Low Mean Perfusion Pressure Indexed to Body Surface Area is a Powerful Predictor of Poor Outcomes After Heart Transplantation in Patients With High Pre-Transplant Venous Pressure: A Clinical Study With Physiological Insights From Mathematical Modelling of Biventricular Heart Failure.

BACKGROUND & AIM: The deleterious consequences of chronically elevated venous pressure in patients with profound right ventricular or biventricular dysfunction are well known, including renal and hepatic dysfunction, and volume overload. The only option for these patients, if they fail optimal medical treatment, is a heart transplant, as they are not candidates for left ventricular assist device therapy. Mean perfusion pressure (MPP) is important in the outcomes of critically ill patients with high venous pressure. The question arises whether MPP is important for the outcomes of heart transplants in patients with elevated pre-transplant venous pressure. Medical management of heart failure patients with reduced ejection fraction involves lowering the systemic afterload with vasodilators while awaiting a transplant. We hypothesised that when venous pressure is elevated prior to transplant, a substantial reduction in systemic arterial elastance (Ea) through vasodilation may significantly decrease MPP, resulting in compromised end-organ function and consequent unfavourable outcomes after heart transplantation. This study aims to investigate whether a low MPP serves as a risk factor for adverse outcomes in heart transplant recipients with high venous pressure. METHOD: A retrospective analysis was conducted on 250 heart transplant recipients undergoing isolated heart transplantation at a single institution from October 2012 to March 2020. Right atrial pressure (RAP) of more than 15 mmHg was considered high. Additionally, Ea calculated as the ratio of end-systolic pressure to stroke volume, and MPP calculated as the difference between mean arterial pressure and RAP were considered in our analysis. The outcomes of transplantation were measured in terms of 90-day mortality and survival up to 7 years. RESULTS: High RAP was a significant risk factor for short-term and medium-term survival if Ea was low (<2.7 mmHg/mL, the median value). This group had 39.39% in-hospital mortality compared to 14.49% for RAP<15 mmHg (p∼0.005). When Ea was high, this difference in survival was not evident: 8% for RAP<15 mmHg vs 4.8% for RAP>15 mmHg (p∼0.550). This effect was mediated through a lower MPP, and the mortality due to lower MPP increased strikingly with higher body surface area (BSA). A negative correlation was observed between MPP indexed to BSA (MPPI) and the Model for End-Stage Liver Disease score (r∼-0.3580, p<0.0001) as well as creatinine (r∼-0.3551, p<0.0001). MPPI less than 40 mmHg/m2 was associated with poorer short-term (23.2% for MPPI<40 mmHg/m2 vs 7.1% for MPPI>40 mmHg/m2, p∼0.001) and medium-term survival. The impact of high RAP and low Ea on survival was evident even on medium-term follow-up; only 30% survival at 7 years follow-up for high RAP and low Ea vs 75% for RAP<15 mmHg (p∼0.0033). CONCLUSION: The acceptable blood pressure during vasodilator therapy in patients with high RAP needs to be higher, especially in those with higher BSA. MPPI less than 40 mmHg/m2 is a risk factor for survival, in the short and medium-term, after heart transplantation.

VLBI measurement of the vector baseline between geodetic antennas at Kokee Park Geophysical Observatory, Hawaii.

We measured the components of the 31-m-long vector between the two very-long-baseline interferometry (VLBI) antennas at the Kokee Park Geophysical Observatory (KPGO), Hawaii, with approximately 1 mm precision using phase delay observables from dedicated VLBI observations in 2016 and 2018. The two KPGO antennas are the 20 m legacy VLBI antenna and the 12 m VLBI Global Observing System (VGOS) antenna. Independent estimates of the vector between the two antennas were obtained by the National Geodetic Survey (NGS) using standard optical surveys in 2015 and 2018. The uncertainties of the latter survey were 0.3 and 0.7 mm in the horizontal and vertical components of the baseline, respectively. We applied corrections to the measured positions for the varying thermal deformation of the antennas on the different days of the VLBI and survey measurements, which can amount to 1 mm, bringing all results to a common reference temperature. The difference between the VLBI and survey results are 0.2 ± 0.4 mm, -1.3 ± 0.4 mm, and 0.8 ± 0.8 mm in the East, North, and Up topocentric components, respectively. We also estimate that the Up component of the baseline may suffer from systematic errors due to gravitational deformation and uncalibrated instrumental delay variations at the 20 m antenna that may reach ± 10 and -2 mm, respectively, resulting in an accuracy uncertainty on the order of 10 mm for the relative heights of the antennas. Furthermore, possible tilting of the 12 m antenna increases the uncertainties in the differences in the horizontal components to 1.0 mm. These results bring into focus the importance of (1) correcting to a common reference temperature the measurements of the reference points of all geodetic instruments within a site, (2) obtaining measurements of the gravitational deformation of all antennas, and (3) monitoring local motions of the geodetic instruments. These results have significant implications for the accuracy of global reference frames that require accurate local ties between geodetic instruments, such as the International Terrestrial Reference Frame (ITRF).

HLA-DR polymorphisms influence in vivo responses to staphylococcal toxic shock syndrome toxin-1 in a transgenic mouse model.

Toxic shock syndrome toxin-1 (TSST-1) is a potent superantigen produced by Staphylococcus aureus. In addition to menstrual and nonmenstrual toxic shock syndromes, TSST-1 is also implicated in the immunopathogenesis of pneumonia, infective endocarditis, neonatal exanthematous disease, and atopic dermatitis among others. Superantigens first bind to major histocompatibility complex (MHC) class II molecules and then activate a large proportion of T cells by cross-linking their T cell receptor. As binding to MHC class II molecules is a critical step in the robust activation of the immune system by TSST-1 and other superantigens, polymorphic variations between different HLA-DR alleles could potentially influence the magnitude of immune activation and immunopathology caused by TSST-1. As TSST-1 is highly toxic to humans and given that multiple variations of alleles of HLA-DR and HLA-DQ are expressed in each individual, it is difficult to determine how HLA-DR polymorphisms quantitatively and qualitatively impact immune activation caused by TSST-1 in humans. However, such investigations can be conducted on transgenic mice lacking all endogenous MHC class II molecules and expressing specific HLA class II alleles. Therefore, transgenic mice expressing different HLA-DRB1 alleles (HLA-DRB1*15:01, HLA-DRB1*15:02, HLA-DRB1*03:01, HLA-DRB1*04:01), and sharing HLA-A1*01:01 chain, were systemically challenged with purified TSST-1 and multiple immune parameters were assessed. Among the HLA-DR alleles, mice expressing HLA-DRB1*15:01 allele elicited a significantly higher serum cytokine/chemokine response; greater splenic T cell expansion and most severe organ pathology. Our study highlights the potential utility of human leukocyte antigen (HLA) transgenic mice in understanding the impact of HLA polymorphisms on the outcomes of diseases caused by TSST-1 and other superantigens.

Influence of HLA-DR polymorphism and allergic sensitization on humoral immune responses to intact pneumococcus in a transgenic mouse model.

Asthma is independently associated with HLA-DR3 and increased risks of pneumococcal diseases. We aimed to determine whether HLA-DR polymorphism (HLA-DRB1*03), sensitization to house dust mite (HDM), or their interaction affects humoral immune responses to pneumococcal polysaccharide and protein antigens of intact pneumococci. Induction of serum titers of anti-pneumococcal polysaccharide and anti-surface protein IgM and IgG in response to immunization with intact pneumococci (Pn) serotype 14 was determined using humanized HLA-DR3 and DR2 transgenic mice. Transgenic mice were sensitized by injecting HDM and challenged with intranasal HDM. Mice were subsequently immunized with heat-killed Pn14 at day 24. Serum titers of anti-phosphorylcholine (PC) IgM and IgG, anti-pneumococcal polysaccharide, capsular type 14 (PPS14) IgM and IgG, and anti-pneumococcal surface protein A (PspA) IgG were measured. We included a total of 44 mice (22 DR3 and 22 DR2 mice) and half of mice in each group were sensitized with HDM (i.e. 22 HDM-sensitized and 22 control mice). HDM-sensitized mice, irrespective of HLA-DR polymorphism, had significantly lower humoral immune responses. HLA-DR3 mice, irrespective of HDM sensitization, elicited a significantly lower anti-PC IgG response. In contrast, the anti-PspA IgG response was higher in DR3 relative to DR2 mice. The effect of HDM sensitization on lowering humoral immune responses to Pn14 was observed in DR3 mice regardless of the nature of the antigen, whereas such decreases were observed only for the anti-PPS14 IgG and anti-PC IgM responses in DR2 mice. HDM sensitization lowered humoral immune responses to intact pneumococcus and this effect was significantly modified by the HLA-DR polymorphism.

HLA-DR polymorphism modulates response to house dust mites in a transgenic mouse model of airway inflammation.

We and others have reported that HLA-DRB1*03 is associated with childhood asthma. To extend this observation and to prove this association, we sensitized and challenged either HLA-DR2 (HLA-DRB1*1502) or HLA-DR3 (HLA-DRB1*0301) transgenic mice with house-dust mite extract. Inflammatory cell counts and cytokine levels in the bronchoalveolar lavage (BAL) fluid between HLA-DR3 and DR2 mice were compared. HLA-DR3 transgenic mice had significantly elevated eosinophil counts, Interleukin-4 and Interleukin-13 levels in the BAL fluid but not interferron gamma-γ. Thus, our study suggests that HLA-DRB1*0301 plays an important role in mounting a Th2-predominant immune response to house dust mite and Th2-type inflammation in the lung.

Evaluating the role of HLA-DQ polymorphisms on immune response to bacterial superantigens using transgenic mice.

Bacterial superantigens bind directly to human leukocyte antigen (HLA) class II molecules and vigorously activate T cells expressing certain T-cell receptor variable region families. As interaction with HLA class II molecules is the primary step in this process, polymorphic variations in HLA class II can determine the extent of superantigen binding to HLA class II molecules, govern the magnitude of immune activation induced by given superantigens and determine the outcome of superantigen-mediated diseases. As direct assessment of the influence of HLA class II polymorphism in humans is impossible because of expression of more than one HLA class II alleles in a given individual and toxicity of superantigens, transgenic mice expressing HLA-DQ6 (HLA-DQA1*0103 and HLA-DQB1*0601) and HLA-DQ8 (HLA-DQA1*0301 and HLA-DQB1*0302) were used to achieve this goal. HLA-DQ6 and HLA-DQ8 elicited comparable in vitro and in vivo immune response to staphylococcal enterotoxins (SE) A, SEB, SEH and SEK, toxic shock syndrome toxin-1, streptococcal pyrogenic exotoxin (SPE) A and SPEC and streptococcal mitogenic exotoxin Z (SMEZ). However, each superantigen had a unique T-cell receptor activation profile. In vivo challenge with Streptococcus pyogenes, H305, capable of elaborating SPEA and SMEZ, yielded a similar clinical outcome in HLA-DQ6 and HLA-DQ8 transgenic mice. In conclusion, HLA-DQ6 and HLA-DQ8 elicited comparable response to certain bacterial superantigens. Our report highlights the advantages of HLA class II transgenic mice in such studies.

Expression and function of HLA-DR3 and DQ8 in transgenic mice lacking functional H2-M.

H2-M or HLA-DM are non-classical class II molecules encoded by the MHC and play an important role during antigen presentation. They catalyze exchange of CLIP (Class II-associated invariant chain peptide) or other low-affinity peptides bound to class II molecules for peptides capable of more efficient binding. The phenotype of mice lacking H2-M is determined by the allotype of the MHC class II molecules expressed. In general, H2-M deficiency does not affect the surface expression of mature class II molecules. The class II molecules in such cases predominantly contain CLIP in their peptide-binding groove. In some mice strains, H2-M deficiency results in defective CD4+ T-cell development accompanied by defective responses to conventional antigens and superantigens. Even though the HLA class II molecules show similar dependency for HLA-DM for presenting antigens in vitro, their interaction in vivo is not known. By using transgenic approach we show here that DQ8 and DR3 are expressed at normal levels in H2-M-deficient mice and the CD4+ T-cell development is unaltered. However, the ability of DQ8 molecules to present peptide antigens is compromised in a H2-M-deficient state. Presentation of exogenous bacterial superantigens by both DQ8 and DR3 is unaffected in H2-M-deficient mice. Unexpectedly, Staphylococcal Enterotoxin B-induced systemic IFN-gamma production was significantly higher in H2-M-deficient DQ8/DR3 transgenic mice and these mice were susceptible to SEB-induced toxic shock at doses that are non-lethal to H2-M-sufficient counterparts.

Follicular growth, endometrial thickness, and serum estradiol levels in spontaneous and clomiphene citrate-induced cycles.

OBJECTIVES: To evaluate follicular growth, endometrial thickness, and serum estradiol levels in spontaneous cycles and cycles induced by clomiphene citrate (CC). METHODS: A 2-year prospective study of spontaneous cycle followed by a CC-induced cycle to compare paired data. Twenty couples with unexplained infertility were recruited from the Infertility Clinic of the Jawaharlal Institute of Postgraduate Medical Education and Research. An oral dose of 150 mg of CC was administered on days 5 through 9 of the CC-induced cycle. Each woman was evaluated using transvaginal sonography and serum estradiol level estimation from day 10 of the menstrual cycle until ovulation. Results were analyzed using the paired t-test. RESULTS: The leading follicular diameter was significantly larger, endometrial thickness was significantly decreased, and serum estradiol levels were significantly higher in the follicular phase of CC-induced cycles. CONCLUSIONS: Clomiphene citrate-induced cycles showed different follicular, endometrial growth patterns, and serum estradiol levels compared with spontaneous cycles.

Placenta accreta and percreta: a review of 5 cases.

Five cases of placenta accreta and percreta are reviewed. Three cases, one a recurrence in the same patient, presented with acute abdominal pain; in one case perforation resulting from placenta percreta was discovered at laparotomy. In another case, placenta accreta was recognized during cesarean delivery. Total or subtotal hysterectomy was performed in three cases; piecemeal removal of placental tissue and closure of the tear was performed in two of the patients. There were no maternal deaths, but the infants were stillborn in three cases of perforation or uterine rupture.