Tibial bone strength is negatively affected by volumetric muscle loss injury to the adjacent muscle in male mice.

This study's objective was to investigate how contractile strength loss associated with a volumetric muscle loss (VML) injury affects the adjacent tibial bone structural and functional properties in male C57BL/6J mice. Mice were randomized into one of two experimental groups: VML-injured mice that were injured at age 12 weeks and aged to 20 weeks (8 weeks postinjury, VML) and 20-week-old age-matched uninjured mice (Uninjured-20). Tibial bone strength, mid-diaphysis cortical geometry, intrinsic material properties, and metaphyseal trabecular bone structure were assessed by three-point bending and microcomputed tomography (µCT). The plantar flexor muscle group (gastrocnemius, soleus, plantaris) was analyzed for its functional capacities, that is, peak-isometric torque and peak-isokinetic power. VML-injured limbs had 25% less peak-isometric torque and 31% less peak-isokinetic power compared to those of Uninjured-20 mice (p < 0.001). Ultimate load, but not stiffness, was significantly less (10%) in tibias of VML-injured limbs compared to those from Uninjured-20 (p = 0.014). µCT analyses showed cortical bone thickness was 6% less in tibias of VML-injured limbs compared to Uninjured-20 (p = 0.001). Importantly, tibial bone cross-section moment of inertia, the primary determinant of bone ultimate load, was 16% smaller in bones of VML-injured limbs compared to bones from Uninjured-20 (p = 0.046). Metaphyseal trabecular bone structure was also altered up to 23% in tibias of VML-injured limbs (p < 0.010). These changes in tibial bone structure and function after a VML injury occur during a natural maturation phase between the age of 12 and 20 weeks, as evidenced by Uninjured-20 mice having greater tibial bone size and strength compared to uninjured-aged 12-week mice.

Compromised Muscle Properties in a Severe Hypophosphatasia Murine Model.

Hypophosphatasia (HPP) is a rare metabolic bone disorder characterized by low levels of tissue non-specific alkaline phosphatase (TNAP) that causes under-mineralization of the bone, leading to bone deformity and fractures. In addition, patients often present with chronic muscle pain, reduced muscle strength, and an altered gait. In this work, we explored dynamic muscle function in a homozygous TNAP knockout mouse model of severe juvenile onset HPP. We found a reduction in skeletal muscle size and impairment in a range of isolated muscle contractile properties. Using histological methods, we found that the structure of HPP muscles was similar to healthy muscles in fiber size, actin and myosin structures, as well as the α-tubulin and mitochondria networks. However, HPP mice had significantly fewer embryonic and type I fibers than wild type mice, and fewer metabolically active NADH+ muscle fibers. We then used oxygen respirometry to evaluate mitochondrial function and found that complex I and complex II leak respiration were reduced in HPP mice, but that there was no disruption in efficiency of electron transport in complex I or complex II. In summary, the severe HPP mouse model recapitulates the muscle strength impairment phenotypes observed in human patients. Further exploration of the role of alkaline phosphatase in skeletal muscle could provide insight into mechanisms of muscle weakness in HPP.

Differential effects of Western diet and traumatic muscle injury on skeletal muscle metabolic regulation in male and female mice.

BACKGROUND: This study was designed to develop an understanding of the pathophysiology of traumatic muscle injury in the context of Western diet (WD; high fat and high sugar) and obesity. The objective was to interrogate the combination of WD and injury on skeletal muscle mass and contractile and metabolic function. METHODS: Male and female C57BL/6J mice were randomized into four groups based on a two-factor study design: (1) injury (uninjured vs. volumetric muscle loss [VML]) and (2) diet (WD vs. normal chow [NC]). Electrophysiology was used to test muscle strength and metabolic function in cohorts of uninjured + NC, uninjured + WD, VML + NC and VML + WD at 8 weeks of intervention. RESULTS: VML-injured male and female mice both exhibited decrements in muscle mass (-17%, P < 0.001) and muscle strength (-28%, P < 0.001); however, VML + WD females had a 28% greater muscle mass compared to VML + NC females (P = 0.034), a compensatory response not detected in males. VML-injured male and female mice both had lower carbohydrate- and fat-supported muscle mitochondrial respiration (JO2 ) and less electron conductance through the electron transport system (ETS); however, male VML-WD had 48% lower carbohydrate-supported JO2 (P = 0.014) and 47% less carbohydrate-supported electron conductance (P = 0.026) compared to male VML + NC, and this diet-injury phenotype was not present in females. ETS electron conductance starts with complex I and complex II dehydrogenase enzymes at the inner mitochondrial membrane, and male VML + WD had 31% less complex I activity (P = 0.004) and 43% less complex II activity (P = 0.005) compared to male VML + NC. This was a diet-injury phenotype not present in females. Pyruvate dehydrogenase (PDH), ß-hydroxyacyl-CoA dehydrogenase, citrate synthase, α-ketoglutarate dehydrogenase and malate dehydrogenase metabolic enzyme activities were evaluated as potential drivers of impaired JO2 in the context of diet and injury. There were notable male and female differential effects in the enzyme activity and post-translational regulation of PDH. PDH enzyme activity was 24% less in VML-injured males, independent of diet (P < 0.001), but PDH enzyme activity was not influenced by injury in females. PDH enzyme activity is inhibited by phosphorylation at serine-293 by PDH kinase 4 (PDK4). In males, there was greater total PDH, phospho-PDHser293 and phospho-PDH-to-total PDH ratio in WD mice compared to NC, independent of injury (P ≤ 0.041). In females, PDK4 was 51% greater in WD compared to NC, independent of injury (P = 0.025), and was complemented by greater phospho-PDHser293 (P = 0.001). CONCLUSIONS: Males are more susceptible to muscle metabolic dysfunction in the context of combined WD and traumatic injury compared to females, and this may be due to impaired metabolic enzyme functions.

Resistance wheel running improves contractile strength, but not metabolic capacity, in a murine model of volumetric muscle loss injury.

The primary objective of this study was to determine if low- or high-resistance voluntary wheel running leads to functional improvements in muscle strength (i.e., isometric and isokinetic torque) and metabolic function (i.e., permeabilized fibre bundle mitochondrial respiration) after a volumetric muscle loss (VML) injury. C57BL/6J mice were randomized into one of four experimental groups at age 12 weeks: uninjured control, VML untreated (VML), low-resistance wheel running (VML-LR) and high-resistance wheel running (VML-HR). All mice, excluding the uninjured, were subject to a unilateral VML injury to the plantar flexor muscles and wheel running began 3 days post-VML. At 8 weeks post-VML, peak isometric torque was greater in uninjured compared to all VML-injured groups, but both VML-LR and VML-HR had greater (∼32%) peak isometric torque compared to VML. All VML-injured groups had less isokinetic torque compared to uninjured, and there was no statistical difference among VML, VML-LR and VML-HR. No differences in cumulative running distance were observed between VML-LR and VML-HR groups. Because adaptations in VML-HR peak isometric torque were attributed to greater gastrocnemius muscle mass, atrophy- and hypertrophy-related protein content and post-translational modifications were explored via immunoblot; however, results were inconclusive. Permeabilized fibre bundle mitochondrial oxygen consumption was 22% greater in uninjured compared to VML, but there was no statistical difference among VML, VML-LR and VML-HR. Furthermore, neither wheel running group demonstrated a change in the relative protein content of the mitochondrial biogenesis transcription factor, peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α). These results indicate that resistance wheel running alone only has modest benefits in the VML-injured muscle. NEW FINDINGS: What is the central question of the study? Does initiation of a resistance wheel running regimen following volumetric muscle loss (VML) improve the functional capacity of skeletal muscle? What is the main finding and its importance? Resistance wheel running led to greater muscle mass and strength in mice with a VML injury but did not result in a full recovery. Neither low- nor high-resistance wheel running was associated with a change in permeabilized muscle fibre respiration despite runners having greater whole-body treadmill endurance capacity, suggesting resilience to metabolic adaptations in VML-injured muscle. Resistance wheel running may be a suitable adjuvant rehabilitation strategy, but alone does not fully mitigate VML pathology.

Pharmaceutical Agents for Contractile-Metabolic Dysfunction After Volumetric Muscle Loss.

Volumetric muscle loss (VML) injuries represent a majority of military service member casualties and are common in civilian populations following blunt and/or penetrating traumas. Characterized as a skeletal muscle injury with permanent functional impairments, there is currently no standard for rehabilitation, leading to lifelong disability. Toward developing rehabilitative strategies, previous research demonstrates that the remaining muscle after a VML injury lacks similar levels of plasticity or adaptability as healthy, uninjured skeletal muscle. This may be due, in part, to impaired innervation and vascularization of the remaining muscle, as well as disrupted molecular signaling cascades commonly associated with muscle adaptation. The primary objective of this study was to assess the ability of four pharmacological agents with a strong record of modulating muscle contractile and metabolic function to improve functional deficits in a murine model of VML injury. Male C57BL/6 mice underwent a 15% multimuscle VML injury of the posterior hindlimb and were randomized into drug treatment groups (formoterol [FOR], 5-aminoimidazole-4-carboxamide riboside [AICAR], pioglitazone [PIO], or sildenafil [SIL]) or untreated VML group. At the end of 60 days, the injury model was first validated by comparison to age-matched injury-naive mice. Untreated VML mice had 22% less gastrocnemius muscle mass, 36% less peak-isometric torque, and 27% less maximal mitochondrial oxygen consumption rate compared to uninjured mice (p < 0.01). Experimental drug groups were, then, compared to VML untreated, and there was minimal evidence of efficacy for AICAR, PIO, or SIL in improving contractile and metabolic functional outcomes. However, FOR-treated VML mice had 18% greater peak isometric torque (p < 0.01) and permeabilized muscle fibers had 36% greater State III mitochondrial oxygen consumption rate (p < 0.01) compared to VML untreated mice, suggesting an overall improvement in muscle condition. There was minimal evidence that these benefits came from greater mitochondrial biogenesis and/or mitochondrial complex protein content, but could be due to greater enzyme activity levels for complex I and complex II. These findings suggest that FOR treatment is candidate to pair with a rehabilitative approach to maximize functional improvements in VML-injured muscle. Impact statement Volumetric muscle loss (VML) injuries result in deficiencies in strength and mobility, which have a severe impact on patient quality of life. Despite breakthroughs in tissue engineering, there are currently no treatments available that can restore function to the affected limb. Our data show that treatment of VML injuries with clinically available and FDA-approved formoterol (FOR), a beta-agonist, significantly improves strength and metabolism of VML-injured muscle. FOR is therefore a promising candidate for combined therapeutic approaches (i.e., regenerative rehabilitation) such as pairing FOR with structured rehabilitation or cell-seeded biomaterials as it may provide greater functional improvements than either strategy alone.

Sexually Dimorphic Effects of a Western Diet on Brain Mitochondrial Bioenergetics and Neurocognitive Function.

A Western diet (WD), high in sugars and saturated fats, impairs learning and memory function and contributes to weight gain. Mitochondria in the brain provide energy for neurocognitive function and may play a role in body weight regulation. We sought to determine whether a WD alters behavior and metabolic outcomes in male and female rodents through impacting hippocampal and hypothalamic mitochondrial bioenergetics. Results revealed a sexually dimorphic macronutrient preference, where males on the WD consumed a greater percentage of calories from fat/protein and females consumed a greater percentage of calories from a sugar-sweetened beverage. Both males and females on a WD gained body fat and showed impaired glucose tolerance when compared to same-sex controls. Males on a WD demonstrated impaired hippocampal functioning and an elevated tendency toward a high membrane potential in hippocampal mitochondria. Comprehensive bioenergetics analysis of WD effects in the hypothalamus revealed a tissue-specific adaption, where males on the WD oxidized more fat, and females oxidized more fat and carbohydrates at peak energy demand compared to same-sex controls. These results suggest that adult male rats show a susceptibility toward hippocampal dysfunction on a WD, and that hypothalamic mitochondrial bioenergetics are altered by WD in a sex-specific manner.

Lifelong Ulk1-Mediated Autophagy Deficiency in Muscle Induces Mitochondrial Dysfunction and Contractile Weakness.

The accumulation of damaged mitochondria due to insufficient autophagy has been implicated in the pathophysiology of skeletal muscle aging. Ulk1 is an autophagy-related kinase that initiates autophagosome assembly and may also play a role in autophagosome degradation (i.e., autophagy flux), but the contribution of Ulk1 to healthy muscle aging is unclear. Therefore, the purpose of this study was to investigate the role of Ulk1-mediated autophagy in skeletal muscle aging. At age 22 months (80% survival rate), muscle contractile and metabolic function were assessed using electrophysiology in muscle-specific Ulk1 knockout mice (MKO) and their littermate controls (LM). Specific peak-isometric torque of the ankle dorsiflexors (normalized by tibialis anterior muscle cross-sectional area) and specific force of the fast-twitch extensor digitorum longus muscles was reduced in MKO mice compared to LM mice (p < 0.03). Permeabilized muscle fibers from MKO mice had greater mitochondrial content, yet lower mitochondrial oxygen consumption and greater reactive oxygen species production compared to fibers from LM mice (p ≤ 0.04). Alterations in neuromuscular junction innervation patterns as well as changes to autophagosome assembly and flux were explored as possible contributors to the pathological features in Ulk1 deficiency. Of primary interest, we found that Ulk1 phosphorylation (activation) to total Ulk1 protein content was reduced in older muscles compared to young muscles from both human and mouse, which may contribute to decreased autophagy flux and an accumulation of dysfunctional mitochondria. Results from this study support the role of Ulk1-mediated autophagy in aging skeletal muscle, reflecting Ulk1's dual role in maintaining mitochondrial integrity through autophagosome assembly and degradation.

Cognitive development in low risk preterm infants at 3-4 years of life.

BACKGROUND: Major neurological handicaps and neuropsychological disturbances are more common in ex-preterm children than their counterparts born at term. OBJECTIVE: To establish in a prospective study whether a characteristic neuropsychological profile exists in ex-preterm children who do not exhibit neurodevelopmental deficits on routine clinical examination. METHODS: Thirty intellectually normal children born preterm (30-34 weeks gestation) without major neurological disabilities and a control group of term children matched for age, sex, and parental educational and occupational status were assessed at 3-4 years of age to obtain a complete neuropsychological profile. Intellectual ability, language comprehension and expression, perceptual and visual motor function, working memory, and attention and behavioural problems were investigated. RESULTS: Even in the absence of major neurological signs, children born preterm achieved lower mean scores than controls on the Stanford-Binet intelligence scale (110.8 v 121, p<0.001), visual perception test (33.8 v 42.7, p<0.001), visual motor integration test (42.6 v 47.4, p = 0.049), memory for location test (8.4 v 9.5, p = 0.007), sustained attention test (41.6 v 51.5, p = 0.009), and the picture vocabulary test (33.3 v 44.7, p = 0.021). CONCLUSIONS: Neuropsychological abnormalities can be detected early in childhood in apparently normal ex-preterm children and are consistent with a growing body of evidence that prematurity may be associated with long term neuropsychological morbidity in childhood and adolescence.

Estudio de la IORT para la búsqueda de dosis tras la prostactetomía radical (PR) en el cáncer de próstata / A dose-finding study of IORT after radical prostatectomy (RP) in prostate cancer

No disponible

Controverasias en el diagnóstico y tratamiento del carcinoma de pene / Controversies in the diagnosis and treatment in the carcinoma of the penis

El diagnóstico y tratamiento del tumor primario en el cáncer de pene, no ofrece dificultad para el urólogo. Sin embargo, mientras los ganglios inguinales positivos deben ser tratados inmediatamente, el manejo de los ganglios inguinales clínicamente negativos es controvertido y debería considerarse: vigilancia y tratamiento conservador, biopsia guiada por ecografía, biopsia dinámica del ganglio centinela o biopsia escisional y eventual linfadenectomía, según las características del tumor primario. Realizamos un estudio retrospectivo de 20 pacientes tratados en nuestra institución entre enero de 1981 y julio de 2002 con diagnóstico de cáncer de pene. Los tumores indiferenciados comúnmente se asocian con la presencia de metástasis en los ganglios inguinales. La presentación con ganglios inguinales negativos (NO) está vinculada con menor incidencia de metástasis inguinales, al igual que el ganglio solitario (N1). Sin embargo, las metástasis son frecuentes en el estadio N2 (ganglios múltiples inguinales). La radioterapia inguinal no cumple con las expectativas de control y curación de la enfermedad. (AU)

Controverasias en el diagnóstico y tratamiento del carcinoma de pene / Controversies in the diagnosis and treatment in the carcinoma of the penis

El diagnóstico y tratamiento del tumor primario en el cáncer de pene, no ofrece dificultad para el urólogo. Sin embargo, mientras los ganglios inguinales positivos deben ser tratados inmediatamente, el manejo de los ganglios inguinales clínicamente negativos es controvertido y debería considerarse: vigilancia y tratamiento conservador, biopsia guiada por ecografía, biopsia dinámica del ganglio centinela o biopsia escisional y eventual linfadenectomía, según las características del tumor primario. Realizamos un estudio retrospectivo de 20 pacientes tratados en nuestra institución entre enero de 1981 y julio de 2002 con diagnóstico de cáncer de pene. Los tumores indiferenciados comúnmente se asocian con la presencia de metástasis en los ganglios inguinales. La presentación con ganglios inguinales negativos (NO) está vinculada con menor incidencia de metástasis inguinales, al igual que el ganglio solitario (N1). Sin embargo, las metástasis son frecuentes en el estadio N2 (ganglios múltiples inguinales). La radioterapia inguinal no cumple con las expectativas de control y curación de la enfermedad.

Conducta ante el informe tomográfico de quiste renal complejo / Management of complex renal cyst at helical CT report

Introducción: El manejo del quiste renal complicado es un desafío para el urólogo.La clasificación de Bosniak ayuda a la correcta interpretación de las masas renales quísticas, ya que está relacionada en orden creciente con la posibilidad de malignidad. Objetivo: Evaluar la utilidad de los procedimientos indicados para definir el diagnóstico y la conducta frente a los quistes complejos diagnosticados por omografía computada helicoidal. Material y método: Se estudiaron 630 pacientes con diagnóstico de quiste renal por tomografía helicoidal de abdomen realizadas entre julio de 1997 y octubre del 2000. Se realizó medición de unidades Hounsfield pre y postinyección del material de contraste. Resultados: Un total de 11 pacientes con diagnóstico de quiste renal complejo. Dos de ellos fueron diagnosticados como Bosniak tipo 2 y 9 como Bosniak tipo 3. Se realizó RMN a 4 pacientes. Dos pacientes presentaron citología positiva por punción. Sólo dos pacientes fueron sometidos a nefrectomía radical. No se confirmó la presencia de cáncer. Conclusiones: La clasificación de Bosniak es un método útil en la interpretación de lesiones rena- les quísticas. La tomografía helicoidal con contraste constituye el método de elección para diag- nóstico. El quiste complejo tipo Bosniak 3 requiere otras modalidades diagnósticas más invasivas como la exploración quirúrgica. (AU)

Nefrectomía laparoscópica en donante vivo: caso inicial / Laparoscopic live donor nephrectomy: initial case

Introducción: El transplante renal de donante vivo resulta en una opción válida para mitigar la creciente escasez de órganos. Sin embargo, la potencial morbimortalidad quirúrgica desalienta los donantes. La aplicación de técnicas minimamente invasivas puede revertir esta situación. La nefrectomía laparoscópica de donante vivo constituye un desafío de la cirugía urológica actual Objetivo: Presentar caso inicial y técnica quirúrgica de nefrectomía laparoscópica en donante vivo Paciente y método: En agosto de 2001 se realizó la primera nefrectomía laparoscópica de donante vivo. Se evaluaron antecedentes y criterios de selección. Se analizó tiempo de isquemia caliente tiempo operatorio, complicaciones, sangrado y necesidad de transfusiones. También requerimientos analgésicos y estadía hospitalaria. Control de función renal en el receptor hasta la actualidad Técnica: Decúbito lateral izquierdo modificado. Por vía transperitoneal, colocación de tres trocares en mesogastrio, supraumbilical y fosa ilíaca derecha. Incisión transversa en idéntica fosa para disección con asistencia manual y extracción del órgano. Utilización de clips LT 400 para he mostasia de arteria y vena. Preservación del uréter con su meso. Resultados: Se seleccionó una paciente de 47 años para nefrectomía laparoscópica derecha asistencia manual. Tiempo operatorio de 2,5 horas. Isquemia caliente de 2,5 minutos. No presento complicaciones ni requirió transfusiones. Buena respuesta con analgésicos por vía oral en 2 días. Alta hospitalaria al tercer día. Conclusiones: La nefrectomía laparoscópica en donante vivo es un procedimiento reproducible el entrenamiento adecuado y factible de realizar con nuestros recursos. Podría en el futuro incrementar la tasa de donantes vivos. (AU)

Conducta ante el informe tomográfico de quiste renal complejo / Management of complex renal cyst at helical CT report

Introducción: El manejo del quiste renal complicado es un desafío para el urólogo.La clasificación de Bosniak ayuda a la correcta interpretación de las masas renales quísticas, ya que está relacionada en orden creciente con la posibilidad de malignidad. Objetivo: Evaluar la utilidad de los procedimientos indicados para definir el diagnóstico y la conducta frente a los quistes complejos diagnosticados por omografía computada helicoidal. Material y método: Se estudiaron 630 pacientes con diagnóstico de quiste renal por tomografía helicoidal de abdomen realizadas entre julio de 1997 y octubre del 2000. Se realizó medición de unidades Hounsfield pre y postinyección del material de contraste. Resultados: Un total de 11 pacientes con diagnóstico de quiste renal complejo. Dos de ellos fueron diagnosticados como Bosniak tipo 2 y 9 como Bosniak tipo 3. Se realizó RMN a 4 pacientes. Dos pacientes presentaron citología positiva por punción. Sólo dos pacientes fueron sometidos a nefrectomía radical. No se confirmó la presencia de cáncer. Conclusiones: La clasificación de Bosniak es un método útil en la interpretación de lesiones rena- les quísticas. La tomografía helicoidal con contraste constituye el método de elección para diag- nóstico. El quiste complejo tipo Bosniak 3 requiere otras modalidades diagnósticas más invasivas como la exploración quirúrgica.

Nefrectomía laparoscópica en donante vivo: caso inicial / Laparoscopic live donor nephrectomy: initial case

Introducción: El transplante renal de donante vivo resulta en una opción válida para mitigar la creciente escasez de órganos. Sin embargo, la potencial morbimortalidad quirúrgica desalienta los donantes. La aplicación de técnicas minimamente invasivas puede revertir esta situación. La nefrectomía laparoscópica de donante vivo constituye un desafío de la cirugía urológica actual Objetivo: Presentar caso inicial y técnica quirúrgica de nefrectomía laparoscópica en donante vivo Paciente y método: En agosto de 2001 se realizó la primera nefrectomía laparoscópica de donante vivo. Se evaluaron antecedentes y criterios de selección. Se analizó tiempo de isquemia caliente tiempo operatorio, complicaciones, sangrado y necesidad de transfusiones. También requerimientos analgésicos y estadía hospitalaria. Control de función renal en el receptor hasta la actualidad Técnica: Decúbito lateral izquierdo modificado. Por vía transperitoneal, colocación de tres trocares en mesogastrio, supraumbilical y fosa ilíaca derecha. Incisión transversa en idéntica fosa para disección con asistencia manual y extracción del órgano. Utilización de clips LT 400 para he mostasia de arteria y vena. Preservación del uréter con su meso. Resultados: Se seleccionó una paciente de 47 años para nefrectomía laparoscópica derecha asistencia manual. Tiempo operatorio de 2,5 horas. Isquemia caliente de 2,5 minutos. No presento complicaciones ni requirió transfusiones. Buena respuesta con analgésicos por vía oral en 2 días. Alta hospitalaria al tercer día. Conclusiones: La nefrectomía laparoscópica en donante vivo es un procedimiento reproducible el entrenamiento adecuado y factible de realizar con nuestros recursos. Podría en el futuro incrementar la tasa de donantes vivos.

Ureteral stent forgotten in renal transplanted patient. Its removal.

The emblematic case of a forgotten ureteral stent in a renal transplanted patient is reported. The removal was performed with no more difficulties than in a not transplanted patient, but we would emphasize the importance of removing the stent when its function of protecting the anastomosis finished, but before its permanence could compromise the graft.

Cirrhosis and muscle cramps: evidence of a causal relationship.

The aim of the study was to define the features, prevalence, and pathophysiology of therapy for muscle cramps in cirrhotic patients. The first protocol study included 294 cirrhotic patients and 194 age- and sex-matched controls. Controls were defined as inpatients or outpatients without any clinical and laboratory evidence of liver disease. Features and prevalence of muscle cramps were defined on the basis of a standard questionnaire. As far as the pathophysiological associations of muscle cramps were concerned, the following parameters were evaluated: mean arterial pressure (MAP), nutritional status, liver function tests, plasma volume (PV), plasma renin activity (PRA), and electrolyte, mineral, and acid-base status. The prevalence of cramps was higher in cirrhotic patients than in controls, and it was related to the duration of recognized cirrhosis and to the severity of liver function impairment. At a multiple regression analysis, the presence of ascites, low values of MAP, and high values of PRA were the independent predictive factors for the occurrence of cramps in cirrhosis. In the second protocol study, the effects of a sustained expansion of the effective circulating volume induced by intravenous infusion of human albumin were compared with those of a placebo in 12 cirrhotic patients with more than three cramp crises a week. Compared with the placebo, albumin reduced the cramp frequency (P < .01). In conclusion, an increased prevalence of true muscle cramps occurs in patients with cirrhosis. Our data indicate that the pathophysiological link between cirrhosis and cramps may be represented by the reduction of the effective circulating volume. They also indicate that weekly infusion of human albumin may be an effective treatment for cramps in cirrhosis.

Randomized clinical study of the efficacy of amiloride and potassium canrenoate in nonazotemic cirrhotic patients with ascites.

Although some clinical studies seem to prove the efficacy of nonantialdosteronic potassium-sparing diuretics in the treatment of ascites, no controlled study has compared the efficacy of these drugs with that of antialdosteronic diuretics. Forty nonazotemic cirrhotic patients were randomized to receive amiloride (group A, n = 20) or potassium canrenoate (group B, n = 20). The initial doses of amiloride and potassium canrenoate were 20 mg and 150 mg, respectively. The doses were increased in stepwise fashion to 60 and 500 mg/day, respectively, if no response ensued. Nonresponders to the highest doses of each drug were later treated with potassium canrenoate and amiloride, respectively. Seven of 20 group A patients responded to amiloride, whereas 14 of 20 group B patients responded to potassium canrenoate (p < 0.025). Seven of 13 nonresponders to amiloride later responded to potassium canrenoate, whereas only two of the nonresponders to potassium canrenoate later responded to amiloride. The diuretic responses to amiloride and potassium canrenoate were related to the activity of the renin-aldosterone system. All responders to amiloride (n = 9) had normal values of plasma aldosterone. All nonresponders to amiloride who later responded to potassium canrenoate (n = 7) had increased levels of plasma aldosterone. Moreover, on comparison of all responders (n = 21) and nonresponders (n = 12) to potassium canrenoate, a higher degree of renal proximal sodium reabsorption (with consequent limitation of sodium delivery to the distal tubule) was found to be the main difference.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of amiloride on renal lithium handling in nonazotemic ascitic cirrhotic patients with avid sodium retention.

The reliability of lithium clearance as an index of distal fluid delivery in cirrhosis with ascites and in other clinical conditions characterized by low fractional sodium excretion has not yet been proven. In particular, lithium reabsorption in the amiloride-sensitive segment of the distal tubule, as evidenced in experimental studies, has not been excluded in such clinical conditions. Thus the acute effect of amiloride on renal lithium handling in 15 nonazotemic ascitic cirrhotic patients with avid sodium retention was evaluated after at least 5 days of controlled sodium intake. Renal plasma flow, glomerular filtration rate, fractional sodium excretion, fractional lithium excretion, fractional potassium excretion, fractional excretion of uric acid, plasma renin activity, plasma aldosterone and human atrial natriuretic peptide were evaluated before and for 6 hr after the administration of amiloride (20 mg/os). After amiloride administration a volume replacement scheme was enacted with intravenous amounts of saline solution, determined by the diuretic and natriuretic effect of the drug, to avoid volume depletion. Amiloride induced a prompt and sustained increase in fractional sodium excretion (from 0.28% +/- 0.09% to 1.0% +/- 0.41%, p less than 0.001) and a decrease in fractional potassium excretion (from 9.38% +/- 5.98% to 3.28% +/- 2.24%, p less than 0.0025), whereas it did not affect fractional lithium excretion and fractional excretion of uric acid. No change was observed in renal plasma flow, glomerular filtration rate, plasma renin activity, plasma aldosterone and human atrial natriuretic peptide. It was concluded that lithium is not reabsorbed in the amiloride-sensitive segment of the distal tubule in nonazotemic ascitic cirrhotic patients with avid sodium retention.