Splanchnic and leg substrate exchange after ingestion of a natural mixed meal in humans.

The disposal of a mixed meal was examined in 11 male subjects by multiple (splanchnic and femoral) catheterization combined with double-isotope technique (intravenous [2-3H]glucose plus oral U-[14C]starch). Glucose kinetics and organ substrate balance were measured basally and for 5 h after eating pizza (600 kcal) containing carbohydrates 75 g as starch, proteins 37 g, and lipids 17 g. The portal appearance of ingested carbohydrate was maximal (1.0 mmol/min) between 30 and 60 min after the meal and gradually declined thereafter, but was still incomplete at 300 min (0.46+/-0.08 mmol/min). The total amount of glucose absorbed by the gut over the 5 h of the study was 247+/-26 mmol (45+/-6 g), corresponding to 60+/-6% of the ingested starch. Net splanchnic glucose balance (-6.7+/-0.5 micromol x kg(-1) x min(-1), basal) rose by 250-300% between 30 and 60 min and then returned to baseline. Hepatic glucose production (HGP) was suppressed slightly and only tardily in response to meal ingestion (approximately 30% between 120 and 300 min). Splanchnic glucose uptake (3.7+/-0.6 micromol x kg(-1) x min(-1), basal) peaked to 9.8+/-2.0 micromol x kg(-1) x min(-1) (P<0.001) at 120 min and then returned slowly to baseline. Leg glucose uptake (34+/-5 micromol x leg(-1) x min(-1), basal) rose to 151+/-29 micromol x leg(-1) x min(-1) at 30 min (P<0.001) and remained above baseline until the end of the study, despite no increase in leg blood flow. The total amount of glucose taken up by the splanchnic area and total muscle mass was 161+/-16 mmol (29+/-3 g) and 128 mmol (23 g), respectively, which represent 39 and 30% of the ingested starch. Arterial blood lactate increased by 30% after meal ingestion. Net splanchnic lactate balance switched from a basal net uptake (3.2+/-0.6 micromol kg(-1) x min(-1) to a net output between 60 and 120 min and tended to zero thereafter. Leg lactate release (25+/-11 micromol x leg(-1) x min(-1), basal) drastically decreased postprandially. Arterial concentration of both branched-chain amino acids (BCAA) and non-branched-chain amino acids (N-BCAA) increased significantly after meal ingestion (P<0.001). The splanchnic area switched from a basal net amino acid uptake (31+/-16 and 92+/-48 micromol/min for BCAA and N-BCAA, respectively) to a net amino acid release postprandially. The net splanchnic amino acid release over 5 h was 11.3+/-4.2 mmol for BCAA and 37.8+/-9.7 mmol for N-BCAA. Basally, the net leg balance of BCAA was neutral (-3+/-5 micromol x leg(-1) x min(-1)), whereas that of N-BCAA indicated a net release (54+/-14 micromol x leg(-1) x min(-1)). After meal ingestion, there was a net leg uptake of BCAA (20+/-6 micromol x leg(-1) x min(-1)), whereas leg release of N-BCAA decreased by 50%. It is concluded that in human subjects, 1) the absorption of a natural mixed meal is still incomplete at 5 h after ingestion; 2) HGP is only marginally and tardily inhibited; 3) splanchnic and peripheral tissues contribute to the disposal of meal carbohydrate to approximately the same extent; 4) the splanchnic area transfers >30% of the ingested proteins to the systemic circulation; and 5) after meal ingestion, skeletal muscle takes up BCAA to replenish muscle protein stores.

Effect of cutaneous hypoxia upon erythema and pigment responses to UVA, UVB, and PUVA (8-MOP + UVA) in human skin.

The effect of oxygen deprivation upon UVA-, UVB-, and PUVA-induced pigment and erythema responses in normal human skin was examined. Before exposure, varying degrees of hypoxia in the skin of the forearm were achieved by inflating a sphygmomanometer cuff applied to the upper arm. After the transcutaneously measured pO2 had stabilized, sites on the inner forearm were exposed to UVA, UVB, or 8-MOP + UVA radiation, to determine dose thresholds for the induction of erythema and pigmentation at different cuff pressures. Inflation of the cuff to greater than systolic pressure completely inhibited immediate and delayed pigment responses (IPD, DT) to UVA doses greater than 10 times the normal pigmentation threshold dose. UVA-induced delayed erythema responses were partially inhibited by cuff inflation: 2.7 times the minimal erythema dose of UVA was necessary to cause an erythema response when exposure occurred during vascular occlusion. In contrast, erythema and pigment responses to UVB and PUVA were unaltered by cuff pressures exceeding systolic pressure during exposure. Inhibition of UVA-induced erythema and pigment responses by vascular occlusion were reversed by the transcutaneous diffusion of 100% O2. These findings indicate that the cutaneous responses to UVA and UVB occur by separate pathways differing with respect to O2 dependence. Our findings agree with those of other studies which indicate that PUVA-induced phototoxicity and melanogenesis are not O2-dependent.

Sodium retention in preascitic stage of cirrhosis.

Renal Na+ handling abnormalities have been shown in preascitic cirrhosis. To investigate the underlying pathophysiology, the effects of different sodium intakes on Na(+) balance and renal hemodynamics were assessed at 100 mEq Na+/day (low-sodium diet [LSD]) and after 6 days of 250 mEq Na+/day (high-sodium diet [HSD]). Eight asymptomatic patients with cirrhosis (Pugh-Child A class) (PAC) and 10 healthy controls (CON) were studied. At HSD, although CON readjusted Na+ excretion within the fourth day, PAC did not reach the new balance and developed a final greater Na+ retention (+437 mEq in PAC v +228 mEq in CON, P<.001). In PAC, fractional Na+ excretion (FENa) was significantly lower than in CON at LSD (P<.05), and, after HSD, increased in both groups (P<.05). In PAC, renal vascular resistances (RVR) at LSD resulted lower than in CON (P<.05) and failed to decrease after HSD. As a consequence, after HSD, glomerular filtration rate and renal plasma flow failed to increase in PAC. PRA and plasma aldosterone were significantly lower in PAC, than in CON at LSD (P<.05), and decreased in both groups after HSD (P<.05). Proximal Na+ reabsorption (RProx) [as indicated by fractional free water clearance measured in a state of maximal water diuresis] at LSD was lower in PAC than in CON (P<.05) and decreased in both groups after HSD (P<.05). In summary, early stages of cirrhosis are characterized by: (1) a reduction of RVR, probably associated with splanchnic vasodilation; (2) a Na+ retention already at LSD, as indicated by the lower FENa observed in PAC, that produces extracellular volume (ECV) expansion, with a consequent RProx and renin-angiotensin-aldosterone axis (RAS) suppression; (3) a greater Na+ retention after HSD, associated with an abnormal adaptation of renal hemodynamic, a greater ECV expansion and a consequent Rprox and RAS suppression. These data show the presence of early renal hemodynamic dysfunction in PAC. Our findings also show in this phase of the disease a preserved adaptation of RProx and RAS, thus suggesting that the observed tubular Na+ reabsorption derangement is probably related to abnormal ANP behavior.

Cultured skin as a 'smart material' for healing wounds: experience in venous ulcers.

The healing of chronic wounds is a difficult and varied problem. The engineering of a cultured skin tissue offers an adaptive therapy for chronic wounds. Our hypothesis has been that living tissue can act as a 'smart material' to heal wounds. We have examined the healing characteristics of a bilayered cultured skin equivalent (Graftskin) in a controlled study and present clinical data from interim analyses for 233 patients over 6 months of treatment. All venous ulcer patients will be followed for up to 1 year. We report on three basic scenarios of healing: (i) promotion of healing by secondary intention, (ii) persistent biological wound closure with stimulation of underlying healing, and (iii) healing by frank graft take of the cultured material with remodelling of the tissue over time. Our results indicate that the cultured skin equivalent is responsive to individual wound conditions and thus acts as a 'smart material' in the chronic wound.

Purpura fulminans. A cutaneous manifestation of severe protein C deficiency.

Protein C, when activated, is a vitamin K-dependent serine protease that has anticoagulant and profibrinolytic activities. An increased risk of thrombotic disease is associated with deficiency of this enzyme. A neonate developing purpura fulminans with internal thrombotic complications and congenital absence of protein C is described. Family studies showed partial protein C deficiency in the subject's symptom-free parents and two of three siblings. Clinically and histopathologically similar lesions are also seen in two acquired conditions in which there is a thrombotic tendency: coumarin necrosis and purpura fulminans of childhood, both of which are probably the result of transient protein C deficiency. We conclude that purpura fulminans can represent a cutaneous marker of acquired or congenital protein C deficiency.

Rapid healing of venous ulcers and lack of clinical rejection with an allogeneic cultured human skin equivalent. Human Skin Equivalent Investigators Group.

OBJECTIVE: To test the safety, efficacy, and immunological impact of a cultured allogeneic human skin equivalent (HSE) in the treatment of venous ulcers. DESIGN: Prospective, randomized study. SETTING: Multicenter study in the outpatient setting. INTERVENTION: Each patient with a venous ulcer received either compression therapy alone or compression therapy and treatment with HSE. The patients were evaluated for HSE safety, complete (100%) ulcer healing, time to wound closure, wound recurrence, and immune response to the HSE. OUTCOME: The study was completed as planned in 293 randomized patients. RESULTS: Treatment with HSE was more effective than compression therapy in the percentage of patients healed by 6 months (63% vs 49%; P=.02, Fisher exact test, 2-tailed) and the median time to complete wound closure (61 days vs 181 days; P=.003, log-rank test). Treatment with HSE was superior to compression therapy in healing larger (> 1000 mm2; P=.02) and deeper ulcers (P=.003) and ulcers of more than 6 months' duration (P=.001). Occurrence of adverse events was similar in both groups. No symptoms or signs of rejection occurred in response to treatment with HSE, and no HSE-specific immune responses were detected in vitro to bovine collagen or to alloantigens expressed on keratinocytes or fibroblasts. CONCLUSIONS: Treatment with HSE healed venous ulcers more rapidly and in more patients than compression therapy alone. There was no clinical or laboratory evidence of rejection or sensitization in response to HSE application. These data suggest that HSE represents a significant advance in the treatment of venous ulcers, particularly those that are difficult to heal.

Insulin and glucagon degradation in liver are not affected by hepatic cirrhosis.

Hyperinsulinemia and impaired glucose tolerance are associated with liver cirrhosis. To investigate whether insulin-degrading activity in liver tissue plays a role in hyperinsulinemia, we assayed this activity in biopsy tissue from healthy and cirrhotic subjects. There was no difference in insulin degradation between these two groups. Also glucagon-degrading activity in liver tissue, which is catalyzed by the same enzyme as insulin-degrading activity, did not differ between the two groups studied. Therefore, insulin-degrading activity does not appear to be involved in the hyperinsulinemia that occurs in liver cirrhosis. The study provides indirect evidence that hyperinsulinemia and impaired glucose metabolism in liver cirrhosis are due to different mechanisms (receptorial and post-receptorial defects, and altered feedback inhibition of insulin secretion).

Urinary excretion of free and acetylated polyamines in hepatocellular carcinoma.

Polyamines (putrescine, spermidine and spermine) are essential for the proliferation of normal and neoplastic cells, and have been repeatedly recommended as tumor markers, with contrasting and elusive results. In the present study the urinary excretion of free and acetylated polyamines was measured in patients with hepatocellular carcinoma (HCC), cirrhotics and control subjects. Separation and quantification of dansyl-derivatives of free, acetylated and total polyamines was performed by reverse-phase high-performance liquid chromatography. The results show that the urinary excretion of total, free, and acetylated polyamines is significantly higher in HCC patients than in cirrhotics and controls (p < 0.001). The N1/N8 acetyl-spermidine molar ratio was found to be higher in HCC patients than in cirrhotics and controls (p < 0.001). No correlation was found between urinary excretion of polyamines and serum alpha-fetoprotein, tumor size and severity of liver cirrhosis. The results show that increased urinary excretion of free and acetylated polyamines, as well as an altered N1/N8-acetyl-spermidine molar ratio, is a sensible but not specific feature of HCC patients; polyamines may play a role in human carcinogenesis, but their determination does not seem reliable for the early detection of liver cancer.

Pattern and concentration of free and acetylated polyamines in urine of cirrhotic patients.

The pattern and concentration of urinary, free, monoacetylated and total polyamines were determined in 31 cirrhotic patients, divided into three classes according to Child's classification, and in 28 healthy subjects. Cirrhotic patients had increased levels of free, monoacetylated and total polyamines. They also showed a significant increase in N1-acetylspermidine to N8-acetylspermidine molar ratio. Urinary polyamine excretion was not related to the severity of liver disease nor to the values of laboratory liver function tests. Furthermore, polyamine excretion was not significantly different in cirrhotics with or without diabetes or IGT, while plasma insulin and glucagon levels were increased in all cirrhotic patients. The results suggest that enhanced polyamine biosynthesis and catabolism, particularly N1-acetylation, occur in cirrhotic patients, probably due to hepatic regeneration and/or increased levels of insulin and glucagon.

Serum neopterin levels in liver cirrhosis.

Neopterin is a pyrazino-pyrimidine compound which is biosynthesized by macrophages. Increased concentrations of neopterin have been reported in conditions causing a stimulation of cellular immunity, such as viral and other infections, graft versus host disease, autoimmune disease and different malignancies. Recently, urinary neopterin levels have been found increased in patients with acute viral hepatitis and NANB chronic hepatitis. In the present study, neopterin serum levels have been measured in 23 cirrhotic patients (6 HBV related, and 17 cryptogenetic cirrhosis, 7 of them occurring in alcoholic subjects) and in 24 normal subjects. Mean values of serum neopterin were significantly increased in cirrhotics (3.92 +/- 3.28 ng/ml versus 1.24 +/- 0.51 ng/ml in controls, p less than 0.01). Serum neopterin values were not found to be significantly different in cirrhotics assessed in three different clinical classes according to Child's classification and in cirrhotics with and without serological findings of active disease. In fact, in cirrhotic patients, serum neopterin levels did not correlate with the values of serum AST, ALT, ALP, GGT and gamma-globulin. These data show that increased levels of serum neopterin occur in cirrhotic patients, but there is no relation between serum neopterin values and the activity or the clinical severity of the disease. The results are consistent with the hypothesis that activated macrophages are involved in all stages of liver cirrhosis irrespective of its aetiology.

Pulmonary hypertension associated with liver cirrhosis: an echocardiographic study.

Conflicting results about the prevalence of pulmonary hypertension, ranging from 0.25% to 20%, in liver patients with portal hypertension, have previously been reported. The aim of this study was to evaluate pulmonary arterial pressure in a consecutive series of cirrhotic patients, using a noninvasive method. A complete clinical, laboratory, ultrasonographic, and endoscopic evaluation were performed in 83 consecutive liver patients assessed according to Child's classification and Pugh's score and according to evidence of ultrasonographic and/or endoscopic signs of portal hypertension. A complete echocardiographic evaluation was also performed and pulmonary arterial systolic pressure (PASP) was estimated by measuring tricuspidal regurgitation, using the modified Bernoulli equation. These same evaluations were performed by the same observers in a group of 60 healthy volunteers. The results showed a surprisingly high prevalence (about 20%) of pulmonary hypertension. Patients with more severe liver damage and portal hypertension showed a high prevalence for pulmonary hypertension. A progression in the frequency of portopulmonary hypertension (PPH) was found in Child's classification A to C, and in patients without to patients with evidence of portal hypertension. However, increased PASP was detected in some patients belonging to Child's class A, without evidence of portal hypertension. In conclusion, the echocardiographic examination (a noninvasive technique), appears suitable for detecting pulmonary hypertension in patients with compensated liver cirrhosis, and can elucidate some aspects of the clinical course of the so-called PPH syndrome.

[Membranoproliferative glomerulonephritis as an unusual initial manifestation in a case of plasmacytoma]. / Glomerulonefrite membranoproliferativa quale insolita manifestazione d'esordio in un caso di plasmocitoma.

The Authors describe a case of membranoproliferative glomerulonephritis associated with nephrotic syndrome in a 50-year-old man with plasmocytoma. The bone marrow and the immunoelectrophoresis of the serum and urine showed a Bence-Jones positive multiple myeloma with plasma cells secreting only k light chain. The patient responded immediately to monthly courses of cyclophosphamide, melphalan, vincristine and prednisone. He showed still, 27 months after the diagnosis, complete remission of the disease.

[Pyomyositis in Italy: report of a clinical case]. / Piomiosite in Italia: descrizione di un caso clinico.

Pyomyositis is an infection of the striated muscle seen frequently in Africa but rarely in Western countries with a temperate climate. Over the last few years it has been observed with increasing frequency, especially in immunocompromised hosts. An unusual case of pyomyositis in a 65-year-old immunocompetent woman is described. The disease emerged during septicemia caused by Staphylococcus aureus. It was associated with pleuropneumonia and affected two different and opposite groups of muscles. Diabetes mellitus, a known predisposing factor, was diagnosed during the infection. The diagnosis of pyomyositis was based on microbiological cultures, computed tomography, and radio-labelled granulocyte scintigraphy. Follow-up until recovery was based on computed tomography. Surgical drainage of abscesses was avoided thanks to early diagnosis and specific antibiotic therapy.

POEMS syndrome: an Italian case with diagnostic and therapeutic implications.

A young Italian patient with a multisystem disorder and a solitary osteosclerotic bone lesion is described. His clinicopathological situation involved sensory-motor polyneuropathy, organomegaly, endocrine dysfunction, skin alterations, edema of the lower limbs and generalized lymphadenopathy. These features were consistent with the diagnosis of POEMS syndrome, reported primarily in Japanese patients. M components were not found in this patient's serum or urine. Bone marrow biopsy showed only a slight plasma cell infiltrate; histological study of the sural nerve evidenced a mixture of both axonal degeneration and segmental demyelinization. Lymph node biopsy revealed peculiar pathological changes resembling those of type II Castleman-like disease. A wide bone defect with osteosclerotic margins and trabeculation was evidenced in the right ilium. The relationship of these findings to plasma cell dyscrasias is discussed. After prednisone and local radiotherapy failed, the patient was treated with human recombinant interferon for 18 months. After three months of therapy he has experienced remarkable improvement of his neurological symptoms and almost complete recovery of organomegaly and lymphadenopathy. These improvements have continued to the present.

[Blood levels of neopterin in patients with liver cirrhosis]. / Studio dei livelli sierici di neopterina in pazienti con cirrosi epatica.

Neopterin is a pyrazino-pyrimidine compound which is biosynthesized by macrophages. Increased concentrations of neopterin have been reported in conditions causing stimulation of cellular immunity, such as viral and other infections, graft versus host disease, autoimmune diseases and different malignancies. Recently, increased urinary neopterin levels have been found in patients with acute viral hepatitis and NANB chronic hepatitis. In the present study, neopterin serum levels were measured in 23 cirrhotic patients (6 HBV related, 7 alcoholic and 10 cryptogenetic cirrhosis) and in 24 normal subjects. Mean values of serum neopterin were statistically increased in cirrhotics (3.92 +/- 3.28 ng/mL versus 1.24 +/- 0.51 ng/mL in controls, p less than 0.01). Serum neopterin values were not statistically different either in cirrhotics assessed in three different classes according to Child's classification or in cirrhotics with or without serological findings of active disease. In fact, in cirrhotic patients, serum neopterin levels did not correlate with serum aspartate and alanine aminotransferases, alkaline phosphatase, gamma-glutamyltransferase and gammaglobulins values. These data show that increased levels of serum neopterin occur in cirrhotic patients, but there is no relation between serum neopterin values and the histological activity or the clinical severity of the disease. The results are consistent with the hypothesis that activated macrophages are involved in all forms and in all stages of liver cirrhosis.

Local anesthesia for dermatologic surgery.

Knowledge of local anesthesia is critically important to perform dermatologic surgery. The objective of this article is to provide an updated review of local anesthesia. The principles of local anesthesia as it pertains to dermatologic surgery are reviewed. New methods of delivering local anesthesia are also presented. Local anesthetics are safe, effective drugs that provide transient insensibility to pain in a limited area of skin. There are a variety of methods of inducing local anesthesia which can be tailored to the requirements of the contemplated procedure. Local anesthetics allow dermatologists to perform a range of procedures safely. Recent developments in topical anesthetics and in tumescent local anesthesia have provided the dermatologic surgeon other methods of delivering local anesthesia.

Insulin-degrading activity in experimental liver cirrhosis of the rat.

Liver cirrhosis in man is often associated with hyperinsulinemia but its pathogenesis is still unexplained. To investigate whether insulin degradation is impaired in cirrhotic liver, the specific insulin-degrading enzyme activity (EC 3.4.22.11) was assayed in liver cytosol of rats with CCl4-induced liver cirrhosis. No difference was found between liver cytosol of cirrhotic and control rats. The results show that experimental CCl4-induced liver cirrhosis does not damage the specific insulin-degrading activity and support the hypothesis that impaired hepatic insulin handling is not an important cause of hyperinsulinemia in liver cirrhosis.

Local anesthesia in dermatologic surgery.

With the growth of dermatologic surgery the appropriate use of local anesthesia is becoming an important issue. Thoughtful use of local anesthesia can improve the patient's experience and facilitate the surgical procedure. In this review we discuss historical and pharmacologic aspects of local anesthetic agents. Emphasis is placed on clinical considerations, including contraindications, toxic reactions, and detailed descriptions of anesthetic use.

Receptor-mediated endocytosis and degradation of insulin-like growth factor I and II in neonatal rat astrocytes.

Receptor-mediated internalization and degradation of insulin-like growth factors, IGF-I and IGF-II, were studied in primary cultures of neonatal rat astrocytes. Surface-bound IGF-II was rapidly internalized, and 80% of cell-associated radioactivity was located intracellularly after 30 min. IGF-I was internalized at a slower rate, and only 40% of cell-associated radioactivity was inside the cell after 30 min. A pulse-chase experiment demonstrated that 55% and 70% of internalized IGF-I and IGF-II, respectively, was degraded to free amino acids after a 3-hr chase. Lysosomal and protease inhibitors had different effects on the binding, internalization, and processing of IGF-I and IGF-II. Inhibition of lysosomal acidification by chloroquine increased the amounts of surface-bound IGF-II and intracellular IGF-I and reduced the degradation of IGF-I. The chelating agent phenanthroline increased the surface binding of IGF-I and IGF-II and internalization of IGF-II and reduced the degradation of IGF-I and IGF-II. Finally, receptor-bound IGF-II on the cell surface was decreased with increasing cell density, whereas IGF-I binding was unaltered. Our data suggest that cell-surface expression of IGF-I receptors and IGF-II receptors is regulated by different mechanisms and that receptor-bound IGF-I and IGF-II are trafficked and processed by different intracellular pathways in neonatal rat astrocytes.