Protective effect of dipeptidyl peptidase-4 inhibitors in testicular torsion/detorsion in rats: a possible role of HIF-1α and nitric oxide.

Spermatic cord torsion is a serious and common urologic emergency. It requires early diagnosis for prevention of subfertility and testicular necrosis. Vildagliptin and sitagliptin are anti-diabetic drugs of the dipeptidyl peptidase-4 (DPP-4) inhibitors that have a protective role against cerebral ischemic stroke and cardiac ischemia reperfusion. This study aimed to investigate the role and mechanism of action of vildagliptin and sitagliptin in a model of testicular ischemia/reperfusion injury by testicular torsion/detorsion (T/D). Testicular T/D was done and vildagliptin and sitagliptin were administered either alone or in combination with nitric oxide synthase (NOS) inhibitor. Serum total cholesterol and testosterone were measured, while in testicular tissue testosterone, malondialdehyde (MDA) level, total antioxidant capacity (TAC), nitric oxide level, caspase-3, superoxide dismutase (SOD), hypoxia-inducible factor-1α (HIF-1α), tumor necrosis factor-α (TNF-α) and endothelial NOS (eNOS), and inducible NOS (iNOS) and neuronal NOS (nNOS) were measured. Histopathology of testicular tissue was done. Vildagliptin and sitagliptin increased serum testosterone, expression, and activity of SOD and testicular TAC. It also reduced total serum cholesterol, testicular MDA, caspase-3, HIF-1α, TNF-α, and expression of eNOS, iNOS, and nNOS. Vildagliptin and sitagliptin also improved histopathological picture of testicular tissue. NOS inhibitor produced similar result to DDP-4 inhibitors; however, its co-administration augmented the effect of vildagliptin and sitagliptin on these parameters. DPP-4 inhibitors, vildagliptin, and sitagliptin were protective against testicular T/D-induced injury mostly by anti-oxidative stress, and anti-apoptotic and anti-inflammatory actions that was augmented by NOS inhibition with a possible role for HIF-1α expression.

Divertículo de Meckel gigante torsionado. Una presentación inusual / Giant Meckel’s diverticulum torsioned. An unnusual presentation

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A case of ovarian torsion in a patient carrier of a FSH receptor gene mutation previously affected by spontaneous ovarian hyperstimulation syndrome.

We here report a case of ovarian torsion in a patient with an history of two previous episodes of spontaneous ovarian hyperstimulation syndrome during her two pregnancies. A mutation of follicle-stimulating hormone receptor (FSHr) gene was identified in this patient and in other members of the family. Two years after her successful second pregnancy, the patient showed signs of severe thyroiditis during administration of oral contraceptive, with suppressed TSH and increased thyreoglobulin, in the absence of any abnormalities of the auto-antibodies. In few days, she developed severe pelvic pain and ultrasonographic evidence of increased ovarian volume. She underwent laparoscopy with unilateral adnexectomy for ovarian ischemic necrosis due to adnexal torsion. Our experience suggests that patients' carrier of a mutation of FSHr gene are at risk of ovarian pathologies also when non-pregnant and in the presence of low TSH levels. Further investigations are needed for an appropriate knowledge of typical and atypical manifestations of spontaneous ovarian hyperstimulation syndrome.

Arterial tortuosity and aneurysm in a case of Loeys-Dietz syndrome type IB with a mutation p.R537P in the TGFBR2 gene.

We report a 13-year-old girl with Loeys-Dietz syndrome (LDS) caused by a known transforming growth factor beta receptor II (TGFBR2) gene mutation, who developed aortic root dilatation and saccular aneurysm of the internal carotid artery. LDS is a rare, autosomal dominant aortic aneurysm syndrome with multisystem involvement. The disease is typically characterized by the triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula/cleft palate. The characteristic LDS symptoms observed in the reported case included craniofacial dysmorphism (hypertelorism, cleft palate, blue sclerae, malar hypoplasia, retrognathia), skeletal deformities (scoliosis, talipes equinovarus, pectus deformity, arachnodactyly), congenital heart defects (patent ductus arteriosus, PDA), and arterial tortuosity and aneurysms. Molecular genetic testing revealed a heterozygous mutation (c.1610 G>C, p.R528C) in the serine-threonine kinase domain of the TGFBR2 gene. Magnetic resonance (MR) angiography showed aortic dilatation, tortuosity of bilateral supraaortic arteries, and saccular aneurysm on the right cervical internal carotid artery. LDS resembles Marfan-related disorders (Marfan, Shprintzen-Goldberg and vascular Ehlers-Danlos syndrome), but arterial tortuosity and aneurysms are characteristic for LDS, so a timely diagnosis of LDS is important for early diagnosis and intervention of aneurysms to prevent vascular events. Here, we describe a LDS patient who presented with arterial tortuosity and saccular aneurysm.

Cardiomyopathy is common in patients with the mitochondrial DNA m.3243A>G mutation and correlates with mutation load.

Although neuromuscular clinical features often dominate the clinical presentation of mitochondrial disease due to the m.3243A>G mitochondrial DNA (mtDNA) mutation, many patients develop cardiac failure, which is often overlooked until it reaches an advanced stage. We set out to determine whether cardiac complications are sufficiently common to warrant prospective screening in all mutation carriers. Routine clinical echocardiography and 3 Tesla cardiac MRI were performed on ten m.3243A>G mutation carriers and compared to age and gender matched controls, with contemporaneous quadriceps muscle biopsies to measure respiratory chain activity and mtDNA mutation levels. Despite normal echocardiography, all ten m.3243A>G mutation carriers had evidence of abnormal cardiac function on MRI. The degree of cardiac dysfunction correlated with the percentage level of mutant mtDNA in skeletal muscle. Sub-clinical cardiac dysfunction was a universal finding in this study, adding weight to the importance of screening for cardiac complications in patients with m.3243A>G. The early detection of cardiac dysfunction with MRI opens up opportunities to prevent heart failure in these patients through early intervention.

Megacystis, megacolon, and malrotation: a new syndromic association?

Chronic intestinal pseudo-obstruction (CIPO) can occur as a consequence of neuropathies including diffuse Intestinal Neuronal Dysplasia (IND), a relatively rare enteric nervous system (ENS) abnormality. Although various authors reported of diffuse IND associated either with intestinal malrotation or megacystis, the co-existence of these three entities in the same patient has never been described before. The aim of this paper is to report for the first time in literature a series of patient with such association, focusing on one who carries a de novo duplication of chromosome 12, suggesting a new syndromic association (megacolon, megacystis, malrotation).

Increased left ventricular torsion in hypertrophic cardiomyopathy mutation carriers with normal wall thickness.

BACKGROUND: Increased left ventricular (LV) torsion has been observed in patients with manifest familial hypertrophic cardiomyopathy (HCM), and is thought to be caused by subendocardial dysfunction. We hypothesize that increased LV torsion is already present in healthy mutation carriers with normal wall thickness. METHODS: Seventeen carriers with an LV wall thickness <10 mm, and seventeen age and gender matched controls had cardiovascular magnetic resonance (CMR) cine imaging and tissue tagging. LV volumes and mass were calculated from the cine images. LV torsion, torsion rate, endocardial circumferential strain and torsion-to-endocardial-circumferential-shortening (TECS) ratio, which reflects the transmural distribution in contractile function, were determined using tissue tagging. RESULTS: LV volumes, mass and circumferential strain were comparable between groups, whereas LV ejection fraction, torsion and TECS-ratio were increased in carriers compared to controls (63 ± 3% vs. 60 ± 3%, p = 0.04, 10.1 ± 2.5° vs. 7.7 ± 1.2°, p = 0.001, and 0.52 ± 0.14°/% vs. 0.42 ± 0.10°/%, p = 0.02, respectively). CONCLUSIONS: Carriers with normal wall thickness display increased LV torsion and TECS-ratio with respect to controls, which might be due to subendocardial myocardial dysfunction. As similar abnormalities are observed in patients with manifest HCM, the changes in healthy carriers may be target for clinical intervention to delay or prevent the onset of hypertrophy.

[Association of Sp4 gene polymorphism with pathological tortuosity of internal carotid arteries].

Aim of the study was identification of genes and their polymorphisms associated with pathological tortuosity (PT) of internal carotid arteries (ICA) for elucidation of etiological causes of this anomaly taking into consideration its high prevalence and clinical significance. We invited for examination 61 families of children with previously diagnosed PT ICA and used color Doppler duplex scanning of brachiocephalic zone in examination of close relatives of a proband. Samples of venous blood were taken from a family member in whom PT ICA had been detected and the affected child. The group of patients for genotyping comprised 100 individuals with PT ICA. Control group (n=245) was formed from DNA bank on the basis of population approach. The following genetic methods of diagnosis were applied: clinico-genealogical, allele specific polymerase chain reaction, search in available data bases of PT ICA candidate genes and their polymorphisms. According to data of genealogy analysis in most cases inheritance of pathological sign of tortuous ICA was autosomal dominant (37.7%) or autosomal-recessive (39.3%). Association of A80807T polymorphism of the transcriptional factor Sp4 gene with PT ICA was established. Probability of PT ICA in A80807/A80807 homozygotes was 1.64 times higher than in carriers of 2 other genotypes (A80807/T80807 and T80807/T80807).

Chronic isolated fallopian tube torsion.

OBJECTIVE: To describe a case of chronic isolated fallopian tubal torsion in a woman without identifiable risk factors and discuss the difficulty of diagnosis. DESIGN: Case report. SETTING: University-based reproductive endocrinology and infertility center. PATIENT(S): Multiparous woman with no risk factors of torsion of the fallopian tube presenting with chronic right lower quadrant pain. INTERVENTION: Laparoscopy with subsequent salpingectomy. MAIN OUTCOME MEASURE(S): Resolution of symptoms. Preservation of ovary and future fertility. RESULT(S): Patient's symptoms resolved after salpingectomy. Information regarding future fertility is pending. CONCLUSION(S): Isolated fallopian tube torsion is rare and often difficult to diagnose. Despite ultrasonographic evidence of arterial and/or venous flow to the adnexa, adnexal torsion cannot be ruled out. If clinical suspicion for torsion is high, early diagnosis and treatment via laparoscopy is encouraged as a means of preserving fallopian tube integrity and maintaining fertility, especially in reproductive-age women.

A case of carotid aneurysm in familial retinal arterial tortuosity.

A 44-year-old woman who showed recurrent vitreous hemorrhages with vascular tortuosity received CT angiography which revealed an internal carotid artery aneurysm. A case of internal carotid aneurysm was associated with a pattern of retinal arteriolar tortuosity pathognomic for familial retinal arterial tortuosity (fRAT), suggesting possible involvement of the cerebral circulation. We present a case of internal carotid aneurysm associated with a pattern of retinal arteriolar tortuosity pathognomic for fRAT.

Familial wandering spleen: a first instance.

We report on 2 sisters presenting with acute torsion of a wandering spleen within a 3-year interval. The diagnosis was made preoperatively by computed tomography (CT) in both cases. A high index of suspicion because of our experience with the first patient, who underwent splenectomy, enabled a correct early diagnosis in the sibling. On urgent surgery, reversible ischemic changes were found, and detorsion and splenopexy resulted in preservation of the spleen.

Evaluation of lung lobe torsion in Pugs: 7 cases (1991-2004).

OBJECTIVE: To determine whether there is a predis-position for lung lobe torsion (LLT) in Pugs and describe clinical findings associated with LLT in that breed, compared with findings in other breeds. DESIGN: Retrospective case series. ANIMALS: 7 Pugs and 16 dogs of other breeds. PROCEDURE: Information collected from records included signalment, history, lung lobe affected, results of clinicopathologic testing, histologic findings, diagnostic imaging results, surgical treatment, and outcome. RESULTS: 23 dogs were diagnosed with LLT, 10 of which were large-breed dogs and 13 of which were small-breed dogs. Seven of the small-breed dogs were Pugs. Pugs with LLT were significantly overrepresented, compared with the general hospital population. Affected Pugs ranged in age from 4.5 months to 4 years (median, 1.5 years). Six of the 7 Pugs had no predisposing conditions, and 6 were male. Six Pugs survived to discharge. Of the other small- and large-breed dogs, 3 of 6 and 5 of 10 survived to discharge, respectively. None of the Pugs were readmitted for complications or recurrence. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that young male Pugs may be predisposed to developing spontaneous LLT. The prognosis for survival and resolution of clinical signs in Pugs with LLT appeared to be excellent. Factors contributing to the development of LLT in Pugs are not known.

Ovarian torsion: to pex or not to pex? Case report and review of the literature.

STUDY OBJECTIVE: We report the case of a 7-year-old girl who underwent laparoscopic ovariopexy for a suspected ovarian torsion after a previous oophorectomy. We consider the role of elective ovariopexy of the contralateral ovary in the case of adnexal torsion. DESIGN: Case study and review of the literature. RESULT: There was evidence to suggest a very recent adnexal torsion and an unusually long ovarian pedicle, with a possible familial linkage. The patient underwent laparoscopic ovariopexy for the remaining normal ovary, which was found to be loosely twisted at operation. After detorsion, ovariopexy was performed laparoscopically, by suturing the ovary to the back of uterus. There are no other descriptions in the literature of a familial linkage with ovarian torsion. CONCLUSION: The case presented reminds doctors of the strong possibility of ovarian torsion in young girls presenting with pelvic pain. Laparoscopic ovariopexy for the contralateral ovary should be considered in all women with evidence of torsion, including children and adolescents, as is standard for testicular torsion.

A new type of Ehlers-Danlos syndrome associated with tortuous systemic arteries in a large kindred from Qatar.

AIM: To describe the clinical spectrum of anomalies of a new type of Ehlers-Danlos syndrome in 32 patients from a large inter-related extended family in Qatar. METHODS: Among the 32 patients (from 22 families), there were 6 affected pairs of siblings and 2 families with 3 affected siblings. The male to female ratio was 2:1, ages ranging from birth to 18 y (mean 7.4 y). RESULTS: Anomalies included a variable degree of skin hyperextensibility, hypermobility of small and large joints, and tortuous systemic arteries. Peculiar facial features included epicanthic folds, flat saggy cheeks, elongated faces and micrognathia. The combination of an elongated aortic arch and tortuous brachiocephalic arteries was seen in 30 patients (93.8%), aneurysm of the ascending aorta in 3 patients (9.4%), bifid pulmonary artery in 27 patients (84.4%) and multiple severe peripheral stenosis of the right and/or left pulmonary artery in 7 patients (21.9%). A prominent aortic knuckle was observed on the chest roentgenograms of 30 patients (93.8%); inguinal hernia in 11 patients (34%), diaphragmatic hernia and/or hiatus hernia in 7 patients (21.9%); and laryngo-tracheomalacia in 2 patients (6.3%). Generalized muscle hypotonia was found in 15 neonates (46.9%). Parental consanguinity involved in all the patients was traced to a common ancestor from a large Bedouin tribe in Qatar. These patients are at risk for potentially catastrophic arterial rupture. Linkage to the major loci involved in Ehlers-Danlos syndrome and other connective tissue disorders, such as Cutis Laxa, Familial Aneurysm, and Osteogenesis imperfecta, was excluded by using specific DNA markers, confirming the uniqueness of this disorder. CONCLUSION: The study describes a large cohort of patients from the same closely related family, sharing peculiar dysmorphisim and consistent radiological and echocardiographic features different from known types of Ehlers-Danlos syndrome. As known loci involved in Ehlers-Danlos syndrome and other connective tissue disorders were excluded by specific DNA markers, this appears to be a new type of Ehlers-Danlos syndrome or even a new syndrome.

Renal abnormalities in patients with Kallmann syndrome.

OBJECTIVE: To report experience in patients with Kallmann syndrome (KS) in whom urography was used to establish the type and frequency of renal anomalies associated with the disorder. PATIENTS AND METHODS: Of 19 patients with KS, 15 had the X-linked recessive form of the disease, whereas the remaining four were sporadic. Each patient underwent intravenous pyelography (IVP) using a non-ionic, low osmolarity contrast medium. RESULTS: Of the 19 patients with KS, 10 had kidney abnormalities; four presented with unilateral renal agenesis and six had less severe forms of renal abnormality (renal malrotation in four and bilateral dilatation of the calyces and pelves in two). One of the patients with unilateral renal agenesis carried a deletion in KAL, the gene responsible for the X-linked type of KS. Three of the four patients with renal malrotation had a confirmed X-linked recessive form and one carried a point mutation in KAL. CONCLUSION: These results suggest that kidney abnormalities are more frequent and diverse in patients with KS than previously reported. They also indicate that defects in the KAL gene may contribute to abnormal renal development. However, a review of the literature revealed no close correlation between KAL mutations and kidney anomalies in the X-linked type of disease. Taken together, these data suggest that KAL mutations are not invariably associated with failure of renal development and that additional factors (epigenetic or local) may compensate for defects in the KAL protein.