Heterozygous and homozygous gene knockout of the 5-HT1B receptor have different effects on methamphetamine-induced behavioral sensitization.

The psychostimulant drug methamphetamine (METH) causes euphoria in humans and locomotor hyperactivity in rodents by acting on the mesolimbic dopamine (DA) pathway and has severe abuse and addiction liability. Behavioral sensitization, an increased behavioral response to a drug with repeated administration, can persist for many months after the last administration. Research has shown that the serotonin 1B (5-HT1B) receptor plays a critical role in the development and maintenance of drug addiction, as well as other addictive behaviors. This study examined the role of 5-HT1B receptors in METH-induced locomotor sensitization using 5-HT1B knockout (KO) mice. To clarify the action of METH in 5-HT1B KO mice the effects of METH on extracellular levels of DA (DAec) and 5-HT (5-HTec) in the caudate putamen (CPu) and the nucleus accumbens (NAc) were examined. Locomotor sensitization and extracellular monoamine levels were determined in wild-type mice (5-HT1B +/+), heterozygous 5-HT1B receptor KO (5-HT1B +/-) mice and homozygous 5-HT1B receptor KO mice (5-HT1B -/-). Behavioral sensitization to METH was enhanced in 5-HT1B -/- mice compared to 5-HT1B +/+ mice but was attenuated in 5-HT1B +/- mice compared to 5-HT1B +/+ and 5-HT1B -/- mice. In vivo, microdialysis demonstrated that acute administration of METH increases DAec levels in the CPu and NAc of 5-HT1B KO mice compared to saline groups. In 5-HT1B +/- mice, METH increased 5-HTec levels in the CPu, and DAec levels in the NAc were higher than in others.5-HT1B receptors play an important role in regulating METH-induced behavioral sensitization.

Current status of long-term follow-up system for women with a history of hypertensive disorders of pregnancy: the HDP-PPAP study (HDP-Postpartum in Aomori prefecture study).

OBJECTIVE: Women with a history of hypertensive disorders of pregnancy (HDP), especially those with gestational hypertension and preeclampsia, are more likely to develop hypertension, cerebrovascular disease, ischemic heart disease, diabetes mellitus, dyslipidemia, and chronic kidney disease later in life. However, the risk of lifestyle-related diseases in the immediate postpartum period among Japanese women with preexisting HDP is unclear, and a follow-up system for women with preexisting HDP has not been established in Japan. The purpose of this study was to examine the risk factors for lifestyle-related diseases in Japanese women in the immediate postpartum period and the usefulness of HDP follow-up outpatient clinics based on the situation of the HDP follow-up outpatient clinic at our hospital. METHOD: We included 155 women with a history of HDP who visited our outpatient clinic between April 2014 and February 2020. We examined the reasons for dropout during the follow-up period. We also examined the number of new cases of lifestyle-related diseases and compared Body Mass Index(BMI), blood pressure values, and blood and urine test results at 1 and 3 years postpartum in 92 women who had been continuously followed for more than 3 years postpartum. RESULTS: The average age of our patient cohort was 34.8 ± 4.5 years. A total of 155 women with previous HDP were continuously followed for more than 1 year, of whom 23 had new pregnancies, and eight had recurrent HDP (recurrence rate 34.8%). Of the 132 patients who were not newly pregnant, 28 dropped out during follow-up, the most common reason being that the patient did not show up. The patients in this study developed hypertension, diabetes mellitus, and dyslipidemia within a short period. Both systolic and diastolic blood pressures were at normal high levels at 1-year postpartum, and BMI significantly increased at 3 years postpartum. Blood tests revealed significant deterioration in creatinine (Cre), estimated glomerular filtration rate (eGFR), and γ-glutamyl transpeptidase (γGTP) levels. CONCLUSION: In this study, women with preexisting HDP were found to have developed hypertension, diabetes, and dyslipidemia several years postpartum. We also found a significant increase in BMI and worsening of Cre, eGFR, and γGTP levels at 1 and 3 years postpartum. Although the 3-year follow-up rate at our hospital was relatively good (78.8%), some women discontinued follow-up due to self-interruption or relocation, suggesting the need to establish a nationwide follow-up system.

Spontaneous partial uterine laceration in primigravida at 16 weeks of gestation: A case report.

INTRODUCTION: Although uterine rupture is well discussed, uterine laceration and partial myometrial laceration are little known. A previous report hypothesized that the stress of labor was associated with uterine laceration. PRESENTATION OF CASE: We present a rare case of uterine laceration in a patient in the second trimester. A 34-year-old primigravida woman at 16 weeks' gestation without a history of uterine surgery complained of sudden low abdominal pain. Ultrasonography showed fetal death and intraperitoneal free fluid. A laparotomy was performed, and partial uterine laceration in the posterior wall along with active bleeding was confirmed. DISCUSSION: The etiology of uterine laceration in early pregnancy might be different from both classical uterine rupture and previously published uterine laceration. We hypothesized that tissue inadaptable for uterine enlargement, such as that owing to endometriosis and subtle injury by surgical approach, may be associated with the onset mechanism. CONCLUSION: The diagnosis of uterine laceration in early pregnancy is quite difficult because of the absence of specific clinical findings. However, it sometimes causes massive intraperitoneal bleeding and has poor prognosis. Therefore, when uterine laceration is suspected as a cause of hemoperitoneum in a pregnant women, clinicians should perfume exploratory laparotomy appropriately.

In Silico Prediction of Chemical-Induced Hepatocellular Hypertrophy Using Molecular Descriptors.

In silico prediction for toxicity of chemicals is required to reduce cost, time, and animal testing. However, predicting hepatocellular hypertrophy, which often affects the derivation of the No-Observed-Adverse-Effect Level in repeated dose toxicity studies, is difficult because pathological findings are diverse, mechanisms are largely unknown, and a wide variety of chemical structures exists. Therefore, a method for predicting the hepatocellular hypertrophy of diverse chemicals without complete understanding of their mechanisms is necessary. In this study, we developed predictive classification models of hepatocellular hypertrophy using machine learning-specifically, deep learning, random forest, and support vector machine. We extracted hepatocellular hypertrophy data on rats from 2 toxicological databases, our original database developed from risk assessment reports such as pesticides, and the Hazard Evaluation Support System Integrated Platform. Then, we constructed prediction models based on molecular descriptors and evaluated their performance using independent test chemicals datasets, which differed from the training chemicals datasets. Further, we defined the applicability domain (AD), which generally limits the application for chemicals, as structurally similar to the training chemicals dataset. The best model was found to be the support vector machine model using the Hazard Evaluation Support System Integrated Platform dataset, which was trained with 251 chemicals and predicted 214 test chemicals inside the applicability domain. It afforded a prediction accuracy of 0.76, sensitivity of 0.90, and area under the curve of 0.81. These in silico predictive classification models could be reliable tools for hepatocellular hypertrophy assessments and can facilitate the development of in silico models for toxicity prediction.

Hypertensive disorders of pregnancy increase the risk for chronic kidney disease: A population-based retrospective study.

Hypertensive disorders of pregnancy (HDP) and chronic kidney disease (CKD) are well-known risk factors for cardiovascular disease (CVD) in later life. However, few studies have investigated the association of HDP with CKD. Moreover, these studies utilized either registry- or clinical-based data and did not include subclinical CKD patients. To address this gap in the literature, we investigated whether HDP is related to CKD, diagnosed based on the estimated glomerular filtration rate (eGFR), in later life. We designed a population-based, retrospective study, and reviewed the results of blood and physiological examinations as well as the results of pregnancy data available in patients' Maternity Health Record Books for 312 women. We identified 15 women with a diagnosis of CKD based on the eGFR, and 14 women with HDP. We found that women who experienced HDP had a high risk of CKD in later life compared with women without HDP (odds ratio (OR): 4.854; 95% confidence interval (CI): 1.042-22.621). Compared with normotensive women, those who were hypertensive at the time of the examination were significantly associated with CKD (OR: 3.109; 95% CI: 1.213-11.510). Awareness regarding the risk for CKD and CVD in a relatively young age can enable women to prevent diseases effectively.

The effects of interleukin-6 signal blockade on fertility, embryo-fetal development, and immunization in vivo.

Possible effects of interleukin-6 (IL-6) on reproductive performance, embryonal development, parturition, and postnatal development have been suggested based on protein/mRNA expression level of IL-6 in related organs, but less is known about functions of IL-6 signals in these areas. Following two different approaches have been employed to investigate the role of IL-6 signals in fertility and pre-/postnatal development: administration of a rat anti-mouse IL-6 receptor antibody, MR16-1, to mice as a neutralizing antibody system, and B6.129S2-Il6(tm1Kopf)/J (IL-6 knockout [KO]) mice as a KO system. By intravenously dosing 50 mg/kg of MR16-1 every 3 days, animals in male and female fertility studies and dams in a pre-/postnatal development study exhibited plasma MR16-1 concentrations much higher than the effective plasma concentration, indicating that MR16-1 exposure was sufficient to completely block IL-6 signals. The concentration of MR16-1 in the plasma of fetuses exceeded that in the plasma of pregnant animals, and MR16-1 concentration in milk was about one-fourth of that in plasma. Both the transient IL-6 signal blockade by MR16-1, and the constitutive IL-6 signal inhibition using IL-6 KO mice in a combined fertility and pre-/postnatal development study, revealed no biologically important effects on fertility, early embryonic development to implantation, or pre-/postnatal development, including IgG/IgM production by keyhole limpet hemocyanin sensitization. These results indicate that IL-6 signals have no unique, noncompensable roles in reproduction and development in the whole body system, although contributions of IL-6 in the signaling network appear to exist, as suggested by previously published investigations.

Scrub typhus-induced serious gastric ulcer bleeding.

A 67-year-old woman presented with melena and general weakness. Upper gastrointestinal (GI) endoscopy revealed multiple ulcers and projectile bleeding in the stomach. She also complained of a 10-day history of a fever and was diagnosed with scrub typhus based on a positive result of the eschar polymerase chain reaction (PCR) testing. She fully recovered with endoscopic hemostasis, and administration of minocycline and omeprazole. In a patient with GI manifestations, scrub typhus, a condition with pathologically systemic vasculitis, should be considered in the possible background in endemic areas. The eschar PCR testing is a rapid and useful diagnostic tool to identify a specific strain.

'Goose bumps'-associated anaemia.

A 36-year-old woman presented to our hospital for further evaluation of anaemia screened by regular check-up. She was diagnosed with iron-deficiency anaemia (IDA) but refractory to iron supplementation. She had negative results of occult blood in the stool and no gynaecologic disease potentially causing hyper menorrhea. Upper endoscopy revealed a nodular gastritis, which has been called 'Torihada-ien', a Japanese word meaning 'gastritis with goose bumps-like appearance', associated with Helicobacter pylori (Hp) infection. After Hp eradication therapy, her anaemia resolved with an improved response to iron supplementation. In an unexplained IDA patient, Hp-associated gastritis should be considered in the possible background.

When does the sex ratio of offspring of the paternal 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure decrease: in the spermatozoa stage or at fertilization?

Recent animal experiments confirmed that paternal 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure decreases the sex ratio of offspring at birth without altering litter size. However, the timing of this decrease remained unclear. Male mice were administered TCDD at 7-12 weeks of age and mated with non-treated females. The Y-bearing/X-bearing sperm ratio was examined by real-time PCR and FISH methods, and the sex ratio of the 2-cell embryos collected from non-treated females that had been mated with TCDD-exposed males were investigated by nested PCR. The Y-bearing/X-bearing sperm ratio was not significantly decreased in the TCDD group. However, the sex ratio of the 2-cell embryos of the TCDD group was significantly lower than that of the control group. These results may have resulted from a decrease in fertility of Y-bearing sperm. Thus, the results of this study suggested that the sex ratio of the offspring was decreased at fertilization and not during the spermatozoa stage.

Morphological analyses of sex differences and age-related changes in C3H mouse midbrain.

While it is commonly hypothesized that sexual differentiation in the mammalian brain is initiated mainly by gonadal sex steroids, recent evidence has suggested that dopaminergic (DA) neurons within the rodent midbrain have sex differences independent of gonadal secretions. More recently, it has been reported that Sry (the sex-determining region of the Y chromosome) is directly involved in this difference. The possibility of sexual dimorphism in the mouse midbrain needs to be elucidated. In the present study, the midbrain of C3H mice, which is little understood, was investigated histologically and immuno-histoplanimetrically to reveal sexual and developmental differences. The female ventral tegmental area appeared to contain higher immunoreactivity to tyrosine hydroxylase (TH) than that of males at 11 weeks of age, whereas general histological differences between the sexes were not clearly found. The TH-immunoreactive (TH-ir) neurons within the A8, A9, and A10 mesencephalic areas were examined separately. There was the sex difference in the time period when TH-ir cell numbers significantly increased, indicating that the growth rate of midbrain DA nuclei also differs and that the midbrain DA system may trace different processes of sexual maturation between the sexes. These differences between female and male may reflect the direct regulation by Sry or the multiple effects of both Sry and sex steroids. Further experiments are needed to determine which factor forms this difference in the growth pattern in the numbers of TH-ir neurons.

Fetal and neonatal exposure to three typical environmental chemicals with different mechanisms of action: mixed exposure to phenol, phthalate, and dioxin cancels the effects of sole exposure on mouse midbrain dopaminergic nuclei.

A major question is whether exposure to mixtures of low-dose endocrine disruptors (EDs) having different action mechanisms affects neurodevelopment differently than exposure to EDs individually. We therefore investigated the effects of fetal and neonatal exposure to three typical EDs - bisphenol A (BPA), di-(2-ethylhexyl)-phthalate (DEHP), and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) - on the midbrain dopaminergic system associated with functions - including motor activity, emotion, and cognition - affected by neuropsychiatric diseases such as attention-deficit/hyperactivity disorder. ICR mouse dams and their pups were orally treated with BPA (5mg/(kg day)), DEHP (1mg/(kg day)), or TCDD (8ng/kg) individually, or with mixtures thereof, to compare the effects between sole and mixed administration. We analyzed tyrosine hydroxylase (TH)- and Fos-immunoreactive (ir) neurons as markers of dopamine and neuronal activation, respectively. The numbers of TH- and/or Fos-ir neurons and the intensity of TH-immunoreactivity within midbrain dopaminergic nuclei (A9, A10, and A8) of each sole administration group significantly differed from controls at 2, 4, and 6 weeks of age. In contrast, no significant differences were detected in the mixture groups, suggesting counteractions among those chemicals. These results indicate that ED mixtures as pollution have unique and elusive effects. Thyroid hormones and/or aryl hydrocarbon receptor-related mechanisms may be responsible for this counteraction.

Does paternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) affect the sex ratio of offspring?

UNLABELLED: In 1976, men who were exposed to the highest concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) after an explosion at a chemical plant near Seveso, Italy, produced more girls than boys. However, few studies have examined the possibility that the exposure of laboratory animals to TCDD, especially that of males, could lead to a lower male/female sex ratio. The aim of this study was to investigate whether direct paternal exposure to TCDD affects the sex ratio of offspring using a relatively large-scale experimental design. Male ICR mice (n=120) were randomly assigned to three, one of which served as a vehicle control, the other two were administered TCDD orally with an initial loading dose of 2 or 2,000 ng TCDD/kg, followed by a weekly maintenance dose of 0.4 (T2/0.4 group) or 400 (T2000/400 group) ng/kg prior to mating. The major organs of each mouse were weighed and histopathologically and immunohistologically investigated, and the sex ratio of offspring [males/(males + females) x 100] was calculated in each dam. There were no significant effects on organ weights, or on the structure of the testis and epididymis between the control and TCDD-exposed males, but TCDD administration produced a significantly lower proportion of male offspring from T2000/400-exposed sires despite no alteration in litter size ( CONTROL: 53.1 +/- 1.7; T2/0.4: 48.8 +/- 2.5; T2000/400: 46.2 +/- 2.1). In addition, we further divided the T2000/400 group into 3 subgroups based on the proportion of CYP1A1-immunoreactive areas in the liver; there was a significant correlation between sex ratio and CYP1A1 immunoreactivity. Thus, the present study confirms that direct paternal exposure to TCDD might be associated with an alteration in the sex ratio of offspring. Possible mechanisms through which TCDD might decrease the fertility potential of Y-bearing gametes before conception are discussed.

Sugar-based gemini surfactants with peptide bonds-synthesis, adsorption, micellization, and biodegradability.

The sugar-based gemini surfactant with peptide bonds, N,N'-bisalkyl-N,N'-bis[2-(lactobionylamide)ethyl]hexanediamide (2C(n)peLac, in which n represents hydrocarbon chain lengths of 12 and 16), was synthesized by reacting adipoyl chloride with the corresponding monomeric surfactant N-alkyl-N'-lactobionylethylenediamine (C(n)peLac), which was obtained by reacting ethylenediamine with alkyl bromide and lactobionic acid. The adsorption and micellization properties of C(n)peLac and 2C(n)peLac were characterized by the measurement of their equilibrium and dynamic surface tension, steady-state fluorescence using pyrene as a probe, dynamic light scattering (DLS), and time-resolved fluorescence quenching (TRFQ), and their biodegradability was also investigated. The critical micelle concentration (cmc) decreases with an increase in the hydrocarbon chains from monomeric to gemini surfactants, whereas it increases with an increase in the chain length from 12 to 16 for both systems. The increases in both the hydrocarbon chain and the chain length of sugar-based surfactants reduce surface activities such as the ability to lower the surface tension, the occupied area per molecule, and the adsorption rate at the air/water interface. The sugar-based surfactants C(n)peLac and 2C(n)peLac exhibit unique aggregation behavior in aqueous solution. The DLS results indicate that the apparent hydrodynamic diameter of C(n)peLac micelles decreases sharply with increasing concentration, whereas that of 2C(n)peLac micelles decreases gradually. From the TRFQ measurement, it was observed that, as concentration increases, the aggregation numbers are almost constant for C(n)peLac, whereas they increase for 2C(n)peLac. These results imply that loosely packed micelles formed by sugar-based surfactants become tightly packed micelles as the concentration increases. Furthermore, it was found that 2C(n)peLac shows lower biodegradability than does C(n)peLac because it contains tertiary amines in the molecule.