Loeys-Dietz syndrome with a novel in-frame SMAD3 deletion diagnosed as a result of postpartum aortic dissection: A case report.

OBJECTIVE: Loeys-Dietz syndrome (LDS) is a rare, autosomal dominant connective tissue disorder which can aggressively affect the aortic vasculature. Limited information is available regarding its impact on pregnancy and postpartum outcomes. CASE REPORT: A pregnant 38-year-old nulliparous woman with mild aortic regurgitation and family history of aortic aneurysms presented with an aortic root measuring 49 mm. Despite concerns of an underlying connective tissue disorder, a definitive diagnosis was not reached. She delivered under strict blood pressure control, developed intractable uterine atony, and underwent uterine artery embolization. On the second postpartum day, aortic dissection was incidentally diagnosed, and aortic root replacement surgery was performed. Genetic testing revealed a novel in-frame SMAD3 deletion [NM_005902.4: c.703_708del, (p.Ile235_Ser236del)], leading to a diagnosis of LDS type 3. CONCLUSION: This case highlights the high postpartum aortic dissection risk in women with LDS, emphasizing the importance of early diagnosis in pregnant women with few clinical symptoms.

Endometritis risk factors after arterial embolisation for postpartum haemorrhage.

Various complications of arterial embolisation (AE) for postpartum haemorrhage (PPH) are reported. Endometritis (EM) frequently causes abscesses, increasing hysterectomy risk. However, risk factors for EM after AE for PPH are unclear. We explored these risk factors. We included patients who underwent AE for PPH in our hospital from 2005 to 2020 and compared those who did (EM group) and did not develop EM after AE (non-EM group) in a case-control study. Twenty patients met the study criteria; eight patients (40%) had EM. There were no differences in risk factors between groups involved in infection, such as premature rupture of membranes. However, the contrast medium extravasation rate on computed tomography scans before the AE procedure was significantly higher in the EM group (p=.019) compared to the non-EM group. The greatest EM risk factor was contrast medium extravasation before AE for PPH, determined by classification and regression tree modelling (relative risk: 4.5).Impact StatementWhat is already known on this subject? Reportedly, the clinical success rate of arterial embolisation (AE) for critical haemorrhage in obstetrics is high, around 90%. However, information regarding AE complications is limited. Endometritis is one of these complications, which not only causes prolonged hospitalisation but may also require further treatment, such as hysterectomy. However, the incidence rate and risk factors for EM remain unknown.What do the results of this study add? In this study, 40.0% of patients developed EM after AE for PPH. Extravasation of contrast medium was the top risk factor (relative risk: 4.5 compared to those without EM, p=.019). The second-leading risk factor was a bleeding volume greater than 2500 mL (relative risk: 4.5 compared to those without EM, p=.019).What are the implications of these findings for future clinical practice and/or future research? We created an EM prediction model using extravasation and a bleeding volume greater than 2500 mL. The model was 87.5% sensitive and 66.7% specific. This prediction model allows for the early detection and treatment of EM by recognising high-risk patients and providing intensive postpartum management.

The perinatal outcomes by gestational weight gain range at 30 weeks of gestation among pre-pregnancy underweight women.

AIMS: To evaluate the perinatal outcomes by gestational weight gain (GWG) range at 30 weeks of gestation among underweight pregnant women (pre-pregnancy body mass index ≤ 18.5 kg/m2 ) in Japan. METHODS: This retrospective study was conducted at a hospital in Japan from 2003 to 2020. The underweight pregnant women (UPW; n = 3643) were divided into quartile groups based on the weight gain at 30 weeks of gestation: group Q1 ≤ 5.7 kg, 5.7 kg < Q2 ≤ 7.2 kg, 7.2 kg < Q3 ≤ 8.8 kg, and 8.8 kg < Q4. Clinical characteristics and outcomes were compared using the t-test, chi-square test, and multivariable logistic regression analysis. RESULTS: The cumulative incidences of preterm births were 7.5% (n = 70), 5.0% (n = 45), 5.4% (n = 50), and 4.9% (n = 44), and the birth rates of small for gestational age (SGA) infants were 15.7% (n = 147), 9.6% (n = 87), 6.9% (n = 64), and 5.9% (n = 53) in Q1, Q2, Q3, and Q4, respectively. Multivariable analysis revealed that Q1 was significantly associated with preterm births (adjusted odds ratio [aOR] = 1.6; 95% confidence interval [CI] = 1.0-2.3), and Q1 and Q2 were significantly associated with SGA (adj. OR = 3.0; 95% CI = 2.2-4.3; adj. OR = 1.7; 95% CI = 1.2-2.5, respectively). None of the quartile groups were significantly associated with the incidence of primary cesarean sections, gestational diabetes mellitus, and macrosomia. CONCLUSIONS: In UPW, GWG at 30 weeks of ≤5.7 kg and ≤7.2 kg are associated with preterm birth and SGA rates, respectively.

Benign metastasising leiomyoma with endometrial carcinoma, with a differential diagnosis of metastatic lung cancer.

Benign metastasising leiomyoma (BML) is a rare disease in which histologically benign uterine fibroids spread throughout the body. It is thought to originate from the hematogenous metastasis of myoma cells following myomectomy. To date, BML has been noted in patients with respiratory symptoms, even during regular checkups. There are few case reports of co-occurrence with gynaecological cancer. We report the case of a suspected stage IVb carcinoma based on preoperative examination for endometrial cancer, that indicated lung metastasis. However, postoperative pathology revealed a grade 1, pT1a pN0 tumour. We suspected BML based on the discrepant findings and history of myomectomy, and this was confirmed by lung biopsy. In metastatic lesions of a carcinoma patient with a history of myomectomy, the co-occurrence of BML should be considered when there is discrepancy between the preoperative suspected stage and postoperative pathology.

Velamentous cord insertion ruptured during labour leading to acute fetal blood loss.

Umbilical cord rupture (UCR) in utero is a very rare and critical emergency that can cause fetal death within minutes. A 38-year-old nulliparous woman was admitted at 39 weeks in labour. Sudden watery vaginal discharge and bleeding with a rapid drop in the fetal heart rate to 60 beats/min necessitated an emergency caesarean section. A male infant weighing 2632 g was delivered 21 min after the onset of bradycardia; Apgar scores were 0 and 1 at 1 and 5 min, respectively. He was extremely pale; the umbilical arterial blood pH was 6.89 and haemoglobin was 9.0 g/dL. The umbilical cord had a velamentous insertion and was lacerated, with haemorrhage in the outer layer of an umbilical artery close to the placental end. The presentation was typical of UCR: vaginal bleeding following the rupture of membranes. Prompt diagnosis of UCR and termination of pregnancy are essential for fetal survival.

Prehypertension in early pregnancy is a risk factor for hypertensive disorders during pregnancy: A historical cohort study in Japan.

Objective: We evaluated the association between pre-hypertension (120-139 or 80-89 mmHg) in early pregnancy, hypertensive disorders of pregnancy (HDP), and perinatal adverse outcomes. Methods: We included 14,066 pregnant women, treated between 2003 and 2019 in Japan. Based on a blood pressure chart review recorded before 20 weeks of gestation, we stratified participants into the prehypertension (n = 3,806) and normotensive (n = 10,260) groups. Results: Prehypertension, an independent risk factor for HDP in the multivariate analysis (P< 0.001), was significantly associated with preterm and small-for-gestational age infants. Conclusion: Prehypertension potentially confers a risk for adverse perinatal outcomes in apparently normal pregnancies.

Steroid withdrawal based on lymphocyte sensitivity to endogenous steroid in renal transplant recipients.

Though steroid withdrawal is done in many renal transplant recipients, some patients must restart steroids. Little report has investigated steroid withdrawal under pharmacodynamic monitoring. We assessed lymphocyte sensitivity to endogenous cortisol as a biomarker for determining the safety of steroid withdrawal in renal transplant patients, as we hypothesized that patients hyposensitive to cortisol could not be sufficiently immunosuppressed by their intrinsic cortisol as a substitute for the reduced or withdrawn steroid. Lymphocyte sensitivity to cortisol was examined in 30 long stable renal transplant recipients. Lymphocyte sensitivity to cortisol and its relationship with the clinical outcome after steroid reduction and withdrawal was investigated. The lymphocyte sensitivities to cortisol were estimated as IC(50) of lymphocyte blastogenesis. The lymphocyte proliferation rate for concentration of serum cortisol compared between incident and non-incident groups. Serum creatinine levels (S-Cr) increased in a significantly higher number of patients hyposensitive to cortisol (IC(50)≧10000 ng/ml) than in normally sensitive patients (IC(50)<10000 ng/ml). The incidences of steroid withdrawal syndrome and necessity for increasing steroid dose or restarting steroid administration were also higher in the patients hyposensitive to cortisol. The patients in whom the lymphocyte proliferation rate was less than 60% did not show increase in S-Cr, experience steroid withdrawal symptoms, or require an increase in the steroid dose or restart of steroid administration. The patients who have the normal IC(50) values of cortisol, can withdraw steroid more safely. The lymphocyte sensitivity to cortisol may be a useful biomarker for selecting patients who can sustain steroid withdrawal.

Irinotecan hydrochloride (CPT-11) in dialysis patients with gastrointestinal cancer.

We investigated changes in drug disposition and toxicities with CPT-11 in 15 dialysis patients with gastrointestinal cancers to clarify whether CPT-11 could be administered safely in such patients. For comparison, the same parameters were also investigated in 10 cancer patients not undergoing dialysis. Items investigated included (1) plasma concentrations of SN-38, SN-38G and CPT-11 at 0, 1, 12, 24, 36, 48 and 72 h after administration, together with a comparison of mean AUC values for 3 dose levels of CPT-11 (50, 60 and 70 mg/m2) in dialysis patients and controls; and (2) occurrence of adverse events. Several findings emerged from this study: (1) No significant difference was observed in the AUC for SN-38 or CPT-11 between the dialysis and control groups; (2) The AUC for SN-38G at each dose was significantly higher in dialysis patients; and (3) Grade 1-4 leucopenia was observed in 11 of the dialysis patients. One patient developed grade 4 leucopenia and died due to sepsis. Anorexia, diarrhea, nausea, alopecia and interstitial pneumonia occurred in 6 dialysis patients. We found changes in drug dispositions of CPT-11, SN-38 and SN-38G in dialysis patients, suggesting that hepatic excretion, especially that of SN-38G, was increased. No significant difference in occurrence of adverse events was observed between the 2 groups. This indicates that CPT-11 can be administered safely in patients on dialysis.

Comparative study of the cellular pharmacodynamics of calcineurin inhibitors between patients with chronic renal failure awaiting renal transplantation and cirrhosis patients awaiting liver transplantation.

The in vitro response of peripheral blood mononuclear cells (PBMCs) to the suppressive effects of calcineurin inhibitors is known to correlate with the clinical efficacy of drugs used in renal transplantations. The present study was conducted to examine the differences of PBMC responses to calcineurin inhibitors between chronic renal failure (CRF) patients awaiting renal transplantation and cirrhosis patients awaiting liver transplantation. The study included 99 CRF patients awaiting renal transplantation and 27 cirrhosis patients awaiting liver transplantation. Twenty milliliters of venous blood was taken 1-7 days before transplantation. The in vitro drug concentrations giving 50% inhibition of PBMC blastogenesis stimulated with concanavalin A (IC(50)s) were calculated. The suppressive effects of tacrolimus against PBMC blastogenesis were more than 10-100 times stronger than those of cyclosporine. The median IC(50) value for cyclosporine against the CRF PBMCs was not significantly different from the median IC(50) value against the cirrhosis PBMCs. In contrast, tacrolimus sensitivity in cirrhosis PBMCs is approximately seven times higher than that in CRF PBMCs. The median IC(50) value for tacrolimus against cirrhosis PBMCs was significantly lower and therefore the effect was stronger in comparison to the CRF PBMCs (p < 0.001). These data suggest that the PBMCs of cirrhosis patients, in comparison to those of CRF patients, are highly sensitive to the suppressive effect of tacrolimus. However, PBMC sensitivity to cyclosporine was not significantly different between the CRF and cirrhosis patients. These observations raise the possibility that treatment with tacrolimus, rather than cyclosporine, may therefore be a better choice to reduce the risks of allograft rejection in liver transplantation.

Clinical significance of the cellular pharmacodynamics of tacrolimus in living-donor liver transplantation.

Successful immunosuppressive therapy is critical for liver transplantation; however, a considerable number of patients experience fatal rejection or alternatively exhibit serious infection resulting from excessive immunosuppression. The in vitro tacrolimus response of peripheral blood mononuclear cells (PBMCs) before transplantation was compared to the clinical outcome up to 4 weeks after operation in 28 living-donor liver transplant recipients treated with tacrolimus. The tacrolimus IC(50) values against concanavalin A-induced PBMC blastogenesis in vitro were calculated. These recipients were classified into two groups with the mean tacrolimus IC(50) (0.18 ng/ml) as the cutoff point, after which the clinical outcome between the patient groups was compared. The allograft rejection incidence in the low-sensitivity group (IC(50) < 0.18 ng/ml; n = 16) was 6/12 (50.0%), which was significantly higher than the incidence of 2/16 (12.5%) in the high-sensitivity group (IC(50) > 0.18 ng/ml; n = 12) (p = 0.0297). In contrast, the infection incidence in the high-sensitivity group was 6/16 (37.5%), which was significantly higher than that of the low-sensitivity group (1/12; 8.3%) (p = 0.0401). These data suggest that patients exhibiting a low PBMC sensitivity to tacrolimus have a risk of rejection, whereas highly sensitive patients have a risk of infection in living-donor liver transplantations under tacrolimus therapy.

A nonsuture anastomosis using magnetic compression for biliary stricture after living donor liver transplantation.

Magnetic compression anastomosis involves the use of two magnets that are attracted transmurally between two internal organs resulting in compression and subsequent fistula formation (1). We report on the clinical use of magnetic compression anastomosis using extracorporeal magnetic guidance for the treatment of complete obstruction of the common bile duct (CBD) following living donor liver transplantation. This novel treatment has the advantages of low invasiveness and simplicity, and it should be considered as a feasible alternative therapy for biliary obstruction.

Influence of bacterial superantigen TSST-1 against the anti-proliferative efficacy of immunosuppressive drugs and interleukin 2 production in peripheral blood mononuclear cells of hemodialysis patients and healthy subjects.

We investigated the influence of bacterial superantigen on the efficacies of immunosuppressive drugs on the blastogenesis of peripheral-blood mononuclear cells of 27 hemodialysis patients awaiting renal transplantation. The IC(50) values for prednisolone, methylprednisolone, cyclosporine, and tacrolimus evaluated in the superantigen-stimulated cells were significantly higher than those evaluated in concanavalin A-stimulated cells (p = 0.0002-0.018). Interleukin-2 amounts produced from superantigen-stimulated cells were significantly larger than those from concanavalin A-stimulated cells (p = 0.0363). These results suggest that superantigen attenuates the suppressive efficacies of glucocorticoids and calcineurin inhibitors by stimulating lymphocytes of hemodialysis patients awaiting transplantation to overproduce interleukin-2.

Evidence of different pharmacokinetics including relationship among AUC, peak, and trough levels between cyclosporine and tacrolimus in renal transplant recipients using new pharmacokinetic parameter--why cyclosporine is monitored by C(2) level and tacrolimus by trough level--.

The clinical efficacy of calcineurin inhibitors administered to renal transplant patients is considered to be a strong function of the area under the concentration time curve (AUC). Interestingly, monitoring timings of blood concentrations for two similar calcineurin inhibitors, cyclosporine (CYA; Neoral) and tacrolimus (TAC; Prograf) are different. Namely, CYA blood concentration is usually monitored at 2 h after administration (C(2)) substituted for peak concentration (C(p)) and TAC at trough concentration (C(t)). In the literature, data describing such characteristics of CYA and TAC have been presented in the past. However, each of these patient groups had different backgrounds. We have attempted to examine the behavior of blood concentration curves simultaneously for both CYA and TAC by establishing controlled groups of renal transplant patients with similar clinical backgrounds. Furthermore, we have analyzed the correlation with C(p) and C(t) versus AUC implementing area under the trough level (AUTL), or area above the trough level (AATL) as new pharmacokinetic parameters, such that C(2) for CYA and C(t) for TAC have been verified using controlled clinical data. We have also found distinct differences in the pharmacokinetics between CYA and TAC with the relationships between AUC, C(p), and C(t).

Long-term follow-up ABO-incompatible adult living donor liver transplantation in cirrhotic patients.

ABO-incompatible liver transplantation is usually contraindicated. The presence in the recipient of preformed anti-A/B antibodies located on endothelial cells raises the risk of antibody-mediated humoral rejection of the graft. We describe four successful cases of steroid withdrawal in adult patients who had living-donor liver transplantation from ABO-incompatible donors. Antirejection therapy included multiple perioperative plasmapheresis, splenectomy, and a triple immunosuppressive regimen with tacrolimus, methylprednisolone (MPSL), and cyclophosphamide or mycophenolate mofetil (MMF). The maintenance dose of immunosuppression did not differ from that of ABO-identical cases. After transplantation, intrahepatic arterial infusion therapy with prostaglandin E1 (PG E1) was used. As a result, all four patients were able to achieve long-term graft survival without steroid use. They all have good liver function and are leading normal lifestyles. Our experience with these four patients suggests the feasibility of controlling humoral rejection and other complications in adult ABO-incompatible living donor liver transplantations with intrahepatic arterial infusion of PGE1, splenectomy, and plasmapheresis with a regular base of immunosuppression protocol to prevent antibody-mediated humoral rejection.

Bacterial superantigen TSST-1 attenuates suppressive efficacy of glucocorticoids and calcineurin inhibitors against blastogenesis of peripheral blood mononuclear cells from patients with chronic renal failure on hemodialysis treatment.

BACKGROUND: Many cases of patients with chronic renal failure (CRF) on hemodialysis are known to be infected with Staphylococcus aureus (S. aureus) from the sites of blood vessel puncture for hemodialysis and the custody of the vascular access catheter. S. aureus produces superantigens, such as toxic shock syndrome toxin-1 (TSST-1), which may influence the sensitivity of peripheral-blood mononuclear cells (PBMCs) to immunosuppressive drugs after they are received postrenal transplantation. METHODS: We examined the drug-sensitivities of PBMCs stimulated with TSST-1 in 18 CRF patients on hemodialysis. PBMCs were isolated from venous blood before hemodialysis, and were cultured in the presence of concanavalin A (ConA) or TSST-1 and serial concentrations of the drugs. In vitro drug concentrations giving 50% inhibition (IC(50)) of PBMC blastogenesis were calculated. INF-gamma and IL-4 in supernatants of cultured PBMCs were measured with ELISA. RESULTS: The median (range) IC(50) values (ng/ml) for four drugs; tacrolimus, cyclosporine, methylprednisolone, and prednisolone, evaluated in ConA-stimulated PBMCs of CRF patients were 0.04 ng/ml (0.03-0.21), 3.0 (0.1-15.1), 3.0 (1-104), and 16.2 (5.9-35.4), respectively. The values for the four drugs evaluated in TSST-1-stimulated PBMCs were 0.22 (0.08-0.36), 18.9 (5.1-38.2), 328.3 (1.9-1000), and 150.9 (94.7-880), respectively, which were significantly higher than those evaluated in the ConA-stimulated PBMCs (p=0.003-0.023). Amounts of INF-gamma and IL-4 produced from cells were not significantly different between the ConA-or TSST-1-stimulated PBMCs in the presence or absence of immunosuppressive drugs. CONCLUSION: These observations raise the possibility that TSST-1 induced by S. aureus infection attenuates the clinical efficacy of glucocorticoids and calcineurin inhibitors in CRF patients after renal transplantation. Furthermore, INF-gamma and IL-4 related pathways appear not to play major roles in the TSST-1-induced attenuation of the drug sensitivities.

Application of machine perfusion preservation as a viability test for marginal kidney graft.

BACKGROUND: This study evaluated the usefulness of machine perfusion preservation parameters as indicators of kidney graft viability. METHODS: Eighty-eight cadaveric kidneys were analyzed in this study. Of these, 74 kidneys (84.1%) were procured from nonheartbeating donors. The criteria for an acceptable kidney for transplantation were a perfusion flow of more than 0.4 mL/min/g with a concurrent decreasing perfusion pressure. The average perfusion pressure was 30-50 mmHg. We divided the kidneys into three groups: group 1 (n=35), 0.45-0.65 mL/min/g machine perfusion flow (MPF); group 2 (n=30), 0.65-0.90 mL/min/g MPF; and group 3 (n=23), more than 0.9 mL/min/g MPF. RESULTS: A higher rate of primary nonfunction (PNF; 25.7%) was found in group 1, compared with 6.7% in group 2 and 0% in group 3. A higher rate of 30.4% immediate function was found in group 3, compared with 16.7% in group and 8.6% in group 1. However, a longer period of acute tubular necrosis (ATN; 12.0 days) was found in group 1 compared with 8.6 days in group 2 and 8.7 days in group 3. PNF was detected in 7 (77.8%) cases with more than 16 hr of total ischemic time (TIT) in group 1. In contrast, all of nine cases with more than 16 hr of TIT in group 3 were functional. CONCLUSIONS: MPF is a reliable indicator of graft viability based on the rate of PNF and immediate renal allograft function, especially in marginal donors.

[Cord blood transplantation after successful treatment of brain abscess caused by Bacillus cereus in a patient with acute myeloid leukemia].

Central nervous system infection caused by Bacillus cereus is a rare condition, which often progresses rapidly and is fatal in immunocompromised patients. A 54-year-old woman with acute myelogenous leukemia fell into a coma with high fever during severe neutropenia while undergoing chemotherapy. A blood culture demonstrated the presence of B. cereus and magnetic resonance imaging showed multiple abnormal lesions in her brain. The patient was treated with meropenem and vancomycin, and recovered from the coma in a week. Antibiotic therapy was administered for seven weeks, and then she underwent cord blood transplantation for refractory acute myelogenous leukemia with successful engraftment without exacerbation of the brain abscess. This case demonstrates that brain abscess caused by B. cereus can be treated without surgical treatment.

Increased sensitivities of peripheral blood mononuclear cells to immunosuppressive drugs in cirrhosis patients awaiting liver transplantation.

Successful immunosuppressive therapy is critical for liver transplantation. However, a considerable number of patients show clinical resistance to the therapy and experience rejection episodes, or alternatively exhibits serious adverse effects of drugs. We examined the in vitro response of peripheral blood mononuclear cells (PBMCs) to immunosuppressive drugs in cirrhosis patients awaiting liver transplantation. We evaluated the suppressive efficacy of prednisolone, methylprednisolone, cyclosporine, and tacrolimus on the in vitro blastogenesis of PBMCs obtained from 22 cirrhosis patients and 31 healthy subjects. In vitro drug concentrations giving 50% inhibition of PBMC blastogenesis (IC50s) were calculated. Two out of these 22 patients received liver transplantation from living donors, and their clinical courses were surveyed until 5 weeks after operation. The median IC50 values for prednisolone, cyclosporine, and tacrolimus against blastogenesis of PBMCs from cirrhosis patients were significantly lower than those of PBMCs from healthy subjects (p < 0.01). However, large individual differences were observed in the IC50 values of the immunosuppressive drugs examined, especially in the cirrhosis patients. One recipient exhibiting high PBMC sensitivity to tacrolimus (IC50 = 0.001 ng/ml) showed good clinical course without rejection until 5 weeks after liver transplantation. The other recipient exhibiting relatively low PBMC sensitivity to taclolimus (IC50 = 0.30) showed allograft rejection at 1 week after operation. We concluded from these observations that PBMCs of cirrhosis patients are vulnerable to the immunosuppressive effects of prednisolone and calcineurin inhibitors. However, large individual variations in the IC50 values suggest that patients exhibiting relatively lower sensitivity to these drugs may have risks of rejection, whereas highly sensitive patients are possibly able to reduce the dose of immunosuppressive drugs to avoid serious drug-adverse effects, after liver transplantation.

Early graft function in kidney transplantation from non-heart-beating donors.

The shortage of kidneys for transplantation is a universal problem. The non heart beating donor (NHBD) is one such source. This study evaluates the early graft function after kidney transplantation from NHBD. We report our experience with 126 kidney transplantations retrospectively. As a result, the kidney from NHBD over 50 years of age, led to the longer ATN and high PNF (13.8+/-12.6 days and 16.9% respectively). TIT more than 720 min or less had statistically correlated with the length of ANT (13.3 v. 8.4 days). Significant higher incidence of PNF (19.3%) was shown in the group of TIT more than 720 min with WIT of 20.8+/-31.6 min. Significant low flow by machine perfusion was resulted in PNF. In conclusion, we suggest that early and delayed graft function of kidneys from NHBD should be recognized as a separate clinical entity with its own significant effects.