards an increased risk for deteriorated TME quality (OR 0.88; 95% CI 0.76-1.0; p = 0.06). Anastomotic leakage was associated with anemia (OR 2.77; 95% CI 1.0-7.7; p = 0.047). Association between pelvic diameters or pelvic volume and anastomotic leakage or urinary dysfunction was not observed. Perioperative blood transfusions were administered more often in patients with postoperative urinary dysfunction (OR 17.67; 95% CI 2.44-127.7; p = 0.004). CONCLUSION: Shorter obstetric conjugate diameter might be a risk factor for incompleteness of total mesorectal excision. Anastomotic leakage seems to be influenced more by clinical factors such as anemia rather than pelvic dimensions. Further studies have to prove the influence of pelvic diameter on local recurrence of rectal cancer after LAR.

Modelling the growth of plants with a uniform growth logistics.

BACKGROUND AND AIMS: The increment model has previously been used to describe the growth of plants in general. Here, we examine how the same logistics enables the development of different superstructures. METHODS: Data from the literature are analyzed with the increment model. Increments are growth-invariant molecular clusters, treated as heuristic particles. This approach formulates the law of mass action for multi-component systems, describing the general properties of superstructures which are optimized via relaxation processes. RESULTS: The daily growth patterns of hypocotyls can be reproduced implying predetermined growth invariant model parameters. In various species, the coordinated formation and death of fine roots are modeled successfully. Their biphasic annual growth follows distinct morphological programs but both use the same logistics. In tropical forests, distributions of the diameter in breast height of trees of different species adhere to the same pattern. Beyond structural fluctuations, competition and cooperation within and between the species may drive optimization. CONCLUSION: All superstructures of plants examined so far could be reproduced with our approach. With genetically encoded growth-invariant model parameters (interaction with the environment included) perfect morphological development runs embedded in the uniform logistics of the increment model.

Expression analysis of genes lying in the NF1 microdeletion interval points to four candidate modifiers for neurofibroma formation.

The hallmark of neurofibromatosis type 1 (NF1) are multiple dermal neurofibromas. They show high inter- and intrafamilial variability for which the influence of modifying genes is discussed. NF1 patients presenting microdeletions spanning NF1 and several contiguous genes have an earlier onset and higher number of dermal neurofibromas than classical NF1 patients, pointing to one of the deleted genes as modifier. Expression analysis of 13 genes of the microdeletion region in dermal neurofibromas and other tissues revealed four candidates for the modification of neurofibroma formation: CENTA2, RAB11FIP4, C17orf79, and UTP6.

Pluto's Interaction With Energetic Heliospheric Ions.

Pluto energies of a few kiloelectron volts and suprathermal ions with tens of kiloelectron volts and above. We measure this population using the Pluto Energetic Particle Spectrometer Science Investigation (PEPSSI) instrument on board the New Horizons spacecraft that flew by Pluto in 2015. Even though the measured ions have gyroradii larger than the size of Pluto and the cross section of its magnetosphere, we find that the boundary of the magnetosphere is depleting the energetic ion intensities by about an order of magnitude close to Pluto. The intensity is increasing exponentially with distance to Pluto and reaches nominal levels of the interplanetary medium at about 190R P distance. Inside the wake of Pluto, we observe oscillations of the ion intensities with a periodicity of about 0.2 hr. We show that these can be quantitatively explained by the electric field of an ultralow-frequency wave and discuss possible physical drivers for such a field. We find no evidence for the presence of plutogenic ions in the considered energy range.

The general growth logistics of cell populations.

An increment model based on thermodynamics lays bare that the cell size distributions of archaea, prokaryotes and eukaryotes are optimized and belong to the same universal class. Yet, when a cell absorbs mass or signals are processed, these conditions are disturbed. Relaxation re-installs ideal growth conditions via an exponential process with a rate that slows down with the cell size. In a growing ensemble, a distribution of relaxation modes comes in existence, exactly defined by the universal cell size distribution. The discovery of nano-mechanic acoustic activities in cells led us to assume that in a growing ensemble acoustic signals may contribute significantly to the transmission of essential information about growth-induced disturbances to all cells, initiating that way coordinated relaxation. The frequency increases with the cell number shortening the period between successive signals. The completion of rearrangements occurring at a constant rate is thus progressively impaired, until cellular growth stops, totally. Due to this phenomenon, the so-called "relaxation-frequency-dispersion" cell colonies should exhibit a maximum cell number. In populations with large cell numbers, subsystems, behaving similar-like colonies, should form network-like patterns. Based on these ideas, we formulate equations that describe the growth curves of all cell types, verifying that way the general nature of the growth logistics.

Restoring functional neurofibromin by protein transduction.

In Neurofibromatosis 1 (NF1) germ line loss of function mutations result in reduction of cellular neurofibromin content (NF1+/-, NF1 haploinsufficiency). The Ras-GAP neurofibromin is a very large cytoplasmic protein (2818 AA, 319 kDa) involved in the RAS-MAPK pathway. Aside from regulation of proliferation, it is involved in mechanosensoric of cells. We investigated neurofibromin replacement in cultured human fibroblasts showing reduced amount of neurofibromin. Full length neurofibromin was produced recombinantly in insect cells and purified. Protein transduction into cultured fibroblasts was performed employing cell penetrating peptides along with photochemical internalization. This combination of transduction strategies ensures the intracellular uptake and the translocation to the cytoplasm of neurofibromin. The transduced neurofibromin is functional, indicated by functional rescue of reduced mechanosensoric blindness and reduced RasGAP activity in cultured fibroblasts of NF1 patients or normal fibroblasts treated by NF1 siRNA. Our study shows that recombinant neurofibromin is able to revert cellular effects of NF1 haploinsuffiency in vitro, indicating a use of protein transduction into cells as a potential treatment strategy for the monogenic disease NF1.

Structured treatment interruptions following immediate initiation of HAART in eight patients with acute HIV-1 seroconversion.

BACKGROUND: The immunological and clinical benefits of structured treatment interruptions (STIs) during primary HIV-1 infection remain largely unclear. PATIENTS AND METHODS: Eight patients identified during primary HIV-1 infection were immediately treated with HAART and underwent subsequent STIs after reaching complete viral suppression of HIV-RNA in peripheral plasma. HAART was re-initiated if either HIV-1 RNA >5000 copies/ml, CD4-cells <200 cells/microl or symptomatic HIV-1 disease was observed. RESULTS: After treatment discontinuation, four of eight patients were able to persistently control HIV-1 viremia below 5000 copies/ml until the last time point of follow-up (median 3 years). CD4-cell counts were within the interquartile range of untreated individuals compared to historical reference data from the MACS cohort. In the remaining study subjects persistent virological control was not reached despite repeated STIs. Moreover, compared to the MACS cohort repetitive virological failures during STIs appeared to induce an accelerated decline of CD4-cells. CONCLUSION: Spontaneous HIV-1 control after treated primary HIV-1 infection was possible in four out of eight individuals, however, if STIs after treated primary infection ameliorate the overall HIV-1 disease progression remains unknown. In the absence of viral control, repetitive viral exposure during STIs might be associated with accelerated decline of CD4-cell counts.

The small satellites of Pluto as observed by New Horizons.

The New Horizons mission has provided resolved measurements of Pluto's moons Styx, Nix, Kerberos, and Hydra. All four are small, with equivalent spherical diameters of ~40 kilometers for Nix and Hydra and ~10 kilometers for Styx and Kerberos. They are also highly elongated, with maximum to minimum axis ratios of ~2. All four moons have high albedos (~50 to 90%) suggestive of a water-ice surface composition. Crater densities on Nix and Hydra imply surface ages of at least 4 billion years. The small moons rotate much faster than synchronous, with rotational poles clustered nearly orthogonal to the common pole directions of Pluto and Charon. These results reinforce the hypothesis that the small moons formed in the aftermath of a collision that produced the Pluto-Charon binary.

Severe episode of high fever with rash, lymphadenopathy, neutropenia, and eosinophilia after minocycline therapy for acne.

Minocycline is a tetracycline agent frequently used for acne therapy. It has a few rare but severe side effects that are not widely known but should be recognized early as drug related. These include acute hepatitis and liver failure; a Löffler-like syndrome with pulmonary infiltrates, wheezing, fever, and eosinophilia; skin eruptions, eosinophilic cellulitis, and pustular folliculitis with eosinophilia; and a lupuslike syndrome. Side effects that are better known and recognized include photosensitization, skin exanthema with pruritus, and pseudotumor cerebri.

Virological and immunological characteristics of HIV treatment failure.

BACKGROUND: Resistance to antiretroviral treatment is prevalent. There is limited knowledge of the determinants of disease evolution in subjects infected with multidrug-resistant HIV (MDR-HIV). METHODS: Infectivity, replication, chemokine receptor usage, and env, gag, protease and reverse transcriptase sequence analysis was performed for MDR-HIV isolates from 14 HIV-infected individuals and compared to wild-type HIV isolates from individuals naive to antiretroviral treatment. Expression of CD45RO/RA, Ki67 and interferon-gamma and CD4 proliferative response to various antigens was determined for individuals infected with MDR-HIV and compared to that in individuals with optimal suppression of viral replication. RESULTS: Infectivity and replication are diminished for various MDR-HIV isolates, usually in the context of an increase in CD4 and CD4+CD45RA+ T-cell counts. However, a number of MDR-HIV isolates are associated with high in vivo viraemia and pronounced immunosuppression, and display in vitro levels of infectivity and replication comparable to those of wild-type strains. No specific genetic sequence or chemokine receptor usage predicted the fitness of an MDR isolate. CONCLUSIONS: Despite the biological diversity of resistant viruses and the range of host responses observed, our descriptive analysis indicates that viral factors play a role in determining the degree of immune damage observed in the context of MDR-HIV infection.

Identification of a melanoma progression antigen as integrin VLA-2.

The expression of the integrin receptors VLA-1, -2, -3, and -6 was studied in normal cultured melanocytes and in five melanoma cell lines. Normal melanocytes synthesized VLA-3, but did not reveal detectable levels of VLA-1, -2, and -6. All melanoma cell lines, however, expressed VLA-2, -3, and -6. VLA-1 was synthesized by two of five melanoma lines. In parallel, we had analyzed the expression of four previously characterized melanoma cell surface antigens. One of them (antigen A.1.43), which is associated with tumor progression of human melanoma, revealed a striking similarity to VLA-2. In sequential immunoprecipitation experiments, we show that A.1.43 is identical with the integrin VLA-2, a cell surface receptor for collagen, laminin, and fibronectin.

Post-transcriptional regulation of neurofibromin level in cultured human melanocytes in response to growth factors.

Among the symptoms that characterize neurofibromatosis type 1 (NF1) are pigmentation anomalies such as cafe au lait spots. It has been suggested that the reduction of the neurofibromin level in the epidermis of NF1 patients is responsible for the observed signs such as altered melanogenesis and altered density of melanocytes. Our studies show that in cultured normal human melanocytes, the neurofibromin level can be varied in vitro over a wide range by using different culture conditions. The influence of factors that control differentiation and proliferation of melanocytes on neurofibromin levels was studied. Immunoprecipitation followed by western blotting showed a 3- to 4-fold increase of neurofibromin after stimulation by PMA or bFGF, respectively, and a 1.5-fold increase in cells stimulated with steel factor. The increase of neurofibromin was not paralleled by a higher NF1 mRNA level as proved by northern blotting. Pulse-chase experiments with 35S-labeled melanocytes revealed an approximately 3-fold increase in the half-life of neurofibromin in bFGF- or PMA-stimulated cells compared to controls. These results indicate that the neurofibromin level of cultured melanocytes can be regulated by a mechanism independent of NF1 gene transcription and translation, which might influence the degradation rate of the protein.

Segmental neurofibromatosis is caused by somatic mutation of the neurofibromatosis type 1 (NF1) gene.

Segmental neurofibromatosis (NF) is generally thought to result from a postzygotic NF1 (neurofibromatosis type 1) gene mutation. However, this has not yet been demonstrated at the molecular level. Using fluorescence in situ hybridisation (FISH) we identified an NF1 microdeletion in a patient with segmental NF in whom café-au-lait spots and freckles are limited to a single body region. The mutant allele was present in a mosaic pattern in cultured fibroblasts from a café-au-lait spot lesion, but was absent in fibroblasts from normal skin as well as in peripheral blood leukocytes. These findings prove the hypothesis that the molecular basis of segmental cutaneous NF is a mutation in the NF1 gene and that the regional distribution of manifestations reflects different cell clones, commensurate with the concept of somatic mosaicism.

Total pancreatectomy in the pig for islet transplantation. Technical alternatives.

Pigs appear to be a suitable biological and logistical animal donor of islets for xenotransplantation in human diabetic type I recipients. To improve the islet isolation technique in this species, to evaluate the islet function in vivo, and to assess the toxic effects of various immunosuppressive regiments on transplanted islets will necessitate a model of the pancreatectomized pig suitable for islet autotransplantation. We describe three techniques of total pancreatectomy in pigs. The first removed the pancreas in order to study postoperative management and pig survival; no attempt was made to preserve the pancreas for islet isolation. The second consisted of a pancreatectomy in a surviving pig, with careful preservation of the whole pancreas for subsequent islet isolation. The third was rapid en bloc procurement of the pancreas and duodenum, to obtain a pancreas solely for the purpose of islet isolation. We conclude that pigs tolerate and survive a total pancreatectomy--they are suitable animals for islet isolation and possible autotransplantation. The result of islet isolation does not appear related to the pancreas procurement technique; however, the islet yield must be improved before autotransplantation can be functionally successful.

The effects of roxatidine acetate on 24-hour intragastric acidity. Investigations in healthy volunteers and comparison with ranitidine and placebo.

In a series of double-blind randomised studies in normal volunteers with continuous intragastric pH monitoring, the effects of different dosage regimens of roxatidine acetate, a new H2-receptor antagonist, were compared with placebo and ranitidine. Roxatidine acetate 75 mg twice daily decreased median 24-hour gastric acidity from pH 1.6 to 3.2 and median nocturnal acidity from 1.5 to 3.0. Roxatidine acetate 150 mg at bedtime raised median 24-hour pH in the same 17 subjects to 2.4 and nocturnal pH to 5.9. In the second experiment, in 14 volunteers, roxatidine acetate 150 mg at bedtime was as effective as ranitidine 300 mg at night, raising median nocturnal pH from 1.4 to 6.65 compared to 6.7 for ranitidine. However, when drugs were taken after the evening meal (post cenam nocte; PCN) roxatidine acetate 150 mg was less potent than ranitidine 300 mg, with median night-time pH rising from 1.3 to 3.2 and 4.0, respectively, in 28 volunteers. Roxatidine acetate 300 mg PCN produced the greatest rise of pH, to 4.9, suggesting that the true potency ratio of the 2 drugs is between 1 and 2.

The effects of roxatidine acetate (HOE-760) on 24-hour intragastric acidity in healthy volunteers: comparison with ranitidine and placebo.

In a series of double-blind randomized studies in normal volunteers using continuous intragastric pH monitoring, the effects of different dosage regimens of roxatidine, a new H2-receptor antagonist, were compared with placebo and ranitidine. Roxatidine acetate, 75 mg twice daily, decreased median 24 h gastric acidity from pH 1.6 to 3.2 and median nocturnal acidity from 1.5 to 3.0. Roxatidine acetate, 150 mg at bedtime, raised median 24 pH of the same 17 subjects to 2.4 and nocturnal pH to 5.9. In another series of experiments, 150 mg roxatidine acetate at bedtime was as effective as ranitidine 300 mg nocte raising median nocturnal pH (14 volunteers) from 1.4 to 6.65 compared to 6.7, respectively. However, when drugs were taken after the evening meal (post cenam nocte, pcn) roxatidine acetate 150 mg was less potent than ranitidine 300 mg with median night-time pH rising from 1.3 to 3.2 and 4.0, respectively, in 28 volunteers. Roxatidine acetate 300 mg pcn raised the pH to 4.9 suggesting that roxatidine is 1-2 times as potent as ranitidine, on a milligram-for-milligram basis.

Comparison of ranitidine 300 mg twice daily, 300 mg at night and placebo on 24-hour intragastric acidity of duodenal ulcer patients.

Continuous measurement of 24-hour intragastric acidity was performed in 12 duodenal ulcer patients in remission during treatment with placebo, ranitidine 300 mg nocte and ranitidine 300 mg b.d. Median 24-hour acidity was 79.4 mmol litre-1 during placebo treatment; it decreased to 28.2 mmol litre-1 during treatment with ranitidine 300 mg nocte and to 3.6 mmol litre-1 during treatment with ranitidine 300 mg b.d. The two regimens decreased intragastric acidity to a similar degree during the night, but significantly greater inhibition of daytime and 24-hour acidity followed use of ranitidine 300 mg b.d.

EVI2B, a gene lying in an intron of the neurofibromatosis type 1 (NF1) gene, is as the NF1 gene involved in differentiation of melanocytes and keratinocytes and is overexpressed in cells derived from NF1 neurofibromas.

The EVI2B gene is one of three genes embedded in intron 27b of the neurofibromatosis type 1 (NF1; M. Recklinghausen) gene, which are transcribed in the direction opposite that of the NF1 gene. The function of EVI2B and its relation to NF1 symptoms is unknown. Here, the amounts of NF1 and EVI2B mRNA were investigated in detail in cells involved in NF1 manifestations as café-au-lait macules and neurofibromas. These investigations showed that aside from the NF1 gene, EVI2B is involved in melanocyte and keratinocyte differentiation. Whereas in NF1 melanocytes from café-au-lait macules, EVI2B expression was not altered, in fibroblast-like cells derived from neurofibromas, an increased level of EVI2B mRNA was found. We investigated whether this increase was attributable to an influence of NF1 gene expression on the expression of the EVI2B gene, as suggested by the fact that the EVI2B primary transcript is antisense to the NF1 primary transcript. Investigations of cells derived from patients with different amounts of NF1 pre-mRNA showed no correlation between the amount of NF1 pre-mRNA and the increased level of EVI2B mRNA.

Long-term tamoxifen citrate use and potential ocular toxicity.

PURPOSE: To estimate the prevalence of abnormalities in visual function and ocular structures associated with the long-term use of tamoxifen citrate. METHODS: A single-masked, cross-sectional study involving multiple community and institutional ophthalmologic departments was conducted with a volunteer sample of 303 women with breast cancer currently taking part in a randomized clinical trial to determine the efficacy of tamoxifen (20 mg/day) in preventing recurrences. Participants included women who had never been on drug (n=85); women who had taken tamoxifen for an average of 4.8 years, then been off the drug for an average of 2.7 years (n=140); and women who had been on tamoxifen continuously for an average of 7.8 years (n=78). Women were evaluated by questionnaire, psychophysical testing, and clinical examination to determine any abnormalities in visual function and the comparative prevalences of corneal, lens, retinal, and optic nerve pathology. RESULTS: There were no cases of vision-threatening ocular toxicity among the tamoxifen-treated participants. Compared with nontreated participants, the tamoxifen-treated women had no differences in the activities of daily vision, visual acuity measurements, or other tests of visual function except for color screening. Intraretinal crystals (odds ratio [OR]=3.58, P=.178) and posterior subcapsular opacities (OR=4.03, P=.034) were more frequent in the tamoxifen-treated group. CONCLUSIONS: Women should have a thorough baseline ophthalmic evaluation within the first year of initiating tamoxifen therapy and receive appropriate follow-up evaluations.