Renal albumin handling: a look at the dark side of the filter

Renal albumin handling is of major interest because albuminuria is an important risk factor for reno-cardiovascular diseases. In this issue a challenging study attempts to shift the paradigm of very low fractional albumin filtration and degradation in proximal tubule cells. The conclusions are of great potential relevance but require urgent validation so that we gain a clearer view of the dark side of the glomerular filter.     

Renal handling of beta-2-microglobulin, amylase and albumin in acute pancreatitis.

The renal handling of beta-2-microglobulin, amylase and albumin was studied in patients with acute pancreatitis. The data were compared with results obtained from patients with glomerular proteinuria and from patients with tubular proteinuria. Initially during acute pancreatitis, the clearance ratio (clearance protein/clearance creatinine) for beta-2-microglobulin was increased dramatically (77-fold) compared to normals. After four to seven days this ratio had fallen and was elevated only 7-fold. The corresponding figures for amylase were 3.3 and 1.8 times and for albumin 9 and 5 times respectively. In glomerular disease, the clearance ratios for beta-2-microglobulin, amylase and albumin were increased 6, 1.1, and 154 times and in tubular disease 448, 1.1, and 28 times, respectively. The electrophoretic pattern of the urinary proteins during pancreatitis was mostly normal. In a few cases, slight tubular proteinuria was noticed. Amylase activity in serum and urine from patients with pancreatitis was found to sediment, (S20,W = 4.6) in a sucrose gradient, identical to amylase from normal serum and urine. The marked increase in the excretion of beta-2-microglobulin probably reflects interference of the kidney function at the proximal tubular level. Determinations of this protein in urine may be of value in studies of kidney dysfunction that can accompany pancreatitis.     

Proximal tubular handling of phosphate: A molecular perspective

Members of the SLC34 gene family of solute carriers encode for three Na+-dependent phosphate (P i) cotransporter proteins, two of which (NaPi-IIa/SLC34A1 and NaPi-IIc/SLC34A3) control renal reabsorption of P i in the proximal tubule of mammals, whereas NaPi-IIb/SCLC34A2 mediates P i transport in organs other than the kidney. The P i transport mechanism has been extensively studied in heterologous expression systems and structure-function studies have begun to reveal the intricacies of the transport cycle at the molecular level using techniques such as cysteine scanning mutagenesis, and voltage clamp fluorometry. Moreover, sequence differences between the three types of cotransporters have been exploited to obtain information about the molecular determinants of hormonal sensitivity and electrogenicity. Renal handling of P i is regulated by hormonal and non-hormonal factors. Changes in urinary excretion of P i are almost invariably mirrored by changes in the apical expression of NaPi-IIa and NaPi-IIc in proximal tubules. Therefore, understanding the mechanisms that control the apical expression of NaPi-IIa and NaPi-IIc as well as their functional properties is critical to understanding how an organism achieves P i homeostasis.     

Biophysical mechanisms of anesthetic action: historical perspective and review of current concepts.

The large number and diversity of anesthetic agents were evident to investigators 80 years ago, and suggested a physicochemical theory of anesthesia. Meyer and Overton were the first to offer a quantitative relationship between a physicochemical property and potency of anesthetic agents. They also focused attention on the lipid phase as the site of anesthetic action. Ferguson realized that the concentration of an agent at its site of action bears a generally unknown relation to the concentration in the external phase. However, at equilibrium the activity of an agent is the same in every phase, motivating Ferguson to suggest that activities rather than concentrations be used as indices of dosage. The critical-volume theory resulted from modification of the Meyer-Overton theory to include the molal volume of the anesthetic. The allowance for molal volume resulted initially from an attempt further to regularize the experimental data. The concept of a critical-volume fraction of anesthetic being necessary for narcosis was discussed in most detail by Mullins. Subsequently, the concept of the effect of the anesthetic has changed from filling of free space to expansion and fluidization of the membrane. The ability of pressure to cause excitant phenomena and antagonize anesthetics is predictable from the critical-volume theory and is therefore highly significant evidence. K. W. Miller and associates are perhaps most prominent in the recent quantification and formalization of the critical-volume theory and HPNS. The existence of a separate convulsant site(s) is suggested by the demonstration of significantly different compressibilities associated with anesthesia and convulsions. Work corroborating a separate convulsant site involved measurement of the partial molal volumes of a series of related convulsant and anesthetic ethers and calculation of each compound's solubility parameter. Multiple convulsant sites may exist, and these two methods may not have accessed the same site. Understanding the anesthetic-convulsant duality will have important practical application to deepwater diving, and may well offer important insight into the neurophysiologic and electrophysiologic effects of anesthetics. The application of ESR and NMR allows investigation at the molecular level of effects of anesthetics on biological and model membranes. Magnetic resonance techniques have generally supported the concept of membrane fluidization by anesthetics. Some investigators have recently attempted to displace the focus of attention from the lipid phase. However, the evidence is clearly against the aqueous-phase theory of Pauling and S.L. Miller. The microtubule theory of Allison and Nunn has not accumulated supporting evidence comparable to the lipid theories. Contradictory evidence makes any evaluation of this theory speculative. Additionally, the interspecies and intracellular variability of microtubules raises questions of the relevance of many studies...     

Occipitocervical fusion: A review and current concepts

Occipitocervical fusion is not a routine operation and is a challenging procedure due to complex anatomy of the craniocervical junction. Its unique anatomic and biomechanical property subjects any instrumentation construct to significant stress. Instability at this region can be caused by a variety of acute and chronic conditions and subtle neurological symptoms in patients. Recognition of OC instability, followed by treatments including reduction, immobilization, and operative fixation, are the goals. Bony fusion is the ultimate goal of OC reconstruction. Several instrumented fixation systems have evolved from wire and cable techniques to plates, rods, and screws. Recently screw-rod constructs are more favored because of ease of use and superior biomechanical properties. Rigid internal fixation eliminates the need for prolonged rigid external orthotics and results in improved arthrodesis rate.     

Rhinosurgery in children: basic concepts

In newborns, the main supporting structure of the nose is the dorsoseptal cartilage, a T-bar-formed complex of septum and upper lateral cartilages, which is essentially an external extension of the cartilage of the anterior cranial base. Later the anatomic situation gradually changes -- a potential pitfall for surgeons and radiologists. The vulnerability of various processes underlying postnatal development of the facial skeleton is discussed. The cartilaginous septum is the dominant growth center. Loss of septal cartilage at different ages leads to different facial syndromes involving nose, maxilla, and orbita. The septal cartilage in children demonstrates thinner fracture-prone areas next to thicker growth zones. Septum fractures have a preference for the thinner regions, corresponding with the most frequent septum deviations observed in growing children. The essential problem in pediatric rhinosurgery is not the age-specific anatomy but the poor wound-healing capacity: fractured or transected septum cartilage will not heal, and disconnected ends tend to overlap, resulting in increasing or recurrent deviations. Based on clinical and experimental evidence, indications and "safe" and "unsafe" techniques of rhinosurgery are presented for children of various age groups.     

Stress and headache: A critical review

Almost all of us, at one time or another, have headaches. A belief held by many is that difficult, stressful, or depressing environmental demands are responsible for their onset. This commonplace notion is among the most compelling in the psychophysiological literature, yet attempts to empirically validate the relationship have been problematic. Examination of the available literature reveals a dearth of evidence from epidemiological and other sources that have traditionally been used to link stress with other disorders such as hypertension and coronary heart disease. In contrast, the wealth of laboratory data designed to examine the effects of acute stress on the physiological responses implicated in headache genesis have yielded contradictory findings. Refinements in knowledge of the biochemical and psychological pathophysiology of chronic headaches would enhance the ability to establish a firm link in the stress-headache relationship. In the meantime, the available evidence warrants a decidedly less sanguine attitude towards the association than that held by most patients, and indeed. by most medical practitioners.     

Introduction: basic concepts and definitions in mechanics

This introduction aims to expound the basic ideas of mechanics of materials to clinicians. What happens when a bone (mechanically a beam) is submitted to standard loads: Centric axial load, bending, eccentric axial load, torque? How does the bone deform? The basic ideas of mechanical engineering are presented using an eraser under load as an illustrative object, and trying to maintain the mathematical formulae as far as possible.     

Psychogenic impotence: A critical review

A critical review of the literature on psychogenic impotence is undertaken with special reference to recent advances in objective evaluation of erectile function and radiographic visualization of the penile arteries. Standardization of nomenclature, subclassification of acute versus insidious erectile dysfunction, insistence on objective criteria for declaring erectile dysfunction or a cure of the same, and the reestablishment of psychogenic impotence as a diagnosis of exclusion are to be encouraged.     

Renal handling of enalaprilat.

Most converting enzyme inhibitors share a predominantly renal dual elimination pathway consisting of glomerular filtration and tubular secretion. Since enalaprilat has two functional acidic groups, it is likely that it may be secreted via the proximal tubule organic acid system and, thus, its clearances would exceed that of glomerular filtration rate markers. We therefore examined the renal clearance of enalaprilat in normal volunteers and compared it with simultaneously measured inulin and creatinine clearances to explore the contribution of tubular secretion to the renal elimination of the drug. Twelve healthy male subjects with an age range of 24 to 58 years (mean +/- SE, 33.1 +/- 2.8) were studied. They had representative height (178.6 +/- 1.99 cm) and weight (73.3 +/- 2.1 kg) and had normal renal function as judged by blood urea nitrogen (BUN) (6 +/- 0.3 mmol/L [17 +/- 0.8 mg/dL]), plasma creatinine (88 +/- 3 mumol/L [1.0 +/- 0.03 mg/dL]), and creatinine clearance determined by a prestudy 24-hour urine collection (123.2 +/- 6.2 mL/min). Results are as follows: mean creatinine clearance, 2.12 mL/s (127 mL/min); mean inulin clearance, 119.1 ml/min mean creatinine clearance/inulin clearance, 1.07 mean enalaprilat protein binding, 37.9% unbound enalaprilat clearance, 222.4 ml/min; and the mean fractional enalaprilat clearances were: enalaprilat clearance/creatinine clearance, 1.72 (P less than 0.05, difference from 1.0); enalaprilat clearance/inulin clearance, 1.85, (P less than 0.05, difference from 1.0). Our results demonstrate that the clearance of free enalaprilat exceeds that of inulin and creatinine, suggesting that elimination of the drug proceeds through two complementary pathways, namely glomerular filtration and tubular secretion.     

Renal handling of uric acid under cyclosporin A treatment

The renal handling of uric acid during cyclosporin A (CyA) treatment was investigated by clearance studies using 24-h urine collections in 28 paediatric renal transplant recipients (CyA group), and the results were compared with those of 19 renal transplanted children treated with azathioprine and prednisolone (AZA group), 35 children with chronic renal failure (CRF) and 10 children with normal renal function (N group). Serum uric acid levels were significantly higher in the CyA group (567±156 mol/l) compared with the AZA group (378±98), the CRF group (415±119) and the N group (290±68). Mean uric acid clearances in each group measured 3.9±2.8 ml/min per 1.73 m² (CyA), 5.6±3.4 (AZA), 4.0±2.2 (CRF) and 8.4±3.7 (N). Calculation of the net tubular uric acid reabsorption per millilitre glomerular filtration rate revealed a significantly increased value of 0.53±0.15 mol/ml in the CyA group (P<0.01) compared with 0.34±0.08, 0.29±0.15 and 0.27±0.07 mol/l for the AZA, CRF and N groups respectively. We therefore conclude that CyA treatment is associated with an increased net tubular reabsorption of uric acid, which may lead to hyperuricaemia.     

Advanced or basic life support for trauma: meta-analysis and critical review of the literature

BACKGROUND: The question of whether to use advanced life support (ALS) or basic life support (BLS) for trauma patients in the prehospital setting has been much debated and still lacks a clear answer. The purpose of this study was to conduct a comprehensive critical review of the literature regarding this controversy METHODS: A total of 174 articles on prehospital ALS or BLS for trauma were reviewed. Fifteen of these studies were found to involve mortality statistics for both ALS- and BLS-treated patients. Odds ratios were calculated for survival in ALS versus BLS and summarized across studies on the basis of multivariate scoring systems that incorporated both design and methodological assessment. Overall odds ratios for all studies were calculated on the basis of both raw data from the papers, and weighted odds ratios were calculated from the scoring systems. RESULTS: Six studies were scored as being methodologically average (5 favoring BLS and 1 favoring ALS), two were scored as good (1 favoring BLS and 1 favoring ALS), seven as excellent (6 favoring BLS and 1 favoring ALS). Ten studies had an average study design score (6 favoring BLS and 4 favoring ALS) and seven had a good study design score (6 favoring BLS and 1 favoring ALS). Weighted odds ratio for dying was 2.59 for patients receiving ALS compared with those receiving BLS. The crude odds ratio was 2.92. CONCLUSION: The aggregated data in the literature have failed to demonstrate a benefit for on-site ALS provided to trauma patients and support the scoop and run approach.