Demonstration of a trapped-ion atomic clock in space.

Atomic clocks, which lock the frequency of an oscillator to the extremely stable quantized energy levels of atoms, are essential for navigation applications such as deep space exploration1 and global navigation satellite systems2, and are useful tools with which to address questions in fundamental physics3-6. Such satellite systems use precise measurement of signal propagation times determined by atomic clocks, together with propagation speed, to calculate position. Although space atomic clocks with low instability are an enabling technology for global navigation, they have not yet been applied to deep space navigation and have seen only limited application to space-based fundamental physics, owing to performance constraints imposed by the rigours of space operation7. Methods of electromagnetically trapping and cooling ions have revolutionized atomic clock performance8-13. Terrestrial trapped-ion clocks operating in the optical domain have achieved orders-of-magnitude improvements in performance over their predecessors and have become a key component in national metrology laboratory research programmes13, but transporting this new technology into space has remained challenging. Here we show the results from a trapped-ion atomic clock operating in space. On the ground, NASA's Deep Space Atomic Clock demonstrated a short-term fractional frequency stability of 1.5 × 10-13/τ1/2 (where τ is the averaging time)14. Launched in 2019, the clock has operated for more than 12 months in space and demonstrated there a long-term stability of 3 × 10-15 at 23 days (no drift removal), and an estimated drift of 3.0(0.7) × 10-16 per day. Each of these exceeds current space clock performance by up to an order of magnitude15-17. The Deep Space Atomic Clock is particularly amenable to the space environment because of its low sensitivity to variations in radiation, temperature and magnetic fields. This level of space clock performance will enable one-way navigation in which signal delay times are measured in situ, making near-real-time navigation of deep space probes possible18.

Preoperative mean platelet volume and platelet distribution associated with thyroid cancer.

Thyroid cancer is the most frequent cancer of the endocrine glands and the fifth most frequent cancer in women. Activated platelets play a crucial role in thrombosis, inflammation, and cancer. Mean platelet volume (MPV) and platelet distribution width (PDW) are early index of platelet activation. The purpose of this study is to investigate platelet indices levels in thyroid cancer. The study enrolled 280 patients with thyroid cancer and 280 control subjects. Patients' characteristics and hematologic tests data were collected at the time of diagnosis. Correlations between platelet indices and clinical characteristics were analyzed. The odds ratios (ORs) and 95% confidence intervals (CIs) for thyroid cancer were calculated using multivariate logistic regression analyses across MPV and PDW quartiles. The patients with thyroid cancer had lower MPV and higher PDW compared with control subjects. MPV was correlated with tumor-nodus-metastases (TNM) stage and lymph node metastasis. Moreover, after adjusting for other risk factors, the prevalence risk of thyroid cancer for the lowest quartile of MPV was 7.242 (4.069-12.887) (P < 0.001) and for the highest quartile of PDW was 6.065 (3.321-11.076) (P < 0.001), respectively. The study showed that the patients with thyroid cancer have lower MPV and higher PDW compared to control subjects. Moreover, MPV and PDW were independently associated with the presence of thyroid cancer. Further studies are needed to evaluate the utility of MPV and PDW as novel diagnostic screening tools for thyroid cancer.

[Diagnostic value of carotid atherosclerosis score for ischemic stroke].

OBJECTIVE: To discuss the diagnostic value of carotid atherosclerosis score for ischemic stroke. METHODS: In the study, 151 patients with ischemic stroke were enrolled, who were diagnosed by cranial CT scan or cranial MRI scan, and examined with carotid duplex ultrasound, and 151 healthy check-up cases matched by age and sex were chosen as control group, who were excluded ischemic stroke by cranial CT scan or cranial MRI scan. All the control cases were examined with carotid duplex ultrasound also. Intima-media thickness (IMT), the number of carotid plaques, the size of each plaque, the location of the plaque and each plaque's echo, texture, surface regularity were estimated by carotid duplex ultrasound. RESULTS: The IMT of the case group and the control group were (0.946±0.185) mm and (0.863±0.148) mm, and there were significant differences (P<0.001); The parameters of arterial plaque correlated with ischemic stroke were plaque's echo, texture and surface regularity, however the plaque size and location were not correlated with ischemic stroke. The median and quartile of carotid artery plaque score were 3 and 2 respectively in case group, 1 and 2 respectively in control group, and there were significant differences (P<0.001); The parameters of carotid arterial atherosclerosis associated with ischemic stroke were carotid artery plaque score,carotid stenosis degree and IMT, but not the number of carotid plaques. The median and quartile of carotid arterial atherosclerosis score were 5 and 4 respectively in case group, 2 and 4 respectively in control group, and there were significant differences (P<0.001); The area under the curve (AUC) for IMT, the number of carotid plaques, carotid artery plaque score and carotid arterial atherosclerosis score were 0.679, 0.677, 0.704 and 0.805,respectively (P<0.001). The accuracy of carotid atherosclerosis score was the highest. CONCLUSION: Carotid artery plaque score and carotid atherosclerosis score can be used for the diagnosis of ischemic stroke, and the accuracy of carotid atherosclerosis score is higher.

Non-alcoholic fatty liver disease is associated with progression of arterial stiffness.

BACKGROUND AND AIMS: NAFLD is an independent risk factor for increased cardiovascular disease. Arterial stiffness is an index of subclinical atherosclerosis. The aims of this study were to examine prospectively the relationship between Non-alcoholic fatty liver disease (NAFLD) and the progression of arterial stiffness. METHODS AND RESULTS: A prospective study of 728 men and 497 women free of hypertension, and diabetes at the baseline were conducted. The subjects were followed for 5 years. The progression rate of arterial stiffness was measured by calculating the increase in brachial-ankle pulse wave velocity (baPWV) the changes of the baPWV (adjusted for age) during the study period was significantly greater in the patients with NAFLD (172.4 ± 42.1 cm/s for men, 95.8 ± 36.7 cm/s for women) than in the subjects without NAFLD (70.3 ± 56.5 cm/s for men, 55.4 ± 42.2 cm/s for women). For the subjects with metabolic syndrome, after adjusting for multiple risk factors, NAFLD was a significant predictor of baPWV progression (for male, ß = 0.843; P < 0.001; for female, ß = 0.575; P < 0.001, respectively). In addition, results were unmodified in subjects without metabolic syndrome. CONCLUSIONS: NAFLD was found to be an independent predictor of faster progression of baPWV even after adjusting other cardiovascular risk factors. These prospective data support a pathogenic role for NAFLD in the development of arterial stiffness.

Elevated mean platelet volume is associated with silent cerebral infarction.

BACKGROUND: The presence of silent cerebral infarction (SCI) increases the risk of transient ischaemia attack, symptomatic stroke, cardiovascular disease and dementia. Mean platelet volume (MPV) is a surrogate marker of activated platelets and is considered a link between inflammation and thrombosis. In addition, MPV is a risk predictor for cardiovascular disease, stroke and overall vascular mortality. AIMS: The purpose of the study was to assess the MPV levels in SCI patients. METHODS: A cross-sectional study was conducted to evaluate the association between MPV and SCI in 2215 subjects (1385 men and 830 women). RESULTS: The participants with SCI had higher MPV levels than those without SCI (10.4 ± 1.3 fL vs. 9.2 ± 1.2 fL; P < 0.001). Moreover, the subjects with a high MPV had a higher prevalence of SCI. Multivariate logistic regression analyses revealed that the odds ratios and 95% confidence intervals for SCI according to MPV quartiles were 1.000, 2.131 (1.319-3.444), 3.015 (1.896-4.794), 7.822 (4.874-12.554) respectively (P < 0.001). CONCLUSION: MPV is a novel index for SCI regardless of classical cardiovascular risk factors.

Decreased serum bilirubin is associated with arterial stiffness in men.

BACKGROUND AND AIMS: The brachial-ankle pulse wave velocity (baPWV) is a marker for early atherosclerotic changes. Serum total bilirubin (TB) is an effective antioxidant and has been associated with carotid intima-media thickness, cardiovascular disease, stroke and peripheral arterial disease, all of which may be caused by arteriosclerosis. This study aimed to investigate the association of TB with arterial stiffness. METHODS AND RESULTS: In this cross-sectional study, we investigated the relationship between TB and baPWV in 2207 participants (1331 men, 876 women) in a general health examination. Different metabolic parameters were compared across TB quartiles. Age-adjusted mean values of baPWV gradually decreased with TB quartiles in men (Q1 = 1348, Q2 = 1266, Q3 = 1215, and Q4 = 1154 cm/s). However, the age-adjusted means of baPWV had no significance in women according to TB quartiles. Univariate analysis showed that age, smoking status, BMI, SBP, DBP, AST, ALT, GGT, TB, TG, and HDL-C were significantly associated with baPWV in men, whereas only age, BMI, SBP, DBP, TG and FPG were significantly associated with baPWV in women. In addition, BMI, SBP, TB, age, TG, and AST were significant factors in the multivariate model with baPWV in men; only BMI and FPG were significant factors with baPWV in women. CONCLUSION: The findings show that serum total bilirubin concentration is negatively correlated to arterial stiffness in Chinese men. Early detection of abnormal bilirubin levels could potentially serve as an early biomarker for arterial stiffness.

[A physician-patient survey for primary immune thrombocytopenia: Chinese subgroup analysis of I-WISh International Survey].

Objective: To explore the impact of primary immune thrombocytopenia (ITP) on patient's quality of life and emotional well-being, and both the physician and the patient's perception of the treatment. Methods: This study was a Chinese Subgroup analysis of I-WISh survey, including 102 physicians and 286 ITP patients invited to complete the survey. A descriptive analysis of the results of the physician-patient survey was conducted in three parts: symptoms, impact of ITP on quality of life and emotion, and treatment perception. Results: Fatigue and anxiety about unstable platelet counts were the main symptoms after treatment. Physicians reported inadequate frequency of anxiety and fatigue. In terms of quality of life, over 90.0% of patients thought that ITP had a negative impact on their working life/studies, daily tasks, energy, capacity to exercise, and sexual life. With regard to emotion, 60.8% (174/286) patients thought that ITP had a greater impact on overall emotion, concerns about the fluctuation in platelet level (74.8%, 214/286) , disease itself (71.7%, 205/286) and disease progression (68.9%, 197/286) were the common issues, which were similar to the physicians' evaluations. Both physicians and patients agreed that reducing spontaneous bleeding, maintaining a healthy blood count and improving quality of life were the top three important treatment goals. Physicians considered reducing bleeding risk as the most important factor for decision making. Physicians believed that patients receiving glucocorticoid (54.9%, 56/102) were most likely to succeed in achieving sustained response while patients had the best response to thrombopoietin receptor agonist (TPO-RA) treatment, with about 83.9% (240/286) being satisfied with the overall effectiveness of TPO-RA. Conclusions: Physicians in the I-WISh Chinese subgroup had low awareness on patients' fatigue and anxiety. The quality of life and emotion of patients were significantly negatively affected by ITP. There are differences in the selection of treatments between physicians and patients, suggesting that physicians should raise concerns about the quality of life of ITP patients and make individualized treatment options through physician-patient shared decisions.

Centrifugal fibers to the eye in a nonavian vertebrate: source revealed by horseradish peroxidase studies.

A source of efferent fibers to the eye of snakes of the genus Thamnophis has been identified by the use of the retrograde transport of horseradish peroxidase. Cell bodies of the contralateral nucleus of the ventral supraoptic decussation accumulate horseradish peroxidase after intraocular but not intraorbital injections. Intraocular injections also result in anterograde transport of horseradish peroxidase to retinofugal axon terminals. Intraorbital injections result in accumulation of horseradish peroxidase in the cell bodies of the cranial nerve nuclei of extraocular muscles.

Determination of phloroglucinol by HPLC-MS/MS and its application to a bioequivalence study in healthy volunteers.

OBJECTIVE: The aim of this study was to compare the pharmacokinetic characteristics of phloroglucinol between an orally disintegrating tablet and an orally lyophilized tablet of phloroglucinol in healthy volunteers under fasting condition. PATIENTS AND METHODS: A rapid and simple method based on high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method has been developed and validated for the determination of phloroglucinol in human plasma. The plasma sample was prepared by liquid-liquid extraction, and paracetamol was chosen as the internal standard. Phloroglucinol and IS were separated on a C18 column with a mobile phase consisted of methanol/water (80:20 v/v) with 0.02% formic acid. HPLC-MS/MS analyses were performed on a triple- quadruple tandem mass spectrometer by monitoring protonated parent→daughter ion pairs at m/z 125.0→56.9 for phloroglucinol, and m/z 150.2→107.0 for paracetamol (IS). The method was the high sensitivity with a lower limit of quantification (LLOQ) of 1.976 ng/mL. RESULTS: Drug and IS were detected by HPLC/MS/MS with negative electrospray ionization (ESI). Accuracy and precision for the assay were determined by calculating the intra- and inter-batch variation of quality control (QC) samples at three concentration levels. The relative standard deviation (RSD) was less than 15.0%. The detection and quantitation of drug and IS within 4.5 min make this method suitable for high-throughput analyses. In this study, the Cmax of phloroglucinol were calculated to 515.6 ± 134.4 ng/mL and 536.0 ± 144.8 ng/mL for the test drug and the reference drug, respectively. The AUC0-t values were 459.5 ± 81.03 ng·mL-1·h and 491.8 ± 95.17 ng·mL-1·h for the test drug and the reference drug; 24 subjects completed the study, respectively. The geometric mean ratio (GMR) and the 90% confidence intervals (CIs) of Cmax and AUC0-t of phloroglucinol were 97.1 (90.2-103.9) and 93.8 (88.7-99.2), respectively. CONCLUSIONS: The method was employed for the first time during pharmacokinetic studies of phloroglucinol in human plasma following a single dose of phloroglucinol 160 mg tablets. There was no significant difference in pharmacokinetic profiles between the two treatments.

Bone mineral density is associated with left ventricular diastolic function in men with type 2 diabetes.

AIMS: Type 2 diabetes (T2DM) is associated with chronic heart failure and cardiomyopathy. Furthermore, low bone mineral density (BMD) predicts incident heart failure. Abnormal diastolic function reflects early changes in cardiac function and plays a key role in the development of heart failure. The purpose of this study was to investigate the association between BMD with left ventricular (LV) diastolic function in men with T2DM. METHODS: In all, 344 men with T2DM and 331 age-matched control subjects were enrolled. BMD measurements were performed. LV diastolic function and structure were assessed by echocardiographic evaluation. RESULTS: BMD was lower in men with T2DM than in controls. There were significant differences in the level of parameters reflecting cardiac structure and LV diastolic function between two groups. Moreover, LV diastolic function and structure parameters also showed significant differences as BMD reduced in T2DM group. BMD at femoral neck was correlated with LV diastolic function parameters in T2DM after adjusting for confounding factors. Multivariable logistic analysis revealed that osteopenia and osteoporosis were associated with diastolic dysfunction compared to the control in men with T2DM. However, no association between BMD and LV diastolic function was found in subjects without T2DM. CONCLUSION: Osteoporosis may be an independent factor for LV diastolic dysfunction in men with T2DM. Our data suggested that early detection of abnormal BMD should warrant for early search of undetected LV diastolic dysfunction in diabetic men.

On the origins of 718 nm fluorescence from Porphyridium cruentum at 77 K.

Emission spectra and transient behavior of fluorescence in Porphyridium cruentum have been studied in search of the pathway of excitation energy from the phycobilisome to Photosystem I (PS I) of photosynthesis. For activating light at 436 nm, absorbed almost entirely by chlorophyll, fluorescence is dominated by the 718 nm band generally attributed to chlorophyll of PS I. Activating light at 550 nm, absorbed mostly by the phycobilisome, gives rise to the distinctive fluorescence band of PS II chlorophyll at 696 nm but also gives a large component at 718 nm. Analysis depends critically upon the source of emission at 718 nm under 550 nm activation: does it arise from PS I or PS IIC0 Ley and Butler (Ley, A.C. and Butler, W.L. (1976) Proc. Natl. Acad. Sci. U.S.A. 73, 3956-3960) have proposed that the 718 nm arises mostly from PS I, to which it is transferred by spillover from PS II. We suggest a different proposition: that under 550 nm activation most of the 718 emission arises from PS II. Analysis shows that this proposition provides an alternative explanation. Using the small change in fluorescence yield observed under 436 nm activation as a monitor of excitation in PS I, we provide evidence that under 550 activation most of the 718 nm fluorescence arises from PS II.

Hypercalcemia in the neuroleptic malignant syndrome.

The neuroleptic malignant syndrome (NMS) developed in a 32-year-old man following fluphenazine enanthate administration. Hypercalcemia was initially present, perhaps reflecting release of calcium from skeletal muscle stores. The elevated serum calcium levels support the existence of a peripheral muscle abnormality in the pathogenesis of the NMS and provides another point of similarity between NMS and malignant hyperthermia.

Vasectomy and prostate cancer risk in China.

Vasectomy has been reported to be associated with an increased risk of prostate cancer in western countries. A hospital-based case-control study was conducted in 12 cities in China to evaluate the relationship between vasectomy and prostate cancer risk in China, a low-risk country with rising incidence and increasing use of vasectomy. Interviews were conducted with 138 histologically confirmed prostate cancer cases diagnosed during 1989-1992 and 638 controls (158 hospital cancer, 158 hospital noncancer, and 322 neighborhood controls) of similar ages. Vasectomy at least 10 years prior to interview was reported by 10% of the cases versus 3% of the controls. Odds ratios for prostate cancer associated with vasectomy were 2.0 (95% confidence interval, 0.7-6.1), 3.3 (95% confidence interval, 1.0-11.3), and 6.7 (95% confidence interval, 2.1-21.6), respectively, when hospital cancer, hospital noncancer, and neighborhood controls were used for comparison. Although detection bias is of concern, the data suggest that in China, men with a history of vasectomy may experience an increased risk of prostate cancer.

PIP: This paper reports the findings of a hospital-based case-control study that was conducted at major teaching hospitals in 12 cities in China. China reports the lowest incidence in prostate cancer of over 100 registries reporting cancer incidence. This investigation evaluated the relationship between vasectomy and prostate cancer and attempted to identify any etiological factor. A total of 138 study patients (index cases) were identified. Controls used in this study included a cancer control and a noncancer control from the same hospital, and 2 neighborhood controls. Chances of having prostate cancer were statistically determined by logistic regression analysis with age group adjustments made. The analysis reviewed 138 cases and 638 controls. Results indicate that, regardless of the variable control used for comparison, an increased risk of prostate cancer was associated with having had a vasectomy. Statistical odds ratio was 2.0 for hospital cancer controls (95% confidence interval [CI]; 0.7-6.1); 3.3 for hospital noncancer controls (95% CI; 1.0-11.3); and 6.7 for neighborhood controls (95% CI; 2.1-21.6). The authors conclude that, as reported for men in Western countries, Chinese men who have had a vasectomy are at significantly increased risk for developing prostate cancer compared to men who never have had a vasectomy. They report a near 2-fold increase in risk (vasectomy vs. non-vasectomy) in developing the disease. Conclusions about cause and effect are premature, but these findings warrant further investigation of several issues. These include: changes in the endocrine system due to vasectomy; systematic and local immunity changes after vasectomy; and other possible biochemical factors that enhance/inhibit cancer growth in the prostate gland.

Neurogenesis in the vomeronasal epithelium of adult garter snakes. 1. Degeneration of bipolar neurons and proliferation of undifferentiated cells following experimental vomeronasal axotomy.

Postnatal cell proliferation, presumably for the purpose of neuronal replacement, was demonstrated in the vomeronasal epithelium of adult garter snakes using experimental vomeronasal axotomy. The luminal supporting cell layer of the epithelium did not undergo mitosis, nor necrosis, but exhibited some morphological modifications following axotomy. The bipolar layer underwent progressive irreversible degeneration following denervation. Degeneration of neurons progressed initially from alteration of cellular ultrastructure, to gross distortion of neuronal shapes followed by disintegration and disappearance of necrotic neurons. Maximal depletion of neurons occurred two weeks following surgery. The columnar epithelium at that time was characterized by the presence of a cell-depleted zone located between the luminal supporting cell layer and the basal, undifferentiated (Ud) cell layer. This cell-depleted zone occupied 70-80% of each degenerated cell column. Regeneration of axotomized neurons did not occur. The basally located, Ud cells exhibited no changes indicative of necrotic processes, but underwent active cell proliferation following axotomy. Changes in proliferative properties in the Ud cell layer were temporally related to the degeneration of the neuronal cell layer following nerve lesion. The Ud cell proliferation rate was slower than the rate of Bp cell degeneration. Proliferating Ud cells in the denervated epithelium may serve as the source of reconstituted vomeronasal bipolar neurons.

Neurogenesis in the vomeronasal epithelium of adult garter snakes. 2. Reconstitution of the bipolar neuron layer following experimental vomeronasal axotomy.

Postnatal neurogenesis and reconstitution of the neuronal layer of the vomeronasal epithelium have been demonstrated in adult garter snakes following vomeronasal axotomy. Two weeks following axotomy the vomeronasal epithelium was depleted of its bipolar layer but the basal, undifferentiated cells were actively proliferating. In subsequent weeks the undifferentiated cell layer continued to increase its cell population through mitosis and began to occupy the neuron-depleted zone of the receptor cell column. Four weeks following axotomy the denervated epithelium contained an expanded Ud cell layer which occupied the basal one-half to two-thirds of the receptor cell column. The cells at the base of the expanded Ud cell layer were morphologically similar to Ud cells in a normal epithelium whereas the cells at the apex of the columns resembled normal differentiating neurons. A few necrotic cells could still be detected within the apical, cell-depleted zone. By the eighth post-operative week the receptor cell column was fully occupied with cells formed as a result of Ud cell proliferation. The most apical cells, 6-10 cells deep, were morphologically similar to normal bipolar neurons with a dendritic process reaching the lumen of the VN organ. The remaining cells were morphologically similar to normal differentiating or Ud cells. Sixteen weeks following axotomy a larger portion of cells in the receptor cell column were fully differentiated bipolar neurons. The Ud cell population was reduced and, as in the normal epithelium, occupied only the basal portion of each receptor cell column. The regenerated neurons of the VNO were capable of synthesizing and transporting macromolecules to the telencephalon as demonstrated by autoradiography following intraepithelial injections of [3H]proline. Newly formed axons terminated in the accessory olfactory bulb within 8 weeks following axotomy. These results support the view that the basal Ud cells were the source of neurons in the regenerating vomeronasal organ and demonstrate a dynamic process of neuronal proliferation, differentiation and maturation in the denervated vomeronasal epithelia of adult garter snakes.

In vivo and in vitro effects of azaconazole on renal function in the Fischer 344 rat.

Azaconazole is an experimental agricultural fungicide which has shown promise for use in controlling powdery mildew on crops and bean rust. This study examined the nephrotoxic potential of a single intraperitoneal azaconazole injection (0.4 or 0.6 mmol/kg) or daily azaconazole administration (0.1 or 0.3 mmol/kg/day) for 7 days in male Fischer 344 rats. The in vitro effects of azaconazole on the accumulation of organic ions by renal cortical slices also were examined. Acute azaconazole administration (0.4 or 0.6 mmol/kg, i.p.) produced a marked decrease in urine volume at 6 h. By 48 h urine volume was still decreased in the 0.6-mmol/kg group but not the 0.4-mmol/kg group. Proteinuria (++) and slight hematuria were seen in the 0.6-mmol/kg group on both treatment days. Accumulation of p-aminohippurate (PAH) by renal cortical slices was stimulated in both azaconazole-treated groups while tetraethylammonium (TEA) accumulation was not altered. No changes in blood urea nitrogen concentration, kidney weight or renal morphology were produced at 48 h postinjection by either azaconazole dose. Daily administration of azaconazole (0.1 or 0.3 mmol/kg/day) did not significantly alter any of the renal parameters studied. Incubation of renal cortical slices with increasing concentrations of azaconazole from 10(-5) M to 10(-3) M caused a continued reduction in TEA accumulation. PAH accumulation was decreased significantly following incubation with azaconazole 10(-5) or 10(-3) M. These results indicate that azaconazole is capable of producing acute, reversible renal effects at doses equal to or less than 0.6 mmol/kg and altering organic ion transport both in vivo and in vitro. The lack of marked renal effects following exposure to azaconazole is favorable for the development of this compound as an agricultural fungicide.

In vivo and in vitro 4-amino-2,6-dichlorophenol nephrotoxicity and hepatotoxicity in the Fischer 344 rat.

Halogenated anilines and aminophenols are nephrotoxicants and hepatotoxicants in mammals. The purpose of this study was to determine the in vivo and in vitro nephrotoxic and hepatotoxic potential of 4-amino-2,6-dichlorophenol, a putative metabolite of 3,5-dichloroaniline. In the in vivo experiments, male Fischer 344 rats (four/group) were administered a single intraperitoneal (i.p.) injection of 4-amino-2,6-dichlorophenol (0.25, 0.38 or 0.50 mmol/kg) or vehicle (dimethylsulfoxide (DMSO), 1.0 ml/kg) and renal and hepatic function monitored for 48 h. Only minor changes in function or morphology were observed in the 0.25 mmol/kg treatment group. However, in the 0.38 mmol/kg treatment group evidence of both nephrotoxicity and hepatotoxicity were evident. Nephrotoxicity was characterized by increased proteinuria, glucosuria, hematuria, elevated blood urea nitrogen (BUN) concentration and kidney weight, decreased p-aminohippurate (PAH) accumulation and proximal tubular necrosis in the corticomedullary region of the kidney. Hepatotoxicity was characterized by elevated plasma alanine aminotransferase (ALT/GPT) activity and liver weight. Animals administered the 0.5 mmol/kg dose died within 24 h. In the in vitro experiments, the effect of 4-amino-2,6-dichlorophenol on organic ion accumulation, gluconeogenesis and lactate dehydrogenase (LDH) leakage was quantitated in liver and/or renal cortical slices. Organic anion accumulation was inhibited in renal cortical slices by 4-amino-2,6-dichlorophenol bath concentrations of 5 x 10(-6) M or higher, while organic cation uptake was decreased at 4-amino-2,6-dichlorophenol bath concentrations of 1 x 10(-5) M or greater. Renal and hepatic pyruvate-stimulated gluconeogenesis were inhibited and renal LDH leakage increased at 4-amino-2,6-dichlorophenol bath concentrations of 5 x 10(-5) M or greater. Increased LDH leakage from liver slices was not observed. These results demonstrate that 4-amino-2,6-dichlorophenol is a nephrotoxicant and hepatotoxicant in vivo and in vitro and that the kidney is more susceptible to 4-amino-2,6-dichlorophenol toxicity than the liver.

Effect of microsomal enzyme activity modulation on N-(3,5-dichlorophenyl)succinimide-induced nephrotoxicity.

N-(3,5-Dichlorophenyl)succinimide (NDPS) is an experimental agricultural fungicide which has been shown to be a selective nephrotoxin. The purpose of this study was to determine if a NDPS metabolite contributes to acute NDPS-induced nephrotoxicity. Male Sprague-Dawley or Fischer 344 rats were pretreated with a microsomal enzyme inducer [phenobarbital (PB) or 3-methylcholanthrene (3-MC)] or inhibitor [cobalt chloride (CoCl2) or piperonyl butoxide (PIBX)] followed by a single intraperitoneal injection of NDPS (0.2, 0.4 or 1.0 mmol/kg) or vehicle (sesame oil, 2.5 ml/kg). Renal function was monitored at 24 and 48 h. CoCl2 or PIBX pretreatment reduced NDPS-induced diuresis, proteinuria and hematuria, and reduced the increases seen in the blood urea nitrogen (BUN) concentration and kidney weight. NDPS-induced decreases in organic ion accumulation were not markedly altered by CoCl2 or PIBX pretreatment. PB pretreatment enhanced all NDPS- (0.2 mmol/kg) induced renal effects, while 3-MC pretreatment protected against NDPS-induced diuresis, proteinuria, hematuria, and increases in the BUN concentration observed in both rat strains. Kidney weight and organic ion uptake changes were not substantially different between NDPS-treated rats with or without 3-MC pretreatment. It was concluded that a metabolite(s) contributes to or is responsible for acute NDPS-induced nephrotoxicity and that at least 1 toxic metabolite might be of extrarenal origin.

In vivo and in vitro nephrotoxicity of aniline and its monochlorophenyl derivatives in the Fischer 344 rat.

Aniline (A) and its monochlorophenyl derivatives (2-CA, 3-CA and 4-CA) are widely-used chemical intermediates. In the present study, the in vivo and in vitro nephrotoxic potential of these compounds was assessed in Fischer 344 rats. In the in vivo experiments, rats were administered a single intraperitoneal (i.p.) injection of an aniline (0.4, 1.0 or 1.5 mmol/kg) or 0.9% saline (2.0 ml/kg, i.p.), and renal function monitored at 24 and 48 h. 2-CA was the only compound tested which decreased urine volume, elevated the blood urea nitrogen (BUN) concentration and depressed both basal and lactatestimulated p-aminohippurate (PAH) accumulation by renal cortical slices at the 1.0 mmol/ kg dose. Similar results were produced following 3- and 4-CA administration, but these compounds required a dose of 1.5 mmol/kg. Aniline had little effect on renal function at the doses used in this study. In the in vitro experiments, 2-CA (10(-4) M or greater) depressed basal PAH accumulation. Tetraethylammonium (TEA) uptake was decreased by all compounds with an incubate concentration of the aniline at 10(-3) M. Lactatestimulated PAH uptake was not decreased by any test compound. These results indicate that chlorine substitution on the phenyl ring of aniline enhances nephrotoxic potential, and that 2-substitution produces the greatest increase.