High levels of cyclic di-GMP in Klebsiella pneumoniae attenuate virulence in the lung

ABSTRACT The bacterial second messenger bis-(3′-5′)-cyclic dimeric GMP (c-di-GMP) has been shown to influence the expression of virulence factors in certain pathogenic bacteria, but little is known about its activity in the increasingly antibiotic-resistant pathogen Klebsiella pneumoniae . Here, the expression in K. pneumoniae of a heterologous diguanylate cyclase increased the bacterial c-di-GMP concentration and attenuated pathogenesis in murine pneumonia. This attenuation remained evident in mice lacking the c-di-GMP sensor STING, indicating that the high c-di-GMP concentration exerted its influence not on host responses but on bacterial physiology. While serum resistance and capsule expression were unaffected by the increased c-di-GMP concentration, both type 3 and type 1 pili were strongly upregulated. Importantly, attenuation of K. pneumoniae virulence by high c-di-GMP levels was abrogated when type 1 pilus expression was silenced. We conclude that increased type 1 piliation may hamper K. pneumoniae virulence in the respiratory tract and that c-di-GMP signaling represents a potential therapeutic target for antibiotic-resistant K. pneumoniae in this niche. </jats:p

Novel associations in disorders of sex development: findings from the I-DSD registry

Context: The focus of care in disorders of sex development (DSD) is often directed to issues related to sex and gender development. In addition, the molecular etiology remains unclear in the majority of cases.&lt;p&gt;&lt;/p&gt; Objective: To report the range of associated conditions identified in the international DSD (I-DSD) Registry.&lt;p&gt;&lt;/p&gt; Design, Setting, and Patients: Anonymized data were extracted from the I-DSD Registry for diagnosis, karyotype, sex of rearing, genetic investigations, and associated anomalies. If necessary, clarification was sought from the reporting clinician.&lt;p&gt;&lt;/p&gt; Results: Of 649 accessible cases, associated conditions occurred in 168 (26%); 103 (61%) cases had one condition, 31 (18%) had two conditions, 20 (12%) had three conditions, and 14 (8%) had four or more conditions. Karyotypes with most frequently reported associations included 45,X with 6 of 8 affected cases (75%), 45,X/46,XY with 19 of 42 cases (45%), 46,XY with 112 of 460 cases (24%), and 46,XX with 27 of 121 cases (22%). In the 112 cases of 46,XY DSD, the commonest conditions included small for gestational age in 26 (23%), cardiac anomalies in 22 (20%), and central nervous system disorders in 22 (20%), whereas in the 27 cases of 46,XX DSD, skeletal and renal anomalies were commonest at 12 (44%) and 8 (30%), respectively. Of 170 cases of suspected androgen insensitivity syndrome, 19 (11%) had reported anomalies and 9 of these had confirmed androgen receptor mutations.&lt;p&gt;&lt;/p&gt; Conclusions: Over a quarter of the cases in the I-DSD Registry have an additional condition. These associations can direct investigators toward novel genetic etiology and also highlight the need for more holistic care of the affected person.&lt;p&gt;&lt;/p&gt

Vertebral defect, anal atresia, cardiac defect, tracheoesophageal fistula/esophageal atresia, renal defect, and limb defect association with Mayer-Rokitansky-Küster-Hauser syndrome in co-occurrence:two case reports and a review of the literature

Background: The vertebral defect, anal atresia, cardiac defect, tracheoesophageal fistula/esophageal atresia, renal defect, and limb defect association and Mayer-Rokitansky-Küster-Hauser syndrome are rare conditions. We aimed to present two cases with the vertebral defect, anal atresia, cardiac defect, tracheoesophageal fistula/esophageal atresia, renal defect, and limb defect association and Mayer-Rokitansky-Küster-Hauser co-occurrence from our local surgical center and through a systematic literature search detect published cases. Furthermore, we aimed to collect existing knowledge in the embryopathogenesis and genetics in order to discuss a possible link between the vertebral defect, anal atresia, cardiac defect, tracheoesophageal fistula/esophageal atresia, renal defect, and limb defect association and Mayer-Rokitansky-Küster-Hauser syndrome. Case presentation: Our first case was a white girl delivered by caesarean section at 37 weeks of gestation; our second case was a white girl born at a gestational age of 40 weeks. A co-occurrence of vertebral defect, anal atresia, cardiac defect, tracheoesophageal fistula/esophageal atresia, renal defect, and limb defect association and Mayer-Rokitansky-Küster-Hauser syndrome was diagnosed in both cases. We performed a systematic literature search in PubMed ((VACTERL) OR (VATER)) AND ((MRKH) OR (Mayer-Rokitansky-Küster-Hauser) OR (mullerian agenesis) OR (mullerian aplasia) OR (MURCS)) without limitations. A similar search was performed in Embase and the Cochrane library. We added two cases from our local center. All cases (n = 9) presented with anal atresia and renal defect. Vertebral defects were present in eight patients. Rectovestibular fistula was confirmed in seven patients. Along with the uterovaginal agenesis, fallopian tube aplasia appeared in five of nine cases and in two cases ovarian involvement also existed. Conclusions: The co-occurrence of the vertebral defect, anal atresia, cardiac defect, tracheoesophageal fistula/esophageal atresia, renal defect, and limb defect association and Mayer-Rokitansky-Küster-Hauser syndrome is extremely rare. This group of patients has unusual phenotypic characteristics. The long-term outcome after treatment of defects is not well reported. A single unifying cause is not known and the etiology probably includes both genetic and non-genetic causes. We stress the importance of future studies to optimized treatment, follow-up, and etiology.</p

Role of imaging in the diagnosis and management of complete androgen insensitivity syndrome in adults

Complete androgen insensitivity syndrome is an X-linked recessive androgen receptor disorder characterized by a female phenotype with an XY karyotype. Individuals affected by this syndrome have normal female external genitalia but agenesis of the Müllerian duct derivatives, that is, absence of the Fallopian tubes, uterus, cervix, and the proximal part of the vagina, with presence of endoabdominal, labial, or inguinal testes. The estimated prevalence is between 1 and 5 in 100,000 genetic males. Complete androgen insensitivity syndrome can be diagnosed as a result of mismatch between the prenatal sex prediction and the phenotype at birth, can be detected by chance, or remain undetected until investigations for primary amenorrhea. Imaging can be important both to diagnose the pathology and to localize gonads prior to surgical treatment. In this paper, we present three cases of complete androgen insensitivity syndrome in adult women of 34, 22, and 38 years old

Clinical aspects of Mayer-Rokitansky-Kuester-Hauser syndrome: recommendations for clinical diagnosis and staging

BACKGROUND: The Mayer-Rokitansky-Kuester-Hauser (MRKH) syndrome is a malformation of the female genitals (occurring in one in 4000 female live births) as a result of interrupted embryonic development of the Müllerian (paramesonephric) ducts. This retrospective study examined the issue of associated malformations, subtyping, and the frequency distribution of subtypes in MRKH syndrome. METHODS: Fifty-three MRKH patients were investigated using a newly developed standardized questionnaire. Together with the results of clinical and diagnostic examinations, the patients were classified into the three recognized subtypes [typical, atypical and MURCS (Müllerian duct aplasia, renal aplasia, and cervicothoracic somite dysplasia)]. RESULTS: The typical form was diagnosed in 25 patients (47%), the atypical form in 11 patients (21%), and the most marked form—the MURCS type—in 17 patients (32%). Associated malformations were notably frequent among the patients. Malformations of the renal system were the most frequent type of accompanying malformation, with 23 different malformations in 19 patients, followed by 18 different skeletal changes in 15 patients. CONCLUSIONS: In accordance with the literature, this study shows that associated malformations are present in more than a third of cases. Therefore, new basic guidelines for standard diagnostic classification involving patients with suspected MRKH are presente

Uterus transplantation:An update and the Middle East perspective

Uterus transplantation (UTx) is the only available treatment for absolute uterine factor infertility (AUFI), which is caused by either absence (congenital or after hysterectomy) or presence of a non-functioning uterus. Uterus transplantation became a clinical reality after more than 10 years of structured animal-based research. Aside from gestational surrogacy, this procedure is the only alternative for women with AUFI to attain genetic motherhood. In the Middle East, North Africa and Turkey (MENAT) region, out of a population of around 470 million, more than 100,000 women of fertile age are estimated to suffer from AUFI. Introduction of UTx as an infertility treatment in this region will certainly differ in specific countries from ethical, religious and legal standpoints depending on culture and religion. The MENAT region is the cradle of three religions and the geographic area encompasses a variety of cultures and religions with different views on assisted reproduction. In light of these issues, the aim of this article is to give an overview of the research-based development of UTx and its clinical results up until today as well as to explore how UTx would fit into current infertility treatments in the MENAT region, with its existing multifaceted religious perspectives

Acute abdomen in a patient with Mayer-Rokitansky-Kuster-Hauser syndrome

Background. Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome is a malformation of female genital tract (incidence 1 in 4000 female newborn children). It appears as a result of a disorder in the development of Millerian cannals. Etiology is unknown. Syndrome MRKH is the most frequent cause of primary amenorrhoea (90%). Patients with MRKH have a normal female phenotype, with normal pubic hairness and thelarche, and female karyotype (46XX) followed by primary amenorrhoea. Hormonal status corresponds to healthy women, where the appearance of ovarian tumors and tumors on rudiment parts of uterus is possible. Case report. We presented a case of acute abdomen in a patient with previously not diagnosed MRKH. The diagnosis was done during the operation. Small pelvis and an abdominal part were filled with torquated tumor lump, where ovaries, oviducts, uterus or something resembling rudiment of uterus were not recognized through careful examination. Furthemore, the patient had a short, dead-end vagina. Tumorectomy was done and hystopathological finding showed the presence of vascular leiomyoma. Conclusion. The diagnosis of complex syndromes, such as MRKH, can, despite modern diagnostics, be absent for non-medical and psycho-social reasons. We can expect ovarian and uterine pathology on hypoplastic structures in these patients, as well as in healthy women. Vascular leiomyoma in the patients with MRKH was not found in the available literature

Prolapse and sexual function 8 years after neovagina according to Shears: a study of 43 cases with Mayer-von Rokitansky-Küster-Hauser syndrome

Introduction and hypothesis: To investigate sexual and anatomical outcome after Shears neovagina in patients with Mayer-von Rokitansky-Kuster-Hauser syndrome (MRKH). Methods: Forty-three consecutive patients with MRKH syndrome underwent surgery creating a neovagina according to Shears. Follow-up was 8years. Sexual function was assessed using the Female Sexual Function Index (FSFI) as patient reported outcome; anatomical results were assessed measuring anterior, posterior and apical prolapse using the ICS Pelvic Organ Prolapse Score (ICS-POP Score). Pelvic floor contraction was measured applying the Oxford grading system. Results: Thirty-seven of the patients were regularly sexually active and filled in the FSFI; mean total FSFI was 27.2 (range 24-28). No significant prolapse of the neovagina was noted, 11 patients had a grade I cystocele, rectocele or apical descent that was asymptomatic. Oxford grading of the pelvic floor contraction was 4 in median (range 2-5). Conclusion: The neovagina according to Shears is a valuable surgical option with good sexual and anatomical outcome 8 years after therap