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Introduction Although hypovolemia remains the most relevant problem during acute decompensated diabetes in its clinical manifestations (diabetic ketoacidosis, DKA, and hyperglycemic hyperosmolar state, HHS), the electrolyte derangements caused by the global hydroelectrolytic imbalance usually complicate the clinical picture at presentation and may be worsened by the treatment itself. Aim This review article is focused on the management of dysnatremias during hyperglycemic hyperosmolar state with the aim of providing clinicians a useful tool to early identify the sodium derangement in order to address properly its treatment. Discussion The plasma sodium concentration is modified by most of the therapeutic measures commonly required in such patients and the physician needs to consider these interactions when treating HHS. Moreover, an improper management of plasma sodium concentration (PNa+) and plasma osmolality during treatment has been associated with two rare potentially life-threatening complications (cerebral edema and osmotic demyelination syndrome). Identifying the correct composition of the fluids that need to be infused to restore volume losses is crucial to prevent complications. Conclusion A quantitative approach based on the comparison between the measured PNa+ (PNa+ M) and the PNa+ expected in the presence of an exclusive water shift (PNa+ G) may provide more thorough information about the true hydroelectrolytic status of the patient and may therefore, guide the physician in the initial management of HHS. On the basis of data derived from our previous studies, we propose a 7-step algorithm to compute an accurate estimate of PNa+ G.

Background The expansion of scientific publications makes more difficult the mining of relevant information necessary for a productive appraisal of authors' work, scientific interaction and exchange. Papers over-citation is unproductive, under-citation of innovative research generates delay and inefficiency. The extraction of information from the literature is mostly based on keywords (KWs). Methods I computed the chances of citation of one paper as 1/number of papers retrieved by the KWs published in that paper, and compared them with the chances obtained by selecting different KWs. Results Using generic KWs the chances are smaller, at times practically nil, as compared to those calculated with more specific KWs and their association. Conclusions Selecting scientifically-analyzed KWs, specific for the message conveyed by a paper and computing beforehand the theoretical chances of citation, might increase the citations obtained, the retrieval of important scientific and innovative information, optimize scientific exchange and qualitative productivity. Learning points • Retrieval of useful scientific information leaves many important data unrecognized when the KWs selected display a large number of papers. • Redundant information yielded by generic KWs discourages searching and favors the citation of articles published on established and well reputed journals. • A more rational use of KWs narrows the target, offering more selected information, while optimizing the exchange of scientific data and hypothesis. • Appropriately selected KWs might improve the access to, and the diffusion-citation of relevant scientific knowledge. • Trial and error reshaping of KWs allows their best selection to improve the chances of citation, that can be computed by appropriate formulas.

Many anti-diabetic drugs with different mechanisms of action are now available for treatment of type 2 diabetes mellitus. Sulfonylureas have been extensively used for treatment of type 2 diabetes for nearly 50 years and, even in our times, are widely used for treatment of this devastating chronic illness. Here, we review some of the available data on sulfonylureas, evaluating their mechanism of action and their effects on glycemic control. We can conclude that sulfonylureas are still the most used anti-diabetic agents: maybe this is due to their lower cost, to the possibility of mono-dosing and to the presence of an association with metformin in the same tablet. However, sulfonylureas, especially the older ones, are linked to a greater prevalence of hypoglycemia, and cardiovascular risk; newer prolonged-release preparations of sulfonylureas are undoubtedly safer, mainly due to reducing hypoglycemia, and for this reason should be preferred.

Background: Low testosterone levels are a common finding among men with Type 2 Diabetes Mellitus (T2DM) and are inversely related to insulin resistance. Whether this relationship holds true in patients with hypertension, but normal glucose tolerance or prediabetes, is unclear. Methods: We recruited 87 male outpatients with essential arterial hypertension, aged 35–70 years. Anthropometric data were collected, an Oral Glucose Tolerance Test (OGTT) performed, and the homeostasis model assessment of insulin resistance (HOMA-IR) score calculated. Follicle-Stimulating Hormone, Luteinizing Hormone, testosterone, Sex Hormone-Binding-Globulin and free-testosterone were measured. The concentrations of sex hormones were compared between normoglucotolerant, prediabetic and diabetic patients. Non-parametric tests were applied as appropriate to verify differences among groups, while multiple linear regression was used to predict the variability of testosterone and free-testosterone. Results: Total serum testosterone concentration was significantly lower in T2DM in comparison to normoglucotolerant subjects (p Conclusions: In males with hypertension, the link between insulin sensitivity and hypothalamic-pituitary-gonadal axis is maintained along the entire spectrum of glucose tolerance.

Resolution of edema requires a correct interpretation of body fluids-related renal function, to excrete the excess volume while restoring systemic hemodynamics and avoiding renal failure. In heart failure, the intensive diuresis should be matched by continuous fluids refeeding from interstitium to plasma, avoiding central volume depletion. The slowly reabsorbed ascites cannot refeed this contracted volume in cirrhosis: the ensuing activation of intrathoracic receptors, attended by increased adrenergic and Renin release, causes more avid sodium retention, producing a positive fluid and Na balance in the face of continuous treatment. High-dose-furosemide creates a defect in tubular Na causing diuresis adequate to excrete the daily water and electrolyte load in Chronic Renal Failure. Diuretic treatment requires care, caution and bedside "tricks" aimed at minimizing volume contraction by correctly assessing the homeostatic system of body fluids and related renal hemodynamics.

Type 2 Diabetes Mellitus (T2DM) and pre diabetes prevalence is increasing worldwide at an alarming rate. Though many risk factors have been identified, the most appropriate strategy to identify when and who should undergo a more accurate screening, which could allow an earlier diagnosis and a more efficient prevention of complications, is still a matter of debate. In this review we present data from a cohort of 2126 asymptomatic non diabetic subjects, who underwent an Oral Glucose Tolerance Test (OGTT). We have discussed our results sub-classifying our population according to the risk factors for diabetes development previously proposed by the American Diabetes Association. According to our data, OGTT is able to identify a substantial proportion of subjects with prediabetic conditions who, if untreated, could progress to overt T2DM and potentially encounter serious health problems, even in non-at risk subgroups, such as subjects with a normal fasting glucose, who have a normal lipid profile and arterial pressure, who do not have a familiar history of diabetes and who do not fulfil classification criteria for metabolic syndrome. Interestingly, a further proportion of subjects fulfil OGTT criteria for diagnosis of T2DM in each of these subgroups. Therefore, we believe that OGTT execution should be advocated as a screening test in asymptomatic populations to search prediabetes before diabetes.

Human toxocariasis has been reported to cause a broad spectrum of neurological syndromes, including encephalitis, meningitis and meningo-radiculitis. Nevertheless, cerebral infection by Toxocara may go undiagnosed due to its rarity, elusive symptoms and lack of availability of appropriate testing. We report the case of a 54-year-old man who presented with abdominal pain and paralytic ileus approximately 3 weeks after having eaten raw snails (a folk remedy for peptic ulcer). Three weeks later, marked eosinophilia ensued, associated with mental clouding, nystagmus, diplopia, peripheral limbs ataxia, urinary retention, slackened deep tendon reflexes, arthralgias and myalgias. Cerebrospinal fluid (CSF) examination demonstrated an eosinophilic meningitis, and Toxocara canis cerebral infection was diagnosed by positive serology and by the detection of T. canis DNA in the CSF. The patient made a full recovery following treatment with albendazole and corticosteroids. Physicians should be aware of this rare presentation of toxocariasis, whose diagnosis is, today, facilitated by molecular biology techniques. A history of ingestion of raw snails may alert the clinician to consider the possibility of such an uncommon condition.

Aims and Scope. Aims of the paper are to suggest the best treatment to improve the glycemic control in patients with Type 2 diabetes using hypoglycemic agents, in particularly, we think that every patient is different from another one in terms of BMI, family history, duration of the disease and so on. We propose for every clinical aspect the best hypoglycemic agents to use, considering the scientific evidence and physiopathology.

Background: In the present study, we investigated the role of changes in blood lipids in the abolition of the lower cardiovascular risk associated with the female gender in individuals with type 2 diabetes mellitus (T2DM). Methods: An oral glucose tolerance test (OGTT) was performed in 1091 consecutive patients (478 men and 613 women) and patients were divided into groups as follows: (i) those with normal glucose tolerance (NGT; n = 589); (ii) those with pre-diabetes (pre-T2DM), who were further divided into those with impaired fasting glucose (IFG; n = 212), impaired glucose tolerance (IGT; n = 84), and both IFG and IGT (IFG/IGT; n = 102); and (iii) those with T2DM (n = 104). Total cholesterol, triglycerides, high-density lipoprotein–cholesterol (HDL-C), low-density lipoprotein–cholesterol (LDL-C), apolipoprotein (apo) A-I, apoB, and the apoB:apoA-I ratio were determined in each patient. Differences in lipids between the different groups were assessed using Student’s t-test. Results: Significantly higher triglyceride levels and an apoB:apoA-I ratio were found in NGT men (P

Hyponatremia (plasma sodium concentration or P[Na+] 12 mEq/L/24 h) in 41.7 % of the patients, while the low dose did not cause any (P = 0.037). No osmotic demyelination syndrome was observed. A 7.5 mg tolvaptan dose can be considered both effective and safe in treating hyponatremia in the ED, while a 15 mg dose implicates too high risk of overcorrection.

The number of drugs presently marketed is countless, their prescription is relentlessly growing, such that the likelihood of adverse effects is strikingly increasing. As many drugs are cleared by the body through kidney excretion, renal adverse events are likely. In this review we shall concisely describe the pathophysiologic mechanisms of renal damage by drugs, the different clinical presentations outlining renal toxicity in the course of pharmacologic treatment, and the main offending agents.

Cardiovascular (CV) events occur even when LDL-C are100mg/dL. To improve the detection of CV risk we investigated the apoB/apoA-I ratio versus LDL-C in subjects considered normal glucose tolerant (NGT) by oral glucose tolerance test (OGTT).We enrolled 616 NGT (273 men and 343 women), and we measured insulin resistance, lipid profile, apoB/apoA-I and the factors compounding the metabolic syndrome (MetS). An unfavourable apoB/apoA-I (≥0.9 for males and ≥0.8 for females) was present in 13.9% of 108 patients with LDL-C100mg/dL: compared to subjects with lower apoB/apoA-I (0.9 for males and0.8 for females), they had more elements of MetS and their lipid profile strongly correlated with high CV risk. Out of 314 patients with lower apoB/apoA-I, 40.12% had LDL-C ≥130mg/dL: these retained a more favourable lipid profile than corresponding subjects with elevated apoB/apoA-I ratio. Finally, we found a significant correlation between LDL-C and apoB/apoA-I ratio (r=0.48, p0.0001).In NGT with LDL-C100mg/dL, a higher apoB/apoA-I exhibited an atherogenic lipid profile, indicating that LDL-C alone is insufficient to define CV risk. Independent from LDL-level, when apoB/apoA-I is lower, the lipid profile is, in fact, less atherogenic. This study demonstrates that apoB/apoA-I is at least complementary to LDL-C in identifying the "effective" CV risk profile of asymptomatic NGT subjects.

The effectiveness of hypertension treatments is attributed either to the change in blood pressure, independent of the means used, or to an important contribution of appropriate drug selection: this debate probably stems from an inappropriate comparison. Treating essential hypertension in relatively healthy patients without advanced vascular disease and co-morbidities affords cardio-vascular protection by the lowering of the mechanical shear stress determined by blood pressure per se: thus, lowering blood pressure is the critical step, while the methods used can only differ through side effects. This treatment is, in fact, a lifetime prophylaxis, as hypertension, rather than a disease, is a symptom affecting one tail of the Gaussian distribution of blood pressure across the normal population. Treating hypertension in the context of diseases, like diabetes mellitus, congestive heart failure, left ventricular hypertrophy, and advanced atherosclerosis, would be improper if focused on just one symptom, while the appropriate treatment must include options which exhibit a more extended profile to include effectiveness on cardiac hypertrophy, insulin resistance, cardiac output, and systemic hemodynamics: thus, drugs may be different in their effectiveness and in the cardio-vascular protection afforded, even though the trials quoted in favour of this thesis were designed to compare drugs in their ability to lower blood pressure rather than in improving the overall complex clinical derangements. In conclusion, while the answer to the question is a sharp YES when dealing with primary prevention, it might be a NO, still clouded by contradictory and inconclusive evidence when dealing with secondary prevention and/or treatment of complex disease conditions and co-morbidities.

Exact computations of glucose accumulation (GA, mM) and Na anions deficit (ΔNa, mEq) can be obtained in hypo-osmolar hyponatremic hyperglycaemia (HHH), where plasma osmolality (POsm) is lower than normal. In this condition, GA − ΔNa = ∆POsm × TBW (total body water). GA is given by plasma glucose concentration (PG1) times extra-cellular volume (ECV), calculated as TBW − ICV (the known intra-cellular volume). The changes in solute content can then be computed from their concentrations. This model was verified on computer-simulated patients to whom GA was added in variable amounts, lower than those of ΔNa subtracted, generating known ICV, ECV, PNa1, and PG1. True computer-generated values were identical (the correlation coefficient R 2 = 1, p

AIM: To avoid electrolyte derangements during correction of hyperosmolar coma (HC), PNa(PREDICTED) at the end of correction is presently estimated from plasma glucose (P(G), mM/L). When the rise in plasma osmolality (Posm) is entirely due to glucose addition (G(A), mM) to the extracellular volume (ECV), this PNa prediction can be improved by correctly estimating G(A) and any associated water loss (DeltaV), while excluding any concomitant Na loss (DeltaNa). METHODS: Indicating with (0) the normal conditions, with (1) the HC,DeltaPosm=P(G1)xECV1 establishes an exclusive G(A) accumulation. We derived the equations for computing G(A), DeltaV and PNa(PREDICTED). Computer simulations of HC were performed by adding the known G(A) while subtracting the known DeltaV and DeltaNa in different combinations, obtaining exact values of PNa(1) and P(G1). Applying our formulas, we recognized and discarded all cases with concomitant DeltaNa, and we computed G(A), DeltaV and PNa (PREDICTED) from PNa(1) and P(G1), as if they had been measured in patients. We extended these same calculation algorithms to 68 patients with HC. RESULTS: In computer simulations, true and calculated G(A), DeltaV and PNa(PREDICTED) were identical, such that regression and correlation coefficients were 1 (P < 0.0001). Out of the 68 patients recruited, 13 fulfilled the boundary conditions of an exclusive G(A) addition. The true values, obtained by balance studies performed on these patients, were not different from and significantly correlated with the calculated data (R(2) = 0.99, P < 0.001). CONCLUSION: Our new model system for HC and the new formulas improve to near exactness the accuracy in estimating PNa(PREDICTED), helping the physician to avoid unwanted electrolyte derangements during treatment.

INTRODUCTION: With the objective to assess the diagnostic power of the ADA criteria in detecting glucose intolerance, we studied 654 patients by performing an oral glucose tolerance test (OGTT). MATERIAL AND METHODS: The design required computing sensitivity, specificity and predictive values for different cut-off levels of fasting plasma glucose (FPG). The patients were recruited in an outpatient facility of a General Internal Medicine department affiliated to a Medical School. RESULTS: Lowering the threshold from 7.0 to 6.1, 5.6, 5.0 and 4.4 mmol/l (126 to 110, 100, 90 and 80 mg/dl) respectively, resulted in a progressive fall in specificity (99.6, 91.6, 76.0, 45.3 and 15.8%) combined to a rise in sensitivity (8.6, 30.7, 56.4, 76.4 and 92.9%). Two subjects with FPG

Many anti-diabetic drugs with different mechanisms of action are now available for treatment of type 2 diabetes mellitus. Sulfonylureas have been extensively used for treatment of type 2 diabetes for nearly 50 years and, even in our times, are widely used for treatment of this devastating chronic illness. Here, we review some of the available data on sulfonylureas, evaluating their mechanism of action and their effects on glycemic control. We can conclude that sulfonylureas are still the most used anti-diabetic agents: maybe this is due to their lower cost, to the possibility of mono-dosing and to the presence of an association with metformin in the same tablet. However, sulfonylureas, especially the older ones, are linked to a greater prevalence of hypoglycemia, and cardiovascular risk; newer prolonged-release preparations of sulfonylureas are undoubtedly safer, mainly due to reducing hypoglycemia, and for this reason should be preferred.

Sodium and water retention, frequently associated with hyponatraemia, occur commonly in liver cirrhosis because of central hypovolaemia, nephron hypoperfusion, excess fractional reabsorption in the proximal tubule and reduced fluid delivery to the distal nephron. Under these circumstances, whilst solute free water formation is curbed by the reduced delivery of fluid, antidiuretic hormone (ADH)-independent water abstraction can be unaltered, thus reclaiming a larger fraction of the inflow to the distal nephron. This leads to the excretion of a reduced volume of Na-free, concentrated urine, even in the absence of ADH, causing water retention and reduced diluting power. Enhanced ADH secretion further contributes to excessive water retention. Hyponatraemia develops either as a consequence of excessive water retention or solute depletion, or a combination of both. As the normal kidney is capable of excreting any water excess, hyponatraemia requires an important defect in renal diluting ability. Thus, the cause...

Background Angiotensin II (Ang II), arginine vasopressin (AVP) and tromboxane A(2) (TxA(2)) are dissimilar vasoconstrictors involved in regulating renal circulation. Whereas Ang II is primarily a physiological modulator, AVP and TxA(2) play important roles under pathological conditions. Previously, we have shown variable importance of intracellular Ca(2+) and protein kinase C for their mode of action (Ang II > AVP >U-46619), but the cell signalling via rho-associated kinase (ROK) is a common pathway. The aim of this study was to determine their sites of action in the renal vascular bed and the corresponding role of ROK at the microvascular level. Methods Glomerular blood flow (GBF) and luminal diameter of different vessels (10-70 micro m) were measured in the split hydronephrotic kidney of anaesthetized rats. The tissue bath concentration of Ang II, AVP or the TxA(2) agonist U-46619 was adjusted to reduce GBF by approximately 50%. The measurements were repeated after adding a sub-maximal dose of the ROK inhibitor Y-27632 into the bath. Results Ang II constricted all vessels significantly, the constriction being least in the proximal segment of the arcuate artery ( approximately 70 micro m). Significant constrictions due to AVP were found only in interlobular and arcuate arteries (20-70 micro m), but not in the afferent and efferent arterioles. U-46619 constricted only the arcuate artery (> or = 50 micro m). Y-27632 (10(-4) M) dilated all vessels significantly and increased GBF by 65%. Thereafter, effects of all agonists were severely attenuated. Control reductions in GBF could be obtained at higher concentrations of AVP (10-fold) and U-46619 (5-fold) and a lesser GBF reduction with Ang II (100-fold) without changes in the respective patterns of vascular constriction. Conclusions Our data indicate that the agonists, in the order Ang II, AVP and TxA(2), constrict larger vessels within the renal vascular tree via activation of ROK. Therefore, ROK inhibitors may provide a therapeutic tool to antagonize pathological vasospasm of conduit vessels, which are resistant to other vasodilators.

OBJECTIVE—The American Diabetes Association recommended substituting 2hBS (glycemia at the second hour of an oral glucose tolerance test [OGTT]) for fasting blood glucose (FBS) in screening for glucose intolerance. It is debated whether these tests measure the same abnormality and relate to defective insulin secretion or resistance. This study examines the diagnostic effectiveness of FBS versus 2hBS and their relationship with insulin secretion and resistance. RESEARCH DESIGN AND METHODS—Based on history or physical findings suggesting glucose intolerance, we enrolled 398 unselected subjects admitted to a general Internal Medicine ward. After 5 days of a weight-maintaining diet, FBS, 2hBS, and insulin were measured during OGTT. The homeostatic model assessment was used to assess β-cell function and insulin resistance. RESULTS—Excluding 19 patients with diabetes (5%), we identified 284 subjects with normal glucose tolerance (NGT), 22 with isolated impaired fasting glucose (IFG), 59 with isolated impaired glucose tolerance (IGT), and 14 with associated IFG/IGT. The sensitivity of FBS in predicting 2hBS was 19%, specificity 93%. Positive and negative predictive values were 39% and 83%, respectively. Insulin resistance was absent in NGT and IFG and markedly elevated in IGT and IFG/IGT, whereas defective insulin release was significant only in isolated IFG. CONCLUSIONS—In unselected patients, elevated FBS depends primarily on defective insulin secretion, and impaired 2hBS on insulin resistance. Because these tests measure different alterations, they are useful in combination.

In addition to intracellular calcium, which activates myosin light chain (MLC) kinase, MLC phosphorylation and hence contraction is importantly regulated by MLC phosphatase (MLCP). Recent evidence suggests that distinct signaling cascades of vasoactive hormones interact with the Rho/Rho kinase (ROK) pathway, affecting the activity of MLCP. The present study measured the impact of ROK inhibition on vascular F-actin distribution and on vasoconstriction induced by activation/inhibition of distinct signaling pathways in vivo in the microcirculation of the split hydronephrotic rat kidney. Local application of the ROK inhibitors Y-27632 or HA-1077 induced marked dilation of pre- and postglomerular vessels. Activation of phospholipase C with the endothelin ET B agonist IRL 1620, inhibition of soluble guanylyl cyclase with 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ), or inhibition of adenylyl cyclase with the adenosine A1 agonist N6-cyclopentyladenosine (CPA) reduced glomerular blood flow (GBF) by about 50% through vasoconstriction at different vascular levels. ROK inhibition with Y-27632 or HA-1077, but not protein kinase C inhibition with Ro 31-8220, blunted ET B-induced vasoconstriction. Furthermore, the reduction of GBF and of vascular diameters in response to ODQ or CPA were abolished by pretreatment with Y-27632. ROK inhibitors prevented constriction of preglomerular vessels and of efferent arterioles with equal effectiveness. Confocal microscopy demonstrated that Y-27632 did not change F-actin content and distribution in renal vessels. The results suggest that ROK inhibition might be considered as a potent treatment of renal vasoconstriction, because it interferes with constriction induced by distinct signaling pathways in renal vessels without affecting F-actin structure.

Histologically detectable iron (HDI) and HFE mutations were searched for in liver biopsy specimens from 58 Italian patients with chronic hepatitis C, and morphologic features were compared to examine their reciprocal relation and their contribution to disease progression. HDI was evident in 48% of cases with features of nonhemochromatosis iron overload. Total, sinusoidal, and portal HDI increased with stage; grade was related to all iron scores because of the contribution of portal inflammation and interface hepatitis. HFE mutations were seen in 47% of patients with chronic hepatitis C and in 28% of control subjects; they were related to stage and the His63Asp mutation to portal HDI. On multivariate analysis, grade but not stage or HFE mutations was associated with HDI in all sites. Interface hepatitis with its sequelae (sinusoidal capillarization and microshunting) represents a major factor in iron deposition in chronic hepatitis C and justifies the features of HDI. HFE mutations are not responsible for HDI deposition but could favor the progression of virus-induced damage independently from interference with iron metabolism.

Lipoprotein(a) and apolipoprotein(a) isoforms and proteinuria in patients with moderate renal failure.BackgroundAtherosclerotic diseases are a major cause of death in patients with renal failure. Increased serum concentrations of lipoprotein(a) [Lp(a)] have been established as a genetically controlled risk factor for these diseases and have been demonstrated in patients with moderate renal failure, suggesting that this lipoprotein contributes to the increased cardiovascular risk seen in these patients. Variable alleles at the apolipoprotein(a) [apo(a)] gene locus are the main determinants of the serum Lp(a) level in the general population. The purpose of this study was to investigate apo(a) isoforms in patients with moderate renal failure and mild proteinuria (less than 1.0 g/day).MethodsIn 250 consecutive subjects recruited at a hypertension clinic, we assessed the renal function by 24-hour creatinine clearance, proteinuria, and microalbuminuria, as well as the prevalence of atherosclerotic disease, and we also measured apo(a) isoforms, serum albumin, and Lp(a) concentrations.ResultsModerate impairment of renal function (creatinine clearance, 30 to 89 ml/min per 1.73 m2 of body surface area) was found in 97 patients. Lp(a) levels were significantly greater in patients with moderate renal failure (21.7 ± 23.9 mg/dl) as compared with patients with normal renal function (15.6 ± 16.4 mg/dl, P < 0.001), and an inverse correlation was observed between log Lp(a) and creatinine clearance (r = -0.181, P < 0.01). However, no difference was found in the frequency of low molecular weight apo(a) isoforms between patients with normal (25.5%) and impaired (27.8%) renal function. Only patients with the smallest size apo(a) isoforms exhibited significantly elevated levels of Lp(a), whereas the large-size isoforms had similar concentrations in patients with normal and impaired renal function. No significant relationship was found between serum Lp(a) and proteinuria. Clinical and laboratory evidence of one or more events attributed to atherosclerosis was found in 9.8% of patients with normal renal function and 25.8% of patients with moderate renal failure (P < 0.001).ConclusionsThese results indicate that renal failure per se or other genes beside the apo(a) gene locus are responsible for the elevation of serum Lp(a) levels in patients with moderate impairment of renal function. The elevation of Lp(a) levels occurs independently of the level of proteinuria and may contribute to the risk for atherosclerotic disease in these patients.

Objective To assess the site of action of endothelin-1 in vessels of different sizes in the kidney in vivo and investigate the function of endothelin A (ET(A)) receptors in mediating renal and systemic vasoconstriction. Design The luminal diameters of different vessels were measured and glomerular blood flow in cortical glomeruli was determined by intravital videomicroscopy in the split hydronephrotic kidney of anesthetized female Wistar rats. Methods The rats were infused with endothelin-1 (40 pmol/kg per min) with or without pretreatment with the selective ET(A)-receptor antagonist BQ-123 (0.5 mg/kg). Aortic clamping was used to control renal blood pressure during the endothelin-1 infusion. Results Exogenous endothelin-1 induced a significant rise (30+/-3%) in mean arterial pressure and a marked, long-lasting fall in glomerular blood flow (53+/-3%) related to reduction of the inner diameter of arcuate (-30%), interlobular arteries (-33%) and afferent arterioles (-17%). Aortic clamping to normalize renal blood pressure did not attenuate the vasoconstriction and reduction in glomerular blood flow. Pretreatment with BQ-123 significantly reduced both the endothelin-1-induced rise in mean arterial pressure (12+/-1%) and the fall in glomerular blood flow (-23+/-11%). BQ-123 blunted the response to endothelin-1 in arcuate (-12%), interlobular (-11%) and afferent vessels (-5%). Acetylcholine and nitroprusside completely reversed the vasoconstriction in BQ-123-pretreated animals. Conclusions BQ-123 largely prevented the hemodynamic effects of exogenously administered endothelin-1. Our direct in-vivo techniques showed that ET(A) receptors are, at least in part, involved in endothelin-1 -mediated vasoconstriction in the rat kidney, and support the hypothesis that ET(A) receptors may help to control arterial pressure in anesthetized rats.

The purpose of this work was to investigate the prevalence, associated features and effect on survival of portal vein thrombosis (PVT) complicating hepatocellular carcinoma (HCC). The autopsy data of a series of 72 consecutive patients (57 male, 15 female) with HCC were reviewed. PVT was found in 32/72 patients (44%), and tended to be more common in female patients (10/15 versus 22/57, P = 0.052). Stratifying the data according to gender, it appeared that the mean age of patients with PVT compared to those without was greater in woman (71.9 +/- 5.9 versus 63.2 +/- 6.9 years, P = 0.024) and younger in men (58.8 +/- 8.9 versus 66.0 +/- 9.9 years, P = 0.007). When PVT was present, it was more likely that a definite diagnosis of HCC had been obtained before autopsy (P = 0.0001) and that death had been caused by bleeding complications (P = 0.007). Median survival times were similar, irrespective of the presence of PVT. During the natural history of HCC, PVT occurs in a substantial proportion of patients. Hormonal factors may have a permissive role in thrombus formation or neoplastic vascular invasion. Although in the presence of PVT a diagnosis of HCC is rarely missed and bleeding complications are likely to occur, patient survival does not seem to be significantly affected.

The pathogenic role of hepatitis G virus, the recently discovered blood-borne agent, is controversial. Our aim was to ascertain the prevalence of hepatitis G virus infection in hepatic and in extrahepatic malignancies.We studied 166 Italian patients (112 male, 54 female, mean age 61.8+/-9.3, mean+/-SD, range 34-85). One hundred and eighteen had cirrhosis, which was complicated by hepatocellular carcinoma in 66 cases. Forty-eight patients had extra-hepatic malignancies. Circulating HGV RNA was detected by reverse transcriptase-polymerase chain reaction (RT-PCR) of both the nonstructural-3 and 5'noncoding regions of the hepatitis G virus genome. Antibodies to the E2 protein of hepatitis G virus were detected by means of an enzyme-linked immunosorbent assay.Ongoing HGV infection was detected in 30/66 (46%) patients with hepatocellular carcinoma, 12/52 (23%) patients with cirrhosis, and 14/48 (29%) patients with extrahepatic malignancies (p0.05). Evidence of exposure to hepatitis G virus (detection of either HGV RNA or anti-E2 antibodies) was found in 46% of patients with cirrhosis, 66% of patients with hepatocellular carcinoma, and 39% of patients with extrahepatic malignancies. Serum HGV RNA positivity was associated with a hematocrit valueor = 0.35 and with history of exposure to blood products (p0.005).Ongoing hepatitis G virus infection is detected at a very high rate in patients with hepatocellular carcinoma, but is also fairly common in extrahepatic malignancies. Hepatitis G virus infection in these patients is likely to originate from exposure to blood products, and to persist because of deficient immune surveillance.

The relative contribution of intraluminal versus peritubular factors in mediating glomerulo-tubular balance (GTB) is still controversial. We modulated the load of tubular fluid to the proximal tubule of single nephrons of rats by injecting oil into the efferent arteries (EAO). In fifty nephrons the changes in reabsorption induced by obstruction occurred in the same direction as, and were significantly correlated with, the simultaneous changes in single nephron glomerular filtration rate (SNGFR) (y = -0.54 + 0.92x, R = 0.91, P < 0.0001). In an additional set of thirty-nine nephrons the load of tubular fluid was changed, during EAO, by partial collection from Bowman's space or from the early proximal convolution. Thus, the rate of tubular fluid delivery along the proximal tubule was changed in an experimental situation that prevented any modification in the oncotic pressure of peritubular capillaries. The changes in proximal deliveries during this experimental condition were significantly correlated with those during reabsorption (y = -2.87 + 0.71x, R = 0.82, P < 0.0001). These data demonstrate that GTB is fully expressed even when the native peritubular environment is kept constant while the rate of perfusion of proximal tubular segments with native tubular fluid is changed.

We report the results of a combined immunosuppressive schedule for the treatment of patients with idiopathic nephrotic syndrome, in which prednisone and cyclophosphamide were given in four phases: induction, maintenance, tapering and discontinuation.Sixty-seven patients with nephrotic syndrome, followed for an average of 7.1 +/- 4.5 years, were studied. Treatment outcomes were remission, progression, end-stage renal disease and death.At the end of the follow-up, 72% of patients maintained a complete remission. Stepwise logistic regression showed that the cumulative dose of cyclophosphamide was the only independent predictor of a favourable outcome, being associated both with complete remission of the nephrotic syndrome and with lack of progression to chronic renal failure.We suggest that the combination treatment may be indicated in all histological subgroups of nephrotic syndrome, provided that prednisone is given at high doses on alternate days, cyclophosphamide is given for 6 months, and relapses are treated with the same schedule. The adverse effects of treatment, however, require the adoption of a programme to prevent bone loss, infertility, bladder cancer and infections.

The stability of single nephron glomerular filtration rate (SNGFR) is assured by specific mechanisms such as the tubulo-glomerular feedback system and autoregulation. Studies on renal physiology rely heavily on the measurements of SNGFR, which are feasible only in animals. The measurement of SNGFR by collection of total tubular fluid may be influenced by the fall in intratubular hydrostatic pressure that may reflect the negative pressure applied to the sampling pipette. This effect may become more important with shortening of the distance between the sampling site and the Bowman space. We analysed this putative effect by performing collections of total tubular fluid from the late proximal (LP), and then from the early proximal (EP) segment of the same nephrons. In 128 paired collections LP-SNGFR averaged 35 (SEM 2) nl x min(-1), and was no different from the paired mean EP-SNGFR of 37 (SEM 2) nl x min(-1), P0.179. Then EP- and LP- SNGFR were significantly correlated (r = 0.77, P0.001). As expected, the respective paired means of absolute and percentage reabsorptions, and those of collection rates were significantly different. The average SNGFR computed from each LP and EP paired measurement was significantly correlated with the simultaneously measured kidney glomerular filtration rate, GFR (r = 0.60, P0.0001). The ratio of GFR to SNGFR indicated the expected number of glomeruli. These data would indicate that the sampling site does not influence the measurement of SNGFR in the proximal tubule when the total fluid collection technique is correctly performed. They also exclude a time-dependent activation of the macula densa capable of upregulating SNGFR within the interval elapsing between the beginning of LP and the completion of EP collections, which in our study averaged 4.4 (SEM 0.1) min.

Two patients with chronic sialoadenitis had features of Bartter's and Gitelman's syndrome, respectively. The main complaints were leg paraesthesiae and acute arthritis. A good response to oral K+ supplementation, allopurinol and low-dose prednisone was obtained. The features of Sjögren's-related renal diseases are reviewed.

To investigate the relationships between the sympathetic nervous system (SNS) and parameters of glucose metabolism in arterial hypertension, daily urinary excretion of catecholamines and plasma glucose, insulin, and C-peptide response to an oral glucose load (OGL) have been evaluated in 77 untreated patients with mild-to-moderate essential hypertension and in 31 normotensive controls. Urinary excretion of norepinephrine (UNE) was positively correlated with body mass index and with plasma glucose levels both at fast and after OGL. No correlations were found between urinary excretion of catecholamines and plasma insulin and C-peptide levels both at fast and in response to OGL. Because the frequency distribution of UNE was bimodal, hypertensive subjects were separated into two subgroups using an arbitrary cutoff, and the parameters of glucose metabolism were compared. Subjects with UNE205 microg/day had greater levels of fasting glucose and greater glycemic response to OGL than subjects with UNE205 microg/day, whereas no significant differences between the groups were found in fasting and stimulated plasma insulin and C-peptide. Thus, activation of SNS is related to glucose tolerance but not hyperinsulinemia and insulin hypersecretion in essential hypertension. Plasma glucose levels, independent of insulin, may contribute to the relationship between SNS activity and blood pressure in essential hypertension.

Objectives: To verify the diagnostic usefulness of soluble CD44 (sCD44) in liver diseases. Methods: We studied 142 subjects (90 male, 52 female): 14 had acute hepatitis (AH); 45, noncirrhotic chronic liver disease (CLD); 34, cirrhosis; 35 had extrahepatic diseases (EHD); and 14 were healthy controls. sCD44, soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) were measured immunoenzymatically. Results: Patients with AH or cirrhosis had higher sCD44 in comparison to CLD, EHD, and controls (t < 0.01). On univariate analysis, sCD44 was associated with sVCAM-1, sICAM-1, bilirubin, cholinesterase, aspartate aminotransferase, and alkaline phosphatase (t < 0.001). By stepwise discriminant analysis, a set of variables, including sCD44 and sVCAM-1, were entered into a model that allocated correctly 79% of observations (t < 0.0001). However, when adhesion molecules were excluded, the model could still allocate correctly 72% of observations. Conclusion: Although sCD44 concentration increases during severe acute or chronic liver disease, its measurement adds little to the clinical information provided by traditional liver biochemistry.

OBJECTIVE The existence of an oxidative stress in diabetes is still debated. This is largely due to the lack of good tools to assay the level of oxidative stress. The use of total radical-trapping antioxidant parameter (TRAP) has recently been proposed to explore the antioxidant property of a plasma sample. TRAP may be either directly measured by a fluorescence-based method (TRAPm) or calculated (TRAPc) by a mathematical formula, taking into account the serum levels of four natural antioxidants: protein-bound SH (thiol) groups, uric acid, vitamin E, and vitamin C. The difference between TRAPm and TRAPc is due to antioxidants, which are still unidentified, and to the possible synergism among the antioxidants. RESEARCH DESIGN AND METHODS In this study, we evaluated malondialdehyde (MDA), TRAPm, TRAPc, protein-bound SH groups, uric acid, vitamin E, and vitamin C in 40 NIDDM patients and 40 matched normal control subjects. RESULTS TRAPm and TRAPc were significantly lower in diabetic patients. A good correlation between TRAPm and TRAPc was found in both NIDDM patients (r = 0.68, P < 0.0001) and control subjects (r = 0.74, P < 0.0001). Protein-bound SH groups and uric acid were significantly lower in diabetic subjects, while MDA and vitamin E level were significantly higher. After correction for serum triglycerides (MDA) and cholesterol (vitamin E), MDA lost significance, while vitamin E did not. Vitamin C was not different in the two groups. CONCLUSIONS These data show decreased TRAP levels in NIDDM patients, suggesting the existence of lower antioxidant defenses in diabetes. The decrease appears to be due to various antioxidants, some of them not yet clearly defined. TRAP may represent a more reliable estimation of serum antioxidant capacity than the measurement of each known antioxidants. The correlation found between TRAPm and TRAPc values suggests that TRAPc, easier to measure than TRAPm, might be adequately reliable for routine assessment of oxidative stress in diabetic patients.

Exposure to high glucose concentrations increases the mRNA levels of oxygen radical scavenging enzymes in cultured endothelial cells, suggesting a compensatory response to increased free radical production. To test the hypothesis that this response also occurs in vivo, Cu,Zn-superoxide dismutase (Cu,Zn-SOD) and catalase mRNA levels, were measured in the kidneys of Sprague-Dawley rats 17 days after intravenous injection of streptozotocin (60 mg/kg body weight) and compared with those of control rats. Diabetic rats were either left untreated or given differing insulin regimens (2, 3–8, 6–10 IU/day) in two different experiments that were designed to achieve varying degrees of metabolic control. Cu,Zn-SOD and catalase mRNA levels were measured by Northern blot hybridization and standardized by 28S ribosomal RNA determination. Renal Cu,Zn-SOD and catalase mRNA levels were significantly greater in untreated diabetic and in low-dose (2 IU/day) insulin-treated rats than in controls. Treatment with a moderate dose (3–8 IU/day) of insulin normalized catalase but not Cu,Zn-SOD mRNA levels. The highest insulin regimen (6–10 IU/day), in addition to achieving complete metabolic control as evidenced by normal growth and plasma glucose levels, normalized both catalase and Cu,Zn-SOD mRNA levels. Thus, in rats with streptozotocin-induced diabetes Cu,Zn-SOD and catalase renal mRNA levels are greater than in normal rats. This difference is prevented by sufficient insulin dosage to normalize plasma glucose and might be due to an increased production of free radicals. [Diabetologia (1997) 40: 23–29]

To verify its value with regard to the outcomeof therapy in chronic hepatitis C, seruminterferon-α (IFN) was measured by ELISA in 70patients (43 male, 27 female) with chronic hepatitis C,treated with IFN 9 MU/week subcutaneously for up to oneyear. Serum IFN was detectable in 49/70 patients, 16 ofwhom had IFN values >125 pg/ml. Only 1/22 patientswho maintained a sustained response six months after the end of treatment had pretreatment serum IFN> 125 pg/ml, in comparison to 15/48 patients who didnot respond or who relapsed (χ 6.1, P < 0.02). Atmultivariate analysis the predictive value of serum IFN was independent of age, sex, presence ofcirrhosis, infection by genotype 1b (improvement χ7.1, P < 0.01). In patients with chronic hepatitis C,measurement of serum IFN at baseline might be useful for the selection of patients with higherprobability of long-term response.

Background: It is not clear whether gastric B-cell clonal expansion, a possible precursor of mucosa-associated lymphatic tissue (MALT) lymphoma, is exclusively linked to Helicobacter pylori infection and virulence. Methods: In this study we followed up, for up to 33 months, 16 VDJ polymerase chain reaction-positive patients (4 with dyspepsia, 9 with Sjogren's syndrome, and 3 with other autoimmune diseases). Of these, 12 were H. pylori-positive. In addition, in H. pylori-positive patients we tested whether the serum anti-cag-A (a potential marker of virulence) was preferentially associated with B-cell clonality. Results: In all hut one patient clonality appeared temporally unrelated to H. pylori infection. The prevalence of anti-cagA was not higher in H. pylori/VDJ-positive patients than in controls. Conclusions: These data indicate that, in addition to H. pylori, gastric B-cell clonality may be sustained by other agents/mechanisms. Anti-cag-A does not appear to be involved in the pathogenesis of clonality.

We tested the accuracy of the micropuncture technique by performing total collections of tubular fluid followed by immediate recollections from the same site. We studied thirty-one Wistar rats under different conditions of hydration and during maintenance infusions. To assure constancy of body fluid volumes the experiments were performed during continuous reinfusion of urine. Overall we performed 190 paired collections and immediate recollections from 147 proximal and 43 distal tubules. The mean values measured during the first collection were not different from the paired means obtained by recollection. Mean values (+/- S.E.M.) for first collection and recollection were: single nephron glomerular filtration rate (SNGFR), 34.7 +/- 1.3 vs. 34.2 +/- 1.3 nl min-1, P > 0.42; percentage reabsorption, 74 +/- 1 vs. 73 +/- 1, P > 0.53; absolute reabsorption, 26.4 +/- 1.2 vs. 25.9 +/- 1.2 nl min-1, P > 0.47; collection rate, 8.4 +/- 0.6 vs. 8.3 +/- 0.4 nl min-1, P > 0.92. When subdivided according to different physiological conditions and sampling sites, the results for the paired collection-recollection means were still not significantly different. The regression between collected and recollected SNGFRs had a slope of 0.96, r = 0.85, P < 0.0001. In order to exclude the possibility that urine reinfusion per se could obscure putative differences in collection-recollection pairs, the effect of urine reinfusion was separately evaluated. We measured the differences obtained in collection-recollection pairs before and during urine reinfusion in twenty-eight tubules from eleven rats, a sample size that allows the detection of 10% difference as significant. While SNGFR did not change, percentage reabsorption fell significantly from 76 +/- 3% before infusion to 60 +/- 3% during reinfusion, P < 0.003. We conclude that the recollection technique yields a reproducible estimate of SNGFR and tubular reabsorption, independent of the sampling site and of the technique used for fluid maintenance. Thus, it can be used to study the effect of different manoeuvres on the rate of proximal tubular transport. Urine infusion per se depresses proximal transport compared with that measured during maintenance with equivalent amounts of isotonic saline.

The tubular site of furosemide (F) action was studied by the technique of diuretic microinjection (MIJ) into proximal tubules of the rat nephron. F was injected into the last proximal superficial loop of 51 proximal tubules, at the concentration of 3 x 10(-4) mol/l in an infusate that contained 14C-inulin. Collections were performed at the early distal tubule before and after MIJ. Single nephron filtration rate (SNGFR) remained unchanged, while the percent of filtered volume reabsorbed up to the site of collection was 85+/-2 before, 79+/-2% after MIJ, p0.005. The calculated concentration of F in the collected distal tubular fluid during the post-MIJ measurements averaged 3 x 10(-5) mol/l. This experiment was repeated by injecting F into the early proximal convolutions of 43 nephrons, while the collections were performed at the last proximal segments. In these studies of proximal volume absorption, SNGFR was 34+/-3 before, 35+/-4 nl/min after F (p0.6). The respective percent reabsorptions were 70+/-3 and 73+/-3% (p +/- 0.3). In order to determine whether the technique per se was suitable to detect changes in reabsorption, the proximal MIJ study was repeated by using the carbonic anhydrase inhibitor dichlorphenamide 3 x 10(-5) mol/l in the microinjectate: while SNGFR remained unchanged, percent reabsorption fell from 63+/-5 to 45+/-7% during injection of the diuretic, p0.03. We conclude that the technique is adequate to examine the effects of drugs, and that F does not reduce proximal volume absorption at concentrations of 3 x 10(-5) mol/l. The loop diuretic decreases distal volume absorption by abolishing the osmotic gradient between blood and tubular fluid along the early distal convoluted tubule.

Aims/Introduction The conventional oral glucose tolerance test (OGTT) cannot detect future diabetics among isolated impaired fasting glucose (is-IFG) nor normal glucose tolerant (NGT) groups. By analyzing the relationship between fasting (FPG) and 2-h plasma glucose (2hPG), the present study identifies is-IFG subjects liable to worsening glucose homeostasis. Materials and Methods Oral glucose tolerance test was carried out in 619 patients suffering from obesity, hypertension or dyslipidemia, whose FPG was in the 100–125 mg/dL range. We calculated the percentage increment of 2hPG with respect to FPG (PG%) in these patients using the formula: ([2hPG − FPG] / FPG) × 100. Differences in β-cell function within is-IFG patients were assessed by estimated insulin sensitivity index (EISI), first-phase insulin release (1stPH) and 1stPH/1/EISI (1stPHcorrected). Results Diabetes was diagnosed in 69 patients (11.2%), combined IFG/impaired glucose tolerance (IGT) in 185 patients (29.9%) and is-IFG in 365 patients (58.9%). Is-IFG was subdivided into PG% tertile groups: the percentage of females increased from 25% in the lowest to 45.2% in the highest tertile (χ2 = 18.7, P

Helicobacter pylori has been identified as a critical antigenic stimulus to the development of gastric lymphoma, but additional factors should be required for such evolution. This topic is now of major importance to clarify the pathobiology of gastric lymphomagenesis. Peculiar autoimmune diseases, such as Sjögren's syndrome, are well known to predispose to B-cell lymphomas. We report on a patient with Sjögren's syndrome and a widespread B-cell lymphoproliferative disorder. A pathological picture of low-grade lymphoma was observed in the stomach, concomitantly with H. pylori infection. However, the B-cell disorder was definitely nonmalignant in the other tissues involved, i.e., the parotid gland and lymph nodes, which are the characteristic targets of Sjögren's syndrome-associated lymphoproliferation. After H. pylori eradication, a dramatic regression of gastric lymphoma into chronic gastritis was observed, but no amelioration occurred in the parotid and nodal involvement. Multiple molecular analyses showed the expansion of the same B-cell clone in synchronous and metachronous lymph node, parotid, and gastric lesions before and after H. pylori eradication. Thus, H. pylori played a crucial role in the local boosting of B-cell lymphoproliferation, but the underlying B-cell disorder was that associated with the autoimmune disease and was nonmalignant. The comprehensive clinical, pathological, and molecular approach allowed us to then distinguish the role of peculiar individual predisposing factors and of local infection in the pathobiology of mucosa-associated lymphoid tissue-associated lymphoproliferation.

OBJECTIVE: To determine the prevalence of mucosa associated lymphoid tissue (MALT) in the stomach and of a possible antigen driven proliferation, in patients with Sjögren's syndrome (SS). METHODS: Twenty one patients with primary SS and 80 dyspeptic controls underwent upper endoscopy. Lymphoid tissue and Helicobacter pylori were assessed by histopathological analysis. Epstein-Barr virus (EBV) or human herpes virus-6 (HHV-6) genome were studied by polymerase chain reaction (PCR) DNA amplification. Two PCR VDJ procedures were used to detect immunoglobulin heavy chain (IgH) gene rearrangement. RESULTS: Organised MALT was found in 33.3% of the patients, compared with 21.5% of the controls (NS). H pylori infection was seen in 71% of patients and 63% of controls. Genomic EBV or HHV-6 was found in a minor portion of SS gastric tissues. B cell expansion was detected in nine of the 21 patients. Infectious agents in the stomach might have contributed to B cell clonality only in 55.5% of the cases. No strict relationship was found between lymphoid follicles and clonality. CONCLUSION: Lymphoid accumulation in the gastric mucosa is common in Sjögren's syndrome, but full evidence for an antigen driven B cell expansion could not be demonstrated. Only a portion of those with clonal B cell expansion had evidence of an infectious agent. Other unknown infectious agents or factors related to the underlying disease (autoantigen) and its tissue environment may have a further role as possible causes of B clonal expansion in the gastric mucosa.

Blood levels of the circulating form of the integrin intercellular adhesion molecule-1 (ICAM-1), malondialdehyde (MDA), and hemoglobin A1c (HbA1c) were studied at baseline and 3 months after improved metabolic control in 25 type II diabetic patients without signs of macroangiopathy, and were compared with those in 15 matched healthy normal controls. Circulating ICAM-1 and MDA levels were increased in diabetic patients, both at baseline and 3 months later. However, with improving metabolic control HbA1c, circulating ICAM-1, and MDA significantly decreased. A significant correlation between circulating ICAM-1, HbA1c, and MDA was found in diabetic patients at each time. Multiple regression analysis considering circulating ICAM-1 as the dependent variable and HbA1c and MDA as independent variables, showed a significant correlation between the three variable at each time. Similar correlations were found in control subjects. These data show increased levels of circulating ICAM-1 in type II diabetic patients, independent of the presence of macroangiopathy. Moreover, these results suggest that oxidative stress and metabolic control might participate in determining increased circulating ICAM-1 levels in both type II diabetic patients and normal subjects.

We wanted to verify whether the calculations of segmental tubular reabsorption obtained during water diuresis were supported by direct micropuncture measurements.Experiments were performed on 18 rats during baseline water diuresis (B) and after the administration of frusemide (F), 10 mg/kg, by whole-kidney clearance measurements and micropuncture collections from early distal (ED) and last proximal (LP) tubular segments.GFR was 957+/-79 in B, 1053+/-77 microl/min in F, P0.013. SNGFR was 38+/-1 in 166 and 38+/-1 nl/min in 165 tubules respectively, P0.77. In LP collections the percentage reabsorption was 71+/-2 in B and 76+/-2% during F (P0.07) in 99 and 95 samples respectively. The absolute proximal reabsorption was not changed by F (27.6+/-1.5 versus 27.7+/-1.3 nl/min, P0.96) The data were superimposable when the analysis was restricted to paired data. The difference between ED and LP resorption was 17+/-3 during B and fell significantly (P0.008) to 5+/-3% during F, measured by clearance techniques, and the percentage of GFR excreted during F, measured by clearance techniques, and the percentage delivery of filtrate beyond the proximal tubule, measured independently by micropuncture, were not different (27+/-2 versus 24+/-2%, P0.10), while they were significantly correlated (P0.04). The calculations of segmental Na reabsorption along the different nephron segments by clearance techniques were not significantly different from and were significantly correlated with the reabsorptions measured directly by micropuncture.The present experiments validate the calculations of reabsorption by techniques applicable to human studies of clinical physiology.

To evaluate serum alpha-1-antitrypsin (A1AT) as a prognostic factor in hepatocellular carcinoma, we studied 75 consecutive patients (60 male, 15 female, mean age +/- SD 63.0 +/- 9.3 years) in whom hepatocellular carcinoma developed with pre-existing cirrhosis. Median survival time was 245 days (range 4-1568+). 30 patients had serum A1AT concentration ofor = 2.20 g/l (Group A) while 45 (Group B) had alpha-1-antitrypsin2.20 g/l. Median survival was 518 days in Group A and 81 days in Group B (Mantel-Cox 20.95, P0.0001; hazard ratio 0.26, 95% confidence limits 0.15-0.46). By stepwise survival analysis, alpha-1-antitrypsin together with bilirubin, tumour size and blood urea nitrogen were chosen among 17 variables as the only independent predictors of survival. We conclude that measurement of serum A1AT concentration might be useful as an inexpensive, widely available prognostic marker of hepatocellular carcinoma.

To compare the diagnostic usefulness as markers of hepatocellular carcinoma (HCC) of alpha1-antitrypsin, C-reactive protein, and alpha1-acid glycoprotein (all determined by nephelometric methods), we studied 132 subjects (74 male, 58 female): 43 had mild chronic liver disease, 32 cirrhosis, 24 HCC; 33 were controls. A total of 29.2% of the patients with HCC had alpha1-acid glycoprotein > 100 mg/dl, 75.0% had alpha1-antitrypsin > 220 mg/dl, 70.8% had C-reactive protein > 5 mg/L. In cirrhotics, frequencies were 3.1, 50.0 and 59.4%, respectively; in patients with mild chronic liver disease, 14.0, 11.6, and 32.6% (chi2 12.3, p < 0.01; chi2 47.3, p < 0.0001; chi2 38.0, p < 0.0001, respectively). alpha1-fetoprotein performed better than all acute-phase proteins. We conclude that, due to their low specificity and/or sensitivity, none of the three acute-phase reactants tested can be recommended for diagnostic use as biological markers of HCC in Western patients.