Microbial ecosystem assessment and hydrogen oxidation potential of newly discovered vent systems from the Central and South-East Indian Ridge.

In order to expand the knowledge of microbial ecosystems from deep-sea hydrothermal vent systems located on the Central and South-East Indian Ridge, we sampled hydrothermal fluids, massive sulfides, ambient water and sediments of six distinct vent fields. Most of these vent sites were only recently discovered in the course of the German exploration program for massive sulfide deposits and no previous studies of the respective microbial communities exist. Apart from typically vent-associated chemosynthetic members of the orders Campylobacterales, Mariprofundales, and Thiomicrospirales, high numbers of uncultured and unspecified Bacteria were identified via 16S rRNA gene analyses in hydrothermal fluid and massive sulfide samples. The sampled sediments however, were characterized by an overall lack of chemosynthetic Bacteria and the presence of high proportions of low abundant bacterial groups. The archaeal communities were generally less diverse and mostly dominated by members of Nitrosopumilales and Woesearchaeales, partly exhibiting high proportions of unassigned Archaea. Correlations with environmental parameters were primarily observed for sediment communities and for microbial species (associated with the nitrogen cycle) in samples from a recently identified vent field, which was geochemically distinct from all other sampled sites. Enrichment cultures of diffuse fluids demonstrated a great potential for hydrogen oxidation coupled to the reduction of various electron-acceptors with high abundances of Hydrogenovibrio and Sulfurimonas species. Overall, given the large number of currently uncultured and unspecified microorganisms identified in the vent communities, their respective metabolic traits, ecosystem functions and mediated biogeochemical processes have still to be resolved for estimating consequences of potential environmental disturbances by future mining activities.

A novel GPI-anchored dominant-negative TGF-ß receptor II renders T cells unresponsive to TGF-ß signaling.

Transforming growth factor ß (TGF-ß) is a pleiotropic cytokine expressed by a wide range of cell types and is known for hampering the effectiveness of cancer immune cell therapeutic approaches. We have designed a novel construct containing the extracellular domain of the TGF-ß receptor II linked to a glycosylphosphatidylinositol (GPI) anchor (GPI-ecto-TßRII) lacking the transmembrane and cytoplasmic signaling domain of TGF-ß receptor II (TßRII). T cells transduced with lentivirus expressing the GPI-ecto-TßRII construct show 5 to 15 times higher membrane expression compared with a previously established dominant-negative receptor carrying a truncated signaling domain. GPI-ecto-TßRII expression renders T cells unresponsive to TGF-ß-induced signaling seen by a lack of SMAD phosphorylation upon exogeneous TGF-ß treatment. Transduced T cells continue to express high levels of IFNγ and granulocyte-macrophage colony-stimulating factor (GM-CSF), among other cytokines, in the presence of TGF-ß while cytokine expression in untransduced T cells is being markedly suppressed. Furthermore, T cells expressing GPI-ecto-TßRII constructs have been shown to efficiently capture and inactivate TGF-ß from their environment. These results indicate the potential benefits of GPI-ecto-TßRII expressing cytotoxic T cells (CTLs) in future cell therapies.

Prevalence of Fecal Incontinence in Normal Pressure Hydrocephalus: A Prospective Evaluation of 100 Patients.

BACKGROUND: Normal pressure hydrocephalus (NPH) is a frequent disease in elderly patients. The main symptoms are gait disturbance, urine incontinence, and cognitive decline. Fecal urgency and incontinence are described as rare additional symptoms; however, no exact numbers are known. The aim of this study was to investigate the prevalence of fecal disturbances in NPH patients. METHODS: Patients who presented to our department with confirmed diagnosis of NPH between January and December 2021 were interviewed prospectively about fecal function. Additionally, the extent of gait disturbance, cognitive decline, ventriculomegaly (EvansIndex), disproportionate enlarged subarachnoid space hydrocephalus (DESH presence), age, gender, and length of history were documented. In those who were operated with a hydrocephalus shunt postoperative development of stool incontinence was followed up. RESULTS: One hundred patients were evaluated (67 males, 33 females, medium age 77.5 years, medium Evans Index: 0.37; 87 with disproportionate enlarged subarachnoid space hydrocephalus). 97 patients showed gait disturbance, 84 cognitive decline, and 87 bladder dysfunctions. 78 patients had the complete Hakim triad. 32 patients complained about fecal incontinence (20 with urge incontinence, 12 with complete incontinence). Twenty nine patients were shunted, of which 17 (57%) recovered completely, 9 (31%) partially, and 3 (10%) did not show any change. CONCLUSIONS: Fecal urgency and incontinence is a frequent finding in NPH (32%) and is essential for the quality of life. In the general population, fecal incontinence in elderly is found in up to 15%. The more than two-fold higher prevalence in NPH patients and the high percentage of postshunted improvement suggests that NPH causes often directly fecal disturbance.

Taxonomic diversity of microbial communities in sub-seafloor hydrothermal sediments of the active Santorini-Kolumbo volcanic field.

Introduction: Active hydrothermal vents of volcanic origin provide a remarkable manifestation of life on Earth under extreme conditions, which may have consequences for our understanding of habitability on other terrestrial bodies as well. Methods: Here, we performed for the first time Illumina sequencing of bacterial and archaeal communities on sub-seafloor samples collected from the Santorini-Kolumbo volcanic field. A total of 19 (3-m long) gravity corers were collected and processed for microbial community analysis. Results: From a total of 6,46,671 produced V4 sequences for all samples, a total of 10,496 different Operational Taxonomic Units (OTUs) were identified that were assigned to 40 bacterial and 9 archaeal phyla and 14 candidate divisions. On average, the most abundant phyla in all samples were Chloroflexi (Chloroflexota) (24.62%), followed by Proteobacteria (Pseudomonadota) (11.29%), Firmicutes (Bacillota) (10.73%), Crenarchaeota (Thermoproteota) (8.55%), and Acidobacteria (Acidobacteriota) (8.07%). At the genus level, a total of 286 known genera and candidate genera were mostly dominated by members of Bacillus, Thermoflexus, Desulfatiglans, Pseudoalteromonas, and Pseudomonas. Discussion: In most of the stations, the Chao1 values at the deeper layers were comparable to the surface sediment samples denoting the high diversity in the subsurface of these ecosystems. Heatmap analysis based on the 100 most abundant OTUs, grouped the sampling stations according to their geographical location, placing together the two hottest stations (up to 99°C). This result indicates that this specific area within the active Kolumbo crater create a distinct niche, where microorganisms with adaptation strategies to withstand heat stresses can thrive, such as the endospore-forming Firmicutes.

Decision curve analysis confirms higher clinical utility of multi-domain versus single-domain prediction models in patients with open abdomen treatment for peritonitis.

BACKGROUND: Prediction modelling increasingly becomes an important risk assessment tool in perioperative systems approaches, e.g. in complex patients with open abdomen treatment for peritonitis. In this population, combining predictors from multiple medical domains (i.e. demographical, physiological and surgical variables) outperforms the prediction capabilities of single-domain prediction models. However, the benefit of these prediction models for clinical decision-making remains to be investigated. We therefore examined the clinical utility of mortality prediction models in patients suffering from peritonitis with a decision curve analysis. METHODS: In this secondary analysis of a large dataset, a traditional logistic regression approach, three machine learning methods and a stacked ensemble were employed to examine the predictive capability of demographic, physiological and surgical variables in predicting mortality under open abdomen treatment for peritonitis. Calibration was examined with calibration belts and predictive performance was assessed with the area both under the receiver operating characteristic curve (AUROC) and under the precision recall curve (AUPRC) and with the Brier Score. Clinical utility of the prediction models was examined by means of a decision curve analysis (DCA) within a treatment threshold range of interest of 0-30%, where threshold probabilities are traditionally defined as the minimum probability of disease at which further intervention would be warranted. RESULTS: Machine learning methods supported available evidence of a higher prediction performance of a multi- versus single-domain prediction models. Interestingly, their prediction performance was similar to a logistic regression model. The DCA demonstrated that the overall net benefit is largest for a multi-domain prediction model and that this benefit is larger compared to the default "treat all" strategy only for treatment threshold probabilities above about 10%. Importantly, the net benefit for low threshold probabilities is dominated by physiological predictors: surgical and demographics predictors provide only secondary decision-analytic benefit. CONCLUSIONS: DCA provides a valuable tool to compare single-domain and multi-domain prediction models and demonstrates overall higher decision-analytic value of the latter. Importantly, DCA provides a means to clinically differentiate the risks associated with each of these domains in more depth than with traditional performance metrics and highlighted the importance of physiological predictors for conservative intervention strategies for low treatment thresholds. Further, machine learning methods did not add significant benefit either in prediction performance or decision-analytic utility compared to logistic regression in these data.

Pit picking vs. Limberg flap vs. primary open method to treat pilonidal sinus disease - A cohort of 327 consecutive patients.

Background: Minimally invasive methods in pilonidal sinus disease (PSD) surgery are becoming standard. Although long-term results are available for some techniques, long-term outcome data of patients after pit picking is lacking. We aimed at investigating perioperative and long-term outcomes of patients undergoing pit picking, Limberg flap or primary open surgery to treat PSD. Methods: In a single-centre observational study, we evaluated the outcomes of 327 consecutive patients undergoing PSD surgery between 2011 and 2020. Results: PSD had recurred in 22% of Limberg flap patients and 62% of pit picking patients at 5 years (p=0.0078; log rank test). Previous pilonidal surgeries, smoking, body mass index, immunodeficiency, and diabetes did not significantly influence the long-term recurrence rate. Primary open treatment was performed for 72% of female patients presenting with primary disease. Conclusions: Due to its especially dismal long-term results, pit picking should be abandoned, and Limberg flap should be promoted instead, even for primary disease and in females.

Outcome in patients with open abdomen treatment for peritonitis: a multidomain approach outperforms single domain predictions.

Numerous patient-related clinical parameters and treatment-specific variables have been identified as causing or contributing to the severity of peritonitis. We postulated that a combination of clinical and surgical markers and scoring systems would outperform each of these predictors in isolation. To investigate this hypothesis, we developed a multivariable model to examine whether survival outcome can reliably be predicted in peritonitis patients treated with open abdomen. This single-center retrospective analysis used univariable and multivariable logistic regression modeling in combination with repeated random sub-sampling validation to examine the predictive capabilities of domain-specific predictors (i.e., demography, physiology, surgery). We analyzed data of 1,351 consecutive adult patients (55.7% male) who underwent open abdominal surgery in the study period (January 1998 to December 2018). Core variables included demographics, clinical scores, surgical indices and indicators of organ dysfunction, peritonitis index, incision type, fascia closure, wound healing, and fascial dehiscence. Postoperative complications were also added when available. A multidomain peritonitis prediction model (MPPM) was constructed to bridge the mortality predictions from individual domains (demographic, physiological and surgical). The MPPM is based on data of n = 597 patients, features high predictive capabilities (area under the receiver operating curve: 0.87 (0.85 to 0.90, 95% CI)) and is well calibrated. The surgical predictor "skin closure" was found to be the most important predictor of survival in our cohort, closely followed by the two physiological predictors SAPS-II and MPI. Marginal effects plots highlight the effect of individual outcomes on the prediction of survival outcome in patients undergoing staged laparotomies for treatment of peritonitis. Although most single indices exhibited moderate performance, we observed that the predictive performance was markedly increased when an integrative prediction model was applied. Our proposed MPPM integrative prediction model may outperform the predictive power of current models.

Rethinking the causes of pilonidal sinus disease: a matched cohort study.

Our understanding of pilonidal sinus disease (PSD) is based on a paper published 29 years ago by Karydakis. Since then, surgeons have been taught that hair more easily penetrates wet skin, leading to the assumption that sweating promotes PSD. This postulate, however, has never been proven. Thus we used pilocarpine iontophoresis to assess sweating in the glabella sacralis. 100 patients treated for PSD and 100 controls were matched for sex, age and body mass index (BMI). Pilocarpine iontophoresis was performed for 5 min, followed by 15 min of sweat collection. PSD patients sweated less than their matched pairs (18.4 ± 1.6 µl vs. 24.2 ± 2.1 µl, p = 0.03). Men sweated more than women (22.2 ± 1.2 µl vs. 15.0 ± 1.0 µl in non-PSD patients (p < 0.0001) and 20.0 ± 1.9 µl vs. 11.9 ± 2.0 µl in PSD patients (p = 0.051)). And regular exercisers sweated more than non-exercisers (29.1 ± 2.9 µl vs. 18.5 ± 1.6 µl, p = 0.0006 for men and 20.7 ± 2.3 µl vs. 11.4 ± 1.4 µl, p = 0.0005 for women). PSD patients sweat less than matched controls. Thus sweating may have a protective effect in PSD rather than being a risk factor.

[Wound Healing Disorders after Excision and Open Treatment for Pilonidal Sinus]. / Wundheilungsstörungen nach Exzision und offener Behandlung eines Sinus pilonidalis.

INTRODUCTION: Pilonidalis sinus disease is a mostly chronic selective infection of the hairy skin in the area of skin wrinkles, mainly in the area of the natal cleft. Open treatment is still the most common recommended therapy. Nevertheless, there may be healing disorders within the framework of open wound treatment, which can significantly complicate the course. METHODS: The following is an overview of wound healing disorders after excision of pilonidalis sinus. Healing time and frequency are determined on the basis of current data and the causes of the healing disorder are evaluated. In addition, possible treatment options are presented and treatment recommendations are made. RESULTS: The evaluation of published data on wound healing period showed that the wound usually heals after a mean of two months. The results of the German forces cohort study show by way of example that almost all wounds have healed in the period up to three months. However, a small percentage of non-healing wounds remain. The frequency of significantly delayed wound healing is given in the literature as 2 - 5%. The influencing factors for wound healing after sinus pilonidalis excision are not only the size and symmetry of the excision wound but also other details of open wound treatment. In addition to intensification of the previous open wound treatment, the new excision and refreshment of the wound are mentioned as treatment options in the event of a lack of wound healing. Furthermore, changes in strategy for plastic-reconstructive procedures or other surface treatment are also recommended. CONCLUSION: The excision wound of pilonidalis sinus should be healed after three to four months at the latest, after which the wound can be regarded as a wound with significantly delayed healing or as a wound healing disorder. Around this time, the findings should be re-evaluated and, if necessary, a change in the treatment concept should be made.

Transverse vs. median laparotomy in peritonitis and staged lavage: a single center case series.

Background: Staged lavage was first introduced in the 1970s and now serves as a therapeutic option for septic patients with peritonitis. A central aspect of this treatment concept is leaving the abdomen open after a wide incision. To evaluate the influence of transverse vs. median access to the abdomen in staged lavage, data from the authors' patients were analyzed. Methods: To evaluate patients with peritonitis, prospective intensive care data were examined together with data on the surgical details. The main aspects covered here were the surgical details of the lavage (namely, transverse vs. median laparotomy), number of lavages, fascia closure, wound-healing disorders, and observed lethality, in combination with the preoperatively evaluated SAPS-II score, expected hospital lethality, patient age, and the Mannheim Peritonitis Index. Results: Between January 2008 and December 2018, 522 patients were treated with open abdomen and staged lavage. The mean age of the patients was 66.0 years (standard deviation (SD) 15.9 years). A median incision was used in 140 cases, and transverse laparotomy was performed in 382. The mean SAPS-II score was 46.5 (SD 15.7), expected lethality was 39.6% (SD 26.3%), and observed lethality was 19.9%. On average, two lavages were performed after the index operation. Transverse incision was significantly less likely to cause wound-healing disorder (p=0.03), and fascial dehiscence was observed less frequently in the transverse laparotomies group than in median incisions in the statistical trend (p=0.06). Conclusion: In summary, staged lavage reduced expected lethality in patients with peritonitis. Transverse incision caused wound-healing disorders and fascial dehiscence less often. Therefore, the indication for transverse laparotomy should be generous, as this form of treatment is advantageous in case of peritonitis.

BZD9L1 sirtuin inhibitor as a potential adjuvant for sensitization of colorectal cancer cells to 5-fluorouracil.

BACKGROUND: This study aims to investigate the combination effect of a novel sirtuin inhibitor (BZD9L1) with 5-fluorouracil (5-FU) and to determine its molecular mechanism of action in colorectal cancer (CRC). METHODS: BZD9L1 and 5-FU either as single treatment or in combination were tested against CRC cells to evaluate synergism in cytotoxicity, senescence and formation of micronucleus, cell cycle and apoptosis, as well as the regulation of related molecular players. The effects of combined treatments at different doses on stress and apoptosis, migration, invasion and cell death mechanism were evaluated through two-dimensional and three-dimensional cultures. In vivo studies include investigation on the combination effects of BZD9L1 and 5-FU on colorectal tumour xenograft growth and an evaluation of tumour proliferation and apoptosis using immunohistochemistry. RESULTS: Combination treatments exerted synergistic reduction on cell viability on HCT 116 cells but not on HT-29 cells. Combined treatments reduced survival, induced cell cycle arrest, apoptosis, senescence and micronucleation in HCT 116 cells through modulation of multiple responsible molecular players and apoptosis pathways, with no effect in epithelial mesenchymal transition (EMT). Combination treatments regulated SIRT1 and SIRT2 protein expression levels differently and changed SIRT2 protein localization. Combined treatment reduced growth, migration, invasion and viability of HCT 116 spheroids through apoptosis, when compared with the single treatment. In addition, combined treatment was found to reduce tumour growth in vivo through reduction of tumour proliferation and necrosis compared with the vehicle control group. This highlights the potential therapeutic effects of BZD9L1 and 5-FU towards CRC. CONCLUSION: This study may pave the way for use of BZD9L1 as an adjuvant to 5-FU in improving the therapeutic efficacy for the treatment of colorectal cancer.

Detachment tectonics at Mid-Atlantic Ridge 26°N.

Spreading processes associated with slow-spreading ridges are a complex interplay of volcanic accretion and tectonic dismemberment of the oceanic crust, resulting in an irregular seafloor morphology made up of blocks created by episodes of intense volcanic activity or tectonic deformation. These blocks undergo highly variable evolution, such as tilts or dissection by renewed tectonic extension, depending on their positions with respect to the spreading axis, core complexes, detachment or transform faults. Here, we use near-seafloor magnetic and bathymetric data and seismic profiles collected over the TAG Segment of the Mid-Atlantic Ridge to constrain the tectonic evolution of these blocks. Our study reveals that the presence and evolution of oceanic core complexes play a key role in triggering block movements. The deep subvertical detachment fault roots on the plate boundary, marked by a thermal anomaly and transient magma bodies. Thermal and magmatic variations control the structure and morphology of the seafloor above the subhorizontal detachment surface, occasionally leading to relocating the detachment.

[Pilonidal Sinus Disease; What is the Best Treatment Option?] / Sinus pilonidalis ­ was ist die beste chirurgische Therapie?

INTRODUCTION: Sinus pilonidalis is a chronic infection of the hairy skin in the area of skin wrinkles, with the most common localization in the natal cleft. The disease often has a significant impact on the quality of life of the affected person; the treatment may be complex and needs to be adapted to the patient's needs. METHODS: Below is an overview of the origin as well as the treatment alternatives and their peculiarities. The following aspects are presented: early post-operative results, wound healing disorder and long-term results. RESULTS: The pathomechanism of pilonidal sinus disease has still not been conclusively clarified; it must continue to be assumed that the hair in the natal cleft contributes significantly to the formation. However, recent findings indicate that the large tufts of hair that are repeatedly found in the wound cavity are most likely to come from the hairy scalp. Three essential treatment options can be distinguished: The standard treatment of excision and subsequent open wound treatment, has a low recurrence rate, but requires considerable effort in wound treatment and thus leads to protracted time off work. Relatively new treatments include locally destructive treatment that essentially preserves the skin. Important representatives are so-called pit picking, fistuloscopy and other forms of treatment, such as phenol injection and/or laser treatment. In these treatment options, the final evaluation of the results is still pending. The third treatment group is excision and plastic reconstruction. These procedures are technically demanding, often involve inpatient treatment but lead to relatively good results in the long term. CONCLUSION: Treatment of pilonidal disease requires patient-oriented therapy planning. The patient must be taught the different treatment options and a treatment recommendation must be given to the patient. Excision and open granulation continues to serve as a standard procedure with which other treatment options can be compared.

Microbial metal-sulfide oxidation in inactive hydrothermal vent chimneys suggested by metagenomic and metaproteomic analyses.

Metal-sulfides are wide-spread in marine benthic habitats. At deep-sea hydrothermal vents, they occur as massive sulfide chimneys formed by mineral precipitation upon mixing of reduced vent fluids with cold oxygenated sea water. Although microorganisms inhabiting actively venting chimneys and utilizing compounds supplied by the venting fluids are well studied, only little is known about microorganisms inhabiting inactive chimneys. In this study, we combined 16S rRNA gene-based community profiling of sulfide chimneys from the Manus Basin (SW Pacific) with radiometric dating, metagenome (n = 4) and metaproteome (n = 1) analyses. Our results shed light on potential lifestyles of yet poorly characterized bacterial clades colonizing inactive chimneys. These include sulfate-reducing Nitrospirae and sulfide-oxidizing Gammaproteobacteria dominating most of the inactive chimney communities. Our phylogenetic analysis attributed the gammaproteobacterial clades to the recently described Woeseiaceae family and the SSr-clade found in marine sediments around the world. Metaproteomic data identified these Gammaproteobacteria as autotrophic sulfide-oxidizers potentially facilitating metal-sulfide dissolution via extracellular electron transfer. Considering the wide distribution of these gammaproteobacterial clades in marine environments such as hydrothermal vents and sediments, microbially accelerated neutrophilic mineral oxidation might be a globally relevant process in benthic element cycling and a considerable energy source for carbon fixation in marine benthic habitats.

Angiogenesis: Managing the Culprits behind Tumorigenesis and Metastasis.

Deregulated angiogenesis has been identified as a key contributor in a number of pathological conditions including cancer. It is a complex process, which involves highly regulated interaction of multiple signalling molecules. The pro-angiogenic signalling molecule, vascular endothelial growth factor (VEGF) and its cognate receptor 2 (VEGFR-2), which is often highly expressed in majority of human cancers, plays a central role in tumour angiogenesis. Owing to the importance of tumour vasculature in carcinogenesis, tumour blood vessels have emerged as an excellent therapeutic target. The anti-angiogenic therapies have been shown to arrest growth of solid tumours through multiple mechanisms, halting the expansion of tumour vasculature and transient normalization of tumour vasculature which help in the improvement of blood flow resulting in more uniform delivery of cytotoxic agents to the core of tumour mass. This also helps in reduction of hypoxia and interstitial pressure leading to reduced chemotherapy resistance and more uniform delivery of cytotoxic agents at the targeted site. Thus, complimentary combination of different agents that target multiple molecules in the angiogenic cascade may optimize inhibition of angiogenesis and improve clinical benefit in the cancer patients. This review provides an update on the current trend in exploitation of angiogenesis pathways as a strategy in the treatment of cancer.

Anticancer activities of a benzimidazole compound through sirtuin inhibition in colorectal cancer.

AIM: This study aims to investigate the mode of action of a novel sirtuin inhibitor (BZD9L1) and its associated molecular pathways in colorectal cancer (CRC) cells. MATERIALS & METHODS: BZD9L1 was tested against metastatic CRC cell lines to evaluate cytotoxicity, cell cycle and apoptosis, senescence, apoptosis related genes and protein expressions, as well as effect against major cancer signaling pathways. RESULTS & CONCLUSION: BZD9L1 reduced the viability, cell migration and colony forming ability of both HCT 116 and HT-29 metastatic CRC cell lines through apoptosis. BZD9L1 regulated major cancer pathways differently in CRC with different mutation profiles. BZD9L1 exhibited anticancer activities as a cytotoxic drug in CRC and as a promising therapeutic strategy in CRC treatment.

Surgical Treatment for Extramammary Paget's Disease.

OPINION STATEMENT: Extramammary Paget's disease (EMPD) is a rare, slow growing non-melanoma skin cancer.Diagnosis is often significantly delayed, since clinical presentation may resemble common benign dermatoses. Treatment is characterized by high recurrence rates. This is in part due to ill-defined margins and by frequent development of satellites. Improvement of outcome needs a better preoperative planning with fluorescence diagnostics or scouting biopsies. Mohs micrographic surgery has some advantages for patients, such as reduced relapse rates and prolonged relapse-free survival. Improved identification of Paget cells in cryosections by immunostainings or alternatively the use of delayed Mohs with formalin-fixed material reduces the rate of false-negative results. Surgery remains the cornerstone of treatment.

H1N1 vaccination in Sjögren's syndrome triggers polyclonal B cell activation and promotes autoantibody production.

OBJECTIVES: Vaccination of patients with rheumatic disease has been reported to result in lower antibody titres than in healthy individuals. However, studies primarily include patients on immunosuppressive therapy. Here, we investigated the immune response of treatment-naïve patients diagnosed with primary Sjögren's syndrome (pSS) to an H1N1 influenza vaccine. METHODS: Patients with Sjögren's syndrome without immunomodulatory treatment and age-matched and gender-matched healthy controls were immunised with an H1N1 influenza vaccine and monitored for serological and cellular immune responses. Clinical symptoms were monitored with a standardised form. IgG class switch and plasma cell differentiation were induced in vitro in purified naïve B cells of untreated and hydroxychloroquine-treated patients and healthy controls. Gene expression was assessed by NanoString technology. RESULTS: Surprisingly, treatment-naïve patients with Sjögren's syndrome developed higher H1N1 IgG titres of greater avidity than healthy controls on vaccination. Notably, off-target B cells were also triggered resulting in increased anti-EBV and autoantibody titres. Endosomal toll-like receptor activation of naïve B cells in vitro revealed a greater propensity of patient-derived cells to differentiate into plasmablasts and higher production of class switched IgG. The amplified plasma cell differentiation and class switch could be induced in cells from healthy donors by preincubation with type 1 interferon, but was abolished in hydroxychloroquine-treated patients and after in vitro exposure of naïve B cells to chloroquine. CONCLUSIONS: This comprehensive analysis of the immune response in autoimmune patients to exogenous stimulation identifies a mechanistic basis for the B cell hyperactivity in Sjögren's syndrome, and suggests that caution is warranted when considering vaccination in non-treated autoimmune patients.

Stubborn rectal prolapse in systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune connective tissue disorder. Anorectal involvement might typically cause fecal incontinence and rarely rectal prolapse. Here we report three female patients, who were admitted with a mean history of 10 years suffering from SSc. All patients presented with the initial symptom of anal incontinence, in all cases this was associated with rectal intussusception or rectal prolapse. The three women faced prolapse recurrence, independent of the initial procedure. After surgical removal of the prolapse, the incontinence remained. In SSc rectal prolapse syndrome might occur at an earlier age, and a primary prolapse of the ventral aspect of the rectal wall seems to be typical for this disease. If patients with prior diagnosis of SSc appear with third degree of fecal incontinence, it is suspected to be associated with rectal prolapse. The prolapse recurrence rate after surgery in SSc patients is high.