核素肾动态显像对2型糖尿病患者肾功能的研究

目的 了解不同阶段２型糖尿病（ＤＭ）患者肾脏血流动力学的变化及肾功能受损情况。方法 将５７例２型ＤＭ患者根据尿白蛋白排泄率（ＵＡＥＲ）分为三组：（１）ＤＭ正常白蛋白尿组（ＤＭ１组）１１例,ＵＡＥＲ〈２０ｕｇ／ｍｉｎ。（２）ＤＭ微量白蛋白尿组（ＤＭ２组）２６例,ＵＡＥＲ：２０～２００ｕｇ／ｍｉｎ。（３）ＤＭ临床蛋白尿组（ＤＭ３组）２０例,ＵＡＥＲ〉２００ｕｇ／ｍｉｎ。与２０例正常对照组（ＮＣ）一起进     

非胰岛素依赖型糖尿病患者心血管自主神经功能与心率变异性

目的探讨非胰岛素依赖型糖尿病（ＮＩＤＤＭ）患者心血管自主神经功能变化与心率变异性（ＨＲＶ）的关系。方法ＮＩＤＤＭ患者４１例，按照标准心血管自主神经功能试验的结果分成阳性组（ＤＡＮ＋）及阴性组（ＤＡＮ－）；６１例健康人为对照组，进行ＨＲＶ分析。结果ＮＩＤＤＭ患者心血管自主神经功能异常的发生率为５３．７％，其发生率与病程呈正相关。ＤＡＮ＋及ＤＡＮ－组ＨＲＶ多数指标均明显降低（Ｐ值＜０．０５～０．０００１）；ＨＲＶ直方图、散点图、三维立体图均有特征性改变，以ＤＡＮ＋组最为显著。ＤＡＮ－组ＬＦ／ＨＦ值明显增大。结论ＨＲＶ能较全面、立体、直观、定量地反映ＮＩＤＤＭ患者心血管交感神经及迷走神经各自的功能状态，且稳定性、重复性及敏感性较好。因此，ＨＲＶ分析是一种为临床早期发现ＮＩＤＤＭ患者心血管自主神经功能异常的较好方法     

依那普利对糖尿病者肾血流动力学及尿白蛋白的影响

本文比较了２８例老年糖尿病合并微白蛋白尿患者服依那普利（ｅｎａｌｐｒｉｌ）４周前后尿微量白蛋白、血及尿β２－微球蛋白、肾小球滤过率（以内生肌酐清除率表示）等变化。结果显示服药后尿微白蛋白排泄减少、内生肌酐清除率下降；将２８例分成正常（尿白蛋白＜２５ｍｇ／２４ｈ）及亚临床微白蛋白尿组（２５～１００ｍｇ／２４ｈ），发现前组服药后尿白蛋白排泄率无变化，而后组明显减少；按内生肌酐清除率将２８例分成正常组（＜１２０ｍｌ／ｍｉｎ）和升高组（＞１２０ｍｌ／ｍｉｎ），发现前组服药后内生肌酐清除率无改变，而后组明显降低。因此依那普利对老年糖尿病伴有尿微白蛋白和（或）内生肌酐清除率升高患者的肾脏有更明显的保护作用。     

急性心肌梗死心率变异性与临床背景的关系

分析８４例急性心肌梗死（ＡＭＩ）后两周患者的心率变异性（ＨＲＶ），旨在了解ＡＭＩ后ＨＲＶ与临床资料的关系。结果：１．ＨＲＶ各项指标与年龄呈负相关，女性患者的ＨＲＶ较男性低（Ｐ＜０．０５）。２．ＨＲＶ与左室射血分数、心肌梗死部位及是否合并高血压无明显关系，但糖尿病患者时域指标中的Ｓｔ．ｇｅｏｒｇｅｓ指数较无糖尿病患者显著下降（Ｐ＜０．０１）。３．心室晚电位阳性者的ＨＲＶ时域指标ＳＤ、Ｓｔ．ｇｅｏｒｇｅｓ指数较阴性者显著下降（Ｐ＜０．０５）。结论：年龄、性别、晚电位及糖尿病对ＨＲＶ有影响     

糖尿病患者心率变异性的临床观察及评价

用心率变异性（ＨＲＶ）分析技术，观察糖尿病患者ＨＲＶ时域的六项指标变化：①ａｖｇＲＲ：ＲＲ间期平均值；②ＳＤＡＮＮ：４分钟ＲＲ平均值的标准差；③ＣＶ：变异系数；④ＳＤ：每４分钟ＲＲ间期标准差的平均值；⑤ＳＤＳＤ：ＳＤ的标准差；⑥ｒｍＳＡＳＤ：每４分钟内相邻ＲＲ间期差值作均方根后的平均值。Ⅱ型糖尿病患者２５例，正常对照组１８例，两组年龄相似。结果表明，糖尿病组的ＳＤ，ＳＤＡＮＮ及ｒｍＳＡＳＤ显著低于对照组，而ａｖｇＲＲ无显著变化。为分析记录时间上的差异性，选择８１例正常人，分成上午组（４５例）与下午组（３６例），除ＳＤＡＮＮ外，其余五项指标在上午组与下午组之间无显著差别。结论认为糖尿病患者的ＨＲＶ显著减小，说明ＨＲＶ对糖尿病有一定的临床应用价值。     

糖尿病肾病尿唾液酸变化的临床意义

采用Ｆ－８３３６化学比色法，测定了６９例不同白蛋白排泄率（ＡＥＲ）的非胰岛素依赖性糖尿病（ＮＩＤＤＭ）病人及１９例正常人的２４小时尿总唾液酸（ＵＴＳＡ），结果显示：①微量白蛋白尿组ＵＴＳＡ水平明显高于正常对照组及正常白蛋白尿组（均Ｐ＜０．０１）。②伴随尿中白蛋白排泄率增加，尿ＵＴＳＡ值也呈正相关的增加。从而提示ＵＴＳＡ不仅可作为糖尿病肾病（ＤＮ）的早期诊断指标；在一定程度上也反映ＤＮ的肾脏损伤程度。     

高血压合并脑梗塞预后与心率变异性关系

目的 研究原发性高血压（ＰＨ）合并脑梗塞（ＢＥ）时心率变异性（ＨＲＶ）改变及其在预测ＢＥ预后方面的意义。方法 采用ＤＣＧ仪及相关软件，对ＰＨ合并ＢＥ患者（Ａ组ｎ＝５０）及对照组（Ｂ组ｎ＝６０）ＨＲＶ进行分析、比较、随访研究。结果 Ａ组的ＳＤＮＮ，ＳＤ ＡＮ Ｎｉ，Ｓ ＤＮ Ｎｉ明显降低，ｒ ＭＳ ＳＤｅｙ ＰＮ Ｎ５０亦较Ｂ组降低。ＢＥ恶化组（Ａ１组）ＨＲＶ较非恶化组（Ａ２组）者降低。结论 ＨＲＶ     

卡托普利对NIDDM微白蛋白尿患者红细胞膜ATP酶活力和红细胞内离子水平的影响

测定２０例正常人及２０例ＮＩＤＤＭ伴微白蛋白尿患者红细胞膜ＡＴＰ酶活力和红细胞内Ｎａ＋、Ｋ＋、Ｃａ＋浓度。结果与正常组比较，ＮＩＤＤＭ微白蛋白尿患者Ｎａ＋－Ｋ＋－ＡＴＰ酶和Ｃａ＋＋－ＡＴＰ酶活力降低（Ｐ＜０．０５和Ｐ＜０．０１）；红细胞内Ｋ＋浓度降低（Ｐ＜０．０５），Ｎａ＋和Ｃａ＋＋浓度增高（Ｐ均＜０．０１）。给予ＮＩＤＤＭ微白蛋白尿患者卡托普利（１２．５ｍｇ，ｔｉｄ，×２周；２５ｍｇ，ｔｉｄ，×１４周）治疗１６周，红细胞Ｎａ＋－Ｋ＋－ＡＴＰ酶及Ｃａ＋＋－ＡＴＰ酶活力和红细胞内Ｎａ＋、Ｋ＋、Ｃａ＋＋浓度基本恢复正常，尿白蛋白排泄量减少。     

原发性高血压的心率变异性分析

目的通过观察原发性高血压患心率变异性（ＨＲＶ）以及高血压患血压昼夜节律正常与异常患ＨＲＶ的变化,了解高血压患心率变异性改变及血压昼夜节律异常与自主神经功能紊乱之间的关系。方法对１００例原发性高血压患进行２４小时动态血压监测,用时域分析法对心率变异性各项指标进行了检测,并与１００例血压正常组进行对照。结果原发性高血压组与血压正常对照组相比,代表心率总变异程度的ＳＤＮＮ、ＳＤＡＮＮＩ和ＳＤＮ     

卡托普利对高血压病及非胰岛素依赖型糖尿病患者运动血压及微蛋白尿的短期作用

对血压正常的非胰岛素依赖型糖尿病（ＮＩＤＤＭ）患者１４例（ＮＩＤＤＭ组）、高血压病（ＥＨ）患者１２例（ＥＨ组）、ＥＨ合并ＮＩＤＤＭ患者１２例（ＥＨ并ＮＩＤＤＭ组）给予卡托普利口服２５ｍｇｂｉｄ，在１ｄ半内共服３次，服药前后做踏车运动试验测定血压、心率、尿白蛋白排泄率（ｕＡＥＲ）及尿转铁蛋白排泄率（ｕＴＥＲ），并以１０例正常人作对照（对照组）。结果：①服卡托普利后ＥＨ组血压明显下降，ｕＡＥＲ及ｕＴＥＲ无明显改变，而ＥＨ并ＮＩＤＤＭ组却相反；②运动状态下，三组患者服卡托普利后尿白蛋白均明显下降，但与血压互不相关；③ＥＨ组服药后，运动血压有所下降，但血压变化的绝对值服药前后相似；④血压正常的ＮＩＤＤＭ组运动后血压明显升高，服药后这种异常消失。提示：①运动状态下，早期ＥＨ和ＮＩＤＤＭ有不同的病理生理机理，似乎糖尿病更依赖于肾素－血管紧张素系统，卡托普利有较好的疗效。②对于正常血压、尿白蛋白（－）的ＮＩＤＤＭ患者，运动激发是观察尿白蛋白及血压改变的灵敏方法，若被运动激发，应当考虑给予卡托普利治疗。     

老年高血压合并糖尿病患者心率变异性及其昼夜变化临床分析

目的研究老年高血压合并糖尿病患者的心率变异性(HRV)及其昼夜变化规律,探讨老年糖尿病患者心脏自主神经变化的临床意义。方法选择87例原发性高血压患者(EH组)及68例高血压合并糖尿病患者(EH+DM组),监测24 h动态心电图,进行HRV时域指标SDNN、SDANN、SDNN Index、RMSSD、PNN50的分析。比较2组间HRV指标的差异以及HRV昼夜指标差异。结果 EH+DM组较EH组24 h、日间、夜间HRV各项指标均明显降低,且有统计学差异;EH组SDNN以及RMSSD呈昼低夜高,但无明显统计学差异,SDNN Index和PNN50仍呈昼低夜高现象(P0.01);EH+DM组SDNN以及RMSSD呈昼高夜低现象(P0.05),SDNN Index和PNN50昼夜间无统计学差异。结论老年高血压合并糖尿病患者HRV显著降低,高血压患者昼夜节律已有明显受损,高血压合并糖尿病患者昼夜节律进一步受损,心脏自主神经功能失调。     

High prevalence and severity of cardiac autonomic neuropathy in Vietnamese diabetic patients.

AIMS: Malnutrition is frequent in Vietnamese people and may influence cardiac autonomic neuropathy (CAN). The aim of the present study was to investigate cardiac autonomic function in healthy subjects living in Vietnam and the prevalence of CAN in Vietnamese diabetic patients. METHODS: One hundred and five diabetic patients (BMI = 19.8 +/- 0.3 kg/m(2)), 50 Type 1 and 55 Type 2, living in Hué (Vietnam) were selected and compared with 60 non-diabetic healthy Vietnamese controls (BMI = 20.8 +/- 0.2 kg/m(2)) and also European controls. CAN function was evaluated by five standardized tests: three tests for heart rate variations (HRV) which depend mainly on parasympathetic activity, and two tests for blood pressure (BP) response which depend mainly on sympathetic activity. RESULTS: With age taken into account, 41 of the 60 Vietnamese controls had at least mild CAN, as defined by one abnormal test for HRV when compared with the European control series, and 11 of them had two or three abnormal tests. Among the Vietnamese control men, those with abnormal HRV had lower BMI than those without (P = 0.036). Seven Vietnamese controls had postural hypotension and 16 had an abnormal BP response to the handgrip test. Compared with the Vietnamese controls, 71 diabetic patients (67.6%), 40 Type 1 and 31 Type 2, had at least mild CAN, 37 of them had two or three abnormal HRV tests, and 56 diabetic patients (53.3%) had an abnormal BP response to the sympathetic tests. Abnormal HRV were associated with significantly lower BMI, waist and hip circumferences, longer diabetes duration and higher fasting blood glucose. In the logistic regression analyses, abnormal HRV were associated significantly with duration of diabetes and BMI in patients with Type 2 diabetes. CONCLUSIONS: Cardiac autonomic dysfunction is frequent in normal Vietnamese subjects. CAN appears to be a more frequent complication of diabetes in Vietnam than in Western countries and diabetic parasympathetic dysfunction is frequently associated with sympathetic disorders. This confirms the deleterious effect a poor nutritional state has on cardiac autonomic function.     

Effect of essential hypertension on cardiac autonomic function in type 2 diabetic patients.

OBJECTIVES: The aim of this study was to examine the effects of essential hypertension on cardiac autonomic function in type 2 diabetic patients. BACKGROUND: Hypertension is common in type 2 diabetic patients and is associated with a high mortality. However, the combined effects of type 2 diabetes and essential hypertension on cardiac autonomic function have not been fully elucidated. METHODS: Thirty-three patients with type 2 diabetes were assigned to a hypertensive diabetic group (n = 15; age: 56 +/- 8 years, mean +/- SD) or an age-matched normotensive diabetic group (n = 18, 56 +/- 6 years). Cardiac autonomic function was assessed by baroreflex sensitivity (BRS), heart rate variability (HRV), plasma norepinephrine concentration and cardiac 123I-metaiodobenzylguanidine (MIBG) scintigraphic findings. RESULTS: Baroreflex sensitivity was lower in the hypertensive diabetic group than it was in the normotensive diabetic group (p < 0.05). The early and delayed myocardial uptake of 123I-MIBG was lower (p < 0.01 and p < 0.05, respectively), and the percent washout rate of 123I-MIBG was higher (p < 0.05) in the hypertensive diabetic group. However, the high frequency (HF) power and the ratio of low frequency (LF) power to HF power (LF/HF) of HRV and plasma norepinephrine concentration were not significantly different. The homeostasis model assessment index was higher in the hypertensive diabetic group than it was in the normotensive diabetic group (p < 0.01). CONCLUSIONS: Our results indicate that essential hypertension acts synergistically with type 2 diabetes to depress cardiac reflex vagal and sympathetic function, and the results also suggest that insulin resistance may play a pathogenic role in these processes.     

慢性充血性心力衰竭患者心率变异性及其昼夜节律变化

目的分析慢性充血性心力衰竭(CHF)患者心率变异性(HRV)及其昼夜节律的变化,了解CHF患者自主神经功能损害与心功能的关系。方法用24小时动态心电图分析38例CHF患者,20例心功能代偿的心血管病患者心功能代偿组,16例健康体检者对照组的HRV时域指标。比较三组间HRV指标的差异;计算CHF患者HRV昼夜指标差异,分析CHF患者24小时HRV指标变化与心功能NYHA分级的关系。结果心功能代偿组24小时HRV时域指标SDNN、SDANN和SDNNindex较对照组显著下降P<0.01、0.05和0.05rMSSD和pNN50与对照组无显著差别P>0.05;CHF组的HRV各指标均显著低于对照组均P<0.01且昼夜指标变化无差异;将CHF组分为心功能Ⅱ级组n=20和心功能≥Ⅲ级n=18两个亚组结果发现心功能≥Ⅲ级的HRV各指标明显低于心功能Ⅱ级组P<0.01。结论心血管病患者可能在心功能代偿期时自主神经的平衡就已受到损害当出现CHF时交感活性增强迷走神经张力进一步下降,自主神经调节昼夜节律性丧失,且HRV指标的下降与心功能损害程度相关因此HRV时域指标可作为评价CHF预后指标之一。     

Neu initiierte Insulintherapie und kardiale autonome Funktion bei Typ-2-Diabetes

BACKGROUND AND AIM: There is scintigraphic evidence that insulin improves cardiac autonomic innervation in diabetic patients. The aim of the study was to assess the effects of insulin therapy on parameters of cardiac reflex tests in type 2 diabetic patients. PATIENTS AND METHODS: 30 type 2 diabetic patients with an HbA(1c) of > 7.5% under oral antidiabetic agents were included into the 4-month follow-up. Insulin therapy was performed according to standardized clinical guidelines. Parameters of five cardiac reflex tests were assessed to study cardiac autonomic function: Coefficient of variation (CV) of heart rate variation (HRV) at rest and during deep breathing, HRV in response to standing (max./min. 30:15-ratio), Valsalva ratio, systolic blood pressure response (> 1 test abnormal = cardiac autonomic neuropathy [CAN]). QT(QTc)-interval was also assessed in the patients. RESULTS: At 4-months follow-up, mean insulin dosage in the patients was 25 +/- 8 IU/day. HbA(1c) was decreased from 9,2 +/- 0,7 to 7.2 +/- 0.6 % (p < 0.001). Three parameters of cardiac autonomic function were significantly improved: CV of HRV at rest 2.79 +/- 0.84 versus 2.96 +/- 0.85 (p < 0,001), CV of HRV during deep breathing 4.15 +/- 1.46 versus 4.38 +/- 1.68 (p = 0.002), 30:15 ratio 1.06 +/- 0.05 versus 1.09 +/- 0.04 (p < 0.05). Length of QTc- Interval changed significantly from 417 +/- 12 ms at month 0 to 398 +/- 11 ms at month 4 (p<0.05). CONCLUSIONS: The study demonstrates that insulin therapy with regular insulin optimizes cardiac autonomic function in type 2 diabetes mellitus. It emphasizes the value of cardiac reflex tests with regrad to follow-up of cardiac autonomic function in diabetes.     

Incipient cardiovascular autonomic imbalance revealed by wavelet analysis of heart rate variability in Type 2 diabetic patients.

AIM: Incipient cardiovascular autonomic imbalance is not readily diagnosed by conventional methods. Spectral analysis of heart rate variability (HRV) by wavelet transform (WT) was used to measure cardiovascular autonomic function in patients with Type 2 diabetes. METHODS: Thirty-two diabetic patients without (D), 26 with cardiovascular autonomic neuropathy (DAN) and 72 control subjects (C) participated. A 30-min HRV time series was analysed by wavelet transformation and four characteristic frequency intervals were defined: I (0.0095-0.021 Hz), II (0.021-0.052 Hz), III (0.052-0.145 Hz) and IV (0.145-0.6 Hz). RESULTS: When compared with C, in both D and DAN the normalized power and amplitude of interval II were increased and of interval IV decreased, resulting in a significantly higher II/IV ratio. Furthermore, in DAN the normalized power and amplitude of interval I were increased and of interval III decreased when compared with the D and C groups. The diabetic patients were divided in two equal subgroups according to HbA(1c) < 8.0% and >or= 8.0%. In the subgroup with HbA(1c) >or= 8.0%, normalized power in interval II was significantly higher and in interval IV significantly lower than in the subgroup with HbA(1c) < 8.0%. In D, but not in DAN patients prescribed ACE inhibitors, the absolute amplitude and power of oscillations were significantly higher than in patients not taking ACE inhibitor therapy. CONCLUSIONS: Patients with diabetes have increased sympathetic and decreased parasympathetic cardiac activity regardless of the presence of autonomic neuropathy. Glycaemic control and treatment with ACE inhibitors may favourably influence HRV in diabetic patients without autonomic neuropathy.     

Role of heart rate variability in the early diagnosis of diabetic autonomic neuropathy in children

BACKGROUND: Diabetic autonomic neuropathy (DAN) is a major complication of diabetes. DAN has been shown to be closely related to glycemic control. To contribute significantly to the morbidity and mortality of the disease, and to be indicative of an increased risk of cardiovascular events. Tests assessing the function of the autonomic nervous system, such as the response of heart rate and blood pressure to maneuvers stimulating the autonomic nervous system, including deep breathing. Valsalva maneuver and standing, allowed to detect signs of DAN in adolescents; however, the sensitivity of such tests in revealing an early impairment of the autonomic nervous system proved low. Several studies found heart rate variability (HRV) to be useful in assessing the dysfunction of the autonomic nervous system in diabetic children and adolescents, but only few HRV parameters were evaluated in most of them. OBJECTIVE: To study cardiac autonomic nervous system in diabetic children, and to investigate whether the duration of diabetes and the degree of metabolic control are determinants for the development of DAN in children. PATIENTS AND METHODS: We analyzed HRV in 50 asymptomatic patients with insulin-dependent diabetes mellitus (IDDM) and 30 healthy children matched for age and sex. RESULTS: Patients with a history of diabetes > 8 years showed significant alterations of the autonomic nervous system (significant reduction of r-MSSD, pNN50, HF and increase in LF/HF). Conversely, only a reduction in pNN50 was found in patients with a disease duration < 8 years. Furthermore, we also observed significant HRV abnormalities in patients with an impaired metabolic control of diabetes. Compared to controls, patients with glycosylated hemoglobin blood levels (HbA(1C)) > 8% showed a significant reduction of r-MSSD, pHH50 and total power spectrum, whereas no HRV abnormalities were detected in patients with an HbA(1C) < 8%. CONCLUSIONS: HRV analysis can detect early subclinical alterations of the autonomic nervous system in asymptomatic patients with IDDM, which seem to consist mainly in a parasympathetic impairment. Autonomic dysfunction is associated both with the duration and an inadequate metabolic control of the disease.     

急性大脑半球梗塞患者24小时心率变异性变化

目的了解急性脑梗塞患者２４小时心率变异性变化及其与岛叶病变的关系。方法采用动态心电图记录６６例急性脑梗塞患者和３９例对照的２４小时心电信号,分析其心率变异性变化。结果岛叶梗塞组、非岛叶梗塞组和腔梗塞组与对照组比较,仅发现岛叶梗塞组心率变异性指标ＨＦ、ＲＭＳＳＤ、ＰＮＮ５０下降和ＬＦ／ＨＦ增高差异有显著性。结论岛叶及其联系纤维受损在脑梗塞患者心率变异性变化中起主要作用,岛叶病变患者有明显的心脏迷走神经活性降低,心脏交感神经活动优势更加明显。     

糖尿病患者心脏自主神经病变与尿白蛋白排泄的关系

目的探讨糖尿病患者尿白蛋白排出率（ＵＡＥ）与糖尿病自主神经病变之间的关系。方法对５６例糖尿病患者及５４例正常对照者进行了ＵＡＥ测定，并应用２４小时动态心电图心率变异性频谱分析技术测定了两组的心脏自主神经功能。结果糖尿病患者在不同ＵＡＥ阶段，其反映迷走神经功能的入睡后高频成分均显著低于对照组（Ｐ＝０．０００１）。随着ＵＡＥ的增加，心脏自主神经病变的各项指标均值呈明显的减低趋势，同时出现迷走－交感神经的联合损害。结论ＵＡＥ越高，心脏自主神经病变的各项指标越低，即自主神经病变越明显。     

2型糖尿病下肢神经病变心率变异性频域参数的昼夜节律

采用24 h动态心电图检测58例2型糖尿病伴下肢神经病变组、59例2型糖尿病不伴下肢神经病变组(非下肢神经病变组)和50例对照组的心率变异性,比较其频域参数的水平及昼夜间的变化.结果 显示非下肢神经病变组、下肢神经病变组较对照组频域指标减小,平均心率增加;昼夜间比较在对照组差异有统计学意义,在非下肢神经病变组昼夜节律发生改变,在下肢神经病变组昼夜节律消失.提示糖尿病不伴和伴下肢神经病变均存在自主神经功能受损,后者受损更明显.

Abstract：

Heart rate variability(HRV)analysis and its circadian rhythm(CR)were determined in 58patients with type 2 diabetes mellitus with lower extremity neuropathy(diabetic neuropathy group), 59 patients with type 2 diabetes mellitus without lower extremity neuropathy(diabetes group), and 50 healthy controls according to 24-hour Holter recording. Frequency domain parameters of HRV were significantly decreased in both diabetes groups. Frequency domain parameter of HRV in healthy controls,and daytime/nighttime difference were statistically significant. CR of HRV was changed in diabetes group and disappeared in diabetic neuropathy group. Impaired and seriously impaired autonomic nervous function developed in type 2 diabetes mellitus without and with lower extremity neuropathy respectively.