How severity and classification of pulmonary hypertension affect pregnancy outcomes: a systematic review and timeline.

Women with pulmonary hypertension (PH) have increased mortality during pregnancy and the peripartum period. An increasing number of publications suggest improvements in maternal outcomes, so we conducted a systematic review focusing on disease severity and maternal survival. After screening 9097 potential studies from 1967 to 2021, we identified 66 relevant publications. Outcomes improved continuously over time and mortality fell from 11.6% in studies published before 2015 to 8.2% in studies published after 2015. Mortality was lower in patients with mild disease (0.8%) than in those with Eisenmenger syndrome (26.2%) or idiopathic pulmonary arterial hypertension (7.4-24.0%). One major drawback of the published studies is that they define severity using echocardiographic-estimated pulmonary artery pressures, without considering more contemporary parameters. This systematic review provides new insights for preconception counseling on pregnancy risks related to PH and suggests that PH classification and severity should be carefully considered in determining an individual's pregnancy-associated risk.

ErbB3 upregulation by the HNSCC 3D microenvironment modulates cell survival and growth.

Head and neck squamous carcinomas (HNSCC) present as dense epithelioid three-dimensional (3D) tumor nests that can mediate signals via the human epidermal growth factor receptor (ErbB) tyrosine kinase family to promote intratumoral survival and growth. We examined the role of the tumor microenvironment on ErbB receptor family expression and found that the status of intercellular organization altered the receptor profile. We showed that HNSCC cells forced into tumor island-like 3D aggregates strongly upregulated ErbB3 at the level of transcription. Not only was the elevated ErbB3 responsive to HRG-ß1-induced enhanced signaling mechanism, but also analysis by siRNA-knockdown and kinase inhibitor strategies revealed that the ErbB3/AKT signaling pathway was sufficient to enhance tumor cell survival and growth potential. Elevated ErbB3 expression in the high-density 3D culture system was strongly associated with hypoxia-induced HIF-1α. Hypoxia-regulated ErbB3 expression was mediated by the HIF-1α-binding consensus sequence in the ErbB3 proximal promoter. The findings show that the local 3D tumor microenvironment can trigger reprograming and switching of ErbB family members and thereby influence ErbB3-driven tumor growth.

Sofosbuvir and simeprevir combination therapy in the setting of liver transplantation and hemodialysis.

We report safety, tolerability, and 12-week sustained virologic response with half-standard dose sofosbuvir and standard-dose simeprevir combination therapy in a hepatitis C virus genotype 1a-infected liver transplant recipient on hemodialysis - uncharted territory for sofosbuvir-based therapy. The patient was a non-responder to prior treatment with pegylated interferon plus ribavirin. Sofosbuvir efficacy was maintained despite pill-splitting and administration of half-standard dose, 200 mg per day. No drug-drug interactions were noted with tacrolimus-based immunosuppression. Laboratory tests remained stable or improved during therapy. Our observation, if reproduced in a larger study, may lead to significant improvement in clinical outcomes and cost savings in this patient population.

[Chromobacterium violaceum peritonitis: case report and literature review]. / Péritonite à Chromobacterium violaceum: observation et revue de la littérature.

We report a case of Chromobacterium violaceum infection and we review the literature for all published cases. C. violaceum grew from a peritoneal fluid of a 47-year-old woman operated on for peritonitis following perforative gastroduodenal ulcer. She was just coming back from a 1-month-holyday in French Guyana, where she might have been in contact with this micro-organism. The patient fully recovered after surgical management associated with antibiotic therapy consisting of ofloxacin plus piperacillin-tazobactam. Among the more than a hundred of published cases of human infections with C. violaceum that we retrieved, there was not any other case of peritonitis.

Intrinsic efficacy of antipsychotics at human D2, D3, and D4 dopamine receptors: identification of the clozapine metabolite N-desmethylclozapine as a D2/D3 partial agonist.

Drugs that antagonize D2-like receptors are effective antipsychotics, but the debilitating movement disorder side effects associated with these drugs cannot be dissociated from dopamine receptor blockade. The "atypical" antipsychotics have a lower propensity to cause extrapyramidal symptoms (EPS), but the molecular basis for this is not fully understood nor is the impact of inverse agonism upon their clinical properties. Using a cell-based functional assay, we demonstrate that overexpression of Galphao induces constitutive activity in the human D2-like receptors (D2, D3, and D4). A large collection of typical and atypical antipsychotics was profiled for activity at these receptors. Virtually all were D2 and D3 inverse agonists, whereas none was D4 inverse agonist, although many were potent D4 antagonists. The inverse agonist activity of haloperidol at D2 and D3 receptors could be reversed by mesoridazine demonstrating that there were significant differences in the degrees of inverse agonism among the compounds tested. Aripiprazole and the principle active metabolite of clozapine NDMC [8-chloro-11-(1-piperazinyl)-5H-dibenzo [b,e] [1,4] diazepine] were identified as partial agonists at D2 and D3 receptors, although clozapine itself was an inverse agonist at these receptors. NDMC-induced functional responses could be reversed by clozapine. It is proposed that the low incidence of EPS associated with clozapine and aripiprazole used may be due, in part, to these partial agonist properties of NDMC and aripiprazole and that bypassing clozapine blockade through direct administration of NDMC to patients may provide superior antipsychotic efficacy.

Phase II randomized multicenter study evaluating a treatment regimen alternating docetaxel and cisplatin-vinorelbine with a cisplatin-vinorelbine control group in patients with stage IV non-small-cell lung cancer: GFPC 97.01 study.

BACKGROUND: The potential absence of cross-resistance between cisplatin and docetaxel in non-small-cell lung cancer (NSCLC) suggests that alternating regimens of cisplatin-based chemotherapy and docetaxel might increase the activity of chemotherapy in stage IV NSCLC. PATIENTS AND METHODS: Randomized, multicenter, non-comparative phase II study in patients with stage IV NSCLC (Eastern Cooperative Oncology Group performance status of 0-2). Patients randomized to alternating treatment group (A) received docetaxel 100 mg/m2 on days (D) 1 and 43 alternating with cisplatin 100 mg/m2 on D22 and vinorelbine 30 mg/m2 on D22, D29 and D36. Those randomized to the control group (B) received cisplatin 80 mg/m2 on D1, D22 and D43 and vinorelbine 30 mg/m2 once a week from D1 to D57. Treatment was continued for a further 6 weeks in the event of objective response or stabilization. RESULTS: Seventy patients were enrolled (group A: 38, group B: 32). More premature treatment discontinuations due to toxicity were observed in group A (median number of cycles: 3) than in group B (median number of cycles: 5). The intention-to-treat objective response rate was 10.8% [95% confidence interval (CI) 0.8% to 20.8%] in group A compared with 25% (95% CI 10% to 40%) in group B, the median time to treatment failure being 10.2 weeks and 17.3 weeks, respectively. The median survival and 1-year survival were 29.1 weeks and 39% in group A compared with 41.6 weeks and 42% in group B. Febrile neutropenia occurred in 5.9 and 4.9% of the cycles in group A and group B, respectively. Non-hematological toxicity was moderate in the two groups. CONCLUSIONS: The addition of docetaxel alternating with cisplatin-vinorelbine did not enhance the activity of this combination. The development of sequential regimens might be a more promising way of exploiting the absence of cross-resistance between these two drugs.

The making of a gradient: IcsA (VirG) polarity in Shigella flexneri.

The generation and maintenance of subcellular organization in bacteria is critical for many cell processes and properties, including growth, structural integrity and, in pathogens, virulence. Here, we investigate the mechanisms by which the virulence protein IcsA (VirG) is distributed on the bacterial surface to promote efficient transmission of the bacterium Shigella flexneri from one host cell to another. The outer membrane protein IcsA recruits host factors that result in actin filament nucleation and, when concentrated at one bacterial pole, promote unidirectional actin-based motility of the pathogen. We show here that the focused polar gradient of IcsA is generated by its delivery exclusively to one pole followed by lateral diffusion through the outer membrane. The resulting gradient can be modified by altering the composition of the outer membrane either genetically or pharmacologically. The gradient can be reshaped further by the action of the protease IcsP (SopA), whose activity we show to be near uniform on the bacterial surface. Further, we report polar delivery of IcsA in Escherichia coli and Yersinia pseudotuberculosis, suggesting that the mechanism for polar delivery of some outer membrane proteins is conserved across species and that the virulence function of IcsA capitalizes on a more global mechanism for subcellular organization.

[Pseudomonas aeruginosa osteitis of the spinal process after peridural anesthesia]. / Ostéite de l'apophyse épineuse à Pseudomonas aeruginosa après une anesthésie péridurale.

BACKGROUND: Osteitis of the posterior wall of the spinal canal is an exceptional complication after peridural anesthesia. Prognosis depends on early diagnosis based on clinical signs and imaging data. CASE REPORT: A 73-year-old man was hospitalized for lower back pain and fever of 3 weeks duration after a total hip arthroplasty performed under general anesthesia. Computed tomography and magnetic resonance imaging of the lumbar spine disclosed osteitis of the spinal processes. Local bacteriology sample evidenced Pseudomonas aeruginosa. Outcome was favorable after a 6-month treatment. DISCUSSION: Data in the French and English literature (since 1948) on bone infections following epidural anesthesia have included 5 cases of spondylodiscitis and 1 case of posterior wall osteitis. The diagnosis is suggested by the clinical presentation. Standard x-rays contribute little. Early diagnosis in the infraradiological phase can be obtained with bone scintigraphy. Computed tomography or magnetic resonance imaging are currently highly contributive to diagnosis and follow-up after treatment. Contamination may be direct or via the blood stream or result from an extension of a neighboring infectious focus. Antibiotic therapy and immobilization are indicated. Rigorous application of strict aseptic procedures during lumbar puncture and use of the epidural catheter are crucial for prevention.

Tones disappear faster in the right ear than in the left.

In order to gain further information on the characteristics and physiological correlates of tone decay in humans, the tone decay test was administered to 58 normal-hearing subjects, successively in the left and right ears and in absence and presence of a contralateral noise. The results revealed that tone decay was greater in the right than in the left ear and was increased by contralateral noise. The contralateral effect of this noise on cochlear biomechanisms was then estimated by measuring contralaterally induced variations in the amplitude of click-evoked otoacoustic emissions in the same subjects. In the right ear, the increase in tone decay and the decrease in otoacoustic emission amplitude--both induced by contralateral noise--were positively correlated (r = .315, p = .016). Furthermore, the contralateral changes in otoacoustic emission amplitude were found to be on average larger in the right than in the left ear, this asymmetry being correlated with that observed for the tone decay. These findings are discussed in relation to previous results on simple and induced loudness adaptation in the vicinity of threshold, on contralateral attenuation of otoacoustic emissions and on the influence of the auditory efferents on cochlear biomechanisms.

Validation assessment of a French version of the tinnitus reaction questionnaire: a comparison between data from English and French versions.

The present study compares the results obtained on original and French versions of the TRQ (Tinnitus Reaction Questionnaire) initially published by Wilson, Henry, Bowen, and Haralambous (1991) in English to evaluate the psychological distress of tinnitus sufferers. Reliability and validity of the French translation were determined using data from 173 normal hearing or hearing-impaired patients with tinnitus lasting from 1 month to 41 years. They completed the translated questionnaire and a short version of the Minnesota Multiphasic Personality Inventory. The results indicated good internal consistency (Cronbach's alpha = .94), and the reliability of the French version of the TRQ was demonstrated, except for items 5 and 20. High statistically significant correlations were found between the TRQ and Depression, Psychaesthenia, and Anxiety Mini-Mult subscales. The validation demonstrates only minor effects of language. The French version of the TRQ thus is an equally valid tool as the original English version for evaluating tinnitus distress of a patient.

Improved artificial death switches based on caspases and FADD.

A number of "suicide genes" have been developed as safety switches for gene therapy vectors or as potential inducible cytotoxic agents for hyperproliferative disorders, such as cancer or restenosis. However, most of these approaches have relied on foreign proteins, such as HSV thymidine kinase, that primarily target rapidly dividing cells. In contrast, novel artificial death switches based on chemical inducers of dimerization (CIDs) and endogenous proapoptotic molecules function efficiently in both dividing and nondividing cells. In this approach, lipid-permeable, nontoxic CIDs are used to conditionally cross-link target proteins that are fused to CID-binding domains (CBDs), thus activating signaling cascades leading to apoptosis. In previous reports, CID-regulated Fas and caspases 1, 3, 8, and 9 were described. Since the maximum efficacy of these artificial death switches requires low basal and high specific activity, we have optimized these death switches for three parameters: (1) extent of oligomerization, (2) spacing between CBDs and target proteins, and (3) intracellular localization. We describe improved conditional Fas and caspase 1, 3, 8, and 9 alleles that function at subnanomolar levels of the CID AP1903 to trigger apoptosis. Further, we demonstrate for the first time that oligomerization of the death effector domain of the Fas-associated protein, FADD, is sufficient to trigger apoptosis, suggesting that the primary function of FADD, like that of Apaf-1, is oligomerization of associated caspases. Finally, we demonstrate that nuclear-targeted caspases 1, 3, and 8 can trigger apoptosis efficiently, implying that the cleavage of nuclear targets is sufficient for apoptosis.

A comparison of repeated high doses and repeated standard doses of epinephrine for cardiac arrest outside the hospital. European Epinephrine Study Group.

BACKGROUND: Clinical trials have not shown a benefit of high doses of epinephrine in the management of cardiac arrest. We conducted a prospective, multicenter, randomized study comparing repeated high doses of epinephrine with repeated standard doses in cases of out-of-hospital cardiac arrest. METHODS: Adult patients who had cardiac arrest outside the hospital were enrolled if the cardiac rhythm continued to be ventricular fibrillation despite the administration of external electrical shocks, or if they had asystole or pulseless electrical activity at the time epinephrine was administered. We randomly assigned 3327 patients to receive up to 15 high doses (5 mg each) or standard doses (1 mg each) of epinephrine according to the current protocol for advanced cardiac life support. RESULTS: In the high-dose group, 40.4 percent of 1677 patients had a return of spontaneous circulation, as compared with 36.4 percent of 1650 patients in the standard-dose group (P=0.02); 26.5 percent of the patients in the high-dose group and 23.6 percent of those in the standard-dose group survived to be admitted to the hospital (P=0.05); 2.3 percent of the patients in the high-dose group and 2.8 percent in the standard-dose group survived to be discharged from the hospital (P=0.34). There was no significant difference in neurologic status according to treatment among those discharged. High-dose epinephrine improved the rate of successful resuscitation in patients with asystole, but not in those with ventricular fibrillation. CONCLUSIONS: In our study, long-term survival after cardiac arrest outside the hospital was no better with repeated high doses of epinephrine than with repeated standard doses.

Early spontaneous abortions and fetal thymic abnormalities in maternal-to-fetal HIV infection.

The thymus is thought to play a major role in the immunopathogenesis of human immunodeficiency virus (HIV) infection, particularly in maternal-to-fetal HIV transmission. Characteristic lesions of the HIV-infected thymus include a prominent CD4+ CD8+ T lymphocyte depletion at the corticomedullary junction, the region of the thymus where immune selection occurs. At least threefold excess early spontaneous abortions were noted in a cohort of 124 HIV-infected pregnant women. In these 13 abortuses a very high rate (54%) of HIV vertical transmission was documented, with the thymus gland particularly affected. It is possible that the thymic insult in HIV-infected fetuses contributes to immune rejection of the fetus, possibly by an imbalance of maternal and fetal T1- and T2-type cytokines, known to be important in HIV disease progression. We propose, therefore, that the early spontaneous abortions occurring in HIV-infected pregnant women are due, at least in part, to abnormal immune forces created by HIV infection of the thymus.

[Translation and validation of the questionnaire "Tinnitus Handicap Questionnaire, 1990]. / Traduction et validation du questionnaire "Mesure du handicap lié à l'acouphène" (Tinnitus Handicap Questionnaire, 1990).

OBJECTIVE: The Tinnitus Handicap Questionnaire (THQ) measures subjective tinnitus handicap in terms of emotional, social, and health impact (factor 1), hearing (factor 2), and perception of tinnitus (factor 3). A French version of the THQ was used with 178 tinnitus sufferers in ENT consultation. Internal validity was confirmed by correlations between (i) semigroups of items (Cronbach's alpha), (ii) item and total scores, and (iii) individual items, for each factor (Pearson's r), and was found to be strong (alpha = .90). All items (except 25 and 26) showed strong total-score correlations (.30 < or = r < or = .74). All factor 1 items intercorrelated strongly (.34 < or = r < or = .70). The factor 2 axis was coherent, with interitem correlations between .46 and .74, and its concurrent validation in strong factor 2 items correlations with hearing loss, if any (multiple linear regression: r = .67, p < .0001). Moreover, hearing-impaired (mean = 44.47 +/- 31.13) and normal-hearing (mean = 15.2 +/- 21.10) factor 2 scores were significantly different. CONCLUSION: As with the original THQ, factor 3 items were not strongly intercorrelated; moreover, items 25 and 26 failed to correlate with total score, suggesting that factor 3 is to be regarded with great caution.

Molecular analysis of the INK4 family of genes in prostate carcinomas.

PURPOSE: A newly recognized class of INK4 family of cyclin-dependent kinase inhibitors CDKIs) include its prototype, p16 (INK4A/MTS1/CDKN2), and three others, p15 (INK4B/MTS2), p18 (INK4C), and p19 (INK4D). The putative tumor suppressor gene, p16 is frequently altered in certain neoplasms and many cell lines. The potential role of INK4 CDKIs in pathogenesis of prostate carcinoma was studied. MATERIALS AND METHODS: Thirty-two primary prostate cancer samples and two prostate cancer cell lines were examined for alterations of the p16, p15, p18, and p19 genes by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and Southern blot analysis. RESULTS: Alteration of the p16 gene was found in one of 32 primary prostate cancer samples by PCR-SSCP. DNA sequencing of the sample showed a 24-basepair insertion in exon 1 of the p16 gene at codon 11. No other mutations were found in p15, p18, or p19 genes by PCR-SSCP. Furthermore, none of the p16, p15, p18, or p19 genes had alterations by Southern blot analysis. CONCLUSIONS: These results indicate that structural abnormalities of the INK4 CDKIs is a rare event in prostate carcinoma, and the loss of function of INK4 CDKIs by other mechanisms, such as methylation should be further explored.

Mammographic pattern due to residual Lipiodol after galactography.

The purpose of this pictorial essay is to describe the different mammographic aspects of residual Lipiodol ultra fluid (LUF) after galactography, and to define some specific patterns, because it may in some cases mimic microcalcifications and give diagnostic problems. The mammograms of 14 patients, aged 32-63 years, presenting LUF residues related to previous galactography, were analyzed retrospectively. In 12 cases the diagnosis was easy because the patients presented a typical pattern on mammography and came with their initial galactography. In 2 cases the diagnosis was more difficult because the patients did not remember the previous injection and the progressive resorption mimicked perfectly intraductal calcification. Benign duct ectasia with inflammatory reaction to foreign bodies were found in 3 cases in which surgery was performed. Lipiodol ultra fluid is no longer used for galactography, but it may persist in breast ducts or cysts for years and seems to still be used in some countries. There are in most cases specific signs enabling the diagnosis.

[Validation of French translation of the "Tinnitus Reaction Questionnaire", Wilson et al. 1991]. / Validation d'une traduction française du questionnaire "mesure de la détresse liée à l'acouphène (Tinnitus Reaction Questionnaire, Wilson et al. 1991).

The present study proposes a validation of a french translation of the TRQ initially published by Wilson et al., for evaluating the psychological distress of tinnitus sufferers. The 26 items translated into french were used on a sample of 173 tinnitus sufferers, who also filled out the Mini-Mult, a short version of the MMPI proposed by Kincannon. Internal validity was demonstrated by strong correlations (i) between each item (except items 5 and 20) and total TRQ score (0.33 < or = r < or = 0.87, p < or = 0.0001), (ii) between each internal TRQ factor (0.58 < r < 0.81, p < 0.0001) and the others. Cronbach's alpha test also showed the questionnaire to have a good internal validity (alpha = 0.94). The external factors used for testing concurrent validity were the scores on depression, psychaesthenia and anxiety Mini-Mult scales. The strong correlations (one factor ANOVA and simple linear regression tests) between scores on depression and psychaesthenia scales and (1) each TRQ item, (2) each TRQ factor, (3) total TRQ scores, confirmed concurrent validity. Scores obtained on anxiety index showed high correlations only with TRQ score, factor 3 score and some TRQ items (most of them included in factor 3). The internal and concurrent validities of the French version of the TRQ justify the use of this questionnaire, with the reserve that items 5 and 20 appeared irrelevant for the measuring of tinnitus distress in French-speaking countries. Such a questionnaire should improve our knowledge of tinnitus' life-impact and enable detection of patients whose psychological distress necessitates rapid intervention.

[Acute drug-induced agranulocytosis: experience of the Regional Center of Pharmacovigilance of Lyon over 7 years]. / Agranulocytoses aïgues médicamenteuses: expérience du Centre Régional de Pharmacovigilance de Lyon sur 7 ans.

Sixty-two cases of drug-induced agranulocytosis, spontaneously reported to the regional drug monitoring centre in Lyon from 1988 to 1994, have been analysed. The mean age of patients was 58.6 years, and sex ratio was 1:1. The mean delay of onset was 46.2 days and absolute neutrophil counts (ANC) dropped below 0.1 x 10(9)/l in 73 per cent of patients. Bone marrow aspirates disclosed absence of myeloid series in 28 per cent of investigated cases. Neutrophil recovery occurred after a mean of 9.3 days, and the overall fatality rate was 6.5 per cent. Haematopoietic growth factors (HGF) were used in 11 patients with an ANC below 0.1 x 10(9)/l and/or a hypoplastic bone marrow. We have found no clear indication for a potential benefit of HGF treatment, but HGF were usually administered late during the course of neutropenia, i.e., after a mean of 6 days. The incidence rate estimated for people living in the Rhône administrative division was 3.3 per million per year, similar to that found in epidemiological studies. Drugs most frequently involved were anti-infective agents and psychotropic drugs.

p53 transactivation through various p53-responsive elements.

p53 is a nuclear phosphoprotein whose function is classified as tumor suppression. Studies have shown that p53 functions by binding to p53 DNA recognition sequences and regulates transcription of growth-regulatory genes. Various p53 recognition sequences have recently been identified. pOST2 contained two copies of a palindromic high-affinity DNA-binding sequence for p53; the other p53 recognition sequences included p53-binding fragments found in the human ribosomal gene cluster (pRGC) region and in the murine muscle creatine kinase promoter (pMCK). The purpose of this study was to compare the abilities of various p53 recognition sequences to mediate transcription in the presence of endogenously produced wild-type (wt) or mutant p53. Three p53-responsive chloramphenicol acetyltransferase (CAT) reporter constructs (pOST2, pRGC, and pMCK) that contain one or two copies of p53 recognition sequences upstream of a herpes thymidine kinase (TK) promoter and CAT reporter cDNA were constructed. Either a p53-responsive gene or a control reporter gene was transfected into human carcinoma cell lines (having various p53 mutations) either with or without a wt or mutant p53 expression vector. CAT activity was assayed to measure transactivation through the various p53-responsive elements. We showed that pOST2 had a greater ability to mediate transactivation by p53 than either pRGC or pMCK. p53 with a mutation at either codon 175 or 248 was unable to transactivate a reporter gene with pOST2, pRGC, or pMCK. We found it interesting that pOST2, but not pRGC or pMCK, was able to mediate transactivation in cell lines that produce codon 273-mutant p53. These findings suggest that various sensitivities of the different p53-responsive elements to specific mutant and wt p53s may be an important factor in the role of p53 as a transcriptional activator both under normal physiological conditions and during carcinogenesis.

Experimentally induced ulno-carpal instability. A study on 13 cadaver wrists.

This experimental work studies the role of ligamentous structures in suspending the carpal bones from the radius and ulna. Thirteen human cadaver wrists underwent a distal radio-ulnar arthrodesis in a neutral position and an arthrodesis between the three bones of the first carpal row. Progressive postero-anterior forces in a palmar direction were applied to the fused carpal bones. Displacement was measured by two dial gauges before and after sequential section of the different fibrous structures. The largest absolute average displacement (both, dorso-palmar and induced rotational displacement) was observed after section of the ulnar styloid process. No significant differences were observed after section of the extensor retinaculum, extensor carpi ulnaris sheath, posterior ulno-carpal and posterior radio-carpal ligaments. This work suggests that the carpus is suspended not only from the radius, but also from the distal ulna and particularly at the ulnar styloid and the structures which insert onto it.