Sub-acute exposure of male guppies (Poecilia reticulata) to environmentally relevant concentrations of PFOA and GenX induces significant changes in the testis transcriptome and reproductive traits.

Poly- and perfluoroalkyl substances (PFAS) are frequently detected in the environment and are linked to adverse reproductive health outcomes in humans. Although legacy PFAS have been phased out due to their toxicity, alternative PFAS are increasingly used despite the fact that information on their toxic effects on reproductive traits is particularly scarce. Here, we exposed male guppies (Poecilia reticulata) for a short period (21 days) to an environmentally realistic concentration (1 ppb) of PFOA, a legacy PFAS, and its replacement compound, GenX, to assess their impact on reproductive traits and gene expression. Exposure to PFAS did not impair survival but instead caused sublethal effects. Overall, PFAS exposure caused changes in male sexual behaviour and had detrimental effects on sperm motility. Sublethal variations were also seen at the transcriptional level, with the modulation of genes involved in immune regulation, spermatogenesis, and oxidative stress. We also observed bioaccumulation of PFAS, which was higher for PFOA than for GenX. Our results offer a comprehensive comparison of these two PFAS and shed light on the toxicity of a newly emerging alternative to legacy PFAS. It is therefore evident that even at low concentrations and with short exposure, PFAS can have subtle yet significant effects on behaviour, fertility, and immunity. These findings underscore the potential ramifications of pollution under natural conditions and their impact on fish populations.

Malformación venosa cavernosa en musculatura extrínseca ocular. Radioterapia estereotáctica fraccionada como alternativa terapéutica / Intramuscular cavernous venous malformation of extraocular muscles. Fractionated stereotactic radiotherapy as a therapeutic alternative

Las malformaciones venosas cavernosas que afectan a la musculatura extraocular son extremadamente poco frecuentes. Debido a esta localización su resección quirúrgica completa puede resultar difícil. Por este motivo se presenta un caso clínico de compromiso del músculo recto inferior, generando dolor retroocular y diplopía, que fue tratado con radioterapia estereotáctica fraccionada tras su recurrencia posquirúrgica. La radioterapia fraccionada estereotáctica supone un tratamiento alternativo eficaz en lesiones radiosensibles, sobre todo en aquellos casos con pronóstico funcional deficiente tras tratamiento quirúrgico

Intramuscular cavernous venous malformations affecting extraocular muscles are extremely uncommon. Due to their location, complete resection could be difficult. A clinical case is presented of an inferior rectus muscle orbital cavernous malformation treated with fractionated stereotactic radiotherapy after post-surgical excision recurrence. The malformation responded to radiotherapy with a reduction in size and symptoms. Fractionated stereotactic radiotherapy is an alternative and effective treatment for cavernous venous malformations that are surgically challenging due to their radiotherapy sensitivity

Intramuscular cavernous venous malformation of extraocular muscles. Fractionated stereotactic radiotherapy as a therapeutic alternative. / Malformación venosa cavernosa en musculatura extrínseca ocular. Radioterapia estereotáctica fraccionada como alternativa terapéutica.

Intramuscular cavernous venous malformations affecting extraocular muscles are extremely uncommon. Due to their location, complete resection could be difficult. A clinical case is presented of an inferior rectus muscle orbital cavernous malformation treated with fractionated stereotactic radiotherapy after post-surgical excision recurrence. The malformation responded to radiotherapy with a reduction in size and symptoms. Fractionated stereotactic radiotherapy is an alternative and effective treatment for cavernous venous malformations that are surgically challenging due to their radiotherapy sensitivity.

Perioperative outcomes and long-term quality of life after total pancreatectomy.

BACKGROUND: Total pancreatectomy is required to treat diseases involving the entire pancreas, and is characterized by high morbidity rates and impaired long-term quality of life (QoL). To date, risk factors associated with perioperative and long-term outcomes have not been determined fully. METHODS: Data from patients undergoing total pancreatectomy between 2000 and 2014 at two high-volume centres were analysed retrospectively to assess risk factors for major surgical complications. Short Form (SF) 36, European Organisation for Research and Treatment of Cancer QLQ-PAN26 and Audit of Diabetes Dependent questionnaires, as well as an original survey were used to investigate factors influencing QoL. RESULTS: A total of 329 consecutive patients underwent total pancreatectomy in the two centres. Overall, total pancreatectomy was associated with a morbidity rate of 59·3 per cent and a 30-day mortality rate of 2·1 per cent. Age over 65 years and long duration of surgery (more than 420 min) were independently associated with major complications (at least Clavien-Dindo grade III). QoL analysis was available for 94 patients (28·6 per cent) with a median follow-up of 63 (i.q.r. 20-109) months; the most common indication for total pancreatectomy in these patients was intraductal papillary mucinous neoplasms (46 per cent). Both physical (PCS) and mental (MCS) component summary scores of SF-36® were lower after total pancreatectomy compared with scores for a normative population (P = 0·020 and P < 0·001 respectively). Linear regression analysis showed that young age, abdominal pain and worse perception of body image were negatively associated with the PCS, whereas diabetes, sexual satisfaction and perception of body image affected MCS. CONCLUSION: Total pancreatectomy can be performed with acceptable morbidity and mortality rates. Older patients had a higher risk of postoperative complications but reported better QoL than younger patients.

ANTECEDENTES: La pancreatectomía total es una cirugía necesaria para tratar enfermedades que afectan a la totalidad el páncreas y se caracteriza por una alta morbilidad y una disminución de la calidad de vida (QoL) a largo plazo. Hasta la fecha, los factores de riesgo asociados a los resultados perioperatorios y a largo plazo no han sido completamente determinados. MÉTODOS: Los datos de los pacientes que se sometieron a una pancreatectomía total desde el año 2000 al 2015 en dos centros de alto volumen se analizaron retrospectivamente para evaluar los factores de riesgo de las complicaciones quirúrgicas mayores. Se utilizaron el SF-36, el EORTC-PAN-26, los cuestionarios ADD-QoL y una encuesta original para investigar los factores que afectan la QoL. RESULTADOS: Un total de 329 pacientes consecutivos se sometieron a una pancreatectomía total en los dos centros. En general, la pancreatectomía total se asoció a un 59,3% de morbilidad y un 2,1% de mortalidad a los 30 días. La edad > 65 años y el tiempo operatorio prolongado (> 420 minutos) se asociaron de forma independiente a las complicaciones Clavien-Dindo ≥ III. El análisis de QoL estuvo disponible en 94 (28,6%) de los pacientes con una mediana de seguimiento de 63 meses (rango intercuartílico 20-109) y la indicación más común fue una neoplasia papilar mucinosa intraductal (IPMN) (45,7%). Las puntuaciones del SF-36 fueron más bajas en ambos componentes sumatorios físico (PCS) y mental (MCS) (P = 0,002; P < 0,001) en comparación con una población normal. El modelo de regresión lineal mostró que la edad joven, el dolor abdominal y la peor percepción de la imagen corporal se asociaron negativamente con el PCS; mientras que la diabetes, la satisfacción sexual y la percepción de la imagen corporal afectaron al MCS. CONCLUSIÓN: Se puede realizar una pancreatectomía total con morbilidad y mortalidad aceptables. Los pacientes de mayor edad tienen un riesgo más elevado de complicaciones postoperatorias, pero presentaron mejor QoL que los pacientes más jóvenes.

Possible glimpses into early speciation: the effect of ovarian fluid on sperm velocity accords with post-copulatory isolation between two guppy populations.

Identifying mechanisms of reproductive isolation is key to understanding speciation. Among the putative mechanisms underlying reproductive isolation, sperm-female interactions (post-mating-prezygotic barriers) are arguably the hardest to identify, not least because these are likely to operate at the cellular or molecular level. Yet sperm-female interactions offer great potential to prevent the transfer of genetic information between different populations at the initial stages of speciation. Here, we provide a preliminary test for the presence of a putative post-mating-prezygotic barrier operating between three populations of Trinidadian guppies (Poecilia reticulata), an internally fertilizing fish that inhabits streams with different levels of connectivity across Trinidad. We experimentally evaluate the effect of female ovarian fluid on sperm velocity (a predictor of competitive fertilization success) according to whether males and females were from the same (native) or different (foreign) populations. Our results reveal the potential for ovarian fluid to act as a post-mating-prezygotic barrier between two populations from different drainages, but also that the strength of this barrier is different among populations. This result may explain the previous finding that, in some populations, sperm from native males have precedence over foreign sperm, which could eventually lead to reproductive isolation between these populations.

Impaired sperm quality, delayed mating but no costs for offspring fitness in crickets winning a fight.

The outcome of male-male contest competition is known to affect male mating success and is believed to confer fitness benefits to females through preference for dominant males. However, by mating with contest winners, females can incur significant costs spanning from decreased fecundity to negative effects on offspring. Hence, identifying costs and benefits of male dominance on female fitness is crucial to unravel the potential for a conflict of interests between the sexes. Here, we investigated males' pre- and post-copulatory reproductive investment and its effect on female fitness after a single contest a using the field cricket Gryllus bimaculatus. We allowed males to fight and immediately measured their mating behaviour, sperm quality and offspring viability. We found that males experiencing a fight, independently of the outcome, delayed matings, but their courtship effort was not affected. However, winners produced sperm of lower quality (viability) compared to losers and to males that did not experience fighting. Results suggest a trade-off in resource allocation between pre- and post-mating episodes of sexual selection. Despite lower ejaculate quality, we found no fitness costs (fecundity and viability of offspring) for females mated to winners. Overall, our findings highlight the importance of considering fighting ability when assessing male reproductive success, as winners may be impaired in their competitiveness at a post-mating level.

Sexual rest and post-meiotic sperm ageing in house mice.

Fertilization by aged sperm can result in adverse fitness consequences for both males and females. Sperm storage during male sexual rest could provide an environment for post-meiotic sperm senescence causing a deterioration in the quality of stored sperm, possibly impacting on both sperm performance (e.g. swimming ability) and DNA quality. Here, we compared the proportion of sperm with fragmented DNA, an indicator of structural damage of DNA within the sperm cell, among males that had been sexually rested for approximately 2 months, to that of males that had mated recently. We found no evidence of intra-epididymal sperm DNA damage or any impairment in sperm performance, and consequently no evidence of post-meiotic sperm senescence. Our results suggest that male house mice are likely to possess mechanisms that function to ensure that their sperm reserves remain stocked with 'young', viable sperm during periods of sexual inactivity. We also discuss the possibility that our experimental design leads to no difference in the age of sperm among males from the two mating treatments. Post-meiotic sperm senescence is especially relevant under sperm competition. Thus, we sourced mice from populations that differed in their levels of post-copulatory sexual selection, enabling us to gain insight into how selection for higher sperm production influences the rate of sperm ageing and levels of DNA fragmentation. We found that males from the population that produced the highest number of sperm also had the smallest proportion of DNA-fragmented sperm and discuss this outcome in relation to selection acting upon males to ensure that they produce ejaculates with high-quality sperm that are successful in achieving fertilizations under competitive conditions.

Genotype-by-environment interactions underlie the expression of pre- and post-copulatory sexually selected traits in guppies.

The role that genotype-by-environment interactions (GEIs) play in sexual selection has only recently attracted the attention of evolutionary biologists. Yet GEIs can have profound evolutionary implications by compromising the honesty of sexual signals, maintaining high levels of genetic variance underlying their expression and altering the patterns of genetic covariance among fitness traits. In this study, we test for GEIs in a highly sexually dimorphic freshwater fish, the guppy Poecilia reticulata. We conducted an experimental quantitative genetic study in which male offspring arising from a paternal half-sibling breeding design were assigned to differing nutritional 'environments' (either high or low feed levels). We then determined whether the manipulation of diet quantity influenced levels of additive genetic variance and covariance for several highly variable and condition-dependent pre- and post-copulatory sexual traits. In accordance with previous work, we found that dietary limitation had strong phenotypic effects on numerous pre- and post-copulatory sexual traits. We also report evidence for significant GEI for several of these traits, which in some cases (area of iridescence and sperm velocity) reflected a change in the rank order of genotypes across different nutritional environments (i.e. ecological crossover). Furthermore, we show that genetic correlations vary significantly between nutritional environments. Notably, a highly significant negative genetic correlation between iridescent coloration and sperm viability in the high food treatment broke down under dietary restriction. Taken together, these findings are likely to have important evolutionary implications for guppies; ecological crossover may influence sexual signal reliability in unstable (nutritional) environments and contribute towards the extreme levels of polymorphism in sexual traits typically reported for this species. Furthermore, the presence of environment-specific genetic covariance suggests that trade-offs measured in one environment may not be indicative of genetic constraints in others.

Testing the interactive effects of carotenoids and polyunsaturated fatty acids on ejaculate traits in the guppy Poecilia reticulata (Pisces: Poeciliidae).

Using the polyandrous livebearing guppy Poecilia reticulata, this study revealed no main effects of carotenoids in the diet on ejaculate traits, but significant main effects of polyunsaturated fatty acids (PUFAs) on sperm viability and weak but significant interacting effects of both nutrients on sperm length. Collectively, these findings not only add evidence that PUFAs are critical determinants of sperm quality, but also provide tentative evidence that for some traits these effects may be moderated by carotenoid intake.

The biology of the glutamatergic system and potential role in migraine.

Migraine is a common genetically linked neurovascular disorder. Approximately ∼12% of the Caucasian population are affected including 18% of adult women and 6% of adult men (1, 2). A notable female bias is observed in migraine prevalence studies with females affected ∼3 times more than males and is credited to differences in hormone levels arising from reproductive achievements. Migraine is extremely debilitating with wide-ranging socioeconomic impact significantly affecting people's health and quality of life. A number of neurotransmitter systems have been implicated in migraine, the most studied include the serotonergic and dopaminergic systems. Extensive genetic research has been carried out to identify genetic variants that may alter the activity of a number of genes involved in synthesis and transport of neurotransmitters of these systems. The biology of the Glutamatergic system in migraine is the least studied however there is mounting evidence that its constituents could contribute to migraine. The discovery of antagonists that selectively block glutamate receptors has enabled studies on the physiologic role of glutamate, on one hand, and opened new perspectives pertaining to the potential therapeutic applications of glutamate receptor antagonists in diverse neurologic diseases. In this brief review, we discuss the biology of the Glutamatergic system in migraine outlining recent findings that support a role for altered Glutamatergic neurotransmission from biochemical and genetic studies in the manifestation of migraine and the implications of this on migraine treatment.

TRAIL-based therapeutic approaches for the treatment of pediatric malignancies.

Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is a pro-apoptotic ligand that has shown the exquisite ability to trigger extrinsic apoptosis in various types of cancer cells without significant toxicity toward normal cells, when compared to other pro-apoptotic ligands such as tumor necrosis factor (TNF) α or Fas ligand. Consequently, TRAIL-based therapies aim to trigger apoptosis in cancer cells by providing the soluble TRAIL or monoclonal antibodies targeting the death receptors TRAIL-R1 or TRAIL-R2. In this review, we start by highlighting the relevance of the tumor microenvironment in tumor development and elimination. We then address conventional and targeted therapeutic approaches for cancer treatment, highlighting the mechanisms involved or targeted. We describe the extrinsic and intrinsic pro-apoptotic pathways of TRAIL, together with the evidences for its pro-survival signaling, and with the relevance of these pathways in therapy. Possible mechanisms of resistance to TRAIL-induced apoptosis are highlighted (i.e. c-FLIP, Bcl-2, IAPs, p53, NF-κ B) and the rationale for the combined administration of TRAIL with drugs targeting these mechanisms is provided. Preclinical data are reported and show encouraging evidences for TRAIL consideration in pediatric malignancies (i.e., leukemia, lymphomas, neuroblastoma, osteosarcoma, medulloblastoma). Clinical trials of TRAIL-based therapies on the overall population are in phase I or II, and we put particular focus on the pediatric population, on which only few trials have been conducted or are ongoing. Finally, we consider emerging cellular therapies based on TRAIL, such as TRAIL-engineered mesenchymal stem cells or 'inflammatory' dendritic cells.

Hypertonic saline is more effective than normal saline in seasonal allergic rhinitis in children.

Allergic rhinitis (AR) is a very common childhood disease that is associated with a significant reduction in the patients' quality of life. Its treatment combines educating the patients and their parents, immunotherapy and drug administration. However, even the best approach does not relieve the symptoms of a number of patients. Alternative therapies are particularly needed for children because the fear of adverse events frequently reduces parental compliance to the prescribed drugs, and immunotherapy is less easy to administer than in adults. In this prospective investigator-blinded study we evaluated whether children, with a documented history of seasonal grass pollen-related AR, benefit from nasal irrigation by assessing the effects on nasal signs and symptoms, on middle ear effusion and on adenoidal hypertrophy. We randomized children aged 5 to 9 years (median age 82 months) to normal saline or hypertonic saline (a 2.7% sodium chloride solution), administered twice-daily using a disposable 20 ml syringe, or no treatment. Nasal symptoms (rhinorrhea, itching, sneezing, nasal obstruction), swelling of turbinates, adenoid hypertrophy or middle ear effusion were assessed at baseline and after 4 weeks of treatment. Two hundred and twenty children (normal saline: 80; hypertonic saline: 80; no treatment: 60) completed the study. After four weeks, all the considered items were significantly reduced in the group receiving hypertonic saline (P < 0.0001), whereas in the group receiving normal saline only rhinorrhea (P = 0.0002) and sneezing (P = 0.002) were significantly reduced. There was no significant change in any of the items in the control group. The duration of oral antihistamines was significantly lower in the children receiving hypertonic saline than in those treated with normal saline or in controls. No adverse events were reported and parental satisfaction and compliance with the procedure were globally very good, regardless of the solution used. Using our procedure, hypertonic saline is effective, inexpensive, safe, well tolerated and easily accepted by children with seasonal grass pollen-related AR and their parents. Our data suggest that nasal irrigation with hypertonic saline might be included in the wide spectrum of therapies recommended for grass-pollen AR.

Effect of male age on sperm traits and sperm competition success in the guppy (Poecilia reticulata).

Deleterious mutations can accumulate in the germline with age, decreasing the genetic quality of sperm and imposing a cost on female fitness. If these mutations also affect sperm competition ability or sperm production, then females will benefit from polyandry as it incites sperm competition and, consequently, minimizes the mutational load in the offspring. We tested this hypothesis in the guppy (Poecilia reticulata), a species characterized by polyandry and intense sperm competition, by investigating whether age affects post-copulatory male traits and sperm competition success. Females did not discriminate between old and young males in a mate choice experiment. While old males produced longer and slower sperm with larger reserves of strippable sperm, compared to young males, artificial insemination did not reveal any effect of age on sperm competition success. Altogether, these results do not support the hypothesis that polyandry evolved in response to costs associated with mating with old males in the guppy.

The magnitude of early response to methotrexate therapy predicts long-term outcome of patients with juvenile idiopathic arthritis.

OBJECTIVE: To investigate the relationship between the magnitude of clinical response in the first 6 months of methotrexate (MTX) therapy and long-term outcome in children with juvenile idiopathic arthritis (JIA). METHODS: The clinical charts of 125 JIA patients who were started with MTX and then followed for at least 5 years were reviewed. Based on the level of American College of Rheumatology (ACR) Pediatric response at 6 months, patients were divided in four mutually exclusive groups: (1) non-responders, (2) responders at 30%, (3) responders at 50%, and (4) responders at 70%. The long-term outcome in each response group was evaluated by calculating the percentage change in active and restricted joint counts from baseline to 1, 2 and 5 years and the frequency of inactive disease at 5 years. RESULTS: At 6 months, 42 patients were classified as non-responders, 24 as 30% responders, 26 as 50% responders, and 33 as 70% responders. Patients who had achieved a 70% response showed a significantly greater percentage improvement in active joint count between baseline to 5 years compared with non-responders and 30% responders, and a significantly greater percentage improvement in restricted joint count between baseline to 5 years compared with 30% responders. The 70% responders also had a greater frequency of inactive disease at 5 years compared with 30% responders, CONCLUSIONS: Our results show that the achievement of an ACR Pediatric 70 response at 6 months after start of MTX therapy predicts a more favorable long-term outcome of patients with JIA.

Relationship between damage accrual, disease flares and cumulative drug therapies in juvenile-onset systemic lupus erythematosus.

Our objective was to investigate the pattern of damage accumulation in patients with juvenile-onset systemic lupus erythematosus (JSLE) and the relationship between damage accrual, disease flares and cumulative drug therapies. All patients with SLE followed prospectively in three tertiary care centres were identified. Only patients who presented within 12 months of diagnosis and were followed for at least three years were included. Damage was measures based on chart review using the SLICC/ACR damage index (SDI), which was modified (M-SDI) by adding the item growth failure. Mild-moderate and severe disease flares were defined by the increase in SLEDAI-2K. The cumulative duration of drug therapies was calculated in each patient. Fifty-seven patients were included. The mean M-SDI score for the whole patient group increased over time, from 0.1 at one year to 0.8 at three years to 1.5 at five years. Ocular and renal damage and growth failure were observed most frequently. Compared to patients with stable damage, patients who accrued new damage had a significantly greater frequency of severe disease flare in the first three years of follow-up. No significant difference was observed in any cumulative drug therapy between patients who accrued damage and those who did not. Damage accrual was associated with severe disease flares, suggesting that judicious use of immunosuppressive agents to achieve prompt control of severe exacerbation of disease activity is important in minimizing damage in patients with JSLE.

Responsiveness of clinical measures to flare of disease activity in juvenile idiopathic arthritis.

OBJECTIVE: To compare the responsiveness of clinical measures in the assessment of disease flare in patients with juvenile idiopathic arthritis (JIA). METHODS: The clinical records of all consecutive patients with JIA who were diagnosed between 1995 and 2000 were retrospectively reviewed. In each patient, all visits made during follow-up were analyzed and those meeting the criteria for disease flare were recorded. The definition of flare was based on the therapeutic alterations made by the attending physician. Responsiveness of JIA clinical measures to relevant increase in disease activity (a flare) was evaluated by assessing the score change of each measure from a visit made 6 (+/- 3) months before a flare and the flare visit. Responsiveness statistics included the standardized response mean (SRM) and the effect size (ES). RESULTS: A total of 115 patients, who were followed for 0.5 to 6.2 years (mean 2.8 years), were studied. During follow-up, 51 patients (44%) experienced 1 or more disease flares, with the total number of flares being 75. Strong responsiveness (ES and SRM > or = 0.8) to increase in disease activity was demonstrated by the physician's and parent's global assessments, the global articular severity score, and the morning stiffness. The active, swollen and painful joint counts, the swelling, pain on motion/tenderness and limited range of motion (LROM) scores, and the erythrocyte sedimentation rate revealed moderate responsiveness (ES and SRM > or = 0.5). The poorest performances (ES and/or SRM < 0.5) were provided by the parent's assessment of pain, the functional ability tool, the number of joints with LROM, the LROM score, the C-reactive protein, the white blood cell and platelet count, and the hemoglobin level. CONCLUSION: Our analysis suggests that the swollen or painful joint counts are better suited than the count of joints with LROM for the assessment of disease flare in patients with JIA.

Is NF-kappaB a useful therapeutic target in rheumatoid arthritis?

There is increasing evidence that NF-kappaB is a major, if not the major transcription factor regulating inflammation and immunity. While this implies that blocking NF-kappaB might be therapeutically beneficial, it raises clear questions regarding the balance between efficacy and safety. In this brief review we discuss the effects of NF-kappaB blockade in rheumatoid arthritis, inflammation and immunity, and consider possible therapeutic targets within the NF-kappaB family.

TNF-Induced shedding of TNF receptors in human polymorphonuclear leukocytes: role of the 55-kDa TNF receptor and involvement of a membrane-bound and non-matrix metalloproteinase.

A down-modulation of both the 55-kDa (TNF-R55) and the 75-kDa (TNF-R75) TNF receptors is observed in neutrophils exposed to a variety of stimuli. Proteolytic cleavage of the extracellular region of both receptors (shedding) and, with TNF, internalization of TNF-R55 and shedding of TNF-R75 are the proposed mechanisms. We have characterized the TNF-induced shedding of TNF receptors in neutrophils and determined the nature of the involved proteinase. Neutrophils exposed to TNF release both TNF receptors. A release of TNF receptors comparable to that observed with TNF was induced with TNF-R55-specific reagents (mAbs and a mutant of TNF) but not with the corresponding TNF-R75-specific reagents. A hydroxamic acid compound (KB8301) almost completely inhibited shedding of TNF-R55 and to a lesser degree shedding of TNF-R75. KB8301 also inhibited FMLP-induced shedding to a similar extent. Shedding was also inhibited by 1,10-phenanthroline, but this effect was considered nonspecific as the compound, at variance with KB8301, almost completely inhibited TNF and FMLP-induced PMN activation. Diisopropylfluorophosphate partially inhibited shedding of TNF-R75, suggesting the contribution of a serine proteinase to the release of this receptor. Shedding activity was not affected by matrix metalloproteinases inhibitors nor was it released in the supernatants of FMLP-stimulated neutrophils. These results suggest that TNF induces release of its receptors, that such a release is mediated via TNF-R55, and that a membrane-bound and non-matrix metalloproteinase is involved in the process. The possibility that ADAM-17, which we show to be expressed in neutrophils, might be the involved proteinase is discussed.

Role of the 75-kDa TNF receptor in TNF-induced activation of neutrophil respiratory burst.

The exclusive role of the 55-kDa TNF receptor (TNF-R55) as the signaling receptor in TNF-induced activation of respiratory burst by human polymorphonuclear leukocytes residing on biologic surfaces has been inferred from results obtained with receptor-specific monoclonal and polyclonal Abs. In this work, we confirm this assumption by a more direct approach, i.e., by using receptor-specific TNF mutants (p55TNF and p75TNF) and, as a novel contribution, we show that cooperation of the 75-kDa TNF receptor (TNF-R75) is required for a full blown response to the cytokine. This conclusion stems from three sets of data: 1) none of the TNF-R55-specific agonists used, i.e., mAbs or p55TNF, induced a respiratory burst comparable with that induced by TNF; 2) selective down-modulation of TNF-R75 resulted in a diminished response to TNF but not to TNF-R55-specific agonists or to the chemotactic peptide FMLP; and 3) mAbs that either block or stabilize binding of TNF to TNF-R75 inhibited the response to the cytokine, suggesting that cooperation requires not only TNF binding to the receptor but also an appropriate dissociability from it. The inhibitory effect of the Abs increased as the cytokine concentrations decreased, indicating that cooperation by TNF-R75 becomes more relevant at low TNF doses. Such a cooperation does not seem to rely on the activation of a TNF-R75-linked signaling pathway independent of TNF-R55, since the response to p55TNF and p75TNF given in combination was not higher than the response to p55TNF alone. The possible mechanisms of cooperation are discussed.

[An application of mini-invasive surface surgery: the thyroid]. / Un'applicazione della chirurgia mini-invasiva di superficie: la tiroide.

Since its introduction, minimally-invasive surgery has been applied to structures contained in natural cavities such as abdomen, thorax and articulations. At present, its application to surface zones (plastic surgery) gives good results. For this reason, we tried to examine thyroid area through a video-assisted access in a 32 years old woman presenting a nodule with a diameter of about 1 cm, localized in the left parahistmic thyroid area. This approach allowed a good vision of the operative field. In our opinion, this technique could be useful especially to formulate the histological diagnosis of small thyroid nodules for whom the standard surgical biopsy should be considered too invasive.