Granulomatous peritoneal disease associated with oxaliplatin-based chemotherapy for ampullary adenocarcinoma: a case report.

Adenocarcinomas of the ampulla of Vater represent only 0.2% of all gastrointestinal cancers. Due to the low incidence no large clinical trials evaluating efficacy of treatments are available. Adjuvant therapy is often administered in patients with stage IB or higher. Oxaliplatin is considered as an effective and well tolerated therapeutic option. Adverse events associated with this therapy include cardio-, neuro-, nephrotoxicity and myelosuppression. Previously granulomatous pulmonary and liver manifestations have been described in oxaliplatin-based chemotherapy. In this report peritoneal manifestation of granulomatous disease associated with oxaliplatin is described for the first time. Sarcoidlike reactions may be misinterpreted as tumour progression or metastatic disease, and may consequently result in over-treatment.

The EPICAL trial, a phase Ib study combining first line afatinib with anti-EGF vaccination in EGFR-mutant metastatic NSCLC.

INTRODUCTION: Combination of anti-EGFR monoclonal antibodies or immune checkpoint inhibitors with TKIs has shown minimal benefit in EGFR mutant (EGFR-mut) NSCLC patients. Consequently, new combination approaches are needed. PATIENTS AND METHODS: The EPICAL was a single arm, phase 1b study to evaluate safety, tolerability and anti-tumor activity of first line afatinib combined with anti-EGF vaccination in advanced EGFR-mut patients. EGFR status and mutations in liquid biopsies were determined by reverse transcriptase-polymerase chain reaction; serum biomarkers by ELISA and Western blotting analysis. RESULTS: The assay enrolled 23 patients, 21 completed the anti-EGF immunization phase. Treatment was well tolerated and no serious adverse events (SAEs) related to the anti-EGF vaccine were reported. Objective response and disease control rates were 78.3% (95%CI = 53.6-92.5) and 95.7% (95%CI = 78.1-99.9), respectively. After a median follow-up of 24.2 months, median progression-free survival (PFS) was 14.8 months (95% CI = 9.5-20.1) and median overall survival (OS) 26.9 months (95% CI = 23.0-30.8). Among the 21 patients completing the immunization phase, PFS was 17.5 months (95% CI = 12.0-23.0) and OS 26.9 months (95% CI = 24.6-NR). At the end of the immunization phase, all 21 patients showed high serum titers of anti-EGF antibodies, while EGF levels had decreased significantly. Finally, treatment with fully immunized patient's sera inhibited the EGFR pathway in tumor cells growing in vitro. CONCLUSIONS: Combination treatment with an anti-EGF vaccine is well tolerated; induces a sustained immunogenic effect and might enhance the clinical efficacy of EGFR TKIs.

Cell disruption for microalgae biorefineries.

Microalgae are a potential source for various valuable chemicals for commercial applications ranging from nutraceuticals to fuels. Objective in a biorefinery is to utilize biomass ingredients efficiently similarly to petroleum refineries in which oil is fractionated in fuels and a variety of products with higher value. Downstream processes in microalgae biorefineries consist of different steps whereof cell disruption is the most crucial part. To maintain the functionality of algae biochemicals during cell disruption while obtaining high disruption yields is an important challenge. Despite this need, studies on mild disruption of microalgae cells are limited. This review article focuses on the evaluation of conventional and emerging cell disruption technologies, and a comparison thereof with respect to their potential for the future microalgae biorefineries. The discussed techniques are bead milling, high pressure homogenization, high speed homogenization, ultrasonication, microwave treatment, pulsed electric field treatment, non-mechanical cell disruption and some emerging technologies.

A longitudinal analysis of gross motor coordination in overweight and obese children versus normal-weight peers.

BACKGROUND: The relationship of childhood overweight (OW) and obesity (OB) with motor skill and coordination is gaining due attention; however, longitudinal evidence is currently lacking. OBJECTIVE: The dual purpose of this study was (1) to investigate the short-term evolution in the level of gross motor coordination according to children's weight status, and (2) to identify those factors predicting their gross motor coordination performance over a 2-year interval. SUBJECTS: Participants were 50 children with OW, including 8 with OB (aged 6-10 years at baseline, with 52% boys), and 50 with normal-weight (NW) matched for gender and age. MEASUREMENTS: Anthropometrics (body height, body weight, body mass index (BMI), %body fat) and level of gross motor coordination (Körperkoordinationstest für Kinder, KTK) were assessed in 2007 (baseline) and 2 years later in 2009 (follow-up). At baseline, participants completed a survey based on the Flemish Physical Activity Questionnaire (FPAQ) to obtain socio-demographic information and to determine physical activity levels in diverse domains. RESULTS: The evolution in the level of gross motor coordination over time was strongly related to children's weight status. Participants in the NW group showed more progress than their OW/OB peers, who demonstrated significantly poorer performances. Accordingly, between-group differences in KTK outcomes (that is, raw item scores and total motor quotient) became more evident over time. Multiple linear regression analysis further indicated that, in addition to BMI per se (negative predictor), participation in organized sports within a sports club (positive predictor) determines gross motor coordination performance(s) 2 years later. CONCLUSION: Our results provide conclusive evidence for an increasingly widening gap of OW/OB children's gross motor coordination relative to NW peers across developmental time in the absence of targeted initiatives. Special attention is thus needed for OW/OB children, especially for those not practicing sports in a club environment, in terms of motor skill improvement to promote regular participation in physical activity.

Fos induction in the Japanese quail brain after expression of appetitive and consummatory aspects of male sexual behavior.

We investigated the expression of Fos, the protein product of the immediate early gene c-fos in the brain of male Japanese quail after they engaged in either appetitive or consummatory sexual behavior (i. e., copulation). For 1 h, castrated males treated with testosterone were either allowed to copulate with a female or to exhibit a learned social proximity response indicative of appetitive sexual behavior. Control birds were either left in their home cage or placed in the experimental chamber but did not exhibit the appetitive sexual behavior because they had never learned it. Fos expression was studied with an immunocytochemical procedure in two sets of adjacent sections through the entire forebrain. These sections were immunolabelled with 2 different antibodies raised against a synthetic fragment corresponding to the 21 carboxy-terminal residues of the chicken Fos sequence. Contrary to the results of a previous study in which gonadally intact birds were used, Fos induction was observed neither in the medial preoptic nucleus nor in the nucleus intercollicularis in birds that had interacted for 1 h with a female. This may be related to a lower frequency of copulation in the testosterone-implanted birds than in intact birds, or to differences in the time the brains were collected after the birds engaged in sexual behavior between the two studies (60 min in this study, 120 min in the previous study). The performance of copulation and/or appetitive sexual behavior increased the number of Fos-immunoreactive cells in the ventral hyperstriatum, medial archistriatum, and nucleus striae terminalis. These increases were observed using both antibodies, although each antibody produced minor differences in the number of Fos-immunoreactive cells observed. Using one of the antibodies, but not the other, increases in Fos immunoreactivity were also observed in the nucleus accumbens and hyperstriatum after either copulation or appetitive sexual behavior. These differences illustrate how minor technical variations in the Fos immunocytochemical procedure influence the results obtained. These differences also show that Fos induction in a number of brain regions is observed after performance of consummatory (copulation) as well as appetitive (looking at the female) sexual behavior. This induction is, therefore, not related solely to the control of copulatory acts but, presumably, also to the processing in a variety of telencephalic association areas of stimuli originating from the female. The observation that increased Fos immunoreactivity is present in birds that had learned the response indicative of appetitive sexual behavior, and not in those that had not learned the behavior, further indicates that it is not simply the sight of the female that results in this Fos induction, but the analysis of the relevant stimuli in a sexually explicit context. Conditioned neural activity resulting from a learned association between the stimulus female and the performance of copulatory behavior may also explain some aspects of the brain activation observed in birds viewing, but not allowed to interact with, the female.

Colocalization of arginine-vasotocin and chicken luteinizing hormone-releasing hormone-I (cLHRH-I) in the preoptic-hypothalamic region of the chicken.

To characterize a possible relationship between chicken luteinizing hormone-releasing hormone-I (cLHRH-I) and arginine-vasotocin (AVT) we performed immunocytochemical double-stainings throughout the preoptic-hypothalamic region of the chicken brain. This study clearly reveals a partial colocalization between both neuropeptides. Single-labeled neurons, containing either cLHRH-I or AVT are found intermingled with double stained cells, immunoreactive (ir) for both peptides. A significant number of double-labeled perikarya is found in the preoptic area, more specifically in the ventral and external portion of the supraoptic nucleus (SOv and SOe) and in the medial preoptic nucleus (MPOv). At the level of the anterior hypothalamus, double-labeled cells are predominantly observed near the third ventricle in the nucleus paraventricularis magnocellularis (PVN) and the nucleus periventricularis hypothalami (PHN). Next to this colocalization, a number of cLHRH-I-ir cell bodies are found in close apposition to AVT-ir fiber profiles in the very same areas. Taken together, these data are the first to provide morphological evidence indicating that the AVT system might be involved in the regulation of cLHRH-I release and thus of reproductive functions in birds.

Effects of timing and duration of feed restriction during rearing on reproductive characteristics in broiler breeder females.

The objective of this study was to determine whether there exists a critical period during rearing when restricted feeding of broiler breeder hens can be most beneficial on subsequent egg production. Broiler breeder pullets were subjected to combinations of either ad libitum or restricted feeding during three periods before sexual maturity. Body weight gain, feed intake, and egg production were recorded. Ovary and oviduct weights were noted at age of first oviposition. At 15 and 18 wk of age and at age of first oviposition, chicken luteinizing hormone releasing hormone-I (cLHRH-I) in the median eminence and the levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in the pituitary and plasma were determined. The results demonstrated that alternation between ad libitum and restricted feeding during rearing changed the growth curves of the birds. Feed restriction from 7 to 15 wk followed by either ad libitum or restricted feeding led to improved reproductive performance, suggesting that long-term feed restriction may not be necessary to attain good reproductive performance. The birds restricted from 7 to 15 wk of age had higher proportional weights of ovary (> or = 1.7%) and oviduct (> or = 1.58%) at age of sexual maturity. The cLHRH-I levels in the median eminence and gonadotrophin contents in the pituitary followed that of growth in response to feeding levels and timing of feeding and could be related to the timing of the onset of lay. At age of first egg, all groups had similar levels of cLHRH-I, LH, and FSH. However, no clear effect of level of feed intake or time period of restriction could be observed for plasma LH or FSH concentrations.

Validation of a new antiserum directed towards the synthetic c-terminus of the FOS protein in avian species: immunological, physiological and behavioral evidence.

In the past 10 years, the study of the expression of immediate early genes, such as c-fos, in the brain has become a common method for the identification of brain areas involved in the regulation of specific physiological and behavioral functions. The use of this method in avian species has been limited by the paucity of suitable antibodies that cross-react with the FOS protein in birds. We describe in this paper the preparation of an antibody directed against a synthetic fragment of the protein product of the c-fos gene in chickens (Gallus domesticus). We demonstrate that this new antibody can be used in several avian species to study FOS expression induced by a variety of pharmacological, physiological and behavioral stimuli. Western blot studies indicated that this antibody recognizes a protein of the expected size (47 kDa) but also cross reacts to some extent with proteins of lower molecular weight that share sequence homology with FOS (Fos-related antigens). FOS immunocytochemistry was performed with this antibody in four species of birds in three different laboratories utilizing diverse variants of the immunocytochemical procedure. In all cases the antibody provided a reliable identification of the FOS antigen. The new antibody described here appears to be suitable for the study of FOS expression in several different avian species and situations. It is available in substantial amounts and will therefore make it possible to use FOS expression as a tool to map brain activity in birds as has now been done for several years in mammalian species.

Thyrotropin-releasing hormone concentrations in different regions of the chicken brain and pituitary: an ontogenetic study.

The regional distribution of thyrotropin-releasing hormone (TRH) was studied in the chicken brain. The hypothalamus and the brain stem contained the highest concentration of TRH. Lower amounts were present in the telencephalon, the optic lobes and the cerebellum. Within the hypothalamus, TRH was most abundant in the median eminence. Other important TRH sites were the nucleus paraventricularis magnocellularis, nucleus periventricularis hypothalami, nucleus ventromedialis hypothalami, nucleus dorsomedialis hypothalami and nucleus preopticus periventricularis. On the 14th day of embryonic development (E14), TRH was mostly found in the brain stem. Towards hatching, TRH concentrations increased gradually in both the hypothalamic area and the brain stem. TRH concentrations in the telencephalon, optic lobes and cerebellum remained low. Pituitaries from E14 to E16 chickens were characterized by a high TRH concentration, whereas hypophyseal TRH concentrations dropped towards hatching. Our results support the hypothesis that TRH exerts both endocrine and neurocrine actions in the chicken. On the other hand, high pituitary TRH concentrations were present when hypothalamic concentrations were low and vice versa. Therefore, the chicken pituitary may function as an important source of TRH during early in ovo development at least until the moment hypothalamic control develops.

Two-year longitudinal study of parotid salivary flow rates in head and neck cancer patients receiving unilateral neck parotid-sparing radiotherapy treatment.

Radiotherapy (RT) is a common treatment for head and neck cancers, and frequently causes permanent salivary dysfunction and xerostomia. This 2-year longitudinal study evaluated unstimulated and stimulated parotid flow rates in 11 patients with head and neck cancers who received unilateral neck parotid-sparing RT. The results demonstrated that treated parotid glands had essentially no output up to 2 years post-RT. Alternatively, spared parotid flow rates were indistinguishable from pre-RT values at 1 and 2 years post-RT, and increased slightly over time. Total unstimulated and stimulated parotid flow rates 2 years after completion of RT were similar to pre-RT values, suggesting that spared parotid function may compensate for lost function from treated parotid glands. These results demonstrate that unilateral neck parotid-sparing techniques are effective in preserving contralateral parotid glands up to 2 years after the completion of RT.

The effect of food intake from 2 to 24 weeks of age on LHRH-I content in the median eminence and gonadotrophin levels in pituitary and plasma in female broiler breeder chickens.

The present study describes the effect of long-term food restriction on hypothalamopituitary function in the broiler breeder hen during the period prior to sexual maturity. From 1 week of age onward, chickens were divided into 3 groups: one group received food ad libitum (Ad lib); a second group was fed a restricted quantity of food (Res); and a third group was restricted to obtain an intermediate body weight (Int) in between groups one and two. The effects of these feeding regimes on hypothalamopituitary function were assessed by measuring the amounts of cLHRH-I stored in the median eminence (ME) and the pituitary content and plasma levels of gonadotrophins. The Res group had significantly lower levels of cLHRH-I in the ME compared to the Ad lib animals. In all groups, there was a major increase in cLHRH-I in the median eminence about 3 weeks before onset of lay. The age of first oviposition was delayed by 2 and 6 weeks in the Int and Res groups, respectively, compared to the Ad lib animals, indicating that body weight gain patterns are not directly related to the appearance of the first egg. The attainment of sexual maturity may be associated with a threshold value of cLHRH-I stored in the ME in the Ad lib and Int birds. The pituitary LH and FSH contents (after week 16) were positively related to the amount of cLHRH-I in the ME. Plasma FSH concentrations in Ad lib and Int chickens peaked about 3 weeks before the first oviposition and this prepubertal peak was associated with increased pituitary FSH and ME cLHRH-I. There were however no relationships between plasma LH concentrations and pituitary LH content and between plasma LH and cLHRH-I amounts in the ME. The present study demonstrates that the delayed sexual maturation, caused by a chronic food restriction, may be associated with (1) delayed ovarian and oviductal growth, (2) decreased cLHRH-I storage in the ME, and (3) lower levels of LH and FSH in the pituitary. These hormones were however not directly related to levels of food restriction.

The influence of pre-radiation salivary flow rates and radiation dose on parotid salivary gland dysfunction in patients receiving radiotherapy for head and neck cancers.

Radiotherapy (RT) used for head and neck cancers causes permanent salivary gland dysfunction (SGD). Previous short-term studies have demonstrated that pre-RT salivary flow rates and the amount of radiation exposure to parotid glands influence the amount of RT-induced SGD. The purpose of this study was to determine which variables are related to the development of long-term post-RT SGD. Parotid flow rates (PFR) were assessed prior to and 1 year after completion of RT in spared parotid glands from 34 patients from 2 parotid-sparing protocols. The results reveal that spared PFR were not significantly higher 1 year post-RT in patients who had high pre-RT PFR, when compared with patients with low pre-RT PFR. However, patients who received higher doses of RT to spared parotid glands had lower PFR 1 year post-RT, compared with patients who had received lower doses of RT. These one-year findings suggest that high pre-RT PFR do not provide protection against RT-induced SGD. Conversely, reduced RT dosages to contralateral parotid glands are protective of PFR after completion of RT.

Inactivated hepatitis A vaccine: long-term antibody persistence.

During the clinical development of safe, well tolerated and immunogenic vaccines against hepatitis A the persistence of protective antibodies was estimated, based on relatively short observation periods of 18 months to 3 years. We report here on longterm persistence of antibodies in volunteers who participated in one of the early clinical trials on inactivated hepatitis A candidate vaccines. In a randomized trial three groups of altogether 110 healthy adults, initially hepatitis A virus (HAV) seronegative persons were vaccinated with an inactivated hepatitis A vaccine according to the schedule 0-1-2-12 months. One group received 180 ELISA units, one group 360, and one 720 ELISA units per dose. Blood samples were taken prior to the first vaccination and at months 1, 2, 3, 4, 6, 12, 13, 18, 24, 36 and 84. The decrease of antibodies was characterized by two disappearance rates: a rapidly decreasing component and a slower decreasing one becoming predominant ca 12 months after booster vaccination. The disappearance of antibodies could be described by a two-component model which holds for t > or = 13 months. The estimated disappearance rates for the slow component (annual decrease) was found to be 11 and 13% for the 180 and 360 El. U groups, respectively (the 720 El. U group showed no decline, which was probably due to the small sample size). The estimated persistence of antibodies within protective range varied between 24 and 47 years depending on individual titres reached at month 13 and vaccination dose.

Cognitive impairment in the Amish: a four county survey.

BACKGROUND: The prevalence of probable dementia was determined in a rural, homogeneous community of Amish individuals in the Midwestern USA. The Amish are a genetically isolated group with a low level of formal education (< or = 8 years) and few exposures to modern life, who live in intergenerational setting and have strong social support networks. METHODS: Using community directories, trained interviewers administered the Mini Mental State Examination (MMSE) and a medical history survey to all Amish over 64 years old in a four county area. Individuals with scores < 27 (out of a maximum of 30 points) were given additional neuropsychological tests. Results were reviewed by a neuropsychologist and subjects were classified with regard to probable cognitive impairment. RESULTS: The MMSE scores were inversely related with age and directly with education. The Amish have higher MMSE scores than reported for the general US population. The overall prevalence of probable cognitive impairment for those over 64 years was 6.4%. The prevalence increased with age and lower education and was lowest among married individuals. CONCLUSIONS: The MMSE scores among the Amish were higher than the general population despite their low level of formal education. The lower level of cognitive impairment among the Amish could reflect a lack of inherited susceptibility to dementing diseases, or environmental factors characteristic of their traditional lifestyle. Even among this population with < or = 8 years of formal education, education may protect against cognitive impairment.

Parotid sparing study in head and neck cancer patients receiving bilateral radiation therapy: one-year results.

Many patients with head and neck cancers receive radiation therapy as part of their treatment which frequently causes considerable morbidity, including various degrees of permanent salivary gland dysfunction. Three-dimensional treatment planning [3-DTP] and conformational dose delivery constitute a new therapeutic modality that conforms the high-dose radiation volume to the shape of the tumor volume while minimizing the dose to tissue that is not at risk of containing cancer. The treatment volumes for head and neck tumors as well as parotid glands can be well-defined on cross-sectional CT imaging techniques. The purpose of this investigation is to determine if 3-DTP and conformational dose-delivery could minimize radiation dose and salivary gland dysfunction to contralateral parotid glands in patients with head and neck cancers. Eleven patients with head and neck cancers who required bilateral radiation therapy were treated with 3-DTP. Unstimulated and stimulated bilateral parotid saliva was collected prior to radiotherapy, weekly during treatment, and 1, 3, 6, and 12 months after the completion of radiotherapy. Treated parotid glands received an average dose of 5745 cGy, while spared glands received only 1986 cGy (p < 0.0001). Unstimulated and stimulated parotid flow rates decreased dramatically in treated glands after the initiation of radiotherapy, remained at extremely low rates without any improvements, and were significantly lower at 1 year after radiotherapy compared with baseline. Conversely, parotid flow rates in spared glands underwent mild changes during radiotherapy and were approximately 50% of baseline values. The results of this study suggest that with the use of 3-DTP, contralateral parotid gland function can be partially preserved for at least 1 year in patients with head and neck cancers requiring bilateral radiation.

Ipsilateral parotid sparing study in head and neck cancer patients who receive radiation therapy: results after 1 year.

OBJECTIVE: To determine if three-dimensional treatment planning and conformational dose delivery could minimize radiation dose and salivary gland dysfunction to contralateral parotid glands in patients with unilateral head and neck cancers. STUDY DESIGN: Fifteen patients with unilateral head and neck cancers were treated with three-dimensional treatment planning. Unstimulated and stimulated bilateral parotid saliva was collected before radiotherapy, weekly during treatment, and 1, 3, 6, and 12 months after the completion of radiotherapy. RESULTS: Treated parotid glands received an average dose of 4949 cGy, whereas spared glands received only 355 cGy. Unstimulated and stimulated parotid flow rates decreased dramatically in treated glands after the initiation of radiotherapy and were significantly lower at 1 year after radiotherapy compared with baseline. Conversely, parotid flow rates in spared glands underwent mild changes during radiotherapy and were similar at 1 year after radiotherapy compared with baseline. CONCLUSION: Parotid gland function can be preserved for at least 1 year in patients with unilateral head and neck cancers with three-dimensional treatment planning.

Alzheimer's disease and apolipoprotein E-4 allele in an Amish population.

Alzheimer's Disease (AD) is a complex genetic disorder with four loci already identified. Mutations in three of these, the amyloid precursor protein, presenilin I, and presenilin II, cause early-onset AD. The apolipoprotein E (APOE) gene contributes primarily to late-onset AD. The APOE-4 allele acts in a dose-related fashion to increase risk and decrease the age-of-onset distribution in AD. We examined the effect of APOE on AD in a previously unstudied Amish population that has a lower prevalence of dementia compared with other populations. We sampled a large inbred family with 6 late-onset AD members. We also genotyped 53 individuals from the general Amish population as controls for the APOE allele frequency estimates. The frequency of the APOE-4 allele in the Amish controls was 0.037 +/- 0.02. This differed significantly compared with three independent sets of non-Amish white controls (p < 2 x 10(-4), p < 6 x 10(-5), and p < 2 x 10(-6)). In addition, all Amish AD-affected individuals had APOE 3/3 genotypes; no APOE X/4 or 4/4 individuals were observed. We suggest that the lower frequency of dementia in the Amish may be partially explained by the decreased frequency of the APOE-4 allele in this population, and that the inbred nature of this pedigree, with its strong clustering of cases contrasted against the lower frequency of dementia, indicates that additional genetic factors influence late-onset AD.