Effects of Switching From Another Sodium-Glucose Cotransporter 2 Inhibitor to Tofogliflozin on Nocturia in Patients With Type 2 Diabetes.

OBJECTIVE: We aimed to characterize the effects of a switch from another sodium-glucose cotransporter 2 (SGLT2) inhibitor to tofogliflozin, which has a shorter half-life, in Japanese patients with type 2 diabetes. In particular, we aimed to assess the changes in the frequency of nocturnal urination and other parameters after four months of treatment. METHODS: A cohort of 31 patients who were taking SGLT2 inhibitors other than tofogliflozin was selected for a switch to tofogliflozin. After four months, their clinical parameters were assessed. In addition, questionnaires were administered to evaluate changes in the frequency of urination during the day, the amount of water intake, and the quality of sleep of the participants at this time point. RESULTS: Data for 30 of the participants were analyzed. We documented the following comorbid conditions of the urinary system among the participants: prostatic hypertrophy (4, 13%) and prostate cancer (1, 3.3%). The SGLT2 inhibitors that the participants had been using before switching to tofogliflozin were empagliflozin (16, 53%), dapagliflozin (4, 13%), canagliflozin (8, 27%), luseogliflozin (1, 3.3%), and ipragliflozin (1, 3.3%). There was a significant decrease in the frequency of nocturnal urination, from 2.6 ± 0.83 to 2.1 ± 1.3 times (P = 0.014). However, there were no significant changes in any of the other measured parameters from baseline. The questionnaire survey showed that 10 (33%) participants experienced improvements in sleep quality. CONCLUSIONS: The switch from another SGLT2 inhibitor to tofogliflozin may reduce the frequency of nocturnal urination, implying that it may have a positive impact on the quality of life of patients with type 2 diabetes.

A Type 2 Diabetes Mellitus Patient With Severe Diabetic Gastroparesis Successfully Treated With Intravenous Erythromycin.

Gastroparesis, characterized by a decrease in gastric emptying, can lead to worsened diabetes control and a reduced quality of life. The patient was a 32-year-old male with type 2 diabetes. He was initially admitted for control of diabetes, and two months later, he was readmitted due to nausea and vomiting. He showed resistance to various drugs, including antiemetics, and an upper gastrointestinal endoscopy revealed significant gastric residue, leading to a diagnosis of gastroparesis. We administered intravenous erythromycin. After three days of treatment, the vomiting resolved. Gastroparesis is challenging to manage, and there are limited effective treatment options. We experienced a case of diabetic gastroparesis with severe vomiting and loss of appetite that responded remarkably well to intravenous erythromycin treatment. Intravenous administration of erythromycin may be a potentially effective treatment for gastroparesis.

A Diabetic Patient with Prolonged Hyperammonemia Due to Urinary Tract Infection Caused by Urease-producing Bacteria.

Obstructive tract infection caused by urease-producing bacteria can lead to hyperammonemia. We herein report a 73-year-old woman with diabetes and compensated liver cirrhosis who developed obstructive pyelonephritis. Her consciousness level declined on day 3 of hospitalization. Blood tests revealed an elevated ammonia level of 140 µg/dL. Urine and blood cultures identified Proteus mirabilis as a urease-producing bacterium. The treatment included double J (WJ) catheter insertion and administration of antimicrobial agents. On day 7 of hospitalization, the ammonia level gradually decreased, and the patient's consciousness improved. However, despite these interventions, perinephric overflow of urine persisted, necessitating nephrectomy.

Consistently low levels of histidine-rich glycoprotein as a new prognostic biomarker for sepsis: A multicenter prospective observational study.

BACKGROUND: Few sepsis biomarkers accurately predict severity and mortality. Previously, we had reported that first-day histidine-rich glycoprotein (HRG) levels were significantly lower in patients with sepsis and were associated with mortality. Since the time trends of HRG are unknown, this study focused on the time course of HRG in patients with sepsis and evaluated the differences between survivors and non-survivors. METHODS: A multicenter prospective observational study was conducted involving 200 patients with sepsis in 16 Japanese hospitals. Blood samples were collected on days 1, 3, 5, and 7, and 28-day mortality was used for survival analysis. Plasma HRG levels were determined using a modified quantitative sandwich enzyme-linked immunosorbent assay. RESULTS: First-day HRG levels in non-survivors were significantly lower than those in survivors (mean, 15.7 [95% confidence interval (CI), 13.4-18.1] vs 20.7 [19.5-21.9] µg/mL; P = 0.006). Although there was no time × survivors/non-survivors interaction in the time courses of HRG (P = 0.34), the main effect of generalized linear mixed models was significant (P < 0.001). In a univariate Cox proportional hazards model with each variable as a time-dependent covariate, higher HRG levels were significantly associated with a lower risk of mortality (hazard ratio, 0.85 [95% CI, 0.78-0.92]; P < 0.001). Furthermore, presepsin levels (P = 0.02) and Sequential Organ Function Assessment scores (P < 0.001) were significantly associated with mortality. Harrell's C-index values for the 28-day mortality effect of HRG, presepsin, procalcitonin, and C-reactive protein were 0.72, 0.70, 0.63, and 0.59, respectively. CONCLUSIONS: HRG levels in non-survivors were consistently lower than those in survivors during the first seven days of sepsis. Repeatedly measured HRG levels were significantly associated with mortality. Furthermore, the predictive power of HRG for mortality may be superior to that of other singular biomarkers, including presepsin, procalcitonin, and C-reactive protein.

Long-lasting complete response status of advanced stage IV gall bladder cancer and colon cancer after combined treatment including autologous formalin-fixed tumor vaccine: two case reports.

BACKGROUND: The prognosis of advanced (stage IV) cancer of the digestive organs is very poor. We have previously reported a case of advanced breast cancer with bone metastasis that was successfully treated with combined treatments including autologous formalin-fixed tumor vaccine (AFTV). Herein, we report the success of this approach in advanced stage IV (heavily metastasized) cases of gall bladder cancer and colon cancer. CASE PRESENTATION: Case 1: A 61-year-old woman with stage IV gall bladder cancer (liver metastasis and lymph node metastasis) underwent surgery in May 2011, including partial resection of the liver. She was treated with AFTV as the first-line adjuvant therapy, followed by conventional chemotherapy. This patient is still alive without any recurrence, as confirmed with computed tomography, for more than 5 years. Case 2: A 64-year-old man with stage IV colon cancer (multiple para-aortic lymph node metastases and direct abdominal wall invasion) underwent non-curative surgery in May 2006. Following conventional chemotherapy, two courses of AFTV and radiation therapy were administered sequentially. This patient has had no recurrence for more than 5 years. CONCLUSION: We report the success of combination therapy including AFTV in cases of liver-metastasized gall bladder cancer and abdominal wall-metastasized colon cancer. Both patients experienced long-lasting, complete remission. Therefore, combination therapies including AFTV should be considered in patients with advanced cancer of the digestive organs.

Usefulness of urinary glucose excretion after oral glucose tolerance testing to detect insulin secretion failure before the onset of diabetes mellitus.

Sodium-glucose cotransporter 2 inhibitors are commonly used to promote urinary glucose excretion (UGE). However, it remains unclear how UGE reflects glucose metabolism in the natural history of diabetes. Thus, we retrospectively reviewed the prediabetes medical records of 64 patients who had undergone 75-g oral glucose tolerance testing (OGTT) with measurements of UGE at 0 min, 60 min, and 120 min. The mean age and glycated hemoglobin levels were 46 ± 10 years and 5.6 ± 0.3%, respectively. The median UGE (60 min + 120 min) value was 16.8 mg ([interquartile range]: [10.5-150.0 mg]). Thus, we categorized 16 patients as having high UGE (≥150.0 mg) and 48 patients as having low UGE (<150.0 mg). As compared with the low UGE group, the high UGE group exhibited a significantly lower median insulinogenic index (0.23 [0.12-0.35] vs. 0.56 [0.31-1.06], p = 0.001) and homeostasis model assessment of ß-cell function value (46 [26-67] vs. 66 [41-85], p = 0.028). The log-transformed insulinogenic index exhibited a significant inverse association with log-transformed UGE (60 min + 120 min) (r = -0.50, p < 0.001). The association between higher UGE and lower insulinogenic index was also observed in a subgroup analysis of patients with plasma glucose levels of ≥160 mg/dL during the OGTT. Therefore, UGE measurements after OGTT may provide a useful clinical marker for detecting insulin secretion failure and advancing preventive and therapeutic interventions among populations with a high risk of developing diabetes.

Spot test of urinary protein using erythrosin B and a membrane film.

Point-of-care testing is currently one of the subjects of growing interest in analytical chemistry. Elevated levels of urinary protein imply renal failure, which is one of the world's biggest public health problems. In spite of the urgent necessity for a screening test of protein in urine, there are no reports of a simple yet sensitive method for its detection. In this study, we developed a new visual method, using Erythrosin B and a cellulose acetate membrane film as the substrate for a new spot test of urinary protein in the presence of poly(ethylene glycol) (PEG). The noteworthy point of our work is that when a drop of dye-protein solution containing PEG is set on a membrane film, a red ring-shaped stain of the dye-bound protein is formed on the film surface. PEG plays a significant role in eliminating the reagent blank, thus providing a clear contrast. Measurements taken using a dynamic light scattering particle size analyzer indicated that the underlying mechanism of this contrast is brought about by the different sizes of the excess dye and dye-protein particles. The visual detection limit is 0.5 mg dm(-3) for human serum albumin (HSA), the main protein in urine. Our visual method is sufficiently sensitive to detect urinary protein even for healthy subjects, providing a higher sensitivity than test strips by a factor of 60-200. When 0.15 cm(3) of urine is used to prepare 10 cm(3) of sample solution, the practical detection threshold is 30 mg dm(-3) in urine using a 67x dilution factor. The proposed method will be useful as a simple, rapid, and cost-effective screening test for the diagnosis of renal failure at an early stage.

Beverage-specific effects of ethanol consumption on its biological markers.

BACKGROUND: Serum gamma-glutamyltransferase (GGT) and erythrocyte mean corpuscular volume (MCV) are well-known biological markers of excessive ethanol consumption. METHODS: The beverage-specific effects of ethanol consumption on GGT level and MCV value were analyzed cross-sectionally and retrospectively among middle-aged Japanese men who underwent a retirement health checkup (n = 974). RESULTS: Both the consumption of distilled alcohol and that of fermented alcohol positively correlated with the logarithm of GGT [standard regression coefficient (beta) 0.261 and 0.174, respectively]. The prevalence rate of elevated GGT levels > or = 70 IU/L) was higher among heavy drinkers of distilled alcohol than among heavy drinkers of fermented alcohol (38.8% vs. 27.6%, p = 0.013). The MCV value correlated with distilled alcohol consumption (beta: 0.212, p < 0.0001) but not with fermented alcohol consumption (beta: 0.043, not significant). The prevalence rate of an elevated MCV (> or = 97 fL) was higher among heavy drinkers of distilled alcohol than among heavy drinkers of fermented alcohol (35.3% vs. 16.8%, p < 0.001). CONCLUSIONS: These results suggest that MCV is less sensitive for detecting heavy consumption of fermented alcohol than for detecting that of distilled alcohol in apparently healthy middle-aged men.

Beer ethanol consumption and plasma homocysteine among patients with type 2 diabetes.

We analyzed the association between beer and other type of ethanol consumption and tHcy levels among type 2 diabetic patients. Male type 2 diabetic patients without overt nephropathy were studied (n=242). Ethanol consumptions of the patients were 35.1+/-37.8mL/day for total ethanol, 13.9+/-15.2mL/day for beer ethanol and 21.2+/-32.1mL/day for non-beer ethanol. Both, total and non-beer ethanol consumption correlated with tHcy, whereas beer ethanol consumption showed a trend to inverse association with tHcy (standard regression coefficient, 0.184, 0.283 and -0.110, respectively). Each intake of 30mL/day ethanol consumption was associated with an increase of tHcy of 0.6micromol/L for total ethanol and 1.1micromol/L for non-beer ethanol and a decrease of tHcy of 0.7micromol/L for beer ethanol. Similar trend was observed in the analysis model which included only drinkers, and also in an adjusted analysis model. Plasma tHcy of beer only drinkers was lower than that of non-beer alcohol only drinkers (8.9+/-1.9micromol/L versus 11.5+/-5.5micromol/L, P=0.003). Non-beer ethanol consumption might be less healthy compared with beer ethanol consumption among type 2 diabetic patients in terms of the effects on tHcy.

Type 2 diabetes and hearing loss in personnel of the Self-Defense Forces.

The association of type 2 diabetes with hearing loss was evaluated in middle-aged male personnel of the Self-Defense Forces (SDFs). Hearing loss was defined as the pure-tone average (PTA) of the thresholds frequency at 0.5, 1, 2, and 4 kHz greater than 25 dB hearing levels (HL) in the worse ear. Diabetes status was determined by self-report of physician-diagnosed diabetes or by oral glucose tolerance test (OGTT). Of 699 subjects studied (age 52.9+/-1.0 years), 103 subjects were classified as having type 2 diabetes. Fasting plasma glucose of diabetic subjects was 120+/-19 mg/dl. Hearing loss levels were (worse) higher among diabetic subjects compared with subjects with normal glucose tolerance (NGT) (30.7+/-13.0 dB versus 27.4+/-12.3 dB, P=0.014). Hearing loss was more prevalent among diabetic subjects than among subjects with normal glucose tolerance (60.2% versus 45.2%, P=0.006). The odds ratio (OR) of type 2 diabetes for the presence of hearing loss was 1.87 (95% confidence interval 1.20-2.91, P=0.006) in a logistic regression analysis adjusted for age, rank, cigarette smoking and ethanol consumption. These results suggest that type 2 diabetes is associated with hearing loss independently of lifestyle factors in middle-aged men.

A case of primary aldosteronism due to unilateral adrenal hyperplasia.

The case of a patient with primary aldosteronism due to unilateral adrenal hyperplasia (UAH) is reported. A 43-year-old man with an 8-year history of hypertension presented at our institution with hypokalemia, increased plasma aldosterone concentration (PAC), and suppressed plasma renin activity (PRA). An abdominal CT scan showed almost normal adrenal glands with slight enlargement in the left gland. 131I-Norcholesterol adrenal scintigraphy under dexamethasone suppression showed bilaterally decreased uptake. To rule out idiopathic hyperaldosteronism, an adrenal vein sampling before and after ACTH stimulation was performed and a left-sided lateralization of PAC was observed. A left adrenalectomy was performed, and the patient had a good clinical and biochemical response. Micronodular hyperplasia was discovered in the adrenal gland histologically, and in the immunohistochemical analysis, positive staining for 3beta-hydroxysteroid dehydrogenase in micronodular lesions confirmed the diagnosis of UAH. Although UAH is a rare subset of primary aldosteronism, it is surgically correctable as a unilateral autonomous aldosterone-producing lesion. Careful investigations, including bilateral adrenal vein sampling, should be performed for the diagnosis.

Gamma-glutamyl transferase and airflow obstruction in middle-aged men.

BACKGROUND: A relationship between pulmonary dysfunction and cardiovascular mortality has been described. The mechanism responsible for the relationship remains largely unknown. METHODS: The association between airflow obstruction and selected cardiovascular risk factors including gamma-glutamyl transferase (gamma-GT) and total homocysteine was analyzed cross-sectionally in 954 middle-aged men. Airflow obstruction was assessed with %FEV(1) (FEV(1)/FVC). RESULTS: Serum gamma-GT and white blood cell (WBC) count were higher in subjects with airflow obstruction (%FEV(1)<70%) than in those without it (76.9+/-164.3 IU/L vs. 55.9+/-67.9 IU/L, P=0.030; 6290+/-1590/microL vs. 5590+/-1410/microL, P<0.001). Airflow obstruction was not associated with body mass index, total cholesterol, triglycerides, fasting glucose, or systolic blood pressure, but there was a marginal association with total homocysteine. In a logistic regression analysis adjusted for smoking status and alcohol consumption, the odds ratios (95% confidence interval) of Delta100 IU/L increase in gamma-GT and Delta1000/microL increase in WBC count for the presence of airflow obstruction were 1.20 (0.97-1.48, P=0.090) and 1.21 (1.02-1.44, P=0.036), respectively. CONCLUSIONS: Airflow obstruction was associated with gamma-GT. The association was independent of alcohol consumption category, but was attenuated by the addition of cigarette smoking status.

Gamma-glutamyl transferase and metabolic risk factors for cardiovascular disease.

OBJECTIVE: To elucidate the mechanism of the reported association between serum gamma-glutamyl transferase (GGT) activity and cardiovascular mortality. METHODS: Cross-sectional analysis of the relationship between serum GGT activity and the risk factors for cardiovascular disease was performed. PATIENTS AND MATERIALS: Middle-aged Japanese male personnel of the Self-Defense Forces who underwent retirement check-up. RESULTS: Serum GGT activity was associated with total cholesterol, triglyceride, fasting plasma glucose, total homocysteine and systolic blood pressure. The association remained in the analysis adjusted for possible confounders including cigarette smoking, ethanol consumption and body mass index. CONCLUSION: The observed association between serum GGT and cardiovascular risk factors may partly explain the reported relationship between serum GGT activity and cardiovascular disease. Serum GGT activity may be regarded as a marker of cardiovascular risk factors or oxidative stress rather than a mere indicator of excessive ethanol consumption or obesity.

A short-term admission improved brachial-ankle pulse wave velocity in type 2 diabetic patients.

Brachial-ankle pulse wave velocity (baPWV) is a non-invasive method for assessing arterial stiffness associated with atherosclerosis. We examined whether baPWV could improve during a 2-week hospital-based education program in patients with type 2 diabetes and whether improvement associates with changes in known atherogenic risk factors. Body mass index (BMI), blood pressure (BP), fasting plasma glucose (FPG), insulin, lipid profiles and baPWV were measured in 32 type 2 diabetic patients before and after an educational program that included advice about nutrition and exercise. Relationship between the changes in baPWV and additional parameters, 24h-urinary excretion of C-peptide, visceral and subcutaneous fat area by abdominal computer tomography and intima-medial thickness (IMT) of the carotid artery by ultrasonography, were also evaluated. Baseline values of baPWV significantly correlated with age, duration of diabetes, BP, IMT and FPG. BaPWV significantly decreased after the program (-120+/-108.4 cm/s, P<0.0001) and this change significantly correlated with that of systolic BP (r=0.697, P<0.0001) and FPG (r=0.452, P<0.05). These results indicate that short-term hospitalization with an educational program can improve arterial wall stiffness, perhaps due to improvements in BP and glycemic control.

Adiponectin levels and cardiovascular risk factors in Japanese men with type 2 diabetes.

Several cardiovascular risk factors correlate with adiponectin levels. It is not known whether total homocysteine, folate and gamma-glutamyl transferase levels correlate with adiponectin. We cross-sectionally analyzed the association between adiponectin and these cardiovascular risk factors in diabetic patients. One hundred and two male inpatients with type 2 diabetes without overt nephropathy or insulin use were studied. In a regression analysis of the quartiles of adiponectin, plasma levels of adiponectin were associated positively with HDL-cholesterol and age, and inversely with body mass index and HbA1c, but not with total homocysteine, folate or gamma-glutamyl transferase. Non-traditional cardiovascular risk factors such as homocysteine and folate levels were not associated with adiponectin levels in male type 2 diabetic patients who are not subject to insulin therapy.

Plasma vitamin B12, folate and homocysteine levels in gastrectomized men.

BACKGROUND & AIMS: Hyperhomocysteinemia is a risk factor for cardiovascular disease, dementia and depression. Prevalence rate of hyperhomocysteinemia in gastrectomized patients is not well elucidated. METHODS: We compared plasma total homocysteine, vitamin B12 and folate of gastrectomized male patients with those of control subjects. RESULTS: Total homocysteine was higher in gastrectomized patients than in control subjects (11.7 +/- 4.4 micromol/l vs. 9.3 +/- 2.4 micromol/l, P = .011), while vitamin B12 was lower in patients than in control subjects (382 +/- 211 pg/ml vs. 500 +/- 179 pg/ml, P = .020). Folate of the two groups was comparable (5.8 +/- 2.5 ng/ml vs. 5.9 +/- 2.2 ng/ml). Of 31 gastrectomized patients six (19.4%) showed low vitamin B12 (<233 pg/ml), four (12.9%) low folate (<3.0 ng/ml) and seven (22.6%) hyperhomocysteinemia (>14 micromol/l), whereas they were found in one (3.2%), none (0%) and one (3.2%) of 31 control subjects, respectively. Patients who had undergone gastrectomy because of cancer showed higher total homocysteine compared to patients who had undergone it because of peptic ulcer. Type of surgery did not correlate with total homocysteine in the present study. CONCLUSION: Hyperhomocysteinemia is not rare in male Japanese gastrectomized patients.

Plasma folate levels in men with type 2 diabetes.

Limited data suggest that folate levels are higher in patients with type 2 diabetes than in subjects with normal glucose tolerance (NGT). We compared the fasting plasma folate, glucose (FPG), body mass index (BMI), and supplementary vitamin use among male subjects with NGT, those with impaired glucose tolerance (IGT), those with newly diagnosed type 2 diabetes, and those with previously diagnosed type 2 diabetes. Plasma folate of patients with newly diagnosed diabetes and that of patients with previously diagnosed diabetes was significantly higher than that of NGT subjects (p < 0.001). Prevalence of vitamin use was lower in newly diagnosed or previously diagnosed diabetic patients compared with non-diabetic subjects. Self-rated vegetable intake was similar among the four groups. FPG, BMI, triglycerides, and systolic blood pressure correlated with plasma folate levels independently of lifestyle factors studied. These results suggest that plasma folate levels are elevated in male diabetic patients independently of health-conscious behavior that is recommended for diabetic people.

Methimazole-induced aplastic anemia caused by hypocellular bone marrow with plasmacytosis.

Aplastic anemia is a rare but severe complication of methimazole (MMI) treatment for Graves' disease. We present a case of a 53-year-old Japanese female who had been treated with 30 mg/d of MMI for 30 days for Graves' disease and was subsequently admitted to the Japan Self Defense Forces (JSDF) Central Hospital with a mild sore throat and high-grade fever that began the previous day. The patient had a reduced white blood cell count (WBC) count of 0.9 x 10(3) per microliter with severe granulocytopenia and increased lymphocytes, a platelet count of 49 x 10(3) per microliter, and hemoglobin of 10.6 g/dL. Bone marrow (BM) aspirates showed hypocellular bone marrow with plasmacytosis. Because of poor recovery of her peripheral blood values after withdrawal of MMI, she was given transfusions of platelets and erythrocytes thereafter. This is the second report of plasmacytosis in bone marrow of MMI-induced aplastic anemia, and suggests that immunogenic mechanisms may cause this rare complication.

Oral vitamin C ameliorates smoking-induced arterial wall stiffness in healthy volunteers.

We have investigated whether the oral administration of vitamin C could prevent smoking-induced acceleration of arterial stiffness in healthy volunteers. Subjects were pretreated with 2 g vitamin C and their heart rate (HR), mean blood pressure (MBP), and brachial-ankle pulse wave velocity (baPWV) were measured before and after smoking. Smoking significantly increased the HR, MBP, baPWV (13, 6.4, 7.0%). Vitamin C treatment significantly reduced the smoking-induced elevation in baPWV at 0 min (- 58.5%, p = 0.0002) without affecting HR or MBP. These findings suggest that oral vitamin C treatment prevents smoking-induced acceleration in arterial stiffness through reducing endothelial dysfunction.

Newly identified steroid hormone in urine of patients with Cushing's syndrome: 3alpha,11 beta-dihydroxy-4-androsten-17-one.

We have previously reported that the urine of patients with Cushing's syndrome, including pituitary adenoma cases and adrenal adenoma cases, consistently show a conspicuous peak in the chromatographical analysis of 17-ketosteroid fraction but not in the urine of control subjects. The substance emerges just before 11beta-hydroxy-androsterone (11beta-OH-A) in capillary gas chromatography. In the present study, we have identified an "unknown peak substance" observed in the urine of Cushing's syndrome patients using gas chromatography-mass spectrometry (GC/MS). Trimethylsilylether (TMS)-derivative of the substance was found to have a molecular weight (MW) of 448, which is similar to that of 11-OH-A (MW: 450). From these findings, we hypothesized that the substance had the structure of a C-19 steroid with two hydroxyl groups at positions C-3 and C-11, one keto-group at C-17 and a double bond between C-4 and C-5 of the A ring. We hypothesized that the unknown peak substance was 3alpha,11beta-dihydroxy-4-androsten-17-one (3alpha,11beta-DH-A). To confirm this speculation we synthesized 3alpha,11beta-DH-A and compared the elution pattern of it with that of the "unknown peak substance" using GC and GC/MS. We found that both substances were indistinguishable by GC and GC/MS analysis. These results suggest that the unknown substance observed in the urine of patients with Cushing's syndrome is 3alpha,11beta-DH-A.