The Perturbance of Microbiome and Gut-Brain Axis in Autism Spectrum Disorders.

Gastrointestinal problems have been documented in Autism Spectrum Disorder (ASD). Studies have found that these disturbances may be associated with an altered gut microbiome in ASD. Furthermore, in ASD, these alterations are implicated in increased gut permeability, or "leaky gut", which allows bacterial metabolites to cross the gut barrier, impacting neurodevelopment during early childhood in susceptible subjects by way of gut-brain axis. In our review, we will discuss the interaction of gut microbiota and brain development in ASD and the signaling mechanisms underlying this interaction. We will also explore the potential for treatment of ASD by targeting the microbiome with probiotics. Finally, this paper will attempt to provide significance to the aggregation of the research in this area of research; providing our interpretations and assessments of future of this field.

TURP and sex: patient and partner prospective 12 years follow-up study.

OBJECTIVE: • To evaluate the effect of transurethral resection of the prostate (TURP) on sexual function in the short (6 months), medium (6 years) and long (12 years) term and assess the conformity between patient and partner regarding sexual function. PATIENTS AND METHODS: • A prospective cohort study set at the Aberdeen Royal Infirmary University Hospital. • A total of 280 men referred with lower urinary tract symptoms (LUTS) to a university hospital underwent TURP between January 1993 and September 1994; 145 of their partners (partner or spouse) participated. • Assessment included American Urological Association symptom score, flow rates and validated self-reported sexual questionnaires (SQ). • Data were collected at baseline, 3 months, 6 months, 6 years and 12 years of follow-up. RESULTS: • In all, 120 (43%) men were sexually active preoperatively. At 6 months, 73 (61%) of these 120 men completed the SQ and all were sexually active. • No sexually active patient became impotent after the procedure. Moreover, 27 (15%) with pre-existing erectile dysfunction reported improved sexual activity and erection quality. • At 6 years 101 men completed the SQ and 31 (30.7%) were sexually active. At 12 years, 36 (31.9%) of 113 who completed the SQ were sexually active. • Partners agreed with the men's self assessment at all visits. • Limitations include possible attrition bias and lack of information from non-responders. CONCLUSIONS: • Erectile dysfunction associated with LUTS frequently precedes TURP. • The TURP did not adversely affect sexual function. • Pre-operative erectile dysfunction can be improved by TURP and long-term sexual function is maintained after TURP. These findings, corroborated by the partners, were statistically significant.

A Systematic Review of Characteristics Associated with COVID-19 in Children with Typical Presentation and with Multisystem Inflammatory Syndrome.

Setting off a global pandemic, coronavirus disease 2019 (COVID-19) has been marked by a heterogeneous clinical presentation that runs the gamut from asymptomatic to severe and fatal. Although less lethal in children than adults, COVID-19 has nonetheless afflicted the pediatric population. This systematic review used clinical information from published literature to assess the spectrum of COVID-19 presentation in children, with special emphasis on characteristics associated with multisystem inflammatory syndrome (MIS-C). An electronic literature search for English and Chinese language articles in COVIDSeer, MEDLINE, and PubMed from 1 January 2020 through 1 March 2021 returned 579 records, of which 54 were included for full evaluation. Out of the total 4811 patients, 543 (11.29%) exhibited MIS-C. The most common symptoms across all children were fever and sore throat. Children presenting with MIS-C were less likely to exhibit sore throat and respiratory symptoms (i.e., cough, shortness of breath) compared to children without MIS-C. Inflammatory (e.g., rash, fever, and weakness) and gastrointestinal (e.g., nausea/vomiting and diarrhea) symptoms were present to a greater extent in children with both COVID-19 and MIS-C, suggesting that children testing positive for COVID-19 and exhibiting such symptoms should be evaluated for MIS-C.

Partners agree that the treatment of LUTS reduces patients' bother and improves their quality of life: prospective 12 years follow-up study.

OBJECTIVES: To determine if the partner (partner or spouse) can reliably assess the quality of life (QoL) and bother of the patient suffering from lower urinary tract symptoms (LUTS) before and after treatment thereby assisting in management. METHODS: 458 men referred with LUTS to a university hospital and 219 partners were recruited into the study between January 1993 and September 1994. Assessment included AUA score, flow rates, QoL and bother validated self-reported questionnaires completed by patients and spouses throughout the study. Data were collected at baseline, 3, 6 months, 6 and 12 years of follow-up. 280 men underwent TURP and 178 were managed by medical (non-surgical) treatment. RESULTS: For the TURP group, the mean QoL for patient and partner at baseline were 8.16 and 9.90 respectively. At 6 months, 6 and 12 years, these improved to 2.43, 3.71, 3.74 and 1.76, 4.07, 4.76 respectively. For the non-surgical treatment group, the mean QoL for patient and partner at baseline were 7.08 and 8.35 respectively. At 6 months, 6 and 12 years, these improved to 5.0, 3.6, 3.28 and 5.67, 3.61, 2.81 respectively. A similar trend applied to the bother score. Improvements in QoL and bother noted by partners agreed with that of patients and were statistically significant. CONCLUSIONS: The longest prospective in-depth study has shown marked conformity between patients and partners regarding QoL and bother after treatment. Partners are affected by patients' LUTS, appreciate the improvement after treatment and may be valuable contributors in assessment.

Neuroendocrine-immune interaction: Evolutionarily conserved mechanisms that maintain allostasis in an ever-changing environment.

It has now become accepted that the immune system and neuroendocrine system form an integrated part of our physiology. Immunological defense mechanisms act in concert with physiological processes like growth and reproduction, energy intake and metabolism, as well as neuronal development. Not only are psychological and environmental stressors communicated to the immune system, but also, vice versa, the immune response and adaptation to a current pathogen challenge are communicated to the entire body, including the brain, to evoke adaptive responses (e.g., fever, sickness behavior) that ensure allocation of energy to fight the pathogen. This phenomenon is evolutionarily conserved. Hence it is both interesting and important to consider the evolutionary history of this bi-directional neuroendocrine-immune communication to reveal phylogenetically ancient or relatively recently acquired mechanisms. Indeed, such considerations have already disclosed an extensive "common vocabulary" of information pathways as well as molecules and their receptors used by both the neuroendocrine and immune systems. This review focuses on the principal mechanisms of bi-directional communication and the evidence for evolutionary conservation of the important physiological pathways involved.

Increased splenocyte mitogenesis following sympathetic denervation in Xenopus laevis.

Studies in mammals reveal that ablation of the sympathetic nervous system (SNS) can alter in vivo and in vitro parameters of immunity. To shed some light on the phylogenetic history of the interactions between the SNS and the immune system, we studied the effects of chemical sympathectomy on the proliferative response of frog splenocytes to mitogens. Adult Xenopus laevis were injected with 6-hydroxydopamine 3 days before removal of spleen cells for culture with mitogens. Splenocytes from sympathectomized frogs exhibited an increased proliferative response to the T cell mitogens PHA and ConA and the B cell mitogen, LPS. That sympathectomy appears to effect a release from tonic inhibition by the SNS in Xenopus is consistent with comparable experiments in mice. It also reveals a phylogenetically ancient origin for SNS-immune system communications.

Ontogeny of Xenopus NK cells in the absence of MHC class I antigens.

This paper explores the ontogeny of NK cells in control and early-thymectomized (Tx) Xenopus laevis through phenotypic analysis of cells expressing the NK cell antigen 1F8 and by performing in vitro cytotoxic assays. Dual color flow cytometry reveals that a few 1F8positive splenocytes first emerge in late larval life, at approximately 7-weeks post-fertilization. This is about 2-weeks after the time when surface MHC class Ia expression can first be detected. The proportion of splenocytes expressing 1F8 remains very low in 3-4 month-old froglets, but by 1 year there is a sizeable 1F8positive population, which is proportionally elevated in Tx frogs. The ontogeny of NK cell function is monitored by a 5 h DNA fragmentation (JAM) assay. Control and Tx larval splenocytes (from either 5- or 7-week-old tadpoles) fail to kill MHC-deficient thymus-derived tumor cell targets. Such in vitro killing is still relatively poor in 3-4 month froglets, compared with high levels of tumor cell cytotoxicity mediated by splenocytes from older frogs. Immunoprecipitation studies identify that the major ligand for the 1F8 mAb is a 55 kDa polypeptide. Finally, further evidence is provided that 1F8positive lymphocytes are indeed bona fide NK cells, distinct from T cells, since purified 1F8positive splenocytes from Tx Xenopus fail to express fully rearranged TCRbeta V region transcripts. We conclude that NK cells fail to develop prior to MHC class I protein expression and, therefore, do not contribute to the larval immune system, whereas they do provide an important backup for T cells in the adult frog by contributing to anti-tumor immunity.

Bacterial stimulation upregulates the surface expression of the stress protein gp96 on B cells in the frog Xenopus.

The presence of the soluble intracellular heat shock protein gp96 (an endoplasmic reticulum resident protein) at the surface of certain cell types is an intriguing phenomenon whose physiological significance has been unclear. We have shown that the active surface expression of gp96 by some immune cells is found throughout the vertebrate phylum including the Agnatha, the only vertebrate taxon whose members (lamprey, hagfish) lack an adaptive immune system. To determine whether gp96 surface expression can be modulated by pathogens, we investigated the effects of in vitro stimulation by purified lipopolysaccharide (LPS) and the heat-killed gram-negative bacteria, Escherichia coli and Aeromonas hydrophilia. Purified Xenopus B cells are readily activated and markedly proliferate in vitro in response to the heat-killed bacteria but not to purified LPS. Furthermore, messenger ribonucleic acid, and intracellular and surface protein expressions of both gp96 and immunoglobulin were upregulated only after activation of B cells by heat-killed bacteria. These data are consistent with an ancestral immunological role of gp96 as an antigen-presenting or danger-signaling molecule, or both, interacting directly with antigen-presenting cells, T cells, or natural killer cells, (or all), to trigger or amplify immune responses.

Fate of indeterminate lesions detected on noncontrast computed tomography scan for suspected urolithiasis: a retrospective cohort study with a minimum follow-up of 15 months.

OBJECTIVE: To investigate the fate of indeterminate lesions incidentally found on noncontrast computed tomography (NCCT) for suspected urolithiasis. METHODS: A retrospective review of 404 consecutive cases of suspected urolithiasis was undertaken between May 2010 and April 2011. Data were collected for patient demographics, presence of calculus disease, and additional urologic or nonurologic pathologies and their clinical relevance. The indeterminate or suspicious lesions were followed up and the data were reviewed in September 2012. RESULTS: In total, 404 patients underwent NCCT for renal colic (mean age, 50 years [range, 13-91 years]; 165 females). Minimum follow-up period was 15 months. Fifty-eight patients (14%) had ureteric, 85 (21%) had renal, and 39 patients (10%) had combined ureteric and renal stones. Noncalculus pathologies were found in 107 patients (26%). Sixty patients (15%) had indeterminate lesions. Of these patients, 6 required operative intervention, 35 had a benign diagnosis after further imaging and multidisciplinary team meeting, and 13 remained under surveillance after 1 year. Indeterminate pulmonary lesions (8 of 16) were the commonest lesions to remain under surveillance. CONCLUSION: NCCT is vital for the diagnosis of urolithiasis with a pick up rate of 45% and remains the standard of care. However, with incidental detection of potential malignant lesions, a significant minority will need close monitoring, intervention, or both. In our study, approximately one-third of these lesions either remained under surveillance or had intervention.

The genus Xenopus as a multispecies model for evolutionary and comparative immunobiology of the 21st century.

The Xenopus model for immunological research offers a collection of invaluable research tools including MHC-defined clones, inbred strains, cell lines, and monoclonal antibodies. Further, the annotated full genome sequence of Xenopus tropicalis and its remarkable conservation of gene organization with mammals, as well as ongoing genome mapping and mutagenesis studies in X. tropicalis, add a new dimension to the study of immunity. In this paper, we review uses of this amphibian model to study: the development of the immune system; vascular and lymphatic regeneration; immune tolerance; tumor immunity; immune responses to important emerging infectious diseases; and the evolution of classical and non-classical MHC class I genes. We also discuss the rich potential of the species with different degrees of polypoidy resulting from whole genome-wide duplication of the Xenopodinae subfamily as a model to study regulation at the genome level.

Neural-immune system interactions in Xenopus.

In Xenopus, as in mammals, there is a functionally significant bidirectional communication between the neuroendocrine and immune systems. In this review, we describe the evidence for the neural innervation of Xenopus lymphoid organs, review the effects of neurotransmitter and hormone manipulations on measures of immunity, and discuss the role of hormones on immunological changes during metamorphosis. We also speculate as to the phylogenetic significance of these data, and outline possible areas of future research.

Diagnosis of urologic malignancies in patients with asymptomatic dipstick hematuria: prospective study with 13 years' follow-up.

OBJECTIVES: To appraise the outcomes, determine the natural history, and instigate a rationale plan for follow-up of patients with asymptomatic dipstick hematuria. METHODS: A total of 292 consecutive patients with asymptomatic dipstick hematuria referred between January 1992 and December 1994 were investigated and prospectively followed up. The initial investigations included urinalysis, urine culture and sensitivity, cytology, intravenous urography, with or without ultrasonography, and cystoscopy. Baseline data and follow-up events, particularly the development of urologic malignancy, were recorded for a 13-year period. RESULTS: Sixteen patients (5.4%) were found to have urologic malignancies on initial evaluation. Of these, 11 died. During a follow-up of 13 years, 21 patients (7%) were lost to follow-up and 42 died of various unrelated causes (other than urologic malignancies). Of the remaining 213 patients, 180 (84.5%) subsequently had negative urinalysis. None with negative urinalysis developed a urologic malignancy during follow-up. The presence of dipstick hematuria persisted in 33 patients. Of these 33 patients, 10 had nephrologic causes, 8 had urinary tract infection, and 15 underwent repeat investigation with no pathologic cause identified. One patient, discharged with negative findings after full initial investigations, presented 2 years later with frank hematuria and was found to have a new bladder tumor. CONCLUSIONS: Patients presenting with asymptomatic dipstick hematuria who have undergone thorough initial negative investigations can be discharged from tertiary urologic care services. Nephrologic referral is recommended if dipstick hematuria and proteinuria persist. The repetition of the urologic investigations is unwarranted, unless patients present with symptoms or develop frank hematuria.

Improved quality of life and enhanced satisfaction after TURP: prospective 12-year follow-up study.

OBJECTIVES: To assess the long-term clinical effectiveness, quality of life (QOL), bother, and satisfaction, using validated questionnaires, after transurethral resection of the prostate in patients with lower urinary tract symptoms due to benign prostatic enlargement. METHODS: We enrolled men referred to a tertiary university hospital for further evaluation and treatment of lower urinary tract symptoms from January 1993 to September 1994 in a prospective cohort study. A total of 280 consecutive patients underwent transurethral resection of the prostate, mainly for outflow obstructive symptoms. They were recruited into this protocol-based study using validated self-reported questionnaires. The assessments included American Urological Association symptom score, flow rates, and measurement of QOL, bother, and satisfaction. The data were collected at baseline, 3 and 6 months, and 6 and 12 years of follow-up. RESULTS: The mean QOL and bother score at baseline was 8.16 and 15.45, respectively. At 6 months, 6 years, and 12 years, the mean QOL and bother scores had improved to 2.54 and 4.84, 3.71 and 7.14, and 3.74 and 7.67, respectively. The improvements in the QOL and bother scores were consistent and statistically significant. CONCLUSIONS: Transurethral resection of the prostate not only proved to be clinically effective, but also improved patients' QOL and bother symptoms. This was associated with long-term, high patient-rated satisfaction.

Norman Cousins Lecture. The uses and abuses of psychoneuroimmunology: a global overview.

Studies of interactions between the nervous and immune systems that effect immunological and behavioral changes are relevant to our understanding biological issues pertinent to evolution, ethology, ecology, and aging, in addition to our understanding the immune and nervous systems per se. Psychoneuroimmunology also relates to homeland security, science education, and the practice of conventional as well as complementary and alternative medicine. This paper will highlight just some of these global implications of psychoneuroimmunology.

Adaptive immunity and histopathology in frog virus 3-infected Xenopus.

Xenopus has been used as an experimental model to evaluate the contribution of adaptive cellular immunity in amphibian host susceptibility to the emerging ranavirus FV3. Conventional histology and immunohistochemistry reveal that FV3 has a strong tropism for the proximal tubular epithelium of the kidney and is rarely disseminated elsewhere in Xenopus hosts unless their immune defenses are impaired or developmentally immature as in larvae. In such cases, virus is found widespread in most tissues. Adults, immunocompromised by depletion of CD8+ T cells or by sub-lethal gamma-irradiation, show increased susceptibility to FV3 infection. Larvae and irradiated (but not normal) adults can be cross-infected through water by infected adult conspecifics (irradiated or not). The natural MHC class I deficiency and the absence of effect of anti-CD8 treatment on both larval CD8+ T cells and larval susceptibility to FV3 are consistent with an inefficient CD8+ T cell effector function during this developmental period.

Xenopus as an experimental model for studying evolution of hsp--immune system interactions.

The frog Xenopus provides a unique model system for studying the evolutionary conservation of the immunological properties of heat shock proteins (hsps). General methods for maintaining and immunizing isogenetic clones of defined MHC genotypes are presented together with more recently developed protocols for exploring hsp-mediated immune responses in vitro (proliferative and cytotoxic assays) and in vivo (adoptive cell transfer and antibody treatment) in adults and in naturally MHC class I-deficient larvae. Finally, techniques to study modalities of expression of the endoplasmic reticulum resident gp96 at the cell surface of tumor and normal lymphocytes are considered.

Anti-tumor MHC class Ia-unrestricted CD8 T cell cytotoxicity elicited by the heat shock protein gp96.

In Xenopus as in mammals, gp96 stimulates MHC-restricted cellular immunity against chaperoned minor histocompatibility (H) antigens (Ag). In adult Xenopus, gp96 also elicits peptide-specific effectors against MHC class Ia-negative 15/0 tumors. To determine whether gp96 can generate functionally heterogeneous CD8+ effectors (CTL that kill MHC class Ia+ minor H-Ag-disparate lymphoblasts and MHC class Ia- tumor targets), LG-6 isogenetic frogs were immunized with gp96 purified either from MHC-identical but minor H-Ag-disparate LG-15 normal tissues or from the MHC class Ia-negative 15/0 tumor line (derived from LG-15 frogs). LG-15 normal liver-derived gp96 did not induce detectable CD8+ in vitro killing against 15/0 tumor cells. However, 15/0-derived gp96 did induce killing against both MHC class Ia+ LG-15 lymphoblasts and the MHC class Ia- 15/0 tumor, but not against another MHC class Ia- tumor (B3B7) or against LG-6 lymphoblasts. Tumor killing was better when 15/0 rather than normal LG-15 irradiated stimulators were used, but in vitro stimulation without prior in vivo immunization was ineffective. These data suggest that (1) 15/0-derived gp96 chaperones minor H-Ag shared with normal LG-15 lymphocytes and elicits MHC-restricted CTL, and (2) 15/0-derived gp96, but not normal liver-derived gp96, generates CD8+ effectors that kill 15/0 tumor cells in the absence of MHC class Ia expression.

Development and characterization of a model system to study amphibian immune responses to iridoviruses.

The recent realization that viruses within the family Iridoviridae may contribute to the worldwide decline in amphibians makes it urgent to understand amphibian antiviral immune defenses. We present evidence that establishes the frog Xenopus laevis as an important model with which to study anti-iridovirus immunity. Adults resist high doses of FV3 infection, showing only transitory signs of pathology. By contrast, naturally MHC class-I-deficient tadpoles are highly susceptible to FV3 infection. Monitoring of viral DNA by PCR indicates a preferential localization of FV3 DNA in the kidney, with the inbred MHC homozygous J strain appearing to be more susceptible. Clearance of virus as measured by detection of FV3 DNA and also the disappearance of pathological and behavioral symptoms of infection, acceleration of viral clearance, and detection of IgY anti-FV3 antibodies after a second injection of FV3 are all consistent with the involvement of both cellular and humoral adaptive antiviral immune responses.

Minor histocompatibility antigen-specific MHC-restricted CD8 T cell responses elicited by heat shock proteins.

In mammals, the heat shock proteins (HSP) gp96 and hsp70 elicit potent specific MHC class I-restricted CD8(+) T cell (CTL) response to exogenous peptides they chaperone. We show in this study that in the adult frog Xenopus, a species whose common ancestors with mammals date back 300 million years, both hsp70 and gp96 generate an adaptive specific cellular immune response against chaperoned minor histocompatibility antigenic peptides that effects an accelerated rejection of minor histocompatibility-locus disparate skin grafts in vivo and an MHC-specific CD8(+) cytotoxic T cell response in vitro. In naturally class I-deficient but immunocompetent Xenopus larvae, gp96 also generates an antitumor immune response that is independent of chaperoned peptides (i.e., gp96 purified from normal tissue also generates a significant antitumor response); this suggests a prominent contribution of an innate type of response in the absence of MHC class I Ags.

Identification and characterization of Xenopus CD8+ T cells expressing an NK cell-associated molecule.

Growing evidence suggests that some immune responses are mediated not only by conventional and distinct NK cells and CTL, but also by T cell subsets expressing NK receptors and NK cell-associated molecules. Consistent with our previously published finding that the mAb 1F8 identifies non-T/non-B cells in Xenopus that effect NK-like killing in vitro, we now report that in vivo treatment with this mAb impairs rejection of transplanted MHC class I-negative tumor cells. However, we also find that the NK cell-associated molecule recognized by mAb 1F8 is expressed by a minor population of CD8+ T cells, in which fully rearranged TCRbeta mRNA of at least three different V families can be identified, by contrast, 1F8+/CD8- (NK) cells lack such TCRbeta message. Additionally, the expression of the NK cell-associated molecule can be induced in vitro by a transient submitogenic stimulation of naïve CD8+ T cells with PMA and ionomycin. Such induced expression of 1F8 also occurs in alloantigen-activated CTL and is coincident with a down-regulation of MHC-specific cytotoxicity. Taken together, these new data suggest that regulation of CD8+ T cell activity involving NK cell-associated molecules is a general and evolutionarily ancient phenomenon.