Additive value of the right parasternal view for the assessment of aortic stenosis.

BACKGROUND: Although Doppler evaluation using a multiplanar method is recommended to assess the severity of aortic stenosis (AS) with transthoracic echocardiography, evidence on the diagnostic significance of a non-apical method is limited. This study aimed to compare the use of the apical with the use of the right parasternal view (RPV) method to evaluate AS severity and to examine the diagnostic significance of performing the RPV method in addition to the apical method during the evaluation. METHODS: This retrospective observational study included 276 consecutive patients (mean age: 79 ± 10 years; women, 56%) with severe AS (aortic valve area [AVA] ≤1.0cm2 ). The severity of AS according to the apical method and that according to the RPV for all subjects were compared, and the significance of performing the RPV method in addition to the apical method was examined. Furthermore, we compared the concordance group, in which the apical and RPV methods indicated matching in severity, and the discordant group, in which the apical and RPV methods did not indicate matching severity. RESULTS: Peak velocity (Vmax ), mean pressure gradient (MG) were significantly higher and the AVA, AVAi, and Doppler velocity index (DVI) were significantly smaller when the RPV was added to the apical view. Performing the RPV method in addition to the apical method significantly decreased the number of low PG AS cases (MG < 40 mmHg) from 69.9% to 65.0% and it increased the number of very severe AS cases (Vmax ≥ 5 m/s) from 8.7% to 14.5%. Deviation of Doppler angle was significantly greater in the discordant group compared to the concordant group (22.5 ± .6 vs. 31.8 ± 1.7, p < .001). CONCLUSIONS: By performing the RPV method in addition to the apical method to determine AS severity, the diagnosis of AS to be resolved in approximately 10% of cases. These results suggest that AS severity may be underestimated by using the apical method alone.

Uterus in mixed gonadal dysgenesis was detected by continuous irregular vaginal bleeding.

Disorders of sex development (DSD) are a group of congenital conditions presenting with differences in the chromosomal, gonadal, or anatomic sex development. Evaluating the chromosomes, gonads, and internal and external genitalia of the patients is important for understanding DSD. Furthermore, confirming the presence of a uterus is essential for the assessment of the internal genitalia status. Although the uterus can be identified by ultrasonography, magnetic resonance imaging, or laparoscopy, it may be easily overlooked. Here, we report the case of a patient with mixed gonadal dysgenesis, in whom the presence of a uterus could not be confirmed before the initiation of estrogen replacement therapy despite the performance of various tests. The detection of the uterus was prompted by an atypical genital bleeding. This case implies that physicians may have difficulties identifying the uterus in female patients with DSD before the initiation of estrogen treatment.

The dynamics of mercury near Idrija mercury mine, Slovenia: Horizontal and vertical distributions of total, methyl, and ethyl mercury concentrations in soils.

The distributions of the total mercury (T-Hg), methylmercury (MeHg), and ethylmercury (EtHg) concentrations in soil and their relationship to chemical composition of the soil and total organic carbon content (TOC, %) were investigated. Core samples were collected from hill slope on the right and left riverbanks of the Idrija River. Former smelting plant is located on the right bank. The T-Hg average in each of the core samples ranged from 0.25 to 1650 mg kg-1. The vertical T-Hg variations in the samples from the left bank showed no significant change with depth. Conversely, the T-Hg varied with depth, with the surface, or layers several centimeters from the surface, tending to show the highest values in the samples from the right bank. Since the right and left bank soils have different chemical compositions, different pathways of mercury delivery into soils were suggested. The MeHg and EtHg concentrations ranged from n.d. (not detected) to 444 µg kg-1 and n.d. to 17.4 µg kg-1, respectively. The vertical variations of MeHg and EtHg were similar to those of TOC, except for the near-surface layers containing TOC greater than 20%. These results suggest that the decomposition of organic matter is closely related to organic mercury formation.

Gradually increasing ethinyl estradiol for Turner syndrome may produce good final height but not ideal BMD.

Estrogen replacement therapy in Turner syndrome should theoretically mimic the physiology of healthy girls. The objective of this study was to describe final height and bone mineral density (BMD) in a group of 17 Turner syndrome patients (group E) who started their ethinyl estradiol therapy with an ultra-low dosage (1-5 ng/kg/day) from 9.8-13.7 years. The subjects in group E had been treated with GH 0.35 mg/kg/week since the average age of 7.4 years. The 30 subjects in group L, one of the historical groups, were given comparable doses of GH, and conjugated estrogen 0.3125 mg/week ∼0.3125 mg/day was initiated at 12.2-18.7 years. The subjects in group S, the other historical group, were 21 patients who experienced breast development and menarche spontaneously. Final height (height gain < 2 cm/year) in group E was 152.4 ± 3.4 cm and the standard deviation (SD) was 2.02 ± 0.62 for Turner syndrome. The final height in group L was 148.5 ± 3.0 cm with a SD of 1.30 ± 0.55, which was significantly different from the values for group E. The volumetric BMD of group S (0.290 ± 0.026 g/cm3) was significantly different from that of group L or E (0.262 or 0.262 g/cm3 as a mean, respectively). This is the first study of patients with Turner syndrome where estrogen was administered initially in an ultra-low dose and then increased gradually. Our estrogen therapy in group E produced good final height but not ideal BMD.

Risk analysis of falls in patients undergoing allogeneic hematopoietic stem cell transplantation.

To identify fall risks in patients undergoing hematopoietic stem cell transplantation (HSCT), the authors reviewed retrospective data on inpatients from April 2010 to March 2011. Among 77 HSCT patient records reviewed, the authors found that 35 patients had experienced at least one fall, including near-miss episodes (fallers). The main location of the falls was a corridor, and the main activity at the time of the fall was going to the toilet. To investigate fall risks along the HSCT time trajectory, the authors divided the time into pre- and post-engraftment periods and investigated the unique characteristics of each.

Comparison of two transport systems available in Japan (TERUMO kenkiporter II and BBL Port-A-Cul) for maintenance of aerobic and anaerobic bacteria.

The kenkiporter II (KP II) transport system is commonly used in many hospitals in Japan for transporting bacterial specimens to microbiology laboratories. Recently, the BBL Port-A-Cul (PAC) fluid vial became available. However, no reports thus far have compared the effectiveness of these two transport systems. We chose 4 aerobic and facultative anaerobic bacteria as well as 8 anaerobic organisms, and prepared three strains of each bacterium in culture media for placement into PAC and KP II containers. We compared the effectiveness of each transport system for preserving each organism at 6, 24, and 48 h after inoculation at room temperature. Thirty-six strains out of 12 bacteria were used in this study. The PAC system yielded better recovery in quantity of organisms than the KP II system at 6, 24 and 48 h. More strains were significantly recovered with the PAC system than with the KP II at 24 h (36/36 vs. 23/36, P < 0.001) and 48 h (30/36 vs. 12/36, P < 0.001). The PAC system was better in the recovery of viable organisms counted at 24 and 48 h after inoculation compared with the KP II system. The PAC system may be recommended for the transfer of bacterial specimens in clinical settings.

Rapidly progressive symptom development of pulmonary arterial hypertension: a case report of Trousseau syndrome.

Trousseau syndrome is most commonly defined as a hypercoagulability syndrome associated with mucin-producing adenocarcinoma. We report here a rare case of Trousseau syndrome presenting as pulmonary arterial hypertension. The patient complained of cough and increasing exertional dyspnea. Rapidly progressive symptom development of pulmonary arterial hypertension accompanied by right heart failure was observed, and the patient died on hospital day 2. An autopsy revealed Krukenberg tumors on both ovaries and a signet-ring cell gastric carcinoma. In the lungs there was tumor embolism with signet-ring cells to some extent, but the peripheral pulmonary arteries were occupied primarily by pulmonary embolism with platelets, fibroblasts, and fibrotic organized thrombi.

[The effect of self-determination on time perspective and child-care anxiety].

This study examines the effect of self-determination on time perspectives and child-care anxiety from a viewpoint of life course. A total of 1,726 mothers with small children participated in a questionnaire survey. They were classified into four groups based on their planned life courses: mothers who work; mothers who stopped working, but plan on returning to work; mothers who don't want to work and plan to stay at home; and mothers who stopped working, but plan on returning to work when their children grow up. Child-care anxiety was classified into four categories: (a) sense of stagnation and sacrifice, (b) fatigue, (c) diffidence, (d) feeling disaffection. The results show that fulfillment associated with child-care anxiety exists for all groups and factors of child-care anxiety, and that fulfillment was influenced by differences between self-determination and self-determination desires. The effect of self-determination on time perspectives and child-care anxiety differed between groups. It is suggested that society should provide different support to mothers with small children and child-care anxiety related to their different planned life courses.

Interstitial fluid shifts to plasma compartment during blood donation.

BACKGROUND: A vasovagal reaction (VVR) occurs in 0.8% to 0.9% of voluntary blood donors in Japan. However, they generally tolerate the acute loss of 400 mL of whole blood rather well, perhaps because several circulatory defense mechanisms compensate for the loss. This study aimed to determine the extent to which an interstitial fluid shift contributes to the development of a VVR. STUDY DESIGN AND METHODS: Blood hemoglobin (Hb) was measured upon admission, at venipuncture, and immediately after collecting 400 mL of whole blood from 736 donors. Shifted fluid volume was calculated using a formula that included Hb levels and estimated total blood volume. RESULTS: By the end of blood collection, 188 ± 80 and 211 ± 82 mL of fluid, which is equivalent to almost half of the total amount of withdrawn blood, had entered the intravascular space in male and female donors, respectively. The difference between the sexes was significant despite the lower body weight and circulating blood volume of the female donors. Body weight increased, whereas age decreased the volume of shifted fluid in female donors. CONCLUSION: Blood loss after donation is quickly compensated by an interstitial fluid shift into the intravascular space and may not be the only direct cause of VVR in the setting of a whole blood donation of 400 mL.

[A case report of conversion therapy for initially unresectable colorectal cancer liver metastases after cetuximab as third-line treatment].

The introduction of monoclonal antibodies into the treatment protocols for metastatic colorectal cancer(mCRC)has significantly improved outcomes. There are some patients with mCRC, initially judged unresectable, who become resectable after chemotherapy. For patients with isolated liver metastases, surgical resection is recommended when feasible. We experienced a case in which an initially unresectable mCRC liver metastases converted into a resectable one after cetuximab monotherapy as third-line treatment. The sample from hepatectomy was a pathologically complete response; no remnants were detected. The management of liver metastases contributes to improvements in the clinical setting. For conducting a multimodal treatment of mCRC, the participation of various specialists such as medical oncologists, colorectal/hepaticsurgeons and diagnostic/therapeutic radiologists is indispensable. Furthermore, it is necessary to construct an evidence-based consensus on potentially resectable CRC liver metastases in each hospital.

Retrospective analysis of the international standard-dose FOLFIRI (plus bevacizumab) regimen in Japanese patients with unresectable advanced or recurrent colorectal carcinoma.

BACKGROUND: When applying the topoisomerase inhibitor irinotecan (CPT) with the infusional fluorouracil/levofolinate (FOLFIRI) ± bevacizumab chemotherapy regimen in cases of advanced colorectal carcinoma, the international standard dose for CPT is 180 mg/m(2). Despite this, 150 mg/m(2) CPT is widely prescribed and is the maximum dosage covered by Japanese health insurance. Consequently, the safety of dosing at the international standard has not been tested comprehensively and the efficacy of FOLFIRI in Japan may be underestimated. METHODS: To evaluate the safety of FOLFIRI (+bevacizumab) in clinical practice using international standards, we reviewed medical records of 53 patients who received FOLFIRI (+bevacizumab) with CPT 180 mg/m(2) as first-line treatment between September 2004 and August 2009. The primary endpoint of the study was to measure the relative dose intensity (RDI) of CPT after four courses. The secondary endpoint was to assess treatment completion rate, adverse events, response rate, progression-free survival (PFS) and overall survival (OS) among all patients. RESULTS: The RDI and the treatment completion rate were 88.9% and 69.8%, respectively, in the 53 patients. Accompanying grade 3 or 4 adverse events included neutropenia (35.8%), febrile neutropenia (7.5%), and diarrhea (3.8%). Supportive care managed all toxicity symptoms. Median durations for PFS and OS were 10.3 and 26.5 months, respectively. CONCLUSION: FOLFIRI (+bevacizumab) with the international standard dose of CPT is feasible in clinical practice. In order to minimize deviation of the Japanese regimen from global best practice, international dose standards should be followed.

Patients with Hypophosphatemic Osteomalacia Need Continuous Treatment during Adulthood.

The treatment for hypophosphatemic rickets in children includes phosphate and vitamin D preparations. In children, this regimen significantly improves symptoms, while a treatment for adult patients has not been established. We therefore investigated the clinical courses of 15 adult patients who discontinued therapy when final height was achieved in order to assess the necessity of treatment in adulthood. Thirteen patients developed symptomatic complications, including bone fractures. Among the 13, the 10 patients who restarted therapy all showed clinical improvement, and no side effects of treatment were observed. This study shows that there are some patients with hypophosphatemic osteomalacia who need continuous treatment during adulthood.

Ovarian histological findings in an adult patient with the steroidogenic acute regulatory protein (StAR) deficiency reveal the impairment of steroidogenesis by lipoid deposition.

CONTEXT: The steroidogenic acute regulatory protein (StAR) is essential for the production of steroid hormones. The mutations in the StAR gene typically cause congenital lipoid adrenal hyperplasia (lipoid CAH), characterized by severe adrenal insufficiency in both sexes and complete female external genitalia in genetic males. Affected 46, XX females feminize at puberty and menstruate but have progressive hypergonadotropic hypogonadism. It has been hypothesized that the cholesterol accumulation in the steroidogenic cells destroys the residual steroidogenic capacity and progressive ovarian failure occurs (two-hit model). Additionally, ovulation and luteinization in the patients is supposed to be impaired. However, those hypotheses have not been confirmed histologically. OBJECTIVE: We examined whether pathological findings of the ovary in a patient of lipoid CAH corresponded with two-hit model, and whether ovulation and luteinization occurred or not in the patient. SUBJECT: The ovary in an adult 46, XX female with a homozygous nonsense mutation (Q258X) in the StAR gene was examined. When the patient was age 22 yr, the ovary was resected because of enlargement with polycysts and subsequent torsion. RESULT: The affected ovary demonstrated remarkable lipoid deposition and changes of the mitochondrial ultrastructure. Immunohistochemical examination showed decrease of steroidogenic enzymes such as P450 cholesterol side-chain cleavage (P450scc). Additionally, we detected corpus albicans in the affected ovary. CONCLUSION: This is the first detailed report on ovarian histology in an adult 46, XX female with a null type mutation of the StAR gene (Q258X), which indicates the evidence of the impairment of ovarian StAR-independent steroidogenesis by lipoid deposition.

[Hypophosphatemic rickets/osteomalacia. - Mainly on patients with PHEX mutations -].

Most patients with inherited hypophosphatemic Rickets/Osteomalacia have mutations in the PHEX gene. In this brief review, we focus on the treatment for patients with this mutation. First, molecular basis of inherited hypophosphatemic Rickets/Osteomalacia, followed by pathophysiology of PHEX and its related disorders is described. Next, clinical manifestation of patients with PHEX mutations and the principles of the treatment are explained. Finally, a case with this mutation that has been long followed up is presented. The most common treatment for this disorder is administration of phosphate and vitamin D, both internationally and in Japan. Degree of the increment in serum inorganic phosphorus levels one hour after phosphate administration, in addition to a decrease in alkaline phosphatase levels is valuable in the monitoring of the treatment. During childhood, markers in a longer term, namely, improvement of X-ray findings and that of height velocity are also useful.

The pituitary function of androgen receptor constitutes a glucocorticoid production circuit.

Androgen receptor (AR) mediates diverse androgen actions, particularly reproductive processes in males and females. AR-mediated androgen signaling is considered to also control metabolic processes; however, the molecular basis remains elusive. In the present study, we explored the molecular mechanism of late-onset obesity in male AR null mutant (ARKO) mice. We determined that the obesity was caused by a hypercorticoid state. The negative feedback system regulating glucocorticoid production was impaired in ARKO mice. Male and female ARKO mice exhibited hypertrophic adrenal glands and glucocorticoid overproduction, presumably due to high levels of adrenal corticotropic hormone. The pituitary glands of the ARKO males had increased expression of proopiomelanocortin and decreased expression of the glucocorticoid receptor (GR). There were no overt structural abnormalities and no alteration in the distribution of cell types in the pituitaries of male ARKO mice. Additionally, there was normal production of the other hormones within the glucocorticoid feedback system in both the pituitary and hypothalamus. In a cell line derived from pituitary glands, GR expression was under the positive control of the activated AR. Thus, this study suggests that the activated AR supports the negative feedback regulation of glucocorticoid production via up-regulation of GR expression in the pituitary gland.

Premature ovarian failure in androgen receptor-deficient mice.

Premature ovarian failure (POF) syndrome, an early decline of ovarian function in women, is frequently associated with X chromosome abnormalities ranging from various Xq deletions to complete loss of one of the X chromosomes. However, the genetic locus responsible for the POF remains unknown, and no candidate gene has been identified. Using the Cre/LoxP system, we have disrupted the mouse X chromosome androgen receptor (Ar) gene. Female AR(-/-) mice appeared normal but developed the POF phenotype with aberrant ovarian gene expression. Eight-week-old female AR(-/-) mice are fertile, but they have lower follicle numbers and impaired mammary development, and they produce only half of the normal number of pups per litter. Forty-week-old AR(-/-) mice are infertile because of complete loss of follicles. Genome-wide microarray analysis of mRNA from AR(-/-) ovaries revealed that a number of major regulators of folliculogenesis were under transcriptional control by AR. Our findings suggest that AR function is required for normal female reproduction, particularly folliculogenesis, and that AR is a potential therapeutic target in POF syndrome.

Limitations of G-banding Karyotype Analysis with Peripheral Lymphocytes in Diagnosing Mixed Gonadal Dysgenesis.

Mixed gonadal dysgenesis (MGD) is an abnormal sexual differentiation syndrome usually presenting with ambiguous genitalia. Karyotype analysis is one of the essential components in the diagnosis of MGD and is conventionally done with peripheral lymphocytes by the G-banding technique. It is speculated that this conventional karyotype analysis has limitations since there are often difference in gonadal tissue analysis. Here we present four cases of MGD, in which karyotype analysis were performed by peripheral lymphocytes fluorescence in situ hybridization (FISH), gonad fibroblasts FISH and gonad fibroblasts G-banding technique, in addition to the conventional peripheral lymphocytes G-banding technique. In Case 1, the percentage of the 45,X cell line in lymphocytes decreased after birth and detection of mosaicism could only be done by karyotype of gonads at 7 mo of age. In Case 2, FISH analysis with peripheral lymphocytes was more useful for detecting low frequency mosaicism. In all cases, phenotype of gonads and external genitalia were more consistent with karyotype of gonads than that of the peripheral lymphocytes G-banding technique. In conclusion, conventional G-banding karyotype analysis with peripheral lymphocytes has limitations in the diagnosis and evaluation of MGD. Karyotype analysis by FISH or by using gonads is useful for diagnosing MGD and understanding of the phenotype of gonadal tissue.

Mutational Analysis of Androgen Receptor (AR) Gene in 46,XY Patients with Ambiguous Genitalia and Normal Testosterone Secretion: Endocrinological Characteristics of Three Patients with AR Gene Mutations.

The prevalence of abnormalities in androgen receptor gene (AR) among patients with ambiguous genitalia is unknown. Moreover, endocrinological data from prepubertal patients with AR mutation are very limited. Thus, the aim of this study was to examine the prevalence of abnormalities in AR among patients with both ambiguous genitalia, which was defined as a combination of two or more genital abnormalities (i.e. hypospadias, microphallus (penile length < 25 mm), hypoplastic scrotum, bifid scrotum, undescended testis) in this study, and normal to elevated T levels. We also compared the endocrinological data of prepubertal patients with AR mutation and ambiguous genitalia with that of those without the AR mutation. We screened 26 Japanese prepubertal 46,XY patients (five from three families were included) with both ambiguous genitalia and normal to elevated T levels. Mutations in AR were found in three (two of the three were related). Among the 23 patients without mutation in AR, the steroid 5-alpha-reductase 2 gene (SRD5A2) was also examined in eight patients with elevated T/dehydrotestosterone ratio after the hCG (>10) or with undervirilized family members. No mutation in SRD5A2 was found. Characteristics of the three patients with mutation in AR were compared with the 23 patients without mutation. In two patients, basal T levels (0.3, 0.2 ng/ml) and peak T levels after the hCG tests (8.3, 8.5 ng/ml) tended to be higher, and the peak LH/ peak FSH ratios after the GnRH tests (4.6, 4.0) were higher than in patients without mutation, at the ages of 1 yr and 9 mo and 3 yr and 8 mo, respectively. In conclusion, an abnormality in either AR or SRD5A2 was not common among patients with ambiguous genitalia and normal testosterone secretion. Elevated peak LH/peak FSH ratio (≥4) after the GnRH test in addition to detectable basal T levels and elevated peak T levels after the hCG test may infer AR abnormality in prepubertal patients with ambiguous genitalia at the age of one and over, although further study is needed, because our data were limited.

Low level mercury uptake by plants from natural environments--mercury distribution in Solidago altissima L.-.

In order to elucidate the participation of plants in the biogeochemical cycling of mercury in natural environments, total mercury contents in leaves, stems and roots of tall goldenrod (Solidago altissima L.), Compositae, were determined. The mercury content in stems was considerably lower than that in leaves and roots. A positive correlation of mercury content was observed between soil and roots. The leaves at the lower part of the plant tended to have a higher concentration of mercury than the upper leaves. However, the mercury content of the leaves was independent of that in the soil. These observations suggested that the leaves of the plant can accumulate environmental mercury, but the mercury does not come from the soil via the root and stems. The mercury in leaves might originate predominantly from ambient air. The mercury in the leaves accumulated from the air can be delivered to the soil when the leaves fall. The roots also can adsorb the mercury from the soil; however, the mercury does not move from the roots and is not released into the air via the plant body.

Hearing evaluation in two sisters with a T8993G point mutation of mitochondrial DNA.

We report on two sisters with a T8993G point mutation of mitochondrial DNA, and their hearing evaluation. Considering auditory function, hearing in the elder sister remains almost normal. However, in the younger sister, the auditory brainstem response (ABR) threshold has fluctuated remarkably during a 3-year follow-up. The threshold changes of ABR in the younger sister suggest that her hearing problems may well be caused by both cochlear nerves and retrocochlear lesions. Our experience is clinically important because there have been only a few reports on hearing evaluation in patients with a T8993G point mutation of mitochondrial DNA.