Equity, Diversity and Inclusion (EDI) in Organ Transplantation: An ESOT Survey About EDI Within ESOT as an Organization and its Educational Activities, and Transplantation Research and Science.

The European Society of Organ Transplantation (ESOT) strives to promote equity, diversity, and inclusion (EDI) across all its activities. We surveyed the transplant community's experiences and perspectives regarding EDI within ESOT as an organization and its educational activities, and research in general. A total of 299 respondents completed the questionnaire. About half agreed that ESOT's Executive Committee, Council, and Sections/Committees are diverse and inclusive (51%) and that ESOT promotes EDI in its live and digital educational activities (54%). Forty percent of respondents agreed that scientific and clinical trials in the field of transplantation are diverse and inclusive. Despite the wide distribution of the survey, most of the respondents self-identified as White and were either physician or surgeon. However, the results contribute a unique insight into the experiences and perspectives of the transplantation community regarding EDI. Whilst ESOT is committed to the principles of EDI, perceptions and the high number of proposals show the apparent need to prioritize efforts to embed EDI across ESOT and transplantation science. These data should constitute a starting point for change and provide guidance for future efforts to promote EDI within the transplantation community.

Lower levels of the glial cell marker TSPO in drug-naive first-episode psychosis patients as measured using PET and [11C]PBR28.

Several lines of evidence are indicative of a role for immune activation in the pathophysiology of schizophrenia. Nevertheless, studies using positron emission tomography (PET) and radioligands for the translocator protein (TSPO), a marker for glial activation, have yielded inconsistent results. Whereas early studies using a radioligand with low signal-to-noise in small samples showed increases in patients, more recent studies with improved methodology have shown no differences or trend-level decreases. Importantly, all patients investigated thus far have been on antipsychotic medication, and as these compounds may dampen immune cell activity, this factor limits the conclusions that can be drawn. Here, we examined 16 drug-naive, first-episode psychosis patients and 16 healthy controls using PET and the TSPO radioligand [11C]PBR28. Gray matter (GM) volume of distribution (VT) derived from a two-tissue compartmental analysis with arterial input function was the main outcome measure. Statistical analyses were performed controlling for both TSPO genotype, which is known to affect [11C]PBR28 binding, and gender. There was a significant reduction of [11C]PBR28 VT in patients compared with healthy controls in GM as well as in secondary regions of interest. No correlation was observed between GM VT and clinical or cognitive measures after correction for multiple comparisons. The observed decrease in TSPO binding suggests reduced numbers or altered function of immune cells in brain in early-stage schizophrenia.

Pre- and probiotics for allergy prevention: time to revisit recommendations?

Reduced intensity and diversity of microbial exposure is considered a major factor driving abnormal postnatal immune maturation and increasing allergy prevalence, particularly in more affluent regions. Quantitatively, the largest important source of early immune-microbial interaction, the gut microbiota, is of particular interest in this context, with variations in composition and diversity in the first months of life associated with subsequent allergy development. Attempting to restore the health consequences of the 'dysbiotic drift' in modern society, interventions modulating gut microbiota for allergy prevention have been evaluated in several randomized placebo-controlled trials. In this review, we provide an overview of these trials and discuss recommendations from international expert bodies regarding prebiotic, probiotic and synbiotic interventions. Recent guidelines from the World Allergy Organization recommend the use of probiotics for the primary prevention of eczema in pregnant and breastfeeding mothers of infants at high risk for developing allergy and in high-risk infants. It is however stressed that these recommendations are conditional, based on very low-quality evidence and great heterogeneity between studies, which also impedes specific and practical advice to consumers on the most effective regimens. We discuss how the choice of probiotic strains, timing and duration of administration can critically influence the outcome due to different effects on immune modulation and gut microbiota composition. Furthermore, we propose strategies to potentially improve allergy-preventive effects and enable future evidence-based implementation.

Test-retest reproducibility of [(11)C]PBR28 binding to TSPO in healthy control subjects.

PURPOSE: The PET radioligand [(11)C]PBR28 binds to the translocator protein (TSPO), a marker of brain immune activation. We examined the reproducibility of [(11)C]PBR28 binding in healthy subjects with quantification on a regional and voxel-by-voxel basis. In addition, we performed a preliminary analysis of diurnal changes in TSPO availability. METHODS: Twelve subjects were examined using a high-resolution research tomograph and [(11)C]PBR28, six in the morning and afternoon of the same day, and six in the morning on two separate days. Regional volumes of distribution (V T) were derived using a region-of-interest based two-tissue compartmental analysis (2TCM), as well as a parametric approach. Metabolite-corrected arterial plasma was used as input function. RESULTS: For the whole sample, the mean absolute variability in V T in the grey matter (GM) was 18.3 ± 12.7 %. Intraclass correlation coefficients in GM regions ranged from 0.90 to 0.94. Reducing the time of analysis from 91 to 63 min yielded a variability of 16.9 ± 14.9 %. There was a strong correlation between the parametric and 2TCM-derived GM values (r = 0.99). A significant increase in GM V T was observed between the morning and afternoon examinations when using secondary methods of quantification (p = 0.028). In the subjects examined at the same time of the day, the absolute variability was 15.9 ± 12.2 % for the 91-min 2TCM data. CONCLUSION: V T of [(11)C]PBR28 binding showed medium reproducibility and high reliability in GM regions. Our findings support the use of parametric approaches for determining [(11)C]PBR28 V T values, and indicate that the acquisition time could be shortened. Diurnal changes in TSPO binding in the brain may be a potential confounder in clinical studies and should be investigated further.

National needs assessment of patients treated at the United States Federally-Funded Hemophilia Treatment Centers.

AIM: The National Hemophilia Program Coordinating Center, with the U.S. Regional Hemophilia Network conducted a national needs assessment of U.S. Hemophilia Treatment Center (HTC) patients. The objectives were to determine: (i) To what extent do patients report that they receive needed services and education; (ii) How well do the services provided meet their needs; and (iii) What are the patients' perspectives about their care. METHODS: A survey was mailed to active patients of 129 HTCs. Respondents completed the anonymous surveys on line or returned them by mail. Questions focused on management and information, access and barriers to care, coping, resources, and transition. RESULTS: Of 24 308 questionnaires mailed, 4004 (16.5%) were returned. Most respondents reported very few gaps in needed services or information and reported that services and information met their needs. Over 90% agreed or strongly agreed that care was patient-centred and rated HTC care as important or very important. Identified gaps included dietary advice, genetic testing, information on ageing, sexual health and basic needs resources. Minority respondents reported more barriers. CONCLUSION: This survey is the largest assessment of the HTC population. Respondents reported that the services and information provided by the HTCs met their needs. Quality improvement opportunities include transition and services related to ageing and sexual health. Further investigation of barriers to care for minorities is underway. Results will help develop national priorities to better serve all patients in the US. HTCs.

Treatment with botulinum toxin in children with cerebral palsy: a qualitative study of parents' experiences.

BACKGROUND: In children with cerebral palsy everyday movements such as walking, standing and using one's hands can be difficult to perform because of spasticity. Botulinum neurotoxin type A (BoNT-A) are often used to reduce spasticity. The aim of this study was to describe how parents of children with cerebral palsy experienced the child's treatment with BoNT-A, how the child was affected by the treatment and how spasticity affected the child. METHODS: A qualitative study in which 15 parents of children (6-13 years old) with cerebral palsy were interviewed about their experiences of the BoNT-A treatment. The children had received several BoNT-A treatments. An interview guide was used with topics: the child's functions before and after the treatment, the outcomes of the treatment and how they valued the BoNT-A treatment. Content analysis was used to analyse the interviews. RESULTS: The analyses resulted in two themes: 'When softness comes and goes' and 'Both want and do not want'. The reduction of spasticity - softness - was described to promote motor functions, and facilitate the next step in motor development. The children were described as being more active out of their own initiative and having a happier mood. Spasticity, described as stiffness, was described to make walking more strenuous as well as interfering with activities. The BoNT-A injection procedure was perceived as troublesome and painful for the child, and sometimes traumatic for both children and parents. CONCLUSIONS: Treatment with BoNT-A was described as facilitating motor development and activity. The children's and the parents' negative experiences of the injection procedure should be addressed.

Pre- and post-natal Lactobacillus reuteri supplementation decreases allergen responsiveness in infancy.

BACKGROUND: We have previously shown that Lactobacillus reuteri supplementation from pregnancy week 36 and to the infant through the first year of life decreased the prevalence of IgE-associated eczema at 2 years. The underlying immunological mechanisms are unknown, however. OBJECTIVE: To investigate the immunomodulatory effect of probiotic supplementation on allergen- and mitogen-induced immune responses in children until 2 years of age. METHODS: Blood mononuclear cells were collected at birth, 6, 12 and 24 months from 61 children (29 probiotic and 32 placebo treated) and cultured with ovalbumin, birch and cat extract and Phytohaemagglutinin (PHA). Cytokine and chemokine secretion was determined using an in-house multiplexed Luminex assay and ELISA. Real-time PCR was performed to investigate the Ebi3, Foxp3, GATA-3 and T-bet mRNA expression. RESULTS: Probiotic treatment was associated with low cat-induced Th2-like responses at 6 months (IL-5, P = 0.01, and IL-13, P = 0.009), with a similar trend for IL-5 at 12 months (P = 0.09). Cat-induced IFN-γ responses were also lower after probiotic than after placebo treatment at 24 months (P = 0.007), with similar findings for the anti-inflammatory IL-10 at birth (P = 0.001) and at 12 months (P = 0.009). At 24 months, Th2-associated CCL22 levels were lower in the probiotic than in the placebo group after birch stimulation (P = 0.02), with a similar trend after ovalbumin stimulation (P = 0.07). Lower CCL22 levels were recorded at 12 and 24 months (P = 0.03 and P = 0.01) after PHA stimulation. CONCLUSION AND CLINICAL RELEVANCE: Lactobacillus reuteri supplementation decreases allergen responsiveness and may enhance immunoregulatory capacity during infancy. L. reuteri supplementation from week 36 and during the first year of life significantly decreases IgE-associated eczema and lowers allergen and mitogen responsiveness.

US Hemophilia Treatment Center population trends 1990-2010: patient diagnoses, demographics, health services utilization.

For several decades, US government agencies have partially supported regional networks of Hemophilia Treatment Centers (HTC). HTC multidisciplinary teams provide comprehensive and coordinated diagnosis, treatment, prevention, education, outreach and surveillance services to improve the health of people with genetic bleeding disorders. However, national data are scarce on HTC-patient population trends and services. The aim of the study was to examine national trends over the past 20 years in patient diagnoses, demographics and health services utilization among the Health Resources and Services Administration (HRSA) and Centers for Disease Control and Prevention (CDC)-supported HTC network. Diagnoses, demographics and health services utilization data from 1990 to 2010 were aggregated from all HTCs using the Hemophilia Data Set (HDS). From 1990 to 2010, the HTC population grew 90% from 17 177 to 32 612. HTC patients with von Willebrand's disease increased by 148%, females by 346%, Hispanic patients by 236% and African Americans by 104%. Four thousand and seventy-five deaths were reported. From 2002 to 2010, annual comprehensive evaluations grew 38%, and persons with severe haemophilia on a home intravenous therapy programme rose 37%. In 2010, 46% of patients were less than 18 years vs. 24% for the general US population. The Hemophilia Data Set documents the growth and diversity of the US Hemophilia Treatment Center Network's patient population and services. Despite disproportionate deaths due to HIV, the HTC patient base grew faster than the general US population. The HDS is a vital national public health registry for this rare-disorder population.

Quality of life in haemophilia A: Hemophilia Utilization Group Study Va (HUGS-Va).

This study describes health-related quality of life (HRQoL) of persons with haemophilia A in the United States (US) and determines associations between self-reported joint pain, motion limitation and clinically evaluated joint range of motion (ROM), and between HRQoL and ROM. As part of a 2-year cohort study, we collected baseline HRQoL using the SF-12 (adults) and PedsQL (children), along with self-ratings of joint pain and motion limitation, in persons with factor VIII deficiency recruited from six Haemophilia Treatment Centres (HTCs) in geographically diverse regions of the US. Clinically measured joint ROM measurements were collected from medical charts of a subset of participants. Adults (N = 156, mean age: 33.5 ± 12.6 years) had mean physical and mental component scores of 43.4 ± 10.7 and 50.9 ± 10.1, respectively. Children (N = 164, mean age: 9.7 ± 4.5 years) had mean total PedsQL, physical functioning, and psychosocial health scores of 85.9 ± 13.8, 89.5 ± 15.2, and 84.1 ± 15.3, respectively. Persons with more severe haemophilia and higher self-reported joint pain and motion limitation had poorer scores, particularly in the physical aspects of HRQoL. In adults, significant correlations (P < 0.01) were found between ROM measures and both self-reported measures. Except among those with severe disease, children and adults with haemophilia have HRQoL scores comparable with those of the healthy US population. The physical aspects of HRQoL in both adults and children with haemophilia A in the US decrease with increasing severity of illness. However, scores for mental aspects of HRQoL do not differ between severity groups. These findings are comparable with those from studies in European and Canadian haemophilia populations.

Colorectal cancer screening with fecal immunochemical testing or primary colonoscopy: An analysis of health equity based on a randomised trial.

Background: We have addressed health equity attained by fecal immunochemical testing (FIT) and primary colonoscopy (PCOL), respectively, in the randomised controlled screening trial SCREESCO conducted in Sweden. Methods: We analysed data on the individuals recruited between March 2014, and March 2020, within the study registered with ClinicalTrials.gov, NCT02078804. Swedish population registry data on educational level, household income, country of birth, and marital status were linked to each 60-year-old man and woman who had been randomised to two rounds of FIT 2 years apart (n = 60,123) or once-only PCOL (n = 30,390). Furthermore, we geo-coded each study individual to his/her residential area and assessed neighbourhood-level data on deprivation, proportion of non-Western immigrants, population density, and average distance to healthcare center for colonoscopy. We estimated adjusted associations of each covariate with the colonoscopy attendance proportion out of all invited to respective arms; ie, the preferred outcome for addressing health equity. In the FIT arm, the test uptake and the colonoscopy uptake among the test positives were considered as the secondary outcomes. Findings: We found a marked socioeconomic gradient in the colonoscopy attendance proportion in the PCOL arm (adjusted odds ratio [95% credibility interval] between the groups categorised in the highest vs. lowest national quartile for household income: 2·20 [2·01-2·42]) in parallel with the gradient in the test uptake of the FIT × 2 screening (2·08 [1·96-2·20]). The corresponding gradient in the colonoscopy attendance proportion out of all invited to FIT was less pronounced (1·29 [1·16-1·42]), due to higher proportions of FIT positives in socioeconomically disadvantaged groups. Interpretation: The unintended risk of exacerbating inequalities in health by organised colorectal cancer screening may be higher with a PCOL strategy than a FIT strategy, despite parallel socioeconomic gradients in uptake. Funding: This work was supported by the Swedish Cancer Society under Grant 20 0719. CB and US provided economic support from the Swedish Research Council for Health, Working life, and Welfare under Grant 2020-00962.

A Th1/Th2-associated chemokine imbalance during infancy in children developing eczema, wheeze and sensitization.

BACKGROUND: Analyses of circulating chemokines offer novel tools to investigate the T helper (Th)1/Th2 imbalance in allergic disease in vivo. OBJECTIVE: To relate circulating Th1- and Th2-associated chemokines in infancy to allergic disease, sensitization and probiotic supplementation. METHODS: Circulating levels of Th1-associated CXC-chemokine ligand (CXCL)9, CXCL10 and CXCL11 and Th2-associated CC-chemokine ligand (CCL)17 and CCL22 were assessed with Luminex and CCL18 with enzyme-linked immunosorbent assay at birth (n=109), 6 (n=104), 12 (n=116) and 24 months (n=123) in 161 infants completing a double-blind placebo-controlled allergy prevention trial with Lactobacillus reuteri during the last month of gestation and through the first year of life. The infants were followed regarding the development of allergic disease and sensitization until 2 years of age. RESULTS: The Th2-associated chemokines CCL17 and CCL22 were the highest at birth and then decreased, whereas CCL18 and the Th1-associated chemokines increased with age. High Th2-associated chemokine levels were observed in children developing allergic disease. Sensitization was preceded by elevated levels of the Th2-associated CCL22 and reduced levels of the Th1-associated CXCL11 already at birth. The Th2-associated CCL17 was also elevated at birth in infants developing recurrent wheeze. A high Th2/Th1 ratio (CCL22/CXCL10) at birth associated with both sensitization and eczema development. The presence of L. reuteri in stool in the first week of life was associated with low CCL17 and CCL22 and high CXCL11 levels at 6 months of age. High Th1-associated chemokine levels were associated with day-care. CONCLUSION AND CLINICAL RELEVANCE: Allergic disease and sensitization in infancy was associated with low circulating Th1- and high Th2-associated chemokine levels already from birth. Circulating chemokines are useful for investigating the Th1/Th2 imbalance in allergic disease in vivo. Elucidation of the role of chemokines in allergic diseases may lead to future treatments (ClinicalTrials.gov NCT01285830).

Haemophilia utilization group study - Part Va (HUGS Va): design, methods and baseline data.

To describe the study design, procedures and baseline characteristics of the Haemophilia Utilization Group Study - Part Va (HUGS Va), a US multi-center observational study evaluating the cost of care and burden of illness in persons with factor VIII deficiency. Patients with factor VIII level ≤ 30%, age 2-64 years, receiving treatment at one of six federally supported haemophilia treatment centres (HTCs) were enrolled in the study. Participants completed an initial interview including questions on socio-demographical characteristics, health insurance status, co-morbidities, access to care, haemophilia treatment regimen, factor utilization, self-reported joint pain and motion limitation and health-related quality of life. A periodic follow-up survey collected data regarding time lost from usual activities, disability days, health care utilization and outcomes of care. HTC clinicians documented participants' baseline clinical characteristics and pharmacy dispensing records for 2 years. Between July 2005 and July 2007, 329 participants were enrolled. Average age was 9.7 years for children and 33.5 years for adults; two-thirds had severe haemophilia. The distributions of age, marital status, education level and barriers to haemophilia care were relatively consistent across haemophilic severity categories. Differences were found in participants' employment status, insurance status and income. Overall, children with haemophilia had quality of life scores comparable to healthy counterparts. Adults had significantly lower physical functioning than the general US population. As one of the largest economic studies of haemophilia care, HUGS Va will provide detailed information regarding the burden of illness and health care utilization in the US haemophilia A population.

Changes in peripheral immune populations during pregnancy and modulation by probiotics and ω-3 fatty acids.

Allergic diseases have become a major health problem, partly due to reduced microbial stimulation and a decreased dietary ω-3/ω-6 long-chain polyunsaturated fatty acid ratio. Prenatal exposures have been reported to influence allergy development, possibly induced via changes in maternal immune regulation. In a randomized double-blind placebo-controlled multicenter allergy prevention trial (PROOM-3), pregnant women were recruited at gestational week 20, and randomized to four study groups, one receiving both L. reuteri oil drops and ω-3 PUFA capsules (n = 22), the second receiving ω-3 PUFA supplementation and placebo regarding L. reuteri (n = 21), the third receiving L. reuteri and placebo regarding ω-3 PUFA (n = 22) and the fourth group receiving placebo capsules and placebo oil drops (n = 23). In this substudy, supplemental and pregnancy-related effects on maternal peripheral immune cell populations during pregnancy were assessed by flow cytometry immune phenotyping at gestational week 20, 32 and 4 days after delivery. The numbers of activated and regulatory T (Treg) cells (CD45RA- Foxp3++/CD45RA+Foxp3+) were reduced after delivery, with the lowest count in the L. reuteri supplemented group compared with the placebo group 4 days after delivery, while the ω-3 PUFA group did not differ from the placebo group. Several treatment-independent changes were observed during and after pregnancy in lymphocytes (CD4+/8+/19+/56+/45RA+/-), CD14+16+/- monocytes, and in subpopulations of T helper cells (Th) CD4+CD45RA-Tbet+ (Th1) and CD4+CD45RA-RORC+ (Th17) cells. In conclusion, probiotic supplementation to the mother during the second half of pregnancy resulted in immunomodulatory effects among activated and resting Treg cells. Furthermore, several systemic immune modifying effects of pregnancy were observed.

Disease activity in rheumatoid arthritis is inversely related to cerebral TSPO binding assessed by [11C]PBR28 positron emission tomography.

Reumatoid Arthritis (RA) is an autoimmune disorder characterized by peripheral joint inflammation. Recently, an engagement of the brain immune system has been proposed. The aim with the current investigation was to study the glial cell activation marker translocator protein (TSPO) in a well characterized cohort of RA patients and to relate it to disease activity, peripheral markers of inflammation and autonomic activity. Fifteen RA patients and fifteen healthy controls matched for age, sex and TSPO genotype (rs6971) were included in the study. TSPO was measured using Positron emission tomography (PET) and the radioligand [11C]PBR28. The outcome measure was total distribution volume (VT) estimated using Logan graphical analysis, with grey matter (GM) as the primary region of interest. Additional regions of interest analyses as well as voxel-wise analyses were also performed. Clinical evaluation of disease activity, symptom assessments, serum analyses of cytokines and heart rate variability (HRV) analysis of 24 h ambulatory ECG were performed in all subjects. There were no statistically significant group differences in TSPO binding, either when using the primary outcome VT or when normalizing VT to the lateral occipital cortex (p > 0.05). RA patients had numerically lower VT values than healthy controls (Cohen's D for GM = -0.21). In the RA group, there was a strong negative correlation between [11C]PBR28 VT in GM and disease activity (DAS28)(r = -0.745, p = 0.002, corrected for rs6971 genotype). Higher serum levels of IFNγ and TNF-α were found in RA patients compared to controls (p < 0.05) and several measures of autonomic activity showed significant differences between RA and controls (p < 0.05). However, no associations between markers of systemic inflammation or autonomic activity and cerebral TSPO binding were found. In conclusion, no statistically significant group differences in TSPO binding as measured with [11C]PBR28 PET were detected. Within the RA group, lower cerebral TSPO binding was associated with higher disease activity, suggesting that cerebral TSPO expression may be related to disease modifying mechanisms in RA. In light of the earlier confirmed neuro-immune features of RA, these results warrant further investigations regarding neuro-immune joint-to-CNS signalling to open up for potentially new treatment strategies.

[(11)C]-PIB imaging in patients with Parkinson's disease: preliminary results.

[(11)C]-PIB positron emission tomography ([(11)C]-PIB PET) is a sensitive marker of amyloid in Alzheimer's disease (AD), but its specificity has not been fully evaluated. Vascular amyloid-beta deposition is common in Parkinson's disease (PD) and alpha-synuclein, the major component of the Lewy bodies in PD, forms amyloid fibrils. We investigated five apparently cognitively normal PD patients with [(11)C]-PIB PET. The results were compared to 16 patients with AD and six healthy controls from a previous study. [(11)C]-PIB retention was not significantly increased in our patients who all had early stage PD. Further studies of more advanced PD patients are warranted.

Intranasal deferoxamine affects memory loss, oxidation, and the insulin pathway in the streptozotocin rat model of Alzheimer's disease.

Accumulation of metal and the accompanying increase in oxidative stress and inflammation plays an important role in neurodegenerative disease. Deferoxamine (DFO) is a metal chelator found to be beneficial in several animal models of neurodegenerative disease and insult including Alzheimer's disease, Parkinson's disease, stroke, and subarachnoid hemorrhage. In this study, we determine whether intranasally (IN) administered DFO is beneficial in the intracerebroventricular streptozotocin (ICV STZ) rat model of sporadic Alzheimer's disease, which is different from previous models in that it exhibits dysregulation of insulin metabolism as well as oxidative stress and inflammation. Surgical induction of the model included ICV injections of either STZ or citrate buffer (sham in rats), which were treated IN with either saline or DFO (n=10-15/group). Treatment started either before or after injection of STZ to induce the model, and continued throughout the study. IN treatment continued three times per week for three weeks before behavior tests started followed by eventual euthanasia with tissue collection. Spatial memory tests with the Morris water maze showed that STZ rats treated with IN DFO both before and after model induction had significantly shorter escape latencies. Pre-treatment with IN DFO also significantly decreased footslips on the tapered balance beam test. Brain tissue analyses showed DFO treatment decreased oxidation as measured by oxyblot and increased insulin receptor expression. These results further support the potential of IN DFO for use as a treatment for Alzheimer's disease, and show benefit in a non-amyloid/tau rodent model.

Regulation and polarized transfer of the Yersinia outer proteins (Yops) involved in antiphagocytosis.

Pathogenic Yersinia express a number of strictly regulated, plasmid-encoded virulence determinants (Yops), some of which are important in enabling the pathogen to block phagocytosis. The events mediating antiphagocytosis and the regulation of this process are becoming increasingly well understood.

The virulence protein Yop5 of Yersinia pseudotuberculosis is regulated at transcriptional level by plasmid-plB1 -encoded trans-acting elements controlled by temperature and calcium.

The DNA sequence of the structural gene (yopE) of one of the Yersinia pseudotuberculosis virulence plas-mid-plB1-encoded proteins, Yop5, is presented. The deduced protein showed a molecular weight of 22971 Daltons. A specific mutant, having a kanamycin-resistance fragment inserted within the yopE gene was no longer virulent for mice. The expression of the Yop5 protein is regulated at the level of transcription by temperature as well as by the Ca2+ -concentration of the medium. A significant increase in the level of transcription was not detected until 45 min after a temperature shift from 26°C to 37°C in the absence of calcium; addition of Ca2+ inhibited the expression. The yopE promoter is under positive, as well as negative, plB1-encoded control. The positive function is solely regulated by temperature, while the regulation of the negative function involves at least five different plasmid-encoded gene loci; one of these genes encodes the V-antigen.

The use of porcine factor VIII concentrate (Hyate:C) in the treatment of patients with inhibitor antibodies to factor VIII. A multicenter US experience.

The response to a highly purified concentrate of porcine factor VIII was evaluated in 45 bleeding episodes in 38 patients with high responding inhibitor antibodies to factor VIII. A total of 437 infusions were given. The patients came from 25 hemophilia centers in the United States. The majority had a life- or limb-threatening hemorrhage for which other modalities had not been successful. In 32 of 45 episodes, a good to excellent response was obtained. Adverse reactions were minimal, occurring in 17 treatment episodes, and were mostly treated with antihistamines and/or hydrocortisone. No clear predictor of clinical response to porcine factor VIII concentrate was identified, including pretreatment human and porcine inhibitor levels, percentage of cross-reactivity between the human and porcine antibodies, and the presence of measurable levels of factor VIII after the porcine factor concentrate was given. Anamnesis to porcine factor VIII did occur in some instances. Porcine factor VIII is a valuable modality in the treatment of serious hemorrhages in patients with inhibitors to factor VIII. Its use should be considered early in the course of severe hemorrhage in these patients.

Human immunodeficiency virus isolation studies and antibody testing. Household contacts and sexual partners of persons with hemophilia.

Virus isolation studies and human immunodeficiency virus (HIV) antibody testing were performed on 87 household contacts of 68 HIV antibody-positive hemophilic patients to determine the extent that HIV could be transmitted through heterosexual or through nonsexual, but intimate contact. Human immunodeficiency virus seropositivity was established for the 68 hemophiliacs by immunofluorescence method or enzyme-linked immunosorbent assay and confirmed by Western blot testing (for 66 patients). Fifty-one nonsexual contacts and 36 sexual partners of these hemophiliacs were tested for HIV antibody by immunofluorescence or enzyme-linked immunosorbent assay and Western blot. All sexual partners and all nonsexual household contacts were HIV antibody-negative, including six partners and nine parents of hemophiliacs from whom the virus had been isolated and seven parents and six partners of patients with AIDS. This study further demonstrates lack of transmission of HIV in intimate, but nonsexual settings, and suggests that heterosexual transmission, although well known to occur, may be relatively uncommon in hemophilic couples when the male and female partner have no other risk factors. It is hoped that intensive education and counseling programs will reduce exposure and maintain a low risk of heterosexual transmission.