Cationic amino acid fluxes beyond the proximal convoluted tubule of rat kidney

To investigate the fluxes of cationic amino acids beyond the proximal convolution, we micropunctured and microperfused superficial tubules of male Wistar rats in vivo et situ. In free-flow micropuncture experiments, the concentrations of endogenous L-arginine⁺, [Arg], and of intravenously infused L-homoarginine⁺, [HoArg], were determined by HPLC. Fluorescein isothiocyanatelabeled inulin was detected on-line in the same tubular fluid samples. To determine undirectional fluxes, radiolabeled Arg and inulin were (1) microperfused through short loops of Henle and (2) microinfused into different tubule segments to measure urinary recovery of the radiolabel. At a mean [Arg]_plasma of 116 mol/l, [Arg] was 9.3 mol/l in the late proximal tubule (LPT), and 35.6 mol/l in the early distal tubule (EDT) corresponding to fractional deliveries (FD) of 0.055 in LPT and 0.078 in EDT. Fractional urinary excretion (FE) of Arg was 0.00033 (P<0.05 vs FD_EDT). Infusion of HoArg (2.5 or 7.5 mol/min) led to respective mean [HoArg]_plasma values of 1.44 and 3.73 mmol/l, and resulted in respective FD_LPT values for HoArg of 0.23 and 0.53, respective FD_EDT values of 0.29 and 0.41, and finally, respective FE values for HoArg of 0.25 and 0.58. When short loops of Henle were microperfused with 1 or 50 mmol/l [¹⁴C]Arg (+[³H]inulin), fractional recovery (FR) of ¹⁴C (relative to inulin) in the EDT was 0.13 and 0.36, respectively. During microinfusion of radiolabeled Arg (1 or 50 mmol/l) and inulin into LPT, the urinary FR of the radiolabel was 0.14, or 0.59, respectively. If 0.007, 1 or 50 mmol/l radiolabeled Arg were microinfused into EDT, the respective urinary FR of the radioactivity was 1.02, 1.10, or 1.01. Microperfusion of microinfusion of 1 mmol/l [¹⁴C]Arg plus 50 mmol/l HoArg resulted in a FR_EDT of ¹⁴C of 0.43 (loop, perfusion) and an FE for ¹⁴C of 0.69. Five conclusions can be drawn. First, cationic amino acids can enter and leave the lumen of short loops of Henle through specific carrier(s) at high rates, although, secondly, net transport is small or absent. Thus, medullary tubule cells can be supplied with Arg from the lumen of short loops of Henle for urea and nitric oxide production. Thirdly, the distal convolution of superficial nephrons and the collecting duct are not permeable to Arg. Thus, fourthly, the difference between FD_EDT and urinary FE of Arg must be explained by an inter-nephron heterogeneity between deep and superficial nephrons. Finally, the process responsible for the different Arg handling in deep nephrons is not accessible to HoArg or, if so, it is saturated at millimolar concentrations.     

Evaluation of nutritional counselling in HIV-associated malnutrition

In HIV-infected patients, the outcome of counselling as the first step of a nutritional intervention programme was evaluated, in order to identify clinical and nutritional predictors for its efficacy. 75 HIV-infected patients were investigated, most with advanced disease. Nutritional status was determined by body weight, bioelectrical impedance and 7-day food intake record. Prior mean weight loss was 10% (range = +4% to -31%). Counselling facilitated weight gain in 40 75 patients (1-4 months later, overall mean difference +1.4 +/- 6.2%) and in 14 34 patients (8-11 months later, overall mean difference -1.4 +/- 9.0%). Weight changes correlated with changes in body cell mass (r(2) = .69, p < .001) and in body fat (r(2) = .29, p < 0.05), but not extracellular mass. Underlying conditions such as AIDS definition, fever, and diarrhoea correlated to prior weight loss (p < .001) but not to the outcome of counselling. Low energy intake (before counselling, < 31.5 kcal/kg) did not correlate to prior weight loss but it predicted further weight loss (p < 0.05 towards normal intake). High energy intake (> 38.5 kcal/kg) correlated (p < 0.05) with more prior weight loss but not with further weight changes. Nutritional counselling may be an effective first-line intervention for malnourished HIV infected patients. More than half of patients gain weight without other nutritional treatment. Whereas the severity of malnutrition is influenced by the underlying disease, fever, and diarrhoea, the course of weight change after nutritional intervention is not. Counselling may reduce the nutritional impact of these risk factors. In patients with low spontaneous intake, efficacy of counselling alone is limited, but it may help to identify those who require more invasive nutritional treatment.     

Periictal diffusion-weighted imaging in a case of lesional epilepsy

PURPOSE: Diffusion-weighted MR imaging (DWI) has been used for the early diagnosis of acute ischemic lesions in humans and in animal models of focal status epilepticus. We hypothesized that DWI may be a sensitive, noninvasive tool for the localization of the epileptogenic area during the periictal period. METHODS: A periictal DWI study was performed on a 35-year-old patient during focal status epilepticus with repetitive prolonged focal motor seizures originating from a lesion in the right frontal lobe. DWI results were analyzed visually and by calculating apparent diffusion coefficient (ADC) maps. RESULTS: On DWI, a single area of signal increase (decrease in ADC) was found in the region of focal electrocorticographic seizures that was mapped intraoperatively. CONCLUSIONS: Ictal/postictal DWI may be a useful technique for seizure localization in patients with lesional epilepsy.     

Appendicitis: Higher risk in Mexican Americans?

Objectives. Mexican Americans (MAs), compared to white non‐Hispanics (WNHs), have higher rates of biliary disease, noninsulin dependent diabetes, and endstage renal disease but lower rates of lung cancer, hip fractures, and mortality from coronary heart disease. Relatively little research has been done to identify other ethnic differences in disease incidence. We used surgical procedure rates to confirm known ethnic differences and to explore our clinical suspicion that MAs have higher rates of appendectomy than WNHs.

Methods. We used a registry of surgical procedures at two teaching hospitals in South Texas to calculate proportional operation ratios (PORs) for MAs versus WNHs. These two hospitals are the primary source of acute hospital care for the indigent in the area. The POR is arithmetically identical to proportional incidence and mortality ratios.

Results. MAs underwent appendectomy proportionally more often than WNHs at both hospitals (POR = 1.41 and 1.75, p < 0.0001). Other significant PORs were consistent with known ethnic disease differences in biliary tract operations, vascular access for chronic hemodialysis, lung cancer, and coronary artery bypass.

Conclusions. These findings support the hypothesis that MAs may undergo appendectomy more often than WNHs and so may be at higher risk of appendicitis.     

Differential inhibition and potentiation by cell-permeant analogues of cyclic AMP and cyclic GMP and NO-containing compounds of exocytosis in human neutrophils

Summary The chemoattractants, N-formyl-L-methio-nyl-L-leucyl-L-phenylalanine (fMet-Leu-Phe), complement C5a and platelet-activating factor (PAF), induce ß-glucuronidase release and aggregation and an increase in cytosolic Ca²⁺ [Ca²⁺]_i in human neutrophils. We studied the roles of cAMP and cGMP in neutrophil avtivation, using their cell-permeant analogues, N⁶,2-O-dibutyryl adenosine 3:5-cyclic monophosphate (Bt2cAMP) and N² ,2-O-dibutyryl guanosine 3:5-cyclic monophosphate (Bt₂cGMP) and the NO-containing compounds, sodium nitroprusside (SNP), 3-morpholino-sydnonimine (SIN-1) and its prodrug, molsidomine (SIN-10). Bt₂cAMP, Bt₂cGMP, SIN-1 and SIN-10 but not SNP inhibited exocytosis induced by fMet-Leu-Phe. Superoxide dismutase potentiated the inhibitory effect of SIN-1. Bt₂cGMP and SNP potentiated C5a-induced ß-glucuronidase release, Bt₂cAMP, KCN, SIN-1 and SIN-10 being ineffective. KCN partially reversed the stimulatory effect of SNP, and in the presence of superoxide dismutase, SIN-1 potentiated C5a-induced exocytosis. PAF-induced ß-glucuronidase release was not affected by Bt₂cAMP, Bt₂cGMP, SNP and SIN-1. Bt₂cGMP was more effective than Bt2cAMP to inhibit aggregation and the increase in [Ca²⁺]_i induced by fet-Leu-Phe at submaximally effective concentrations. C5a-induced rises in [Ca²⁺]_i were not affected by Bt₂cAMP and Bt₂cGMP. Bt₂cAMP but not Bt₂cGMP inhibited the effect of PAF at submaximally effective concentrations on [Ca²⁺]_i. Our data suggest (I) that Bt2cGMP and Bt2cAMP differentially modulate neutrophil activation, that (II) NO-containing compounds partially mimick the effects of Bt₂cGMP on exocytosis and that (III) cGMP plays an inhibitory role in fMet-Leu-Phe- and a stimulatory role in C5a-induced ß-glucuronidase release. Send offprint requests to R. Seifert at the above address     

The emergency telephone number--the essential weak link in an emergency system. Prospective studies involving cardiac arrests observed by bystanders]

The first link in the "chain of survival" concept is the activation of the emergency medical system (EMS) by a bystander after recognition of cardiac arrest (CA) or its immediate prodrome. Our ongoing study is aimed at evaluating the current effectiveness of bystander EMS activation for all cases of CA in the city and area of Mainz. Methods. Starting February 1991, we began to prospectively examine collapse-intervention intervals in all cases of CA treated by our physician-manned ambulance. Precision voice recorders carried by the ambulance crews are activated and linked to the EMS dispatcher to time the arrival of the ambulance vehicle. Time intervals starting from the time of collapse are then reconstructed from the dispatcher's time and the tapes. The emergency phone number dialled initially by the bystander and the time of collapse in witnessed cardiac arrests are identified. RESULTS. Sixty-six CAs were witnessed and included in this study. In 20% of those cases, the number dialled initially by the bystander was 19222 (EMS dispatcher), in 38% 110 (police), and in 42% other numbers (family practitioners or their on-call service, fire department). The time interval, as median (25th percentile; 75th percentile), between collapse and receipt call by the emergency dispatchers was 4 min (2; 8) for all patients (n = 66), and 6.5 min (3; 12) whenever numbers other than emergency phone numbers were dialled. All following time intervals (start of BLS or ACLS procedures) showed differences (P less than 0.05) between the 110 or 19222 group [BLS: 8.5 min (4.8; 13.1) or 10 min (7.35; 12.1); ACLS: 11.3 min (9.1; 13.45) or 12.9 min (10.6; 21.5)] vs the group, in which other phone numbers were initially dialled [BLS: 15.25 min (9.25; 19.4); ACLS: 20.11 min (12.6; 28.3)]. The first ECG rhythm showed VF in 56% and 54% in case 110 and 19222 were dialled, but only in 32% in the other group. CONCLUSION. Even one single weak link in the "chain of survival" can lower overall survival rates. An indispensable, but apparently underrated component of an effective EMS includes an informed citizenry able to call swiftly for help. Lack of an unequivocal emergency number, well known and accepted by the citizens, produces confusion and delays. In our systems, the correct medical emergency phone number (19222) was dialled in 20% of the cases only, thus demonstrating clearly the lack of public awareness of this 5-digit number. In a higher percentage, the three-digit police number (110) was dialled. In cases where numbers other than emergency numbers were dialled (42%), the longest time intervals between collapse and receipt of call by the dispatchers occurred, associated with the longest time intervals until initiation of CPR and the lowest percentage of patients found in ventricular fibrillation. We conclude that establishment of a simple three-digit EMS phone number, preferentially Europe-wide, in combination with an intensification of public awareness, could be a vital step not only to reduce time intervals between collapse and CPR in our EMS system but also to improve survival.     

Rectal administration of drugs. Fundamentals and applications in anesthesia]

Rectal administration of drugs has become a standard procedure in clinical anesthesia, most notably for anorectal induction in children. Limitations of this method include low bioavailability, a wide scatter of pharmacokinetic and pharmacological results, and poor predictability of the clinical effect in any particular patient. Historically, the rectal route has been used for the administration of smoke ("fumigation") for resuscitation and various other purposes. An ether boiler for rectal application was developed by Pirogoff as early as 1847. The pharmacokinetics of rectally administered drugs are determined by the anatomical properties of the rectum and, owing to interindividual variance, this adds to the inconsistency of absorption. Aspects that can be better controlled include the drug preparation and the vehicle, with hydrophilic solutions resulting in improved absorption. Larger volumes such as are associated with lower concentrations increase the bioavailability by enlarging the mucosal surface in contact with the drug. In contrast to the hypothetical assumption that hepatic circulation may be circumvented--thus avoiding first-pass metabolism--by direct venous drainage from the rectum into the systemic circulation via the vena cava, it has been shown that hepatic clearance is the main factor affecting bioavailability. This may be due to blood flow through anastomoses interconnecting the superior, medium and inferior rectal venous systems. Resorption from the rectum is also determined by physicochemical properties of drugs. According to the pH-partition hypothesis, only the non-ionized moiety of a compound will be available for transmucosal diffusion. The degree of ionization is a function of the local (or microclimate) milieu pH and pKa of the drug; the former is close to neutral in adults but alkaline in most children. Adsorption of feces, intraluminal degradation by microorganisms, metabolism within the mucosal cell, and lymphatic drainage do not significantly affect the fate of rectally administered drugs. In clinical practice, the rectal administration of methohexital and midazolam is an established method of premedication or induction of anesthesia in children; so far, midazolam appears to be associated with fewer complications. Ketamine has been shown to be as effective and as quick-acting as methohexital, but at least in one study its use as sole induction agent was associated with respiratory distress in some cases. However, painful diagnostic or therapeutic procedures in children may be indications for the rectal administration of ketamine. Early trials with rectally administered etomidate have been abandoned since its implication in suppression of cortisol synthesis. Narcotic analgesics in a hydrogel vehicle are effective in adult pain management.(ABSTRACT TRUNCATED AT 400 WORDS)     

About the proposition of strength of animal-experimental results with hip endoprosthesis. A comparative analysis of the stress of the upper thigh of man and of four-leg (author's transl)]

Precise knowledge of the biomechanic of the hip of man and of animal is necessary to evaluate the procedures of adaption of the femur after endoprosthesis with animal experiment and the transfer into the endoprosthesis of the human medicine. After functional-morphological and biomechanical researches (Pauwels), the upper femoral end of the man is highly stressed by bending at direct level while lowly stressed at sagittal level. The present own biomechanical analysis of the hip of the dog reveal - under consideration of the gaits "pace", "trot" and "gallop" - that the coxal end of the femur of the four-leg compared with that of man is highly stressed by bending at sagittal level as well as at direct level. The observations are herewith clearly explained that intense reconstructions of the bone at artificial human thighs are found mainly at lateral and medial circumference of the bed of the prosthesis, at animal experiment however at dorsal, ventral as well as medial circumference.     

Beanspruchung und Umbau bei der Alloarthroplastik des coxalen Femurendes des Hundes mit einer selbsthaftenden Tragrippenprothese

Zusammenfassung Um die zusätzliche Verwendung von Kunstharzen zur Verankerung der Totalprothese der Hüfte zu umgehen, hat Mittelmeier eine selbsthaftende Tragrippenprothese mit besonders gestalteter Oberfläche des Prothesenstieles angegeben. Nach einjähriger Implantationsdauer im Tierexperiment (Hund) wird der endoprothetisch versorgte und der kontralaterale normale Femur des Hundes funktionell und morphologisch untersucht. Unter statischer Belastung werden mit Dehnungsmeßstreifen die Beanspruchung und in photographischen und Röntgenaufnahmen der Umbau des Knochens nach Prothetik untersucht. Im Bereich des Prothesenstieles ergeben sich Umbauvorgänge, welche mit den geänderten Beanspruchungen übereinstimmen. Der Knochen gleicht sich an eine in Richtung und Höhe gänzlich geänderte Beanspruchung durch eine Spongiosierung des oberen Teils der Femurdiaphyse zweckmäßig an. Dieser Vorgang wird als kompensatorische Metaphysierung des Schaftes bezeichnet (Diehl).

---

Stresses and functional adaptation of alloarthroplasty of the proximal femur in dogs using a selfcuring rippled prosthesisA comparative biomechanical and morphological study

Summary A self-adhesive prosthesis for youth patients is developed by Mittelmeier that is implanted without bone cement. After an implantation term of 1 year in animal experiment (dog), an adapted femur is compared with the contra-lateral normal femur. Strain gauges are used to determine bone strain under load. Further is determined external and internal construction change after endoprosthesis. The construction changes found are in connection with the changed bone strength. A cancellous change of bone at entire area of stem of prosthesis is called a ;metaphysation; of bone shaft.

     

Outcome of allogeneic hematopoietic stem-cell transplantation in adult patients with acute lymphoblastic leukemia: no difference in related compared with unrelated transplant in first complete remission.

PURPOSE: The role of unrelated allogeneic stem-cell transplantation in acute lymphoblastic leukemia (ALL) patients is still not clear, and only limited data are available from the literature. We analyzed factors affecting clinical outcome of ALL patients receiving a related or unrelated stem-cell graft from matched donors. PATIENTS AND METHODS: The total study population was 264 adult patients receiving a myeloablative allogeneic stem-cell transplant for ALL at nine bone marrow transplantation centers between 1990 and 2002. Of these, 221 patients receiving a matched related or unrelated graft were analyzed. One hundred forty-eight patients received transplantation in complete remission; 62 patients were in relapse; and 11 patients were refractory to chemotherapy before transplant. Fifty percent of patients received bone marrow, and 50% received peripheral blood stem cell from a human leukocyte antigen-identical related (n = 103), or matched unrelated (n = 118) donor. RESULTS: Disease-free survival (DFS) at 5 years was 28%, with 76 patients (34%) still alive (2.2 to 103 months post-transplantation), and 145 deceased (65 relapses, transplant-related mortality, 45%). We observed an advantage regarding DFS in favor of patients receiving transplantation during their first complete remission (CR) in comparison with patients receiving transplantation in or after second CR (P =.014) or who relapsed (P <.001). We observed a clear trend toward improved survival in favor of B-lineage ALL patients compared with T-lineage ALL patients (P =.052), and Philadelphia chromosome-positive patients had no poorer outcome than Philadelphia chromosome-negative patients. Total-body irradiation-based conditioning improved DFS in comparison with busulfan (P =.041). CONCLUSION: Myeloablative matched related or matched unrelated allogeneic hematopoietic stem-cell transplantation in ALL patients should be performed in first CR.