Megameatus intact prepuce variant reconstruction: Long-term outcomes and comparison to post-circumcision hypospadias repair.

BACKGROUND: Megameatus intact prepuce (MIP) variant is considered a surgical challenge with associated high complication rates. It is usually diagnosed and corrected only after neonatal circumcision, which is discouraged in non-MIP hypospadias. OBJECTIVE: In order to determine whether the features of the MIP variant or the performance of a secondary reconstruction following circumcision comprise the cause of higher complication rates, we now compared the results of post-circumcision MIP hypospadias repair to the results of children who underwent repair of non-MIP hypospadias following neonatal circumcision. STUDY DESIGN: Reoperation rates of children operated for hypospadias repair following neonatal circumcision between 1999 and 2020 were compared between those with MIP and those with classic non-MIP hypospadias. RESULTS: In total, 139 patients who had undergone neonatal circumcision underwent surgical reconstruction at a mean age of 13 months. Sixty-nine had classic hypospadias and 70 had the MIP variant. The median follow-up was 10 years (interquartile range 6,13). The classic group had a higher rate of meatal location below the corona compared to the MIP variant group (53 % vs. 28 %, respectively, p = 0.002). The reoperation rate was comparable for the two groups (32 % vs. 27 %, p = 0.58, Table). Univariate analysis for the MIP hypospadias group showed no association between reoperation and the initial patient characteristics, while a higher probability of reoperation was demonstrated in the presence of ventral curvature (odds ratio 3.5, p = 0.02), and a higher grade of hypospadias (odds ratio 3.3, p = 0.03 for meatal location lower than the coronal sulcus) in the non-MIP group. DISCUSSION: The limitations of our work include its retrospective design wherein the patients' characteristics, including classification as MIP vs. non-MIP, are derived from medical records. More patients in the non-MIP group were documented to have penile curvature. The non-MIP group was composed of more patients with meatal location under the coronal sulcus, a factor which may increase the rates for reoperation in that group. Still, with the comparison of the largest reported cohort of circumcised MIP with circumcised non-MIP patients together with an extended follow-up period, we believe that we present strong evidence of the possible role of previous circumcision in the surgical challenge of reconstructing MIP hypospadias. CONCLUSIONS: Reoperation rates in MIP hypospadias are high but similar to those of classic hypospadias, both following circumcision, suggesting that circumcision, rather than the unique features of the variant, is the cause for complications.

The Age Factor in Postbariatric Body Contouring Surgery Outcome.

BACKGROUND: Increasing life expectancy will likely lead greater numbers of older patients to seek postbariatric body contouring plastic surgery. The impact of age on body contouring plastic surgery outcome is undetermined. METHODS: A retrospective cohort study of 317 postbariatric body contouring plastic surgery cases was performed. Patient demographics and operative and postoperative data were collected. Patients were categorized into three age groups, and univariate analysis examined group differences. Multivariate logistic regression analysis assessed independent associations between age and surgical outcome measures. RESULTS: Patients 60 years and older had a higher mean preoperative body mass index (30.8 ± 3.6 kg/m2, p < 0.001) and higher rates of hypertension (48.9 percent, p < 0.001), dyslipidemia (38.3 percent, p < 0.001), and diabetes mellitus (17 percent, p = 0.012) compared to the younger age groups. They also sustained significantly higher complication rates (any minor complications, p = 0.004; minor surgical site infections, p = 0.005; minor hematomas, p = 0.007; any major complications, p < 0.001; major surgical-site infections, p < 0.001; and major dehiscence, p < 0.001). Increasing age was a significant risk factor for any major complications (p = 0.005), reoperation (p = 0.02), and readmission (p = 0.001). Age greater than or equal to 60 years was a significant risk factor solely for readmission (OR, 3.32; p = 0.03). CONCLUSIONS: Increasing age was a risk factor for adverse postoperative outcome in postbariatric body contouring plastic surgery patients; however, age greater than or equal to 60 years in and of itself was an independent risk factor for readmission only. These findings may aid plastic surgeons in patient consultation and in decision making regarding suitable candidates for these procedures. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.

Helminth-Based Product and the Microbiome of Mice with Lupus.

The hygiene hypothesis claims that the lack of exposure to microorganisms in developed countries correlates with a rise in the incidence of autoimmune diseases. It was also found that helminths are able to modulate the immune response in hosts in order to survive. Consequently, several successful trials using helminths as a treatment for autoimmune patients have been reported. The helminth derivative, phosphorylcholine (PC), was discovered as an immunomodulatory molecule. We have recently shown in a murine model that when a conjugate of tuftsin and PC, termed TPC, is prophylactically administered before the onset of glomerulonephritis, it attenuates the development of systemic lupus erythematosus (SLE). The current study aimed to examine the TPC effect on the gut microbiome in a mouse model of lupus. TPC treatment altered the gut composition in the mice with active lupus, in correlation with a significant decrease in glomerulonephritis, followed by an increased level of anti-inflammatory interleukin 10 (IL-10), decreased levels of proinflammatory mediators, and expansion of the T regulatory cell population. Importantly, we found that TPC treatment altered the mouse gut microbiome composition, in correlation with a significant decrease in protein secretion and improved disease parameters. The major effects of TPC treatment on the gut microbiome included decreased abundances of Akkermansia and increased abundance of several genera, including Turicibacter, Bifidobacterium, unclassified Mogibacteriaceae, unclassified Clostridiaceae, Adlercreutzia, Allobaculum, and Anaeroplasma. Overall, our results associate microbial changes with the immunomodulation of glomerulonephritis in mice with lupus. IMPORTANCE Recently, several papers referred to the association of different bacteria with lupus in mice and humans. This is the first report to demonstrate the effect of a compound derived from helminths on the induction of remission in mice with lupus and its association with a bacterial change. We show that several genera, including Akkermansia, are associated with clinical and serological parameters of lupus, while other genera, including butyrate-producing bacteria, are associated with amelioration of disease following tuftsin and phosphorylcholine treatment.

Immunomodulation of Murine Chronic DSS-Induced Colitis by Tuftsin-Phosphorylcholine.

Helminths or their products can immunomodulate the host immune system, and this phenomenon may be applied as the basis of new anti-inflammatory treatments. Previously, we have shown the efficacy of tuftsin-phosphorylcholine (TPC), based on a helminth product, in four animal models of autoimmune diseases: arthritis, colitis, systemic lupus erythematosus, and experimental autoimmune encephalomyelitis. We demonstrated that TPC reduced inflammatory process ex vivo in peripheral blood lymphocytes (PBLs) and in biopsies from giant-cell arteritis. In the present study, we assessed the therapeutic potential of TPC treatment on a chronic colitis murine model. C57BL/6 mice with chronic colitis were treated with TPC after the third cycle of 2% dextran sodium sulfate (DSS). Oral TPC treatment resulted in amelioration of the colitis clinical manifestations exemplified by reduced disease activity index (DAI) score, expansion of mesenteric lymph nodes (MLN) T regulatory cells (shown by Fluorescence Activated Cell Sorting (FACS)), significant reduction in the expression of pro-inflammatory cytokines (IL-1ß, IL17, IL-6, TNFα), and elevation in the expression of anti-inflammatory cytokine IL-10 (shown by RT-PCR). This study demonstrated the potential immunomodulatory effects of oral administration of TPC in a chronic colitis murine model. Further clinical trials are needed in order to evaluate this novel approach for the treatment of patients with inflammatory bowel disease.

Helminths-based bi-functional molecule, tuftsin-phosphorylcholine (TPC), ameliorates an established murine arthritis.

A novel small molecule named tuftsin-phosphorylcholine (TPC), which is linked to the biological activity of helminths, was constructed. The current study address the effect of TPC treatment in established collagen-induced arthritis (CIA) mice and propose TPC bi-functional activity. TPC treatment was initiated when clinical score was 2 to 4. Arthritis scores in TPC treated mice were lower compared to mice treated with vehicle (P < 0.001). Joint staining showed normal joint structure in TPC-treated mice compared to control groups treated with phosphate buffered saline (PBS), phosphorylcholine, or tuftsin, which exhibited severely inflamed joints. TPC enhanced anti-inflammatory response due to increased IL-10 secretion, and reduced pro-inflammatory cytokine secretion (IL-1-ß, IL-6, TNF-αP < 0.001). Furthermore, TPC therapy increased expansion of CD4+CD25+FOXP3+T regulatory cells and IL-10+CD5+CD1d+B regulatory cells. We propose that the immunomodulatory activity of TPC can be a result of a bi-specific activity of TPC: (a) The tuftsin part of the TPC shifts RAW macrophage cells from pro-inflammatory macrophages M1 to anti-inflammatory M2-secreting IL-10 (P < 0.001) through neuropilin-1 and (b) TPC significantly reduce mouse TLR4 expression via NFkB pathway by HEKTM cells (P < 0.02) via the phosphorylcholine site of the molecule. Our results indicate that TPC, significantly ameliorated established CIA by its immunomodulatory activity. These data could lead to a novel self bi-functional small molecule for treating patients with progressive RA.

Tuftsin-Phosphorylcholine Maintains Normal Gut Microbiota in Collagen Induced Arthritic Mice.

Rheumatoid arthritis (RA) is characterized by chronic autoinflammation of the joints, with a prevalence of about 1% in Western populations. Evidence in recent years has linked RA to changes in the gut microbiota (dysbiosis). Interestingly, helminths have been shown to have therapeutic activity in RA. Specifically, a glycoprotein containing phosphorylcholine (PC) extracted from helminths was found to have immunomodulatory activity. We have previously developed a novel chimeric compound composed of tuftsin-PC (TPC) that attenuates the joint destruction in mice with collagen-induced arthritis (CIA). Here, we address the interrelationship between TPC immunomodulatory activity and the gut microbiota in CIA mice. Preventive therapy with TPC in mice with arthritis maintained a physiological arthritis score as well as a steady gut microbial environment, similar to that of healthy controls, in contrast to CIA mice with severe disease. The microbial composition differed significantly between healthy and phosphate-buffered saline-treated CIA mice, enabling classifying test samples by machine learning based on levels of a small number of bacterial species. Using these bacterial biomarkers, all TPC-treated CIA mice were classified as healthy. Thus, we describe a clear correlation between TPC treatment, healthy gut microbial communities, and prevention of arthritis. This is the first study to demonstrate the immunomodulatory effect of helminth derivatives in autoimmune diseases and the link to gut microbiota.

Successful modulation of murine lupus nephritis with tuftsin-phosphorylcholine.

In areas where helminths infections are common, autoimmune diseases are rare. Treatment with helminths and ova from helminths, improved clinical findings of inflammatory bowel disease, multiple-sclerosis and rheumatoid-arthritis. The immunomodulatory functions of some helminths were attributed to the phosphorylcholine (PC) moiety. We aimed to decipher the tolerogenic potential of Tuftsin-PC (TPC) compound in mice genetically prone to develop lupus. Lupus prone NZBXW/F1 mice received subcutaneously TPC (5 µg/1 ml), 3 times a week starting at 14 weeks age. Autoantibodies were tested by ELISA, T-regulatory-cells by FACS, cytokines profile by RT-PCR and cytokines protein levels by DuoSet ELISA. Glomerulonephritis was addressed by detection of proteinuria, and immunoglobulin complex deposition in the mesangium of the kidneys of the mice by immunofluorescence. Our results show that TPC attenuated the development of glomerulonephritis in lupus prone mice, in particular, it ameliorated proteinuria (p < 0.02), and reduced immunoglobulin deposition in the kidney mesangium. TPC also enhanced the expression of TGFß and IL-10 (p < 0.001), and inhibited the production of IFNγ and IL-17 (p < 0.03). TPC Significantly enhanced the expansion of CD4+CD25+FOXP3+ T-regulatory cells (Tregs) phenotype in the treated mice. These data indicate that TPC hampered lupus development in genetically lupus prone mice which was exemplified by moderate glomerulonephritis, attenuation of pro-inflammatory cytokines and enhancement of anti-inflammatory cytokines expression, as well as Tregs expansion. Our results propose harnessing novel natural therapy for lupus patients.

Unraveling the Hygiene Hypothesis of helminthes and autoimmunity: origins, pathophysiology, and clinical applications.

BACKGROUND: The Hygiene Hypothesis (HH) attributes the dramatic increase in autoimmune and allergic diseases observed in recent decades in Western countries to the reduced exposure to diverse immunoregulatory infectious agents. This theory has since largely been supported by strong epidemiological and experimental evidence. DISCUSSION: The analysis of these data along with the evolution of the Western world's microbiome enable us to obtain greater insight into microorganisms involved in the HH, as well as their regulatory mechanisms on the immune system. Helminthes and their derivatives were shown to have a protective role. Helminthes' broad immunomodulatory properties have already begun to be exploited in clinical trials of autoimmune diseases, including inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, and type-1 diabetes. SUMMARY: In this review, we will dissect the microbial actors thought to be involved in the HH as well as their immunomodulatory mechanisms as emphasized by experimental studies, with a particular attention on parasites. Thereafter, we will review the early clinical trials using helminthes' derivatives focusing on autoimmune diseases.

The mechanisms behind helminth's immunomodulation in autoimmunity.

The incidence of autoimmune diseases has risen throughout the last half a century, mostly in the industrialized world. Helminths and their derivatives were found to have a protective role in autoimmunity and inflammatory conditions, as they manipulate the immune network, attenuating the host's cellular and humoral responses. Indeed, various helminth species used in several human and animal models were shown to limit inflammatory activity in a variety of diseases including inflammatory bowel disease, multiple sclerosis, type 1 diabetes, and rheumatoid arthritis. Our review will focus on the main mechanisms by which helminths and their secreted molecules modulate the host's immune system. The main pathways induce a shift from Th1 to Th2 phenotype, accelerate T regulatory and B regulatory phenotypes, and attenuate the levels of the inflammatory cytokines, leading to a tolerable scenario.

Phosphorylcholine-tuftsin compound prevents development of dextransulfate-sodium-salt induced murine colitis: implications for the treatment of human inflammatory bowel disease.

Improved clinical findings of inflammatory bowel disease (IBD) upon treatment with helminthes and their ova were proven in animal models of IBD and in human clinical studies. The immunomodulatory properties of several helminthes were attributed to the phosphorylcholine (PC) molecule. We assessed the therapeutic potential of tuftsin-PC conjugate (TPC) to attenuate murine colitis. Colitis was induced by Dextransulfate-Sodium-Salt (DSS) in drinking water. TPC was given by daily oral ingestion (50 µg/0.1 ml/mouse or PBS) starting at day -2. Disease activity index (DAI) score was followed daily and histology of the colon was performed by H&E staining. Analysis of the cytokines profile in distal colon lysates was performed by immunoblot. Treatment of DSS induced colitis with TPC prevented the severity of colitis, including a reduction in the DAI score, less shortening of the colon and less inflammatory activity in histology. The immunoblot showed that the colitis preventive activity of TPC was associated with downregulation of colon pro-inflammatory IL-1ß, TNFα and IL-17 cytokines expression, and enhancement of anti-inflammatory IL-10 cytokine expression. In the current study, we demonstrated that TPC treatment can prevent significantly experimental colitis induction in naïve mice. We propose the TPC as a novel potential small synthetic molecule to treat colitis.

Idiotype-specific intravenous immunoglobulin (IVIG) for therapy of autoimmune diseases.

Intravenous immunoglobulin (IVIG) is used successfully for therapy of inflammatory and autoimmune diseases, especially in cases of conventional therapy resistance. Within the broad spectrum of immunomodulatory activities of IVIG in vitro and in vivo, the anti-idiotypic activity, neutralizing the autoimmune disease related idiotypes, is one of the main mechanism. We and others have proven that from the IVIG composition, diverse fractions of autoimmune disease specific IVIG can be affinity purified (sIVIG). This sIVIG was shown to be more efficient than the whole compound of IVIG in experimental animal models of autoimmune diseases.The affinity purification of disease sIVIG encompasses three stages. The first stage is to construct an autoantigen column for affinity purification of the autoantibodies. In the second stage the purified autoantibodies are used to construct a new column composed of the autoantibodies. The later is utilized for affinity purification of anti-autoantibodies (anti- idiotypes) IVIG defined as autoimmune disease specific IVIG- sIVIG.