Recovery of slowed nerve conduction velocity in lead-exposed workers

Summary Maximum motor nerve conduction velocities in the median nerve (MCV) and blood lead (PbB) were repeatedly measured in 14 lead exposed workers with an initial PbB from 0.7 to 4.0 mol/kg (median 2.3 mol/kg) for a period from 3 months to 7 years: A certain dose of Calcium Disodium Ethylenediaminetetraacetic Acid (CaEDTA) was injected intravenously into most of the subjects during the period.In seven subjects, MCV improved by more than 4 m/s during the observation period which involved the first two successive measurements of MCV and PbB, but the remaining seven subjects showed the minimal alteration (within ± 4.0 m/s). The initial value of MCV was significantly slower (P < 0.01) and the decrease in PbB was significantly greater (P < 0.05) in the group of subjects having shown the improvement of MCV by more than 4 m/s.The initial value of MCV was significant in determining the alteration in MCV in multiple regression analysis and, together with the change in PbB, explained 31% of the alteration in MCV between the first two successive measurements. The initial level of PbB, dose of CaEDTA, time interval between the measurements and age played no essential part in the alteration in MCV.The alteration in MCV throughout the whole observation period in each subject significantly correlated with the concurrent change in PbB (r=–0.573, P < 0.001).     

Histopathology and apoptosis in an animal model of reversible renal injury

High adenine phosphate (HAP) diet serves as an animal model of chronic renal failure (RF). Induction of RF and establishment of end organ damage require long exposure periods to this diet. Previously, we have shown that RF is reversible after diet cessation even after protracted administration. In this study, we explored the underlying renal changes and cellular pathways occurring during administration and after cessation of the diet. Kidneys were obtained from rats fed HAP diet for 7 weeks, and from rats fed HAP diet followed a 10 week recovery period on normal diet. The kidneys of HAP diet group were significantly enlarged due to tubular injury characterized by massive cystic dilatation and crystal deposition. Kidney injury was associated with markers of apoptosis as well as with activation of apoptosis related pathways. Diet cessation was associated with a significant reduction in kidney size, tubules diameter, and crystals deposition. The recovery from renal injury was coupled with regression of apoptotic features. This is the first study showing the potential reversibility of long standing RF model, allowing optimal evaluation of uremia-chronic effects.     

胃黏膜肠化生的逆转性问题

胃黏膜肠化生作为胃癌前病变,与胃癌的发病存在密切联系.关于肠化生是否具有逆转性,目前尚有争议.但来自流行病学的证据显示,经过长期随访研究,肠化生可以逆转,但改变程度较小.除H pylori感染外,维生素C缺乏、胃酸减少和/或胆汁返流等亦是其发病因素.肠化生的发病机制尚处于探索阶段,H pylori毒力因子、肠道特异性转录因子、微卫星不稳定性等均参与其发病环节,但尚不能肯定肠化生是由干细胞突变引起的胃上皮细胞表型的改变.肠化生在诊断上存在诸多困难,严格的内镜评估以及正确的取检部位尤为重要.单独根除H pylori似乎不足以逆转肠化生,联合应用其他化学阻断剂以及中医药,可能是一条新的治疗途径.     

Comparison of Reversibility of Rat Forestomach Lesions Induced by Genotoxic and Non-genotoxic Carcinogens

Reversibility of forestomach lesions induced by genotoxic and non-genotoxic carcinogens was compared histopathologically. Groups of 30 to 33 male F344 rats were given dietary 0.1% 8-nitroquinoline, dietary 0.4–0.2% 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide, an intragastric dose of 20 mg/kg body weight N-methyl-N'-nitro-N-nitrosoguanidine once a week, or 20 ppm N-methylnitrosourethane in the drinking water as a genotoxic carcinogen, or 2% butylated hydroxyanisole, 2% caffeic acid, 2% sesamol or 2% 4-methoxyphenol in the diet as a non-genotoxic carcinogen for 24 weeks. Ten or 11 rats in each group were killed at week 24. Half of the remainder were maintained on basal diet alone for an additional 24 weeks and the other half were given the same chemical for 48 weeks, and then killed. Forestomach lesions induced by genotoxic carcinogens did not regress after removal of carcinogens. In contrast, simple or papillary hyperplasia (SPH), but not basal cell hyperplasia (BCH), induced by non-genotoxic carcinogens clearly regressed after cessation of insult. SFH labeling indices in the non-genotoxic carcinogen-treated cases decreased after removal of the carcinogenic stimulus whereas BCH values were low irrespective of treatment. Atypical hyperplasia (AH), observed at high incidences in rats treated with genotoxic carcinogens, was also evident in animals receiving non-genotoxic agents, even after their withdrawal, albeit at low incidences. AH labeling indices remained high even without continued insult. These results indicate that even with non-genotoxic carcinogens, heritable alterations at the DNA level could occur during strong cell proliferation and result in AH development. This putative preneoplastic lesion might then progress to produce carcinomas.     

Investigation of liver fibrosis in clinical practice.

The liver is composed of different hepatic fibrogenic cells: hepatic stellate cells, portal fibroblasts, fibroblasts of the Glisson capsule surrounding the liver and vascular smooth muscle cells and the second layer cells present around centrolobular veins. During liver disease, one or several populations of these cells are activated, transformed into myofibroblasts and secrete the extra-cellular matrix. There are markers to identify hepatic stellate cells either quiescent (CRBP-1) or activated (alpha-smooth muscle actin). Liver biopsy, the current "gold-standard" to estimate liver fibrosis cannot be used anymore as a "gold standard". Furthermore, it is a costly procedure with adverse effects feared by patients and clinicians. Alternative to liver biopsy using non-invasive-tests or technics include FibroTest-ActiTest, transient-elastography, hepatic vein transit time using contrast ultrasonography, magnetic resonance imaging. As a routine test, the FibroTest-ActiTest is a validated one for patients with chronic hepatitis C. The advantage of the non-invasive tests or technics is that they provide a rapid and quantitative estimation of fibrosis. With these new methods, it is possible to follow the progression of the disease and its regression either spontaneously or under treatment. In conclusion, clinicians have in their hands several painless tools to explore liver fibrosis that can be easily repeated.     

Haemodynamic effects of an acute vasodilator challenge in heart failure patients with reduced ejection fraction and different forms of post‐capillary pulmonary hypertension

Aims

The most recent European guidelines have proposed new definitions of pulmonary hypertension (PH) in left heart disease, to better approach the characteristics required to reflect the presence of pulmonary vascular disease. The purpose of this study was to assess whether different haemodynamic definitions of post‐capillary PH imply a different reversibility of PH in response to acute vasodilator administration in heart failure patients with reduced ejection fraction and PH (HFrEF‐PH).

Methods and results

Right heart catheterization and reversibility testing was performed in 156 HFrEF‐PH patients. Patients were classified as combined post‐capillary and pre‐capillary pulmonary hypertension (Cpc‐PH) vs. isolated post‐capillary pulmonary hypertension (Ipc‐PH) and on the basis of diastolic pulmonary gradient (DPG) ≥ 7 vs. < 7 mmHg or of transpulmonary gradient (TPG) >12 vs. ≤12 mmHg. After vasodilator administration, Cpc‐PH patients showed a greater per cent improvement in pulmonary vascular resistance (PVR), DPG and TPG as compared with Ipc‐PH patients (all P_int < 0.001); only pulmonary compliance (PCa) improved less in Cpc‐PH than in Ipc‐PH patients (P_int = 0.007). However, despite vasodilatation, Cpc‐PH patients remained in an unfavourable portion of the inverse hyperbolic relationship between PVR and PCa. The number of patients in whom PVR was reduced below 2.5 wood units was similar in Cpc‐PH, DPG ≥7 mmHg and TPG >12 mmHg groups (28.3, 26.7 and 18.9%, respectively).

Conclusion

Although substantial improvements in PVR, DPG and TPG were observed in Cpc‐PH patients after acute vasodilator administration, this response was associated with persistent abnormalities in the PVR vs. PCa relationship. The link between baseline right heart haemodynamics and pulmonary vascular disease remains elusive.

     

Reversibility of hepatic mitochondrial damage in rats with long-term cholestasis

Background/Aims: Long-term bile duct ligation in rats is associated with secondary biliary cirrhosis and metabolic alterations, e.g. mitochondrial dysfunction. We performed the current studies to characterize the reversibility of hepatic mitochondrial dysfunction after reversing biliary obstruction by Roux-en-Y anastomosis.Methods: Rats were studied after 4 weeks of bile duct ligation, and after 5 or 14 days of reanastomosis. Control rats were pair-fed to treated rats and all rats were studied after starvation for 24 h. Mitochondria were isolated by differential centrifugation and enzyme activities determined by spectrophotometric methods.Results: In comparison to controls, plasma β-hydroxybutyrate concentrations were decreased in bile duct ligated rats (200±70 vs. 790±200 μmol/l) and remained decreased after relief of biliary obstruction. In contrast, plasma free fatty acids were not different between controls and treated rats. Oxidative metabolism of L-glutamate, succinate and duroquinol was decreased in liver mitochondria from bile duct ligated rats. After relief of biliary obstruction, the metabolism of L-glutamate and duroquinol normalized quickly, whereas succinate metabolism remained impaired. Similar results were obtained for the mitochondrial oxidases in disrupted mitochondria. The activities of complex I, II, III and V of the respiratory chain were reduced in bile duct ligated rats. After relief of biliary obstruction, complex I and III normalized quickly, whereas complex II and V remained impaired. Oxidative metabolism of long-chain fatty acids by isolated liver mitochondria was decreased in bile duct ligated rats and did not recover after relief of biliary obstruction.Conclusions: Long-term cholestasis in the rat is associated with a decrease in specific functions of liver mitochondria which recover only partially after Rouxen-Y anastomosis. The persistence of decreased mitochondrial fatty acid metabolism cannot be explained by impaired activity of the respiratory chain, but is more likely due to alterations in mitochondrial β-oxidation.     

Small Airway Pathology and Bronchoreversibility in Advanced Emphysema

ABSTRACT

Background: Poorly reversible airflow obstruction is a hallmark feature of chronic obstructive pulmonary disease (COPD). However, some COPD patients demonstrate significant bronchodilator reversibility (BDR). The pathologic features associated with the presence or absence of this phenomenon are not known. Methods: We analyzed 67 patients with advanced upper lobe predominant emphysema who underwent lung volume reduction surgery and divided them into 2 groups: the reversible group [BD(+)] had a >12% and >200 mL increase in FEV₁ or FVC with bronchodilator; the irreversible group [BD(?)] had a ≤12% and ≤20 mL increase in FEV₁ and FVC. We measured the epithelial height (EH) and areas of epithelium (EA), subepithelium (SEA), smooth muscle (SMWA), and total wall (TWA) of the small airways (<2 mm in internal diameter) in the resected specimens, and adjusted these measurements for basement membrane area (BMA) or perimeter (BMP). Results: Despite similar baseline characteristics, the BD(+) group had a smaller EH (0.036 mm vs. 0.042 mm, p = 0.005) and EH/BMP (0.012 vs. 0.014, p = 0.007), and a greater SMWA/BMA (0.491 vs. 0.430, p = 0.034) compared to the BD(?) group. In addition, EA trended to be smaller in the BD(+) group when compared to the BD(?) group (0.160 mm² vs. 0.184 mm², p = 0.06). In a subset of patients with consistent patterns of BDR on serial testing, the BD(+) group had greater SMWA/BMA (0.518 vs. 0.433, p = 0.049) and TWA/BMA (1.405 vs. 1.266, p = 0.036) compared to the BD(?) group. Conclusions: Small airway smooth muscle mass may play a role in determining BDR in severe emphysema.     

Dementia and subnormal levels of vitamin B12: Effects of replacement therapy on dementia

Routine determination of serum vitamin B₁₂ levels is generally recommended as part of the screening of demented patients, based on the notion that vitamin B₁₂ deficiency is one of the causes of reversible dementia. We studied the effects of vitamin B₁₂ replacement therapy in a prospective longitudinal study at a memory clinic, with special emphasis on assessment of severity of dementia: not only cognitive deterioration, but also disability in the activities of daily life, behavioural problems, and the burden experienced by the caregiver were examined using instruments of proven validity. In a series of 170 consecutive patients with dementia, subnormal serum vitamin B₁₂ levels were found in 26 cases (15%); all but one fulfilled diagnostic criteria for possible Alzheimer's disease. Cobalamin supplementation was given to all patients and the effect was evaluated after 6 months. When the size and pattern of individual change scores, and the mean change scores on all instruments were taken into account, functioning after replacement therapy was not improved. When change scores of treated patients were compared with those of patients with Alzheimer's disease (n = 69), vitamin B₁₂ replacement did not result in slowing of the progression of dementia. Contrary to widely accepted beliefs, subnormal serum vitamin B₁₂ levels are not a (quantitatively) important cause of reversible dementia.     

A prospective study of the cold response of digital vessels in forestry workers exposed to saw vibration

Objectives: To investigate the occurrence of vibration-induced white finger (VWF) and the cold response of digital vessels in a group of 68 forestry workers who underwent a first clinical examination in 1990 and were then reexamined in 1995. Methods: The forestry workers were divided into three groups: group A (n = 27), active workers who did not have VWF in␣1990 and continued to use chain saws; group B (n = 29), workers who did not have VWF in 1990 and retired before 1995; and group C (n = 12), active or retired workers who had VWF in 1990. The subjects underwent a medical interview, a complete physical examination, and a cold provocation test, which were performed by the same physicians at both surveys. The cold test consisted of measurement of the finger systolic blood pressure (FSBP) after local cooling to 10 °C, expressed as a percentage of the pressure recorded at 30 °C (FSBP%_10°). Results: Three new cases of VWF occurred during the follow-up period among workers who had used only antivibration (AV) chain saws. The vasoconstrictor response to cold was unchanged in group A and improved in group B (P < 0.001). A significant decrease in VWF symptoms and abnormal response to cold was observed in group C (P < 0.05). As a result of preventive measures curtailing saw usage time in the VWF workers, the daily vibration exposure in group C was lower in 1995 than in 1990 (P = 0.02). In the retired workers, FSBP%_10° was positively related to the time since the cessation of work with chain saws (P < 0.01). Conclusions: The findings of this follow-up study indicate that a reduction in or cessation of exposure to vibration has a beneficial effect on finger-blanching symptoms and the cold response of digital vessels. The occurrence of new cases of VWF in subjects whose work experience was limited to AV chain saws argues for the maintenance of health surveillance in these workers. Received: 16 March 1998 / Accepted: 12 June 1998