Phase I and pharmacological trial of lapatinib in combination with gemcitabine in patients with advanced breast cancer.

BACKGROUND: Lapatinib has proven efficacy as monotherapy and in combination with capecitabine in patients with metastatic breast cancer (MBC) overexpressing HER2 and/or EGFR. Gemcitabine also has anti-tumor activity in MBC and a favourable toxicity profile. In this phase I study lapatinib and gemcitabine were combined. METHODS: Female patients with advanced BC were given lapatinib once daily (QD) in 28-day cycles with gemcitabine administered on day 1, 8 and 15. Physical examinations, vital signs and blood sampling for hematology, clinical chemistry and pharmacokinetics (PK) and radiological assessments of disease were performed at regular intervals. RESULTS: In total, 33 patients were included. Six dose-limiting toxicities were observed, mostly grade 3 increases in liver function tests. Most common toxicities were fatigue (73%), nausea (70%), diarrhea (58%), increases in ALAT and ASAT (55 and 52%, respectively) and rash (46%). The maximum tolerated dose was lapatinib 1250 mg QD with gemcitabine 1000 mg/m(2). Lapatinib and gemcitabine PK did not appear to be influenced by each other. Anti-tumor activity was observed with one patient (4%) showing complete response and six (23%) partial response. CONCLUSION: Despite a slightly increased toxicity profile compared to their respective monotherapies, lapatinib and gemcitabine can be safely combined while showing signs of anti-tumor activity.

[Balloon dilatation and Stentimplantation of the nasolacrimal duct for chronic epiphora]. / Minimal-invasive Therapie der Epiphora durch Ballonkatheterdilatation und Stentimplantation.

PURPOSE: To examine the clinical outcome of the ballon dilatation in stenosis and obstruction of the nasolacrimal duct. MATERIAL AND METHODS: 63 patients (69 nasolacrimal duct systems) with epiphora and proven obstruction of the nasolacrimal duct were treated with ballon dilatation, respectively Stentimplantation. In 55 cases there was a pre- or postsaccal stenosis, in 14 cases an occlusion of the nasolacrimal duct system. The diagnosis was established by dacryocystography. RESULTS: Technical success was obtained in 61 cases (n=50/55 stenosis; n=11/14 occlusions). Over a mean follow-up of 6 months patency of the nasolacrimal duct system was achieved in 83,6% (46/55) in stenosis. In occlusion the clinical outcome was 42,9% (6/14). CONCLUSION: Balloon dacryocystoplasty and Stentimplantation are minimal-invasive alternatives, performed in local anesthesia that recover the normal anatomy of the nasolacrimal duct system. They are a good alternative in the treatment of epiphora caused by nasolacrimal duct obstructions.

Characterization of the neurochemical content of neuronal populations of the lamina terminalis activated by acute hydromineral challenge.

The lamina terminalis (LT) contains three main regions, namely the subfornical organ (SFO), the median preoptic nucleus (MnPO) and the vascular organ of the LT (OVLT). Although LT is recognized of paramount importance in the regulation of hydromineral homeostasis, identity of the neurocircuits interconnecting the SFO and OVLT to the MnPO is not known. Furthermore, the phenotype of neuronal populations activated during acute hydromineral challenge is not yet determined. By using the high cellular resolution of the in situ hybridization histochemistry (ISHH), we investigated whether a furosemide-induced fluid and electrolyte depletion might modify both putative GABAergic and glutamatergic systems within the LT. We show that acute furosemide treatment (4 h) significantly reduced the expression of GAD67 mRNA, the active holoenzyme predictive of GABA synthesis, within the SFO. A strong tendency toward a reduction of GAD67 signal was also observed in the OVLT and MnPO. The hydromineral challenge did not alter the expression of GAD65 and type 2 vesicular glutamate transporter (vGlut2) mRNA in all the structures of the LT. Furosemide treatment was associated with a reduction in the population of GAD67-containing neurons in the periphery of the SFO and dorsal part of the MnPO. Contrastingly, GAD65-containing cells were shown to be increased in the OVLT and no change was observed for the vGlut2-containing neurons in the whole LT. By combining ISHH with immunohistochemistry (Fos immunoreactivity), we report that furosemide-induced water and sodium depletion did essentially recruit a glutamatergic network throughout the LT, although GABAergic neurons were specifically activated in the ring of the SFO and in the OVLT. The MnPO, the region of the LT that is considered as being an integrative area for sensory inputs arising from the SFO and OVLT, showed exclusive activation of excitatory neuronal populations. Taken together these results suggest that acute water and Na(+) depletion diminish the efficacy of the GABAergic system and mainly activates excitatory neuronal pathways in the regions of the LT.

Medical care in a geriatric psychiatry unit: impact on psychiatric outcome.

The medical care of 49 randomly selected patients admitted to a geriatric psychiatry evaluation unit was assessed to determine the impact on psychiatric care and outcome. Medical factors were identified as directly causing psychiatric symptoms in 12 of the 49 cases, whereas psychiatric decompensation was precipitated by medical illness in 25. Previously undiagnosed significant medical problems were found in ten patients. In 25 cases concomitant medical illness had a major effect on psychiatric treatment, and in 23 the course of the medical illness affected psychiatric outcome. Seventy-nine per cent of the patients had at least moderately improved at the time of discharge, and most were able to return to their homes. Improvement in medical condition was correlated significantly with psychiatric improvement. Implications for the care of geriatric psychiatry patients are discussed.

Prostate-specific membrane antigen and other prostatic tumor markers on the horizon.

The PSM antigen is an exciting new molecule with many potentially valuable applications. Further research with PSM may help us to elucidate the complex process of prostatic neoplasia better. Current avenues of research with PSM include the generation of new and improved monoclonal antibodies targeting different portions of PSM and PSM', which may improve the results of imaging and targeting prostate cancer. Gene therapy using the PSM promoter to drive prostate-specific expression of various cytokines and other factors is another exciting potential application deserving of attention, and refinement of serum PSM assays may greatly add to the present array of diagnostic modalities offered to patients with suspected prostate cancer. Thus, PSM is a potentially valuable addition to our armamentarium of prostate markers. Additionally, a host of other potential markers to increase our understanding of the complex biology of the normal and malignant prostate are on the horizon. Just how far away that horizon is awaits further basic and clinical investigations.

Panleukopenia-like syndrome of FeLV caused by co-infection with FeLV and feline panleukopenia virus.

To study the effect of interferon on feline leukemia virus (FeLV) infection, 30 specific pathogen free (SPF) cats were infected with the apathogenic FeLV A Glasgow. Unexpectedly, between 5 and 8 weeks after FeLV infection, all 19 cats with persistent FeLV infection but not the FeLV-negative cats died from a panleukopenia-like syndrome. No feline panleukopenia virus (FPLV) antigen was found in feces by latex agglutination, enzyme-linked immunosorbent assay (ELISA) or immunoelectron microscopy. No enteropathogenic bacteria were found. Histopathology revealed changes resembling those of FPLV infection such as destruction of crypts and pancytopenia of bone marrow. Neither clinical signs nor seroconversion to FPLV could be induced by transmitting intestinal extracts to two SPF cats. However, FPLV antigen was demonstrated by immunofluorescence assay in intestinal cryostat sections of diseased animals. FPLV could also be demonstrated in intestinal extracts by immunoelectron microscopy, by latex agglutination and ELISA after anti-FPLV antibodies were removed from immune-complexed FPLV by ultracentrifugation over a CsCl gradient at pH 2.0. From these experiments it was concluded that the panleukopenia-like syndrome of FeLV may not be caused by FeLV alone but at least in some cases by co-infection with FeLV and FPLV. In addition, some form of 'cooperation' between FeLV and FPLV must be postulated because neither virus alone induced symptoms.

Paediatric friction hand injuries caused by domestic vacuum cleaners-a review from one unit.

The management of seven children with vacuum cleaner friction burns is described. Six of the children sustained full thickness burns. Four were treated operatively. Indications for surgery are outlined and important accident prevention strategies are highlighted.

Single dose pharmacokinetics of fendiline in humans.

Fendiline was administered intravenously (3 mg) and orally (50 mg and 75 mg) in a cross-over study to six healthy volunteers. The plasma levels of unchanged fendiline and of total radioactivity were measured. Fendiline was absorbed well and its concentration declined biexponentially with mean terminal half-lives of 20-35 h. Since the drug is extensively metabolized, only 12% of total radioactivity in plasma corresponded to fendiline in the case of intravenous administration as compared to less than 2% after oral administration. 56-65% of the administered dose are excreted via the urine and 18-25% with the feces within five days.

[Liberation into the wild of wild felines--danger of the release of virus infections]. / Auswilderung von Wildfeliden--Gefahr der Freisetzung von Virusinfektionen.

There are several felidae amongst the numerous endangered species. Means of aiding survival are the reintroduction to the wild of animals bred under the auspices of man and their relocation from densely populated to thinly populated areas. It is unlikely that the dangers of such reintroduction or relocation projects have been examined sufficiently in respect to the risks of virus infections confronting individuals kept in zoos or similar situations. This report presents three examples to illustrate that accidental virus infections may be expected to occur when relocating and reintroducing wild cats. The first example is the reintroduction of captive snow leopards. Zoo bred snow leopards may be infected with FIV, a virus infection that is highly unlikely to occur in the original himalayan highlands of Tibet and China. A second example is of several cases of FIP that occurred in European wild cats bred in groups in captivity. The third example mentioned is the relocation of lions from East Africa where all the commonly known feline viruses are wide-spread to the Etosha National Park. In the latter, virus infections such as FIV, FCV and FPV do not occur. The indiscriminate relocation and reintroduction of the wild cats mentioned here harbours a potential of undesirable consequences.

[Topical photodynamic therapy in dermatology]. / Topische photodynamische Therapie in der Dermatologie.

Photodynamic therapy (PDT) is an experimental, noninvasive treatment of different malignant tumors. The principle is that applied photosensitizing substance selectively accumulate in neoplastic cells. Exposure to visible light then leads to the destruction of the tumor tissue. Following intravenous or oral administration of the photosensitizer (PS) generalised skin photosensitivity is the major side effect. Topical application of the PS under occlusive foil a novel method. Topical PDT (TPDT) is most investigated with 5-Aminolevulinic acid (ALA) as PS. ALA is a precursor of endogenous porphyrins in the biosynthetic pathway for heme. This new modality is increasingly and successfully used to treat precancerous and cancerous epithelial skin tumors, like actinic keratoses, basal-cell carcinoma, squamous-cell carcinoma and Bowen disease. An other approach of ALA-TPDT are nontumoral applications, especially psoriasis. ALA-TPDT is well tolerated by patients and makes excellent cosmetic results. It is an alternative treatment for various superficial skin tumors.

Current approaches, challenges and future directions for monitoring treatment response in prostate cancer.

Prostate cancer is the most commonly diagnosed non-cutaneous neoplasm in men in the United States and the second leading cause of cancer mortality. One in 7 men will be diagnosed with prostate cancer during their lifetime. As a result, monitoring treatment response is of vital importance. The cornerstone of current approaches in monitoring treatment response remains the prostate-specific antigen (PSA). However, with the limitations of PSA come challenges in our ability to monitor treatment success. Defining PSA response is different depending on the individual treatment rendered potentially making it difficult for those not trained in urologic oncology to understand. Furthermore, standard treatment response criteria do not apply to prostate cancer further complicating the issue of treatment response. Historically, prostate cancer has been difficult to image and no single modality has been consistently relied upon to measure treatment response. However, with newer imaging modalities and advances in our understanding and utilization of specific biomarkers, the future for monitoring treatment response in prostate cancer looks bright.

Metabolic efficiency of volitional and electrically stimulated cycling in able-bodied subjects.

This study compared the metabolic efficiency of volitional cycling and functional-electrical-stimulation (FES) cycling within a subject group of able-bodied individuals, with a view to further elucidating the mechanisms underlying the low efficiency of FES cycling. Previous studies estimated the metabolic efficiency of volitional cycling and anaesthetised FES cycling in able-bodied subjects, and of FES cycling in subjects paralysed by spinal cord injury. The rationale for the experimental model chosen here, i.e. non-anaesthetised able-bodied subjects, was that this lies between normal cycling and paralysed cycling: while using FES, this group has artificial muscle activation and timing like the paralysed group; but it does not have disrupted sensory feedback and vasomotor control; this measurement therefore allows delineation of the magnitude of reduction in metabolic efficiency resulting from: (i) the FES itself and (ii) paralysis (where there is disrupted sensory feedback and vasomotor control). Furthermore, we used the same methods employed previously for estimation of metabolic efficiency in subjects with motor- and sensory-complete paraplegia. The mean metabolic efficiency of volitional cycling was found to be 29.8% and that of FES cycling was 16.4% (n=11). The low efficiency of FES cycling can be explained in large part by the crude timing of muscle activation and by non-physiological muscle fibre recruitment. In FES cycling with paralysed subjects, disrupted sensory feedback and vasomotor control may play a further, albeit smaller, role in the reduced efficiency.

On the efficiency of FES cycling: a framework and systematic review.

Research and development in the art of cycling using functional electrical stimulation (FES) of the paralysed leg muscles has been going on for around thirty years. A range of physiological benefits has been observed in clinical studies but an outstanding problem with FES-cycling is that efficiency and power output are very low. The present work had the following aims: (i) to provide a tutorial introduction to a novel framework and methods of estimation of metabolic efficiency using example data sets, and to propose benchmark measures for evaluating FES-cycling performance; (ii) to systematically review the literature pertaining specifically to the metabolic efficiency of FES-cycling, to analyse the observations and possible explanations for the low efficiency, and to pose hypotheses for future studies which aim to improve performance. We recommend the following as benchmark measures for assessment of the performance of FES-cycling: (i) total work efficiency, delta efficiency and stimulation cost; (ii) we recommend, further, that these benchmark measures be complemented by mechanical measures of maximum power output, sustainable steady-state power output and endurance. Performance assessments should be carried out at a well-defined operating point, i.e. under conditions of well controlled work rate and cadence, because these variables have a strong effect on energy expenditure. Future work should focus on the two main factors which affect FES-cycling performance, namely: (i) unfavourable biomechanics, i.e. crude recruitment of muscle groups, non-optimal timing of muscle activation, and lack of synergistic and antagonistic joint control; (ii) non-physiological recruitment of muscle fibres, i.e. mixed recruitment of fibres of different type and deterministic constant-frequency stimulation. We hypothesise that the following areas may bring better FES-cycling performance: (i) study of alternative stimulation strategies for muscle activation including irregular stimulation patterns (e.g. doublets, triplets, stochastic patterns) and variable frequency stimulation trains, where it appears that increasing frequency over time may be profitable; (ii) study of better timing parameters for the stimulated muscle groups, and addition of more muscle groups: this path may be approached using EMG studies and constrained numerical optimisation employing dynamic models; (iii) development of optimal stimulation protocols for muscle reconditioning and FES-cycle training.

Quality of life after severe hand injury.

This study explores the quality of life in 118 patients following severe and major hand injury with a Hand Injury Severity Score >50. Each patient answered five different validated outcome measures (DASH (Disability of the Arm, Shoulder, and Hand), FLZ(M) ('Fragen zur Lebenszufriedenheit'), HADS (Hospital Anxiety and Depression Score), BDDE-SR (Body Dysmorphic Disorder Examination-Self Report) and FBeK ('Fragebogen zur Beurteilung des eigenen Körpers'), which were incorporated into a single questionnaire. Each of these questionnaires covered one or more of the established quality-of-life domains. Patients with pain and pressure sensations were significantly less satisfied in life, showed lower levels of health satisfaction, had higher levels of anxiety and depression and showed higher body dysmorphic disorder levels (all p < 0.001). General life satisfaction in this hand-injury study group is highly dependent on the patients` satisfaction with their health and appearance as well as self-confidence. The quality-of-life outcomes improve with time, and despite evidence of continued impairment in the injured hand, the majority of patients had a normal quality of life.

Relación entre puntaje de prueba de selección universitaria y nota enseñanza media, y el rendimiento académico de la asignatura de morfología en alumnos de primer año de odontología de la Universidad de los Andes / Relationship between university selection test scores, high school grade point average (GPA) and academic performance in the subject of morphology in dentistry freshmen at the Universidad de los Andes

El estudio de predictores de rendimiento académico presenta gran relevancia en el área de la salud. El objetivo de este trabajo fue evaluar la relación entre el puntaje de Prueba de Selección Universitaria (PSU) y notas de enseñanza media (puntaje nota de enseñanza media) en la asignatura de Morfología en alumnos de primer año de odontología, en la Universidad de los Andes. Estudio descriptivo con 312 estudiantes admitidos en el primer año de la carrera de odontología de la Universidad de los Andes de Chile, de forma regular y que terminaron el año universitario sin deserción los años 2005 a 2008 y 2010. Las variables estudiadas fueron género, promedio puntaje de notas de enseñanza media, puntaje PSU, tipo de colegio de procedencia según sistema de financiamiento (municipal, particular subvencionado y particular) y nota final de la asignatura de morfología de los alumnos del primer año de estudio, en la carrera de odontología. De los 312 alumnos, la mediana de PSU, notas de enseñanza media y nota de morfología fueron 692,6, 702 y 4,4 respectivamente. Del total de la muestra, 221 alumnos (71%) correspondieron al sexo femenino. Del total de la muestra, 290 alumnos (93%) provenían de colegios particulares, 15 alumnos (5%) de colegios particulares subvencionados y 6 alumnos (2%) de colegios municipales. La relación entre puntaje nota de enseñanza media y nota de morfología muestra una correlación de 0,35 (Rho de Spearman, valor-p <0,0001), y puntaje de PSU con nota de Morfología una correlación de 0,39 (Rho de Spearman, valor-p <0,0001). Existe asociación entre nota morfología, puntaje de notas de enseñanza media y PSU, de tal manera, que los mejores puntajes de nota de enseñanza media y PSU, muestran mejor rendimiento en la asignatura de morfología.

The study of predictors of academic performance is of great importance in the area of health. The objective of this study was to assess the relationship between PSU (University selection admission scores) and Secondary Education (High school grade point average score) in the freshmen morphology course in dentistry, at the Universidad de los Andes. A descriptive study of 312 students admitted to the first year of dental school at the Universidad de los Andes in Chile, on a regular basis and who have completed the academic year without dropping out, the years 2005-2008 and 2010. The variables studied were sex, grade point average in high school, PSU score, type of school of origin as financing system (municipal, private subsidized and private) and final grade received in morphology for dentistry students during their freshmen year. Of the 312 students, the median PSU, high school grades and morphology were as follows: 692.6, grade 702, and 4.4 respectively. Of the total sample, 221 students (71%) were female. Of the total sample, 290 students (93%) had attended private schools, 15 students (5%) private subsidized schools and 6 students (2%) municipal schools. The relationship between scores and high school grade point average and grade attained in the morphology course, shows a correlation of 0.35 (Spearman rho, p-value <0.0001) and PSU score with the morphology course grade, a correlation of 0.39 (Spearman rho, p-value <0.0001). There is a relationship between morphology grade scores, high school grades and university selection test scores, indicating that the best high school grades and university selection scores show better student performance in the subject of morphology.