Effects of cardiac growth on electrical dyssynchrony in the single ventricle patient.

Single ventricle patients, including those with hypoplastic left heart syndrome (HLHS), typically undergo three palliative heart surgeries culminating in the Fontan procedure. HLHS is associated with high rates of morbidity and mortality, and many patients develop arrhythmias, electrical dyssynchrony, and eventually ventricular failure. However, the correlation between ventricular enlargement and electrical dysfunction in HLHS physiology remains poorly understood. Here we characterize the relationship between growth and electrophysiology in HLHS using computational modeling. We integrate a personalized finite element model, a volumetric growth model, and a personalized electrophysiology model to perform controlled in silico experiments. We show that right ventricle enlargement negatively affects QRS duration and interventricular dyssynchrony. Conversely, left ventricle enlargement can partially compensate for this dyssynchrony. These findings have potential implications on our understanding of the origins of electrical dyssynchrony and, ultimately, the treatment of HLHS patients.

Implantable cardioverter-defibrillators in congenital heart disease.

Implantable cardioverter-defibrillators (ICD) have an important role in reducing sudden cardiac death in patients with congenital heart disease (CHD); however, the benefit of ICDs needs to be weighed up against both short-term and long-term adverse effects, which are difficult to evaluate in the heterogeneous CHD population. A tailored approach, taking into account risk stratification and patient-specific factors, is needed to select the most appropriate strategy. This review discusses primary and secondary ICD indications, implantation approaches and long-term follow-up. Recent publications have shed light on the concerns of system longevity, lead extractions, inappropriate shocks and impact on the quality of life. All of these factors require consideration prior to commitment to this long-term treatment strategy.

Comparison of three methods for measuring psoriasis severity in clinical studies (Part 1 of 2): change during therapy in Psoriasis Area and Severity Index, Static Physician's Global Assessment and Lattice System Physician's Global Assessment.

BACKGROUND: Accurate and reliable assessment of changes in psoriasis severity is critical in clinical trials of therapies. OBJECTIVE: To compare Psoriasis Area and Severity Index (PASI), static Physician's Global Assessment (sPGA), and the Lattice System Physician's Global Assessment (LS-PGA) in a trial of systemic treatments for plaque psoriasis vulgaris and to assess whether they measure change in psoriasis induced by therapy. METHODS: Patients were randomized to voclosporin or cyclosporine for 24 weeks (the '24-week-treatment' group, n = 366), or placebo for 12 weeks followed by voclosporin for 12 weeks (the 'initial-placebo' group, n = 89). RESULTS: All scoring systems changed in concert and were sensitive enough to detect reductions in severity during placebo therapy as well as with active therapy (P < 0.01 for each measurement). At study onset, there were poorer correlations of sPGA with PASI (r = 0.45) and LS-PGA (r = 0.39) than between PASI and LS-PGA (r = 0.68). After therapy, all correlations were stronger, but sPGA continued to be less well correlated (with PASI, r = 0.85; with LS-PGA, r = 0.79) than LS-PGA with PASI (r = 0.90). Two- or three-step improvements in LS-PGA showed very good to excellent accuracy in corresponding to PASI-50 and PASI-75, respectively, and were more accurate than comparable changes in sPGA. CONCLUSION: PASI, sPGA and LS-PGA are responsive to the varying degrees of improvement in psoriasis induced by either placebo or active therapy. While the three systems capture similar information, each has different reasons for use in a clinical trial.

Correlation of echocardiographic and angiographic measurements of the pulmonary valve annulus in pulmonary stenosis.

OBJECTIVES: The pulmonary valve (PV) annulus is routinely measured angiographically in PV stenosis prior to balloon dilation. We sought to establish whether this radiation exposure is justified, or whether echocardiographic measurements prior to the procedure are sufficient to guide balloon selection. BACKGROUND: Previous studies have found a strong correlation between echocardiographic and angiographic measurements of the PV annulus. However, error of measurement and its implication for procedural practice has not been explored. METHODS: A total of 90 procedures in 84 patients were analyzed, at a median age 7.6 months (range 1 day to 14.2 years). The contemporaneous echocardiographic and angiographic measurements were recorded, and the original echocardiograms were re-measured in the 72 available cases by two independent reviewers. RESULTS: There was a good correlation between the two measurement methods (R(2) = 0.87). However, the echocardiographic PV measurements were smaller on average, with a significant variation in that discrepancy (mean ratio 0.941 (±0.16)). There was no significant reduction in error if extreme measurements (PV annulus z-score <-3) were excluded (P = 0.09), or if the reviewed echocardiographic measurements were used (P = 0.58). CONCLUSIONS: There is an unacceptable discrepancy between the measurement techniques: 95% of patients are predicted to have an echocardiographic measurement error between -37% and +26%. Therefore, there is no correction factor that could be employed to allow safe selection of balloon size, and balloon pulmonary valvoplasty without angiographic PV measurement cannot be advocated.

Etanercept suppresses regenerative hyperplasia in psoriasis by acutely downregulating epidermal expression of interleukin (IL)-19, IL-20 and IL-24.

BACKGROUND: Psoriasis is a Th17/Th1-mediated skin disease that often responds to antitumour necrosis factor (TNF)-α therapies, such as etanercept. OBJECTIVES: To better define mechanisms by which etanercept improves psoriasis and to gain insight into disease pathogenesis. METHODS: We investigated the early biochemical and cellular effects of etanercept on skin lesions in responder patients prior to substantial clinical improvement (≤ 4 weeks). RESULTS: By 1 week, etanercept acutely suppressed gene expression of the interleukin (IL)-20 subfamily of cytokines (IL-19, IL-20, IL-24), which were found to be predominantly epidermis-derived and which are implicated in stimulating epidermal hyperplasia. Additionally, by 1 week of therapy, suppression of other keratinocyte-derived products (chemokines, antimicrobial proteins) occurred, while suppression of epidermal regenerative hyperplasia occurred within 1-3 weeks. Th17 elements (IL-23p19, IL-12p40, IL-17A, IL-22) were suppressed by 3-4 weeks. In vitro, TNF-α and IL-17A coordinately stimulated the expression of the IL-20 subfamily in normal keratinocytes. CONCLUSIONS: Based on the rapid suppression of regenerative hyperplasia, chemokines and other keratinocyte-derived products, including the IL-20 subfamily, we propose that epidermal activation is a very early target of etanercept. As many of these keratinocyte markers are stimulated by TNF-α, their rapid downregulation is likely to reflect etanercept's antagonism of TNF-α. Additionally, decreased epidermal hyperplasia might result specifically from acute suppression of the IL-20 subfamily, which is also a likely consequence of etanercept's antagonism of TNF-α. Thus, the IL-20 subfamily has potential importance in the pathogenesis of psoriasis and therapeutic response to etanercept.

Heart and heart-lung transplantation for idiopathic restrictive cardiomyopathy in children.

OBJECTIVE: To review the outcome of cardiac transplantation for restrictive cardiomyopathy (RCM) in children and to assess the ability of new strategies to modulate the effects of high pulmonary vascular resistance. DESIGN: Retrospective case note analysis of all patients receiving a transplant for RCM. PATIENTS: 18 children with RCM referred for transplantation assessment to Great Ormond Street Hospital, London. RESULTS: Eight boys and 10 girls were referred for assessment. Median age at presentation was 5.0 (mean (SD) 6.1 (4.0)) years. Fourteen orthotopic and two heterotopic transplantations were performed and two patients were referred for heart-lung transplantation. Mean duration from diagnosis to transplantation was 3.3 (3.0) years. Three patients with haemodynamic decompensation before transplantation had increased morbidity in the postoperative period. No patients died while awaiting a transplant. Three patients died in the first year after transplantation, one within 30 days. Five patients received pre-transplantation prostacyclin for a mean duration of 57 (18) days. Transpulmonary gradient was reduced in four of the patients. Mean transpulmonary gradient was 27 (9.8) mm Hg before and 17 (6.7) mm Hg after treatment with prostacyclin (p < 0.05). CONCLUSION: Most children with RCM require transplantation within four years of diagnosis. Referral for transplantation assessment should precede haemodynamic decompensation. Increase of pulmonary vascular resistance is a variable problem but can be modulated with pre-transplantation prostacyclin. With these strategies, orthotopic transplantation is possible in the majority of cases.

The prevalence and predictors of psychological distress in patients with early localized prostate cancer.

OBJECTIVE: To determine the level of psychopathology, traumatic distress and quality of life in men with newly diagnosed clinically localized prostate cancer, the effect on these of a consultation in a combined-specialist early-prostate clinic, and predictors of psychopathology. PATIENTS AND METHODS: Eighty-eight patients were recruited from the combined clinic; they completed a battery of questionnaires including the Hospital Anxiety and Depression Scale (HADS), the revised Impact of Event Scale (IES) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, before their first appointment. Two weeks later they completed the HADS, IES and a patient-satisfaction survey. RESULTS: The overall level of psychopathology varied among the questionnaires used, from 0% on the HADS depression scale, 8% on the HADS anxiety scale and 14% on the IES. Anxiety and traumatic stress symptoms were commoner than depressive symptoms. The quality-of-life scores showed a relatively good level of functioning. Pre-morbid factors and disease status did not predict psychological distress. Younger age was mildly predictive of poorer psychological functioning. Anxiety symptoms reduced slightly after a joint clinic appointment, whereas depressive symptoms showed a slight increase. CONCLUSION: This study suggests that men with early localized prostate cancer have low levels of psychopathology overall. However, some men experience distressing psychological symptoms and it is important that future research is conducted to help develop clear guidelines on the optimal methods of detecting and managing men with prostate cancer who have mental health difficulties.

Early psychological reactions in a group of individuals with pre-existing and enduring mental health difficulties following a major coach accident.

BACKGROUND: The impact of major trauma on individuals with pre-existing and enduring mental health difficulties is poorly understood. METHOD: Twenty individuals with pre-existing and enduring mental health difficulties were assessed with the Clinician Administered Post Traumatic Stress Disorder Scale, the 28-item version of the GHO, the Hospital Anxiety and Depression Scale, and the impact of Event Scale between four and eight weeks after their involvement in a major coach accident. RESULTS: Ten (50%) individuals satisfied the full DSM-IV criteria for a diagnosis of PTSD. The questionnaire scores indicated a high level of psychological suffering among the group. On dividing the sample into those individuals with previous diagnosis of anxiety or depressive disorders and those with a previous diagnosis of chronic schizophrenia, the schizophrenia group displayed less marked psychological sequelae on all measures. CONCLUSION: There was a high incidence of early psychological sequelae among the group as a whole. Some diagnoses (e.g. depression and anxiety) may predispose to psychological sequelae while others (e.g. chronic schizophrenia) may not.

Screening for psychiatric morbidity in subjects presenting with chronic fatigue syndrome.

BACKGROUND: There is a need for a valid self-rating questionnaire to screen for psychiatric morbidity in patients with chronic fatigue syndrome (CFS). This study had the aim of assessing the utility and validity of two commonly used measures. METHOD: Scores obtained on the General Health Questionnaire (GHQ) and the Beck Depression Inventory (BDI) were compared with various diagnostic and severity ratings obtained via a validating clinical interview, the Schedules for the Clinical Assessment of Neuropsychiatry (SCAN) in 95 consecutively referred subjects at a medical out-patient clinic who fulfilled standard criteria for CFS, and 48 healthy controls. Outcome measures were validating coefficients and receiver operating characteristics (ROC) for different thresholds and scoring on GHQ and BDI and index of definition (ID) as measured by SCAN; and Pearson and point by serial correlation coefficients for different diagnostic groups derived via SCAN and defined according to ICD-10 and DSM-III-R. RESULTS: GHQ and BDI perform poorly as screeners of psychiatric morbidity in CFS subjects when compared with various SCAN derived ratings although results for controls are comparable with other studies. CONCLUSIONS: Neither the GHQ nor BDI alone can be recommended as screeners for psychiatric morbidity in CFS subjects.

Antibodies to opacity proteins (Opa) correlate with a reduced risk of gonococcal salpingitis.

Acute salpingitis complicating cervical gonococcal infection is a significant cause of infertility. Relatively little data are available concerning the pathophysiologic mechanisms of this disease. A cohort of 243 prostitutes residing in Nairobi were followed between March 1985 and April 1988. Gonococcal cultures were performed at each visit, and acute salpingitis was diagnosed clinically. Serum at enrollment was tested by immunoblot for antibody to gonococcal outer membrane proteins. 8.6% (146/1689) of gonococcal infections were complicated by salpingitis. Increased risk of salpingitis was associated with younger age, shorter duration of prostitution, HIV infection, number of gonococcal infections, and episodes of nongonococcal salpingitis. Rmp antibody increased the risk of salpingitis. Antibody to Opa decreased the risk of salpingitis. By logistic regression analysis, antibody to Opa was independently associated with decreased risk of gonococcal salpingitis (adjusted odds ratio [OR], 0.35; 95% confidence interval [95%CI], 0.17-0.76); HIV infection (adjusted OR, 3.5; 95% CI, 0.96-12.8) and episodes of nongonococcal salpingitis (adjusted OR, 3.4; 95% CI, 1.8-6.4) were independently associated with an increased risk of salpingitis. Antibody to Opa appears to protect against ascending gonococcal infection, perhaps by interfering with Opa mediated adherence and endocytosis. The demonstration of natural immunity that protects against upper genital tract infection in women suggests that a vaccine to prevent gonococcal salpingitis is possible.

Antibody to Rmp (outer membrane protein 3) increases susceptibility to gonococcal infection.

The severe adverse effects of gonococcal infection on human fertility suggests that Neisseria gonorrhoeae would exert powerful selection for the development of a protective immune response in humans. N. gonorrhoeae is an obligate human pathogen and must persist in humans to survive. Since it is an ecologically successful organism, it must have evolved strategies to evade any human immune response it elicits. In a longitudinal study among 243 women working as prostitutes and experiencing frequent gonococcal infection, younger women, women with HIV infection, and women with antibody to the gonococcal outer membrane protein 3 (Rmp) were at increased risk of infection (adjusted odds ratio 3.4, CI95% 1.1-10.4, P < 0.05). Rmp is highly conserved in N. gonorrhoeae and the blocking of mucosal defences may be one of its functions. As similar proteins occur in many gram negative mucosal pathogens, the enhancing effect of such proteins may be a general strategy whereby bacteria evade human immune responses.

PIP: Between March 1985 and July 1986 researchers enrolled 243 female prostitutes in Pumwani community of Nairobi, Kenya, in a longitudinal study to examine the relationship between the antibody to the gonococcal outer membrane protein 3 (Rmp Ab) and gonococcal mucosal infection. Few women used condoms. 69% were HIV-1 seropositive. Just 9.5% (23) of the women had not had any gonococcal infections, despite probable exposure to them, indicating the possibility of some acquired protective immunity to Neisseria gonorrhoea. 90.5% had had at least 1 gonococcal infection. Women with Rmp Ab faced a greater risk of gonococcal infection than those who were Rmp Ab negative (OR = 3.4;l p .05), denoting that Rmp Ab increases susceptibility to gonococcal mucosal infections. Women older than 29 years were at lower risk of gonococcal infection than those younger than 29 years (odds ratio [OR] = 0.3; p .03). Women who used oral contraceptives (OCs) were also likely to be infected with N. gonorrhoea (OR = 3; p = .062). Further, 31% of OC users had cervical ectopy compared to just 14% of nonusers (OR = 2.8; p .005), suggesting that the effect of OCs on the cervix make it more susceptible to gonococcal infection. Rmp Ab also exists in many other gram-negative mucosal pathogens, often playing the same role as it does in N. gonorrhoea infection. Thus, Rmp Ab may be a common scheme bacteria used to elude human immune responses. These findings provide more understanding as to why N. gonorrhoea is an ecologically successful human pathogen.

Looking at systems as process.

This article proposes that the social systems family therapists are concerned with may usefully be conceived of as interactive processes. It discusses limitations to the organismic view, in which social systems are seen as autonomous entities with boundaries, internal structures, and self-perpetuating behaviors, and argues, from Maturana and Varela, that social systems are qualitatively different from organisms. It develops from chaos theory an alternative view in which social systems are seen as complex nonlinear processes. It proposes that this view can free the therapist from the notions of family dysfunction and the systemic function of symptoms, and from reifications in which the family is seen as having covert rules, keeping secrets, neutralizing the therapist, and the like. This view leads to a redefinition of the therapist's place in the system and to the conclusion that family therapists can only influence systemic process by working with individuals.

Therapist efficiency and clinic accessibility with the Mental Health Research Institute brief therapy model.

A health maintenance organization (HMO) mental health clinic used the Mental Research Institute (MRI) brief therapy model to achieve striking therapist efficiency and clinic accessibility. In the two-year period from January 1985 through December 1986, the clinic averaged 834 separate patients per therapist, compared with a regional average of 456 patients. The rate of hospitalization from the clinic catchment area was two thirds that of the region. This article describes the MRI approach as practiced at the clinic and discusses its applicability to community mental health centers and other mental health clinics.

In-vitro activity of azithromycin, erythromycin, ciprofloxacin and norfloxacin against Neisseria gonorrhoeae, Haemophilus ducreyi, and Chlamydia trachomatis.

The minimum inhibitory concentrations (MICs) of azithromycin, erythromycin, ciprofloxacin and norfloxacin for 300 strains of Neisseria gonorrhoeae, 100 strains of Haemophilus ducreyi and six strains of Chlamydia trachomatis were determined. The two quinolones were more active against gonococcal strains than were the two macrolides. Azithromycin was approximately eight-fold more active against N. gonorrhoeae than was erythromycin (MIC90: 0.25 mg/l azithromycin, 2.0 mg/l erythromycin). The Mtr phenotype of gonococci increased azithromycin MICs approximately four fold. Azithromycin was less active than erythromycin against C. trachomatis. Azithromycin had considerable activity against H. ducreyi and was ten-fold more active than was erythromycin (MIC90: 0.004 mg/l azithromycin, 0.03 mg/l erythromycin). Clinical trials of azithromycin in the treatment of chlamydial infection and genital ulcer disease are indicated.

In-vitro activity of meropenem against Neisseria gonorrhoeae, Haemophilus influenzae and H. ducreyi from Canada and Kenya.

Meropenem, a new parenteral carbapenem demonstrated increased activity as compared to imipenem against 336 strains of Neisseria gonorrhoeae, 119 strains of Haemophilus influenzae, and 110 strains of H. ducreyi. Neither carbapenem was affected by the beta-lactamase activity of the organisms tested. Ceftriaxone and ciprofloxacin demonstrated activity superior to that of both carbapenems while the activity of ceftazidime was similar to that of meropenem.

Epidemiologic evidence for the development of serovar-specific immunity after gonococcal infection.

We tested the hypothesis that strain-specific immunity occurs after gonococcal infection in a longitudinal study of 227 prostitutes resident in one small community who experienced frequent gonococcal infections. Women were examined and cultured for Neisseria gonorrhoeae at 2-wk intervals. Gonococcal isolates were typed according to protein 1 serovar, auxotype, and beta-lactamase plasmid type, and classified as to serovar and strain. The hypothesis was tested by comparing the predictions of the hypothesis with the observations of the study. Over the 14-mo period of the study, major changes in the prevalence of specific serovars were observed in the gonococcal population infecting these women. Women with HIV infection experienced a higher rate of gonococcal infection (0.56 +/- 0.03 vs. 0.46 +/- 0.04, P less than 0.05, t test) compared with HIV-negative women and were more likely to experience multiple infections with the same strain. The duration of prostitution was inversely related to the frequency of gonococcal infection. Women experiencing an infection with a specific gonococcal serovar were at a 2- to 10-fold reduced risk of reinfection with the same serovar, except for the 1B-1 serovar. The results of the study were consistent with all four predictions of the hypothesis. Infection with a specific gonococcal serovar results in specific but incomplete protection against subsequent infection with the homologous serovar. The mechanism of this protection remains to be determined.

Preservation of colonization resistance parameters during empiric therapy with aztreonam in the febrile neutropenic patient.

The role of the anaerobic intestinal flora in maintaining colonization resistance was examined in a study of empiric therapy in febrile neutropenic patients who received aztreonam plus tobramycin, aztreonam plus cloxacillin, or moxalactam plus tobramycin, regimens with differential effects on the anaerobic intestinal flora. Surveillance cultures showed that all regimens eradicated fecal carriage of enteric gram-negative bacilli but that fecal acquisition of fungi occurred in 4 (27%) of 15 aztreonam/tobramycin, 6 (43%) of 14 aztreonam/cloxacillin, and 13 (81%) of 16 moxalactam/tobramycin recipients. Fungi were acquired at 11 (22%) of 49 sites in aztreonam/tobramycin, 15 (31%) of 48 sites in aztreonam/cloxacillin, and 28 (54%) of 52 sites in moxalactam/tobramycin recipients. Aztreonam/tobramycin reduced fecal anaerobe counts by less than 1 log10; aztreonam/cloxacillin, by a mean of 2.5 log10; and moxalactam/tobramycin, by 5.1 log10 colony-forming units (cfu)/g of feces by day 10 +/- 3 of therapy. Elimination of the anaerobes was reflected by a reduction in concentrations of short-chain fatty acids (SCFAs) in fecal supernatants. Fecal specimens containing greater than or equal to 10(6) cfu of Bacteroides fragilis group organisms/g (dry weight) contained significantly higher concentrations of succinic, propionic, and isobutyric acids. Flat SCFA chromatograms were observed in 90% of fecal samples from which no anaerobes were recovered. Preservation of the anaerobic flora appears critical in the prevention of fungal acquisition in neutropenic patients.

Hypoprothrombinemia in febrile, neutropenic patients with cancer: association with antimicrobial suppression of intestinal microflora.

Serial, twice-weekly prothrombin times were determined in 108 febrile, granulocytopenic patients with cancer who were prospectively randomized to receive empiric antimicrobial therapy with moxalactam plus ticarcillin (M/T) or tobramycin plus ticarcillin (T/T). Thirty of 54 patients given M/T and 13 of 54 patients given T/T developed prothrombin times that were greater than or equal to 2 sec beyond control values (P less than .001) after a mean of 6.5 days of antimicrobial therapy. Serious bleeding episodes were more frequent in the group given M/T than in that given T/T (10 and two patients, respectively; P less than or equal to .05). Serial quantitative stool cultures revealed that both Escherichia coli and Bacteroides species were suppressed by greater than or equal to 5 log10 in eight of nine patients given M/T and in three of nine given T/T (P less than .05, Fisher's exact test). A significant reduction of the population of E. coli and Bacteroides fragilis, organisms that are major producers of bacterially synthesized menaquinones, was associated with a high incidence of hypoprothrombinemia. These observations support the hypothesis that menaquinones may play an important physiological role in the maintenance of blood coagulation during episodic dietary deficiency of phylloquinone.

Production of menaquinones by intestinal anaerobes.

Ninety intestinal organisms (71 isolates from fecal samples of neutropenic patients with cancer or from various sites in patients with intraabdominal infections and 19 control strains) were examined by reverse-phase thin-layer chromatography for their ability to produce menaquinones in vitro. Menaquinones were found in all of 24 organisms of the Bacteroides fragilis group. Two other Bacteroides species, Bacteroides disiens and Bacteroides bivius, also produced menaquinones. A single isolate of Bacteroides species lacked menaquinones. These constituents were found in all of five strains of Escherichia coli, all of four strains of Klebsiella pneumoniae, five of eight strains of Propionibacterium species, two of five strains of Eubacterium species, and the one strain each of Arachnia propionica and Veillonella parvula tested. No menaquinones were detected in organisms of the genera Fusobacterium, Clostridium, Bifidobacterium, Lactobacillus, Actinomyces, Peptococcus, or Peptostreptococcus. These findings suggest that E. coli, Bacteroides species, and some gram-positive, anaerobic, non-spore-forming bacilli produce menaquinones that may be a source of vitamin K in patients who are deprived of exogenous vitamin K1.