Abnormal Control of Orbicularis Oculi Reflex Excitability in Multiple Sclerosis

Brain lesions in patients with multiple sclerosis may lead to abnormal excitability of brainstem reflex circuits because of impairment of descending control pathways. We hypothesized that such abnormality should show in the analysis of blink reflex responses in the form of asymmetries in response size. The study was done in 20 patients with relapsing-remitting multiple sclerosis and 12 matched healthy subjects. We identified first patients with latency abnormalities (AbLat). Then, we analyzed response size by calculating the R2c/R2 ratio to stimulation of either side and the mean area of the R2 responses obtained in the same side. Patients with significantly larger response size with respect to healthy subjects in at least one side were considered to have abnormal response excitability (AbEx). We also examined the blink reflex excitability recovery (BRER) and prepulse inhibition (BRIP) of either side in search for additional indices of asymmetry in response excitability. Neurophysiological data were correlated with MRI-determined brain lesion-load and volume. Eight patients were identified as AbLat (median Expanded Disability Status Scale–EDSS = 2.75) and 7 of them had ponto-medullary lesions. Nine patients were identified as AbEx (EDSS = 1.5) and only 2 of them, who also were AbLat, had ponto-medullary lesions. In AbEx patients, the abnormalities in response size were confined to one side, with a similar tendency in most variables (significantly asymmetric R1 amplitude, BRER index and BRIP percentage). AbEx patients had asymmetric distribution of hemispheral lesions, in contrast with the symmetric pattern observed in AbLat. The brainstem lesion load was significantly lower in AbEx than in AbLat patients (p = 0.04). Asymmetric abnormalities in blink reflex response excitability in patients with multiple sclerosis are associated with lesser disability and lower tissue loss than abnormalities in response latency. Testing response excitability could provide a reliable neurophysiological index of dysfunction in early stages of multiple sclerosis.     

Modification of the blink reflex in hemidystonia

With the aim of evaluating the excitability of the brain stem reflex centers, we studied the side-to-side differences in the EMG activity of the early and late components of the blink reflex, in subjects with unilateral dystonia without demonstrable brain lesions. We observed that both early and late responses of direct blink reflex were significantly higher in the affected side than in the contralateral one.     

Associative stimulation of the supraorbital nerve fails to induce timing-specific plasticity in the human blink reflex

Background

Associative high-frequency electrical stimulation (HFS) of the supraorbital nerve in five healthy individuals induced long-term potentiation (LTP)-like or depression (LTD)-like changes in the human blink reflex circuit according to the rules of spike timing-dependent plasticity (Mao and Evinger, 2001). HFS given at the onset of the R2 component of the blink reflex (HFS_LTP) produced a lasting facilitation of the R2, whereas HFS given shortly before R2 (HFS_LTD) caused a lasting suppression of the R2. In patients with benign essential blepharospasm (BEB), a focal dystonia affecting the orbicularis oculi muscles, HFS_LTP induced excessive LTP-like associative plasticity relative to healthy controls, which was normalized after botulinum toxin (BTX) injections (Quartarone et al, 2006).

Methodology/Principal Findings

We used HFS conditioning of the supraorbital nerve to study homeostatic metaplasticity of the blink reflex circuit in healthy subjects and dystonic patients. On separate days, we tested the conditioning effects on the R2 response and paired-pulse R2 inhibition after (i) HFS_LTP, (ii) HFS_LTP followed by HFS_LTP, and (iii) HFS_LTP followed by HFS_LTD. Controls also received (iv) HFS_LTD alone and (v) a non-intervention protocol. In BEB patients, HFS_LTP followed by HFS_LTD was given before and after BTX treatment. We were not able to replicate the bidirectional timing-dependent effects of HFS_LTP and HFS_LTD alone. All HFS protocols produced a non-specific reduction of the R2 response and a relative decrease in paired-pulse inhibition. These R2 changes also occurred in controls when no HFS was applied. There was also no trace of a homeostatic response pattern in BEB patients before or after BTX treatment.

Conclusion/Significance

Our data challenge the efficacy of associative HFS to produce bidirectional plasticity in the human blink reflex circuit. The non-specific decrease of the R2 response might indicate habituation of the blink reflex following repeated electrical supraorbital stimulation. The increase of inhibition after paired pulse stimulation might reflect homeostatic behaviour to prevent further down regulation of the R2 response to preserve the protection of this adverse-effects reflex.     

Is Fluid Overload More Important than Diabetes in Renal Progression in Late Chronic Kidney Disease?

Fluid overload is one of the major presentations in patients with late stage chronic kidney disease (CKD). Diabetes is the leading cause of renal failure, and progression of diabetic nephropathy has been associated with changes in extracellular fluid volume. The aim of the study was to assess the association of fluid overload and diabetes in commencing dialysis and rapid renal function decline (the slope of estimated glomerular filtration rate (eGFR) less than -3 ml/min per 1.73 m²/y) in 472 patients with stages 4-5 CKD. Fluid status was determined by bioimpedance spectroscopy method, Body Composition Monitor. The study population was further classified into four groups according to the median of relative hydration status (△HS =fluid overload/extracellular water) and the presence or absence of diabetes. The median level of relative hydration status was 7%. Among all patients, 207(43.9 %) were diabetic. 71 (15.0%) subjects had commencing dialysis, and 187 (39.6%) subjects presented rapid renal function decline during a median 17.3-month follow-up. Patients with fluid overload had a significantly increased risk for commencing dialysis and renal function decline independent of the presence or absence of diabetes. No significantly increased risk for renal progression was found between diabetes and non-diabetes in late CKD without fluid overload. In conclusion, fluid overload has a higher predictive value of an elevated risk for renal progression than diabetes in late CKD.     

Reduced synthesis of muscle proteins in chronic renal failure

Muscle wasting and weakness occur frequently in patients with chronic renal failure. The mechanism(s) by which these abnormalities occur is unclear. We hypothesized that such findings were due to defective muscle protein synthesis. We measured synthetic rates of mixed muscle proteins, myosin heavy chain, and mitochondrial proteins in serial muscle biopsy samples during a continuous infusion of L[1-(13)C]leucine from 12 patients with chronic renal failure and 10 healthy control subjects under identical study conditions. Patients with chronic renal failure have significantly lower synthetic rates of mixed muscle proteins and myosin heavy chain (27 and 37% reductions, respectively, P < 0.05 and P < 0.02). Significant declines in the synthetic rates of muscle mitochondrial protein (27%) (P < 0.05), muscle cytochrome c-oxidase activity (42%) (P < 0.007), and citrate synthase (27%) (P < 0.007) were also observed in patients with chronic renal failure. The synthetic rates of muscle proteins and activity of mitochondrial enzymes were negatively correlated to the severity of renal failure. These results indicate that in chronic renal failure there is a decrease in the synthesis of muscle contractile and mitochondrial proteins and a decrease in muscle mitochondrial oxidative enzymes. Reduced synthetic rate of several muscle proteins is the likely biochemical basis of muscle loss and muscle weakness in people with chronic renal failure.     

Ultrasonic examination of the parathyroid glands, bone x-ray and calcium deposits of the eye in diagnosis of secondary hyperparathyroidism in light of 12 observed cases]

Twelve patients with chronic renal failure treated with repeated dialysis underwent subtotal parathyroidectomy. Histologic examination revealed hyperplasia parathyroidal adenoma in all patients. Diagnostic correlation between bone X-ray, ultrasound of parathyroid glands, calcium deposits in cornea and conjunctiva, and histological findings has been analysed. Radiological abnormalities have been noted in 8 patients (66%), parathyroid glands hyperplasia in 9 (75%), and corneal and conjunctival calcium deposits in 10 (83%) patients. These data confirm the value of techniques under study for the diagnosis of the secondary hyperparathyroidism in patients with chronic renal failure.     

脂代谢异常对肾病的影响

肾脏疾病发展为慢性肾衰竭是个不可逆的过程,脂质代谢的异常,对肾病患者具有重要的影响。多项实验已经证实,即使在肾病的早期阶段,也会出现不同程度的脂质及脂类代谢的异常,高密度脂蛋白(HDL)、低密度脂蛋白(LDL)、脂联素、瘦素等脂类代谢相关物质发生改变,不仅对血浆脂代谢产生影响,对于肾小球及肾小管的结构及功能也会有一定的损伤作用。肾病患者,如肾病综合征、慢性肾衰竭等疾病,多数有肾小球及肾小管间质的损伤,肾脏的脂毒性加重肾单位的破坏。随着人们对于慢性肾脏病认识的逐渐深入,降脂治疗的普遍应用,人们普遍认为改善血浆中脂类的水平,对于肾病的治疗,尤其对于慢性肾衰竭的预防具有重要作用。     

Dissociation of absorptions of calcium and phosphate after successful cadaveric renal transplantation.

Calcium and phosphate absorptions were studied by radiotracer techniques in 30 patients after successful cadaveric renal transplantation, and results were compared with those in a group of normal subjects and in groups of patients with chronic renal failure (CRF). Both calcium and phosphate absorptions were impared in patients with CRF, including those receiving haemodialysis. Abnormalities of calcium absorption, however, seemed to occur earlier in the course of advanced renal failure than abnormalities in phosphate absorption. Calcium absorption improved dramatically after successful renal transplantation, while phosphate absorption remained the same. A dissociation between calcium and phosphate absorptions is not often seen clinically, and the mechanisms for it are unknown. Phosphate malabsorption may be a further contributing factor in the development of persistent hypophosphataemia after transplantation.     

Bilateral fractures of femoral neck in patients with moderate renal failure receiving fluoride for spinal osteoporosis.

Two patients with moderate renal failure sustained spontaneous bilateral hip fractures during treatment with fluoride, calcium, and vitamin D for osteoporosis. They had been taking sodium fluoride (40-60 mg/day) for 11 and 21 months, respectively. Histological examination of a specimen of the bone showed severe fluorosis in the first case, and quantitative analysis of bone showed osteomalacia and skeletal fluorosis in the other case. These abnormalities were considered to be the consequence of excessive retention of fluoride due to renal insufficiency. As bilateral femoral neck fractures are very rare these data suggest a causal link between fractures and fluoride in patients with renal failure. Thus fluoride should be given at a lower dosage, if at all, to patients with even mild renal failure.     

Natural course of penicillamine nephropathy: a long term study of 33 patients

To elucidate the natural course of the nephropathy associated with penicillamine and thereby facilitate its clinical management 33 patients with rheumatoid arthritis who developed proteinuria during treatment with oral penicillamine were studied in detail throughout their renal illness. Renal biopsies were performed, and creatinine clearance and proteinuria were measured serially for 74 months (range 16-148 months). Fourteen patients developed proteinuria within six months after the start of treatment and 27 within 12 months. When treatment was stopped the proteinuria reached a median peak of 4·2 g/24 h (range 0·3-15·0 g/24 h) at one month (range 0-7 months) before resolving spontaneously by six months (12 patients), 12 months (21), or 18 months (29). In all patients but one, who developed carcinoma of the renal pelvis, proteinuria resolved by 21 months and its median duration was eight months. The median first and last measurements of creatinine clearance showed no appreciable change (80 ml/min and 78 ml/min), and no patient died from or needed treatment for renal failure. The HLA-B8 or HLA-DR3 alloantigen, or both, were identified in 10 patients. Renal biopsy specimens showed membranous glomerulonephritis in 29 patients, minimal change nephropathy in two, and electron dense deposits in the mesangial regions in two.In all the patients whose nephropathy was due solely to treatment with penicillamine the proteinuria resolved completely when the drug was withdrawn; renal function did not deteriorate, and corticosteroids were unnecessary.     

Incidence of advanced chronic renal failure and the need for end stage renal replacement treatment.

OBJECTIVE--To determine the age related incidence of advanced chronic renal failure in two areas of England. DESIGN--Prospective study of patients newly identified as having advanced chronic renal failure within a two year period; subsequent monitoring of patients'' clinical course for a further 26 months. SETTING--Devon and Blackburn. SUBJECTS--Those patients in a population of 708,997 who developed advanced chronic renal failure (serum creatinine concentration greater than 500 mumol/l) for the first time during a two year period. MAIN OUTCOME MEASURES AND RESULTS--210 Patients (148 per million population per year) developed advanced chronic renal failure, 117 (51%) of whom were over 70. The age related incidence rose from 58 per million per year in those aged 20-49 to 588 per million per year in those aged 80 or over. Only 54% (113) of patients were referred to a nephrologist; 120 patients (57%) needed dialysis or died within three months of presenting without receiving dialysis, and 187 (89%) died or needed dialysis within three years. After those unsuitable for further treatment had been excluded, 78 patients per million population per year aged under 80 needed to start long term renal replacement treatment. CONCLUSIONS--Many patients suitable for renal replacement treatment are still not referred for nephrological opinion and are denied treatment. If the treatment rate in the United Kingdom rose from the 1988 rate of 55.1 per million per year to 78 per million per year then the number of patients receiving treatment would rise to about 800 per million. This is double the present number and has considerable but predictable resource implications for the NHS.     

Modulation using racemic and levo-rotary baclofen of the trigeminal reflex in man

Baclofen (Lioresal), a muscle relaxant, exerts a specific action on the trigeminal system by depressing excitatory synaptic transmission in the spinal trigeminal nucleus. To evaluate the effects of racemic and L-baclofen on the human trigeminal reflexes, the area of the blink reflex was measured in seven normal subjects, before and after i.v. administration of racemic baclofen (25 mg.) and oral administration of L-baclofen (15 mg.). The blink reflex is a trigeminal facial reflex consisting of two components (R1 and R2): R1 has a shorter latency and is mediated by an oligosynaptic pontine circuit; R2 has a longer latency and is believed to be relayed via a polysynaptic circuit through the lateral bulbar reticular system. Whereas the R1 response was scarcely affected by administration of racemic baclofen, it was significantly reduced by L-baclofen (P less than 0.01). R2 was depressed by both drugs (P less than 0.01). These results indicate that both racemic and L-baclofen inhibit trigeminal transmission in man, probably because they interfere with excitatory transmission through the interneurons of the lateral reticular formation. In addition, since L-baclofen reduced both R1 and R2 this form of the drug presumably has a more powerful effect than its racemic counterpart, on the few interneurons of the short latency component.     

Reticuloendothelial function in renal allograft recipients.

The phagocytic capacity of the reticuloendothelial system (R.E.S.) was assessed in patients with chronic renal failure and in renal transplant recipients. R.E.S. phagocytosis was increased in the former group. Soon after transplantation R.E.S. phagocytosis was moderately reduced (through levels were comparable with those of normal controls) but was particularly reduced after high-dose corticosteroid treatment for rejection. In long-term allograft recipients R.E.S. phagocytosis was also depressed though steroid maintenance doses were small.     

Should patients with renal failure associated with myeloma be dialysed?

In a study of renal function in multiple myeloma seven patients presented with renal failure and three developed it 16-106 months after diagnosis. All were dialysed. Infection with dehydration was a precipitating factor in all seven cases of acute or acute on chronic renal failure. Of these, two patients recovered normal renal function and one other was left with permanent renal impairment but no longer required dialysis. Results from the seven patients with acute renal failure and for the three with more chronic features support the practice of dialysis for all patients who present with renal failure. Dialysis is not indicated for those patients with progressive myelomatous disease. The study showed no evidence that chemotherapy permitted recovery from established renal failure. The prognosis in this elderly group is heavily dependent on the presence of cardiovascular or other degenerative disease.     

Free tissue transfer in patients with renal disease

Several authors have cited renal disease as a risk factor for free flap failure. The authors performed a retrospective analysis of all patients who underwent free tissue transfer with concomitant renal disease, including acute renal failure, end-stage renal disease, chronic renal insufficiency, and functional kidney transplants, to determine what effect renal disease has on flap survival and overall reconstructive outcome. More than 1053 free flaps were examined. Renal disease was identified in 32 patients who underwent 33 free tissue transfers. Average patient age was 57 years (range, 36 to 80 years). Twelve patients (38 percent) were on chronic dialysis (end-stage renal disease), 18 patients (56 percent) had chronic renal insufficiency, and three patients (9 percent) had the diagnosis of acute renal failure at the time of surgery. Three patients in the chronic renal insufficiency group had a functioning renal transplant. Average follow-up was 16 months. Immediate postoperative complications occurred in 14 patients (42 percent of the 33 flaps). Overall perioperative mortality was 3 percent. Within the first 30 days there were two cases (6 percent) of primary flap failure; an additional four legs were lost as the result of complications related to their bypass grafts. There were no primary flap failures after 30 days; however, within the first year after surgery an additional seven limbs were lost as the result of progressive ischemia or infection, and an additional three patients died. This resulted in a 52 percent incidence of major morbidity or mortality during the first year and a 55 percent reconstructive success rate in survivors at 1 year. No significant difference was seen in postoperative morbidity or mortality when comparing the end-stage renal disease group to the chronic renal insufficiency group; however, patients with renal disease and diabetes tended to have poorer outcomes. Renal disease, especially renal disease associated with diabetes and peripheral vascular disease, can be a strong indicator of possible reconstructive failure. The surgeon and patient should be aware of the medical and surgical complications associated with this procedure at the outset.     

Quantitative Skeletal Histology in Untreated End-stage Renal Failure

Forty-six patients with end-stage renal failure were subjected to iliac crest biopsy before the initiation of a dialysis programme and regardless of the presence of skeletal symptoms. Quantitative studies of undecalcified sections showed osteoporosis in 11 patients, osteosclerosis in 10, and osteomalacia (alone or in combination with other lesions) in 14. Semiquantitative studies showed osteitis fibrosa (alone or in combination with other lesions) in 29. The various abnormalities occurred alone or in combination with one another and, to a large extent, independently of serum biochemistry.Radiological examination failed to diagnose the histological abnormality in 12 of 13 patients with osteomalacia and in 10 of 25 patients with osteitis fibrosa. These abnormalities were commoner in women, in patients with pyelonephritis, and in patients with documented renal failure of long standing. Bone volume changes could not be correlated with any clinical parameters.Skeletal findings in untreated patients should be taken into account when the effects of chronic dialysis or renal transplantation or both are being considered.     

The natural course of gold nephropathy: long term study of 21 patients.

To clarify the natural course of gold nephropathy and thereby facilitate its clinical management 21 patients with rheumatoid arthritis who developed proteinuria during treatment with intramuscular sodium aurothiomalate were studied in detail throughout their renal illnesses. Renal biopsies were performed, and creatinine clearance and proteinuria were measured serially for 60 months (range 16-130 months). Ten patients developed proteinuria after six months'' treatment, 15 after 12 months, and 18 after 24 months. When treatment was stopped the proteinuria reached a median peak of 2.1 g/day (range 0.7-30.7 g/day) at two months (range 1-13 months) before resolving spontaneously, in eight patients by six months, in 13 by 12 months, and in 18 by 24 months. All patients were free of proteinuria by 39 months, the median duration being 11 months. The median first and last measurements of creatinine clearance showed no significant change (77 ml/minute and 59 ml/minute, respectively), and no patient died from or needed treatment for renal failure. HLA-B8 or DR3 alloantigens, or both, were identified in seven patients. Renal biopsy specimens showed membranous glomerulonephritis in 15 patients, a minimal change nephropathy in two, mesangial electron dense deposits in two, and no appreciable glomerular changes in two. In these 21 patients the proteinuria of gold nephropathy resolved completely when treatment was withdrawn. Renal function did not deteriorate, corticosteroids were unnecessary, and several different renal lesions were seen.     

Prevalence of advanced renal failure in Northern Ireland.

OBJECTIVE--To determine the prevalence of advanced chronic renal failure in Northern Ireland as part of an assessment by the Renal Association of the level of service provision for treatment of such patients. DESIGN--Prospective notification of patients reaching a defined level of advanced chronic renal failure (serum creatinine concentration greater than or equal to 500 mumol/l or blood urea concentration greater than or equal to 25 mmol/l) within one year and follow up for at least three, and, at most, four years after notification. SETTING--Northern Ireland. PATIENTS--122 Patients with a serum creatinine or blood urea concentration higher than the defined level newly detected from 1 March 1985 to 28 February 1986. MAIN OUTCOME MEASURE--Survival after notification. RESULTS--77 Patients of all ages/million population/year had advanced chronic renal failure compared with 67/million/year between the ages of 5 and 80 found in an earlier study of the same population. 62% Of the patients were older than 50 years. Seventeen (14%) of the patients either required dialysis or died within one month of notification, 51 (42%) survived for at least three months, and 23 (19%) for one year or longer. Three patients, all of whom were attending a renal clinic, survived for periods of 43, 45, and 46 months respectively without renal replacement treatment. CONCLUSIONS--The increased number of new patients disclosed in this survey compared with the earlier survey is mainly owing to an increased number of older patients. Such patients often have disabilities other than renal failure, are less likely to be capable of self treatment, may develop complications more often and require more frequent hospital admissions, and may not be suitable for transplantation and consequently have considerable resource implications for the NHS.     

AT1 receptor mRNA antisense normalizes enhanced cardiac sympathetic afferent reflex in rats with chronic heart failure

Previous studies showed that the cardiac sympathetic afferent reflex (CSAR) is enhanced in dogs and rats with chronic heart failure (CHF) and that central ANG II type 1 receptors (AT(1)R) are involved in this augmented reflex. The aim of this study was to determine whether intracerebroventricular administration and microinjection of antisense oligodeoxynucleotides targeted to AT(1)R mRNA would attenuate the enhanced CSAR and decrease resting renal sympathetic nerve activity (RSNA) in rats with coronary ligation-induced CHF. The CSAR was elicited by application of bradykinin to the epicardial surface of the left ventricle. Reflex responses to epicardial administration of bradykinin were enhanced in rats with CHF. The response to bradykinin was determined every 50 min after intracerebroventricular administration (lateral ventricle) or microinjection (into paraventricular nucleus) of antisense or scrambled oligonucleotides to AT(1)R mRNA. AT(1)R mRNA and protein levels in the paraventricular nucleus were significantly reduced 5 h after administration of antisense. Antisense significantly decreased resting RSNA and normalized the enhanced CSAR responses to bradykinin in rats with CHF. Scrambled oligonucleotides did not alter resting RSNA or the enhanced responses to bradykinin in rats with CHF. No significant effects were found in sham-operated rats after administration of either antisense or scrambled oligonucleotides. These results strongly suggest that central AT(1)R mRNA antisense reduces expression of AT(1)R protein and normalizes the augmentation of this excitatory sympathetic reflex and that genetic manipulation of protein expression can be used to normalize the sympathetic enhancement in CHF.