Congenital heart block related to maternal autoantibodies: descriptive analysis of a series of 18 cases from a single center

The objective of this study was to describe the clinical and immunological characteristics of maternal autoimmune-mediated fetal congenital heart block (CHB) in a cohort of pregnant women from an autoimmune disease pregnancy clinic. This is a retrospective observational study of all women presenting with CHB in our autoimmune disease pregnancy clinic from January 1997 to December 2014. In addition, perinatal outcome is also described. Fourteen patients accounting for 18 fetuses with CHB were identified. The median age was 32.5 years (range, 22–40). Seven (50 %) patients had Sjögren’s syndrome, and the remaining seven were asymptomatic carriers of autoantibodies. All patients had anti-Ro/SSA antibodies, and 11/13 (85 %) had anti-La/SSB antibodies. The median gestational age at the time of CHB was 22 weeks (range 18–28). Complete third degree CHB was detected in 12 (67 %). Seven cases of CHB were treated with dexamethasone, two with ritodrine, and one with the association of dexamethasone, ritodrine, and terbutaline. In 9 (50 %) cases that presented with, or developed, very poor prognosis factors, such as a ventricular rate below 50–55 bpm and/or the presence of fetal hydrops, parents opted for the termination of pregnancy, after dedicated counseling. Finally, there were nine newborns (seven males [78 %]) with median age at delivery of 37 weeks (range, 32–39). A definitive epicardial pacemaker was placed in six newborns, four of them within 2 weeks of life. CHB is a severe complication related to maternal anti-Ro/SSA and anti-La/SSB antibodies. Our results confirm previous data showing that therapy is ineffective, and most of the surviving patients will require neonatal pacemaker.     

Endoscopic and imaging appearance after injection of an ano-rectal bulking agent

The use of hyaluronic acid and dextranomer (Solesta, Salix) injection in the anal canal is an emerging modal-ity in the treatment of fecal incontinence. However, little is known regarding the endoscopic and radiological appearance following injection of this ano-rectal bulking agent. We report computed tomography and endoscopic findings after hyaluronic acid/dextranomer injection in the ano-rectal area.     

Effects of tracer arrival time on flow estimates in MR perfusion-weighted imaging.

A common technique for calculating cerebral blood flow (CBF) and mean transit time (MTT) is to track a bolus of contrast agent using perfusion-weighted MRI (PWI) and to deconvolve the change in concentration with an arterial input function (AIF) using singular value decomposition (SVD). This method has been shown to often overestimate the volume of tissue that infarcts and in cases of severe vasculopathy to produce CBF maps that are inconsistent with clinical presentation. This study examines the effects of tracer arrival time differences between tissue and a user-selected global AIF on flow estimates. CBF and MTT were calculated in both numerically simulated and clinically acquired PWI data where the AIF and tissue signals were shifted backward and forward in time with respect to one another. Results show that when the AIF leads the tissue, CBF is underestimated independent of extent of delay, but dependent on MTT. When the AIF lags the tissue, flow may be over- or underestimated depending on MTT and extent of timing differences. These conditions may occur in practice due to the application of a user-selected AIF that is not the "true AIF" and therefore caution must be taken in interpreting CBF and MTT estimates.     

Synthesis and biological evaluation of 2,4-diamino-6-(arylaminomethyl)pyrido[2,3-d]pyrimidines as inhibitors of Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase and as antiopportunistic infection and antitumor agents

A series of 2,4-diamino-6-(arylaminomethyl)pyrido[2,3-d]pyrimidines were synthesized and evaluated as inhibitors of Pneumocystis carinii (pc), Toxoplasma gondii (tg), and rat liver (rl) dihydrofolate reductase (DHFR) and as inhibitors of the growth of tumor cell lines in culture. Compounds 4-15 were designed as part of a continuing effort to examine the effects of substitutions at the 5-position, in the two-atom bridge, and in the side chain phenyl ring on structure-activity/selectivity relationships of 2,4-diaminopyrido[2,3-d]pyrimidines against a variety of DHFRs. Reductive amination of the common intermediate 2,4-diaminopyrido[2,3-d]pyrimidine-6-carbonitrile 16 with the appropriate anilines afforded the target compounds 4-12. Nucleophilic substitution or reductive methylation afforded the N10-methyl target compounds 13-15. As predicted, compounds 4-15 were, in general, less potent against all three DHFRs compared to the corresponding 2,4-diamino-5-methyl analogues previously reported; however, the greater decrease in potency against rlDHFR compared to pcDHFR and tgDHFR resulted in appreciable selectivity toward pathogenic DHFRs from different pathogens. The 2',5'-dichloro analogue 8 showed selectivity ratios (IC(50) against rlDHFR/IC(50) against pcDHFR or tgDHFR) of 15.7 and 23 for pcDHFR and tgDHFR, respectively. Thus, the selectivity of 8 for pcDHFR is higher than the first line clinical agent trimethoprim (TMP). In a P. carinii cell culture study, analogue 8 exhibited 88% cell growth inhibition at a concentration of 10 muM and afforded marginal effects in an in vivo study in the T. gondii mouse model. Selected compounds were evaluated in the National Cancer Institute (NCI) in vitro preclinical antitumor screening program and inhibited the growth of tumor cells in culture at micromolar to submicromolar concentrations and were selected for evaluation in a NCI in vivo hollow fiber assay.     

Amniotic Infection Syndrome: Nosology and Reproducibility of Placental Reaction Patterns

Clinically responsive placental examination seeks to provide useful information regarding the etiology, prognosis, and recurrence risk of pregnancy disorders. The purpose of this study was to assemble and validate a complete set of the placental reaction patterns seen with amniotic fluid infection in the hope that this might provide a standardized diagnostic framework useful for practicing pathologists. Study cases (14 with amniotic fluid infection, 6 controls) were reviewed blindly by six pathologists after agreement on a standard set of diagnostic criteria. After analysis of initial results, criteria were refined and a second, overlapping set of cases were reviewed. Majority vote served as the gold standard. Grading and staging of maternal and fetal inflammatory responses was found to be more reproducible using a two- versus three-tiered grading system than a three- versus five-tiered staging system (overall agreement 81% vs. 71%). Sensitivity, specificity, and efficiency for individual observations ranged from 67–100% (24/30 > 90%). Reproducibility was measured by unweighted kappa values and interpreted as follows: < 0.2, poor; 0.2–0.6, fair/moderate; > 0.6, substantial. Kappa values for the 12 lesions evaluated in 20 cases by the six pathologists were: acute chorioamnionitis/maternal inflammatory response (any, 0.93; severe 0.76; advanced stage, 0.49); chronic (subacute) chorioamnionitis (0.25); acute chorioamnionitis/fetal inflammatory response (any, 0.90; severe, 0.55; advanced stage, 0.52); chorionic vessel thrombi (0.37); peripheral funisitis (0.84); acute villitis (0.90); acute intervillositis/intervillous abscesses (0.65), and decidual plasma cells (0.30). Adoption of this clearly defined, clinically relevant, and pathologically reproducible terminology could enhance clinicopathologic correlation and provide a framework for future clinical research.     

The Alabama Preterm Birth Study: diffuse decidual leukocytoclastic necrosis of the decidua basalis, a placental lesion associated with preeclampsia, indicated preterm birth and decreased fetal growth.

OBJECTIVE: Laminar necrosis, a band-like distribution of coagulative necrosis, has been reported at the choriodecidual interface of the free membranes of placentas of women with various adverse neonatal outcomes. Our goal in this study was to evaluate the frequency of an equivalent feature in the decidua basalis, diffuse decidual leukocytoclastic necrosis (DDLN), a diffuse coagulative necrosis admixed with karyorrhectic debris, in preterm births <32 weeks, and to determine its association with various obstetric conditions, markers of placental inflammation, and newborn outcome. STUDY DESIGN: Four hundred and forty-six mother/infant dyads who delivered between 23 and 32 weeks gestational age (GA) had their medical records abstracted, a variety of placental and cord blood cultures performed, cord interleukin-6 (IL-6) levels determined, and the placentas evaluated histologically by a single pathologist (OFP). RESULTS: Women with DDLN (27%) were significantly more likely than other women to have preeclampsia (57.6 vs. 24.8%, p < 0.0001), an indicated preterm birth in this pregnancy (61.9 vs. 26.4%, p < 0.0001), and a prior indicated preterm birth (12.7 vs. 4.1%, p = 0.001), but were not more likely to have an abruption, diabetes, to smoke or be Black. Among DDLN-positive vs. DDLN-negative women, birth weight was significantly lower (1,069 +/- 373 vs. 1,171 +/- 389 g, p = 0.014), despite the GAs being similar (28.6 +/- 2.2 vs. 28.6 +/- 2.3 weeks, p = NS). Women with DDLN were less likely to have a positive placental culture for any organism (50.0 vs. 61.3%p = 0.03), Ureaplasma urealyticum and Mycoplasma hominis in either the placenta or cord blood (29.7 vs. 42.1%, p = 0.02), or an elevated cord blood IL-6 (21.5 vs. 32.9%, p = 0.059). They also were less likely to have acute inflammation of the membranes (27.4 vs. 56.4%, p < 0.0001), chorionic plate (17.0 vs. 48.6%, p < 0.0001) or cord (15.7 vs. 36.6%, p < 0.0001). Decidual necrosis in the free membranes also occurred more frequently in the presence vs. absence of DDLN (25.2 vs. 9.2%, p < 0.0001). Infants whose placentas had DDLN were significantly less likely to have neonatal systemic inflammatory response syndrome (20.7 vs. 35.2%, p = 0.004), but were not significantly different for other neonatal outcomes including respiratory distress syndrome, intraventricular hemorrhage or death. CONCLUSION: DDLN of the decidua basalis is relatively common in placentas of 23-32 week newborns, and, when present, is inversely associated with inflammatory maternal and newborn conditions and positively associated with preeclampsia, indicated preterm birth, and lower birth weight. The positive correlation of DDLN with obstetrical and neonatal conditions associated with underperfusion of the placental bed, suggests that DDLN may be a marker of vascular compromise.     

Longitudinal Diffusion Tensor Imaging Detects Recovery of Fractional Anisotropy Within Traumatic Axonal Injury Lesions

Background

Traumatic axonal injury (TAI) may be reversible, yet there are currently no clinical imaging tools to detect axonal recovery in patients with traumatic brain injury (TBI). We used diffusion tensor imaging (DTI) to characterize serial changes in fractional anisotropy (FA) within TAI lesions of the corpus callosum (CC). We hypothesized that recovery of FA within a TAI lesion correlates with better functional outcome.

Methods

Patients who underwent both an acute DTI scan (≤day 7) and a subacute DTI scan (day 14 to inpatient rehabilitation discharge) at a single institution were retrospectively analyzed. TAI lesions were manually traced on the acute diffusion-weighted images. Fractional anisotropy (FA), apparent diffusion coefficient (ADC), axial diffusivity (AD), and radial diffusivity (RD) were measured within the TAI lesions at each time point. FA recovery was defined by a longitudinal increase in CC FA that exceeded the coefficient of variation for FA based on values from healthy controls. Acute FA, ADC, AD, and RD were compared in lesions with and without FA recovery, and correlations were tested between lesional FA recovery and functional recovery, as determined by disability rating scale score at discharge from inpatient rehabilitation.

Results

Eleven TAI lesions were identified in 7 patients. DTI detected FA recovery within 2 of 11 TAI lesions. Acute FA, ADC, AD, and RD did not differ between lesions with and without FA recovery. Lesional FA recovery did not correlate with disability rating scale scores.

Conclusions

In this retrospective longitudinal study, we provide initial evidence that FA can recover within TAI lesions. However, FA recovery did not correlate with improved functional outcomes. Prospective histopathological and clinical studies are needed to further elucidate whether lesional FA recovery indicates axonal healing and has prognostic significance.