Complex effects of testosterone level on ectoparasite load in a ground squirrel: an experimental test for the immunocompetence handicap hypothesis.

BACKGROUND: The immunocompetence handicap hypothesis suggests that males with a higher testosterone level should be better at developing male secondary traits, but at a cost of suppressed immune performance. As a result, we should expect that males with an increased testosterone level also possess a higher parasite load. However, previous empirical studies aimed to test this prediction have generated mixed results. Meanwhile, the effect of testosterone level on parasite load in female hosts remains poorly known. METHODS: In this study, we tested this prediction by manipulating testosterone level in Daurian ground squirrels (Spermophilus dauricus), a medium-sized rodent widely distributed in northeast Asia. S. dauricus is an important host of ticks and fleas and often viewed as a considerable reservoir of plague. Live-trapped S. dauricus were injected with either tea oil (control group) or testosterone (treatment group) and then released. A total of 10 days later, the rodents were recaptured and checked for ectoparasites. Fecal samples were also collected to measure testosterone level of each individual. RESULTS: We found that testosterone manipulation and sex of hosts interacted to affect tick load. At the end of the experiment, male squirrels subjected to testosterone implantation had an averagely higher tick load than males from the control group. However, this pattern was not found in females. Moreover, testosterone manipulation did not significantly affect flea load in S. dauricus. CONCLUSIONS: Our results only lent limited support for the immunocompetence handicap hypothesis, suggesting that the role of testosterone on regulating parasite load is relatively complex, and may largely depend on parasite type and gender of hosts.

Differential neurovirulence of Usutu virus lineages in mice and neuronal cells.

BACKGROUND: Usutu virus (USUV) is an emerging neurotropic arthropod-borne virus recently involved in massive die offs of wild birds predominantly reported in Europe. Although primarily asymptomatic or presenting mild clinical signs, humans infected by USUV can develop neuroinvasive pathologies (including encephalitis and meningoencephalitis). Similar to other flaviviruses, such as West Nile virus, USUV is capable of reaching the central nervous system. However, the neuropathogenesis of USUV is still poorly understood, and the virulence of the specific USUV lineages is currently unknown. One of the major complexities of the study of USUV pathogenesis is the presence of a great diversity of lineages circulating at the same time and in the same location. METHODS: The aim of this work was to determine the neurovirulence of isolates from the six main lineages circulating in Europe using mouse model and several neuronal cell lines (neurons, microglia, pericytes, brain endothelial cells, astrocytes, and in vitro Blood-Brain Barrier model). RESULTS: Our results indicate that all strains are neurotropic but have different virulence profiles. The Europe 2 strain, previously described as being involved in several clinical cases, induced the shortest survival time and highest mortality in vivo and appeared to be more virulent and persistent in microglial, astrocytes, and brain endothelial cells, while also inducing an atypical cytopathic effect. Moreover, an amino acid substitution (D3425E) was specifically identified in the RNA-dependent RNA polymerase domain of the NS5 protein of this lineage. CONCLUSIONS: Altogether, these data show a broad neurotropism for USUV in the central nervous system with lineage-dependent virulence. Our results will help to better understand the biological and epidemiological diversity of USUV infection.

A rare infective cause of stroke in an immunocompetent child.

BACKGROUND: Infections are a common cause of childhood stroke with variable presentation. The current case describes a rare infective cause of venous and arterial stroke in an immunocompetent girl with management implications. CASE DESCRIPTION: A 12 year old girl, presented with history of fever for 10 days, painful swelling of right eye for 7 days and altered sensorium for 2 days. On examination, she had right eye orbital cellulitis and fullness of right paranasal area. On nervous system examination, she was delirious, had right eye ophthalmoparesis, left upper motor neuron facial palsy and signs of meningeal inflammation. Her contrast enhanced CT head and subsequent MRI brain with arteriography and venography revealed right cavernous sinus and distal internal carotid artery thrombosis. She was started on intravenous ceftriaxone and vancomycin and subcutaneous heparin. In view of persistent symptoms, endoscopic debridement of right nasal cavity was done, which showed growth of aspergillus flavus. Subsequently, she was started on intravenous voriconazole. Within a week, she was afebrile, her inflammatory and neurological signs started improving. She was discharged after 3 weeks of intravenous voriconazole which was continued for 3 more weeks orally. Her procoagulant and immunodeficiency work up were normal. At 4 months follow up, she showed both clinical and radiological resolution. CONCLUSIONS: Despite high mortality described in sino-orbital aspergillosis, early and appropriate treatment led to optimal outcome. In deep seated infections, isolation of etiological organism should be attempted, particularly when patient doesn't respond to conventional antimicrobial therapy.

Primary Pituitary Lymphoma in Immunocompetent Patients: A Report on Two Case Studies and the Review of Literature.

Primary pituitary lymphoma (PPL) represents an extremely rare entity. Here, we have reported two recently identified cases of immunocompetent PPL having diffuse large B-cell lymphoma by surgical biopsy. Both patients had hypopituitarism, with one patient developing right ptosis. In both patients, MRI and FDG-PET/CT depicted sellar mass that extended into the cavernous sinus with the right sphenoid also present in one of the patients. No systemic disease was found in these two patients. Surprisingly, we found that both patients had infiltrative lesions in sphenoid sinus mucosa pathologically, but the sphenoid bones that composed the sellar base were visually intact during the biopsy procedure. Chemotherapy was administered to both patients, where one patient achieved remission at the recent follow-up, whereas the other one did not respond to the treatment. The diagnosis of PPL is usually difficult if solely dependent on history, clinical presentation, biochemical indexes, and radiographic findings. We have also updated and reviewed the epidemiologic features, clinical presentations, pathological characteristics, potential mechanisms, therapeutic orientation, and prognostic advances of PPL. A total of 40 cases (including ours and four pediatric patients), histologically diagnosed, were analyzed in terms of clinical presentation, endocrine abnormality, radiological features, pathology, treatment, and follow-up. Hypopituitarism and headache were the most common presentation of PPL, while diabetes insipidus was reported in 13 patients (43.3%). B cell lymphoma was the most common type of pathology, followed by T-cell and NK/T cell. PPL was more invasive in nature at the suprasellar region (72.5%), cavernous sinus (52.5%), and sphenoidal sinus (27.5%) in 29, 21, and 11 patients, respectively. Pediatric patients with PPL seem to be different compared to their adult counterparts in terms of pathogenesis, clinical presentation, and radiological features. The management of PPL usually follows the treatment protocols for PCNSL but has a poor prognosis compared to the pituitary involvement of systemic lymphoma.

Steroid hormones, energetic state, and immunocompetence vary across reproductive contexts in a parthenogenetic lizard.

Reproduction is energetically expensive and investing in this life history trait is likely accompanied by significant changes in physiological activity. Investment strategy necessary for achieving reproductive success in reptiles can vary with reproductive form and pattern, potentiating different consequences for competing fitness-related traits such as those key to survival. The goal of this study was to assess if and how energetic state (i.e., energy metabolites) and self-maintenance (i.e., immunocompetence) are hormonally modulated across reproductive contexts in an oviparous, parthenogenetic lizard, the Colorado Checkered Whiptail Aspidoscelis neotesselata. Here blood plasma samples were collected from lizards within the US Army Fort Carson Military Installation near Colorado Springs, CO, USA, during seasons of reproductive activity (i.e., June) and inactivity (i.e., August). Measures of reproductive (i.e., estradiol) and energy-mobilizing (i.e., corticosterone) hormones, energy metabolites (i.e., glucose, triglycerides, and free glycerol), and innate immunity (i.e., bactericidal ability) were compared by season and reproductive stage. Levels of energy metabolites and bactericidal ability were compared to levels of E2 and CORT. Bactericidal ability was also compared to levels of energy metabolites. Corticosterone and glucose levels were lower during the reproductive season while triglyceride levels and bactericidal ability were higher, but both estradiol and free glycerol levels did not differ between seasons. Throughout vitellogenesis, corticosterone and glucose levels as well as bactericidal ability did not differ, but estradiol levels were higher during early and mid-stage and both triglyceride and free glycerol levels were lower during gravidity. Corticosterone levels were negatively associated with circulating triglycerides and bactericidal ability, but were not related to glucose nor free glycerol levels. Estradiol levels were positively associated with free glycerol levels and bactericidal ability, but were not related to glucose nor triglyceride levels. Finally, bactericidal ability was negatively associated with glucose, but positively associated with triglycerides. Differences in energetic state and immunocompetence are thus reflected by shifts in hormone secretion across reproductive investment. These findings provide partial support for the hypothesis that energetic state is differentially regulated by steroid hormones to afford reproduction, potentially at the cost of future survival.

Immuno-oncology for surgeons.

Cancer has traditionally been treated with surgery, cytotoxic chemotherapy and/or radiotherapy. The focus of treatment has been the mutated neoplastic cell. Critical advances in genomic and molecular techniques herald the potential for personalized treatments. Incremental breakthroughs in immunology have translated to a step-change in care by providing a mechanistic understanding of the immune system and how it may be mobilized to target cancer cells. As a result, clinical trials of immune-modifying agents have increased at an exponential rate and are revolutionizing cancer care. It is increasingly likely that the surgical oncologist will find themself caring for patients who have had immuno-oncology therapies as part of their neoadjuvant or adjuvant treatment. This review provides an update on immuno-oncology for the surgeon, covering the mechanisms of action of the agents in use. Emerging and surgically relevant toxicities are discussed, and available data on combining and sequencing cancer surgery with immuno-oncology treatments are summarized.

El paradigma del tratamiento del cáncer está evolucionando rápidamente. Tradicionalmente, el cáncer se ha tratado con cirugía, quimioterapia citotóxica y/o radioterapia, pero el foco de atención de su tratamiento se ha polarizado en las mutaciones que dan lugar a la célula neoplásica. Los progresos fundamentales en las técnicas genómicas y moleculares han precedido a los tratamientos personalizados y fármacos dirigidos a dianas terapéuticas, pero los resultados de ensayos clínicos con dichos fármacos han sido en general decepcionantes. En los últimos años, los avances rigurosos y progresivos en inmunología se han traducido en un cambio sustancial en el tratamiento al proporcionar una comprensión mecanicista de cómo interviene el sistema inmune y cómo puede movilizarse mejor para atacar a las células cancerosas. Como resultado, las indicaciones y ensayos clínicos con fármacos modificadores del sistema inmune han aumentado a un ritmo exponencial y están revolucionando el tratamiento del cáncer. Por consiguiente, cada vez es más probable que los cirujanos oncólogos se encuentren tratando pacientes que recibirán terapias inmunooncológicas (immuno-oncology, IO) como parte de los tratamientos neoadyuvantes o adyuvantes. Esta revisión describe y proporciona una guía concisa y exhaustiva de la IO, abarcando los mecanismos de acción de los fármacos en uso. Se discuten las nuevas toxicidades con relevancia para la cirugía y se resumen los datos disponibles sobre la combinación y secuencia de la cirugía oncológica con los tratamientos IO.

Rare presentation of cryptococcal meningitis in an immunocompetent patient.

Cryptococcal meningitis is an opportunistic infection predominantly affecting immunocompromised patients but rarely can affect the immunocompetent. We describe a 53-year-old Caucasian man who presented complaining of a 2-week history of severe bilateral eye pain and diplopia. His only known risk factor was that he lived in a horse farm and recently shot bats and pigeons in his barn. He visited an outside hospital during this time without a diagnosis established. After further deliberation, we obtained a lumbar puncture (LP) which revealed an opening pressure (OP) of 27 cm H2O. Cerebrospinal fluid (CSF) and fungal cultures confirmed the presence of Cryptococcus neoformans The patient was diagnosed with C. neoformans-mediated meningoencephalitis and was initiated on the appropriate induction anti-fungal therapy. This case emphasises the need for clinicians to remain vigilant and consider cryptococcal meningitis in immunocompetent individuals even when classic symptoms of meningitis are absent.

Gender specific differences of immune competence in the sea cucumber Apostichopus japonicus before and after spawning.

The gender differences of immunity have been elucidated in many vertebrates and invertebrates. However, the information of this difference was still not clear in the sea cucumber Apostichopus japonicus, which is one of the most valuable aquaculture species and susceptible to diseases caused by pathogen infection. In the present study, the transcriptome of coelomocytes from female and male A. japonicus before and after spawning was obtained by RNA-sequencing technology. A total of 4,538 and 8,248 differentially expressed genes were identified between female and male A. japonicus before and after spawning, respectively, indicating that the gender differences of gene expression profiles in A. japonicus were more remarkable after spawning. Further KEGG enrichment analyses were conducted for both male and female up-regulated genes before and after spawning. The results revealed that the capacity to kill pathogens in female A. japonicus might be more powerful than that in males no matter before and after spawning; the antioxidant ability in male A. japonicus was probably stronger than that in females after spawning; the complement system in male A. japonicus might be more effective than that in females after spawning; and the apoptosis was likely to be more serious in male A. japonicus before spawning. Moreover, we speculated that the fatty acid composition might be one of the inducements for gender specific immune differences of A. japonicus. Overall, the results of our study illustrated the global gender specific immune differences of A. japonicus and contributed to understanding of the molecular mechanisms underlying sea cucumber immune regulation.

Facial masculinity does not appear to be a condition-dependent male ornament and does not reflect MHC heterozygosity in humans.

Recent studies have called into question the idea that facial masculinity is a condition-dependent male ornament that indicates immunocompetence in humans. We add to this growing body of research by calculating an objective measure of facial masculinity/femininity using 3D images in a large sample (n = 1,233) of people of European ancestry. We show that facial masculinity is positively correlated with adult height in both males and females. However, facial masculinity scales with growth similarly in males and females, suggesting that facial masculinity is not exclusively a male ornament, as male ornaments are typically more sensitive to growth in males compared with females. Additionally, we measured immunocompetence via heterozygosity at the major histocompatibility complex (MHC), a widely-used genetic marker of immunity. We show that, while height is positively correlated with MHC heterozygosity, facial masculinity is not. Thus, facial masculinity does not reflect immunocompetence measured by MHC heterozygosity in humans. Overall, we find no support for the idea that facial masculinity is a condition-dependent male ornament that has evolved to indicate immunocompetence.

Cavernous sinus fungal infection: a rare case.

Intracranial fungal infection of the cavernous sinus is a condition that usually affects immunocompromised individuals and is rarely seen in immunocompetent individuals. It is a potentially life threatening condition which requires prompt treatment. Here we present a case of an immunocompetent patient with a fungal infection of the cavernous sinus.

Human body symmetry and immune efficacy in healthy adults.

OBJECTIVES: More symmetric organisms are perceived as more attractive. Fluctuating asymmetry (FA) i.e. small, random deviations from perfect bilateral symmetry, is supposed to inform about developmental instability. According to the good genes hypothesis, a low level of FA is a putative cue to an organism's biological quality. An important aspect of this quality is the immune system functioning. The aim of this study was to evaluate the relationship between immune system functioning and body symmetry in healthy people. MATERIALS AND METHODS: The composite body FA (cFA) was assessed on the basis of six bilateral traits (on hands and feet). The ISF was determined by many innate (total complement and lysozyme activity, neutrophils function) and adaptive immune parameters (T CD3 and B CD19 lymphocytes, total IgA and IgG and response to flu vaccine). A total of 98 men and 92 women were subjected to flu (among them 37 men and 30 women also to tetanus) vaccination. The blood samples were collected before and 4 weeks after the antigens exposure. Immunomodulatory factors: participant's age, body fat, and free testosterone level, were controlled. RESULTS: Apart from the weak positive association between CD3 or CD19 and cFA in men, we found no association between the level of body symmetry and the rest of the analyzed immune parameters for both sexes. DISCUSSION: Our results are the opposite of the good genes hypothesis prediction and suggest that in western, healthy populations, human mate preferences for more symmetric bodies are not related to immune competence.

Trade-offs between immunity and testosterone in male African ground squirrels.

The immunocompetence handicap hypothesis (ICHH) proposes that testosterone has both beneficial effects on male reproductive potential and negative effects by suppressing the immune system. However, support for the ICHH has been variable and an alternative hypothesis suggests that testosterone may be acting indirectly via cortisol to suppress immunity (the stress-linked ICHH). A third hypothesis is that increased energetic investment in immunity results in the suppression of testosterone. We tested these hypotheses in male Cape ground squirrels (Xerus inauris) through two separate manipulations: first, by triggering a strong immune response using a lipopolysaccharide (LPS) injection and, secondly, by increasing circulating testosterone using silastic testosterone implants. Responding to an immune challenge significantly reduced testosterone, supporting the immune suppression hypothesis, while increasing circulating testosterone had no effect on immunocompetence, body mass, ectoparasite abundances or cortisol levels, failing to support either the ICHH or stress-linked ICHH. Our results add to the increasing body of literature that challenges the ICHH, and we conclude that the trade-off between testosterone and immunity is mediated through immune activation and not through testosterone in male Cape ground squirrels. Being able to test the ICHH, stress-linked ICHH and immune suppression hypotheses in a free-ranging mammal gives us a unique opportunity to examine the mechanisms mediating this trade-off.

Severe Babesia microti infection presenting as multiorgan failure in an immunocompetent host.

A previously healthy 67-year-old farmer presented to an outside hospital after a 2-week history of non-specific respiratory symptoms. A certain diagnosis was not initially apparent, and the patient was discharged home on a regimen for presumed chronic obstructive pulmonary disease exacerbation. He re-presented to the emergency department with shock and hypoxaemic respiratory failure requiring prompt intubation and fluid resuscitation. He was then transferred to our institution due to multiorgan failure. On arrival, the patient demonstrated refractory shock and worsening acute kidney injury, severe anaemia and thrombocytopaenia. The peripheral smear revealed absence of microangiopathic haemolytic anaemia. A closer review of the smear displayed red blood cell inclusion bodies consistent with babesiosis. The patient was started on clindamycin and loaded with intravenous quinidine, and subsequently transitioned to oral quinine. A red cell exchange transfusion was pursued with improvement of the parasite load. The patient was discharged home on clindamycin/quinine and scheduled for outpatient intermittent haemodialysis.

Colorectal cancer in the young: a possible role for immune surveillance?

BACKGROUND: Younger patients with colorectal cancer (CRC) generally have better survival in spite of worse clinical and pathological features. METHODS: Twenty-six patients under 50 years operated for primary CRC were enrolled and matched 1:2:2 according to stage, tumor site and gender with 52 patients from 50 to 70 years and 52 patients over 70 years old. RESULTS: Patients under 50 years had a significantly longer overall, cancer specific and disease free survival (p = .001, p = .007 and p = .05, respectively). However, they had more frequently lymphovascular invasion (p = .006) and they more frequently developed metachronous CRC at follow-up (p = .03). Nevertheless, preoperative lymphocytes blood count/white blood count (LBC/WBC) ratio inversely correlated with age at operation (rho = -.21, p = .04) and it predicted CRC recurrence with an accuracy of 70%, p < .001 (threshold value LBC/WBC = 0.21%) and better overall, cancer specific and disease free survival (p < .0001 for all). At multivariate analysis, stage and LBC/WBC ratio resulted independent predictors of disease free survival (p = .0001 and p = .01, respectively). CONCLUSIONS: Patients under 50 years had a significantly longer survival with a higher LBC/WBC ratio. These results could suggest a possible role of immunosurveillance in neoplastic control.

Nonadditive Effects of Repetitive Administration of Lipoplexes in Immunocompetent Mice.

Repetitive administration is routinely used to maintain therapeutic drug levels, but previous studies have documented an accelerated blood clearance of some lipid-based delivery systems under these conditions. To assess the effect of repetitive administration, non-PEGylated lipoplexes (+/-0.5) were administered 4 times via tail vein injection at 3-day intervals to immunocompetent BALB/c mice bearing 4T1 tumors. This study measured the effect of repeat administration of nontargeted lipoplexes on clearance, cytokine/chemokine response, plasmid distribution, reporter gene expression, and liver toxicity. We do not observe a refractory period or a statistically significant difference in blood clearance between the first administration and subsequent injections of this lipoplex formulation, consistent with the absence of a cytokine/chemokine response. However, we do see a significant effect on both plasmid accumulation and expression, an enhancement of 26-fold and 10-fold in tumor plasmid levels and expression, respectively, after 4 injections as compared to that after a single injection. In addition, in vivo imaging suggests that expression in other organs had diminished rapidly 72 h after each administration, in contrast to relatively constant expression in the tumor. Taken together, the findings indicate that gene delivery to tumors can be dramatically enhanced by employing repetitive administration.