Patients with mutations in NPHS2 (podocin) do not respond to standard steroid treatment of nephrotic syndrome

Nephrotic syndrome (NS) represents the association of proteinuria, hypoalbuminemia, edema, and hyperlipidemia. Steroid-resistant NS (SRNS) is defined by primary resistance to standard steroid therapy. It remains one of the most intractable causes of ESRD in the first two decades of life. Mutations in the NPHS2 gene represent a frequent cause of SRNS, occurring in approximately 20 to 30% of sporadic cases of SRNS. On the basis of a very small number of patients, it was suspected that children with homozygous or compound heterozygous mutations in NPHS2 might exhibit primary steroid resistance and a decreased risk of FSGS recurrence after kidney transplantation. To test this hypothesis, NPHS2 mutational analysis was performed with direct sequencing for 190 patients with SRNS from 165 different families and, as a control sample, 124 patients with steroid-sensitive NS from 120 families. Homozygous or compound heterozygous mutations in NPHS2 were detected for 43 of 165 SRNS families (26%). Conversely, no homozygous or compound heterozygous mutations in NPHS2 were observed for the 120 steroid-sensitive NS families. Recurrence of FSGS in a renal transplant was noted for seven of 20 patients with SRNS (35%) without NPHS2 mutations, whereas it occurred for only two of 24 patients with SRNS (8%) with homozygous or compound heterozygous mutations in NPHS2. None of 29 patients with homozygous or compound heterozygous mutations in NPHS2 who were treated with cyclosporine A or cyclophosphamide demonstrated complete remission of NS. It was concluded that patients with SRNS with homozygous or compound heterozygous mutations in NPHS2 do not respond to standard steroid treatment and have a reduced risk for recurrence of FSGS in a renal transplant. Because these findings might affect the treatment plan for childhood SRNS, it might be advisable to perform mutational analysis of NPHS2, if the patient consents, in parallel with the start of the first course of standard steroid therapy.     

Iridoids as allelochemicals and DNA polymerase inhibitors

Growth inhibitory activities and nutritional indices of catalpol (1), 8-O-acetylharpagide (2), and harpagide (3) were determinated in larvae and adults of Tribolium castaneum, respectively. Compound 1 produced a series of allelochemical effects probably related with the DNA synthesis. This iridoid possessed the highest inhibitory activity against DNA polymerase. Molecular orbital calculations suggest that a pi-pi charge transfer recognition model could explain the action of iridioids toward nucleic acid synthesis.     

Bildgebung bei neuroendokrinen Tumoren

Objective

Comparison of the diagnostic value of imaging modalities in the detection of gastroenteropancreatic neuroendocrine tumors (NET).

Methods

Analysis of the value of ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), and diagnostic strategies according to the current literature.

Results

Depending on the localization of primaries and metastases, a sensitivity of 60% and 90% is described for US and EUS, respectively. Concerning pancreatic lesions and liver metastases, MRI is more sensitive than CT (75–100% vs 72–82%). Concerning lesions of the bowel, these modalities are subject to limitations. In this field somatostatin receptor scintigraphy and endoscopic procedures are superior.

Conclusion

A sufficient diagnostic strategy for NET often requires a combination of various imaging modalities.     

Tissue factor pathway inhibitor-2 (TFPI-2) recognizes the complement and kininogen binding protein gC1qR/p33 (gC1qR): implications for vascular inflammation

Evidence is accumulating to suggest that TFPI-2 is involved in regulating pericellular proteases implicated in a variety of physiologic and pathologic processes including cancer cell invasion, vascular inflammation, and atherosclerosis. Recent immunohistochemical studies of advanced atherosclerotic lesions, demonstrated a similar tissue distribution for TFPI-2, High Molecular Weight Kininogen (HK), and gC1qR/p33 (gC1qR), a ubiquitously expressed, multicompartmental cellular protein involved in modulating complement, coagulation, and kinin cascades. Further studies to evaluate TFPI-2 interactions with gC1qR demonstrated direct interactions between gC1qR and TFPI-2 using immunoprecipitation and solid phase binding studies. Specific and saturable binding between TFPI-2 and gC1qR (estimated Kd: approximately 70 nM) was observed by ELISA and surface plasmon resonance (Biacore) binding assays. Binding was inhibited by antibodies to gC1qR, and was strongly dependent on the Kunitz-2 domain of TFPI-2, as deletion of this domain reduced gC1qR-TFPI-2 interactions by approximately 75%. Deletion of gC1qR amino acids 74-95, involved in C1q binding, had no effect on gC1qR binding to TFPI-2, although antibodies to this region and purified C1q both inhibited binding, most likely via allosteric effects. In contrast, HK did not affect TFPI-2 binding to gC1qR. Binding of TFPI-2 to gC1qR produced statistically significant but modest reductions in TFPI-2 inhibition of plasmin, but had no effect on kallikrein inhibition in fluid phase chromogenic assays. Taken together, these data suggest that gC1qR may participate in tissue remodeling and inflammation by localizing TFPI-2 to the pericellular environment to modulate local protease activity and regulate HK activation.     

Cue-induced activation of the striatum and medial prefrontal cortex is associated with subsequent relapse in abstinent alcoholics

Rationale Animal experiments have provided evidence that the striatum and medial prefrontal cortex play a predominant role in the acquisition and maintenance of drug-seeking behavior.Objectives Alcohol-associated stimuli that were regularly paired with alcohol intake may become conditioned cues and elicit a motivational response that triggers relapse in alcohol-dependent patients.Methods We used functional magnetic resonance imaging and visual alcohol-associated and control cues to assess brain activation in ten abstinent alcoholics and control subjects. Patients were followed for 3 months, and alcohol intake was recorded.Results Alcohol-related versus neutral visual stimuli activated the putamen, anterior cingulate and adjacent medial prefrontal cortex in alcoholics compared with healthy controls. Cue-induced activation of these brain areas was pronounced in the five alcoholics who subsequently relapsed during the observation period. A multiple regression analysis showed that, in alcoholics, the amount of subsequent alcohol intake was associated with the intensity of cue-induced brain activation but not the severity of alcohol craving, amount of previous alcohol intake or duration of abstinence before scanning.Conclusions This pilot study showed that cue-induced activation of the anterior cingulate, medial prefrontal cortex and striatum may play a role in the attribution of incentive salience to alcohol-associated stimuli, thus increasing the motivational value and attentional processing of alcohol cues. Functional brain imaging may help to identify a group of alcoholics with an otherwise undetected high risk of relapse.     

Ureaplasma urealyticum in the development of postpartum endometritis

OBJECTIVE: Investigation of the clinical significance of Ureaplasma urealyticum and its biovars in the development of postpartum endometritis. STUDY DESIGN: Cervical swabs were cultured for U. urealyticum in women presenting endometritis. The positive U. urealyticum cultures (>10(5) cfu/ml) (study group) were compared with those from women without endometritis (control group). Anti-Ureaplasma antibodies were measured and U. urealyticum biovars were determined by polymerase chain reaction. RESULTS: There was no difference between the prevalence of U. urealyticum in the cervical swabs of both groups, however, the number of cfu per culture, showed a significant difference between study and control groups. Out of the culture positive endometritis patients 39% (26/67) had >10(5) cfu/ml compared to 17% of control patients (5/30) P=0.03. No significant disparity between both the groups was found in the prevalence of the parvo biovar (77% versus 71.5%, respectively). The difference in anti-Ureaplasma antibodies reached no statistical significance (30% versus 18% in study and control groups, respectively). CONCLUSIONS: The significant difference in U. urealyticum culture cfu between both groups suggests that U. urealyticum may play a role in the etiology of this infection. This involvement is dependent not only on the presence or absence of U. urealyticum in the culture, but on its colonization rate in the cervix (>10(5) cfu/ml).     

AlphaV- and beta1-integrin subunits are commonly expressed in malignant effusions from ovarian carcinoma patients

OBJECTIVE: The objective was to study expression of alphav- and beta1-integrin subunits in effusions, primary tumors, and solid metastases of ovarian carcinoma patients, as well as to evaluate its potential association with previously studied metastasis-associated molecules and clinicopathologic parameters. METHODS: Sections from 121 malignant effusions and 30 corresponding primary and metastatic lesions were evaluated for protein expression of the alphav- and beta1-integrin subunits using immunohistochemistry (IHC). A subset of effusions was additionally studied using immunoblotting (IB) and flow cytometry (FCM). mRNA in situ hybridization (ISH) was performed in 58 effusions and 30 biopsies. RESULTS: Protein expression of alphav- and beta1-integrin subunits was detected in carcinoma cells in 116/121 (96%) and 113/121 (93%) effusions, respectively. alphav protein expression was limited to carcinoma cells. IB and FCM confirmed IHC results. mRNA for alphav- and beta1-integrin subunits was detected in carcinoma cells in 37/58 (64%) and 33/58 (57%) effusions, respectively. Both protein and mRNA expression were higher in peritoneal effusions, significantly for alphav mRNA (P = 0.042) and beta1 protein (P = 0.023). beta1 protein expression in effusions was more frequently detected in better-differentiated tumors (P = 0.006). alphav-integrin subunit expression correlated with that of the previously studied matrix metalloproteinase-9 (MMP-9) (P = 0.006) and the MMP inducer EMMPRIN (P = 0.001). Expression of beta1-integrin subunit showed an association with that of EMMPRIN (P = 0.029), basic fibroblast growth factor (P < 0.001), and the MMP inhibitor TIMP-2 (P = 0.025). In carcinoma cells of solid lesions, alphav protein was uniformly present, while beta1 expression was limited to 15/30 (50%) specimens. As in effusions, protein expression of alphav subunit was cancer-specific, while beta1 protein was detected also in stromal fibroblasts and endothelial cells. CONCLUSIONS: The alphav- and beta1-integrin subunits are frequently expressed in ovarian carcinoma cells in effusions, and the alphav-integrin subunit is a powerful diagnostic marker for carcinoma cells. The reduced expression of the beta1-integrin subunit in solid lesions may be attributed to the role of other subunits at these stages, such as the beta3 subunit as part of the alphavbeta3-vitronectin receptor. The high expression of integrin subunits with a role of binding mesothelium, invasion, and angiogenesis in carcinoma cells in both peritoneal and pleural effusions suggests that cells at both sites have metastatic potential.     

Effective temporomandibular joint growth and chin position changes: Activator versus Herbst treatment. A cephalometric roentgenographic study

In 138 successfully treated Class II division 1 patients (40 Activator and 98 Herbst) effective temporomandibular joint (TMJ) growth changes (a summation of condylar remodelling, glenoid fossa remodelling, and condylar position changes within the fossa), and their influence on the position of the chin and the rotation of the mandible were analysed retrospectively. Lateral head films in habitual occlusion from before and after an average treatment period of 2.6 years for the Activator patients and 0.6 years for the Herbst patients were evaluated. Two different treatment changes were assessed: (1) overall growth changes and (2) treatment effects (overall growth changes minus age-related normal growth values: Bolton Standards). The comparison between the Activator and the Herbst group revealed larger effective TMJ and chin changes during Activator therapy due to the longer observation period (2.6 years versus 0.6 years). The treatment effects showed marked group differences for both the amount and direction of effective TMJ changes. The changes were vertical and slightly anterior in the Activator group, and predominantly posterior in the Herbst group. Concerning the chin changes, the treatment effects for the Herbst group exceeded those for the Activator group in both directions, caudally and anteriorly. The Activator group showed an anterior rotation and the Herbst group a slight posterior rotation of the mandible. The present investigation revealed that the effective TMJ and chin changes were increased by both Activator and Herbst treatment. However, the Herbst appliance renders more favourable sagittally orientated treatment effects in a much shorter period of time compared with the Activator.