Angiotensin II production and distribution in the kidney--II. Model-based analysis of experimental data

Information on the regional concentrations of angiotensin (Ang) II and its type-1 and -2 receptors (AT(1)R, AT(2)R) in the kidney is still incomplete. Published data on the levels of arterially delivered Ang I and II (Ang Ia, Ang IIa) and intrarenally produced Ang I and II (Ang Ii, Ang IIi) in the renal vein and in whole tissue were analyzed by using a kinetic model of Ang production and distribution in the glomerular and peritubular cortical tissue regions (Glom, Pt). (1) 90% of Ang II is cell-associated, due to its binding to AT(1)R and AT(2)R; (2) most Ang II in the renal cortex is Ang IIi; (3) Ang IIa is mainly localized in Glom; (4) Ang Ii rather than Ang Ia is a substrate of renal angiotensin-converting enzyme; (5) Ang IIi is localized in Pt and its concentration in interstitial fluid is 5-15 times the Ang II concentration in arterial plasma; and (6) in Glom the interstitial concentration of cell surface-bound AT(1)R is above 200K(d), and in Pt the AT(1)R and AT(2)R concentrations are above 10K(d). In conclusion, endocrine Ang II mainly acts in Glom, whereas Pt is exposed to paracrine Ang II generated by the conversion of intrarenally produced Ang I. High AT(1)R concentrations in Glom and Pt favor diffusion-limited binding, so that the apparent binding rate constant at sites closest to the source of Ang II delivery is greatly increased. Results may explain why the kidney is responsive to low levels of endocrine Ang II, despite its high content of paracrine Ang II.     

Differential management of acute peripheral arterial ischemia

Retrospective study of 140 consecutive cases of nontraumatic acute ischemia of the extremities of 48 hours or less duration emphasizes differences in diagnostic features, treatment, and results among 71 patients with arterial embolism (11% mortality rate) and 69 with acute atherosclerotic thrombosis (3% mortality rate). The following principles of management have evolved. (1) Although it is often difficult, differentiation between embolisms and acute thromboses is important. (2) Preoperative angiography is useful. (3) Immediate heparinization is indicated. However, it is not a suitable substitute for a necessary operation. (4) Long-term heparin therapy (instead of operation) does not produce better results for an embolism. However, it is useful for recent acute thrombosis with a viable limb. (5) Thrombectomy alone is not sufficient for acute atherosclerotic thrombosis. (6) Completion angiography is required. (7) Embolisms are more dangerous than acute thromboses, probably because of more serious accompanying cardiac lesions.     

Thalamo-cortical afferents control transient expression of the dopamine D(3) receptor in the rat somatosensory cortex.

The D(3) dopamine receptor (D(3)R) is selectively and transiently expressed in the barrel neurons of the somatosensory cortex (SI) between the first and second postnatal weeks. The D(3)R expression starts after the initial ingrowth of thalamocortical afferents (TCAs) into the barrel cortex and could be induced or controlled by them. We show that unilateral electrolytic lesion of the thalamic ventrobasal complex immediately after birth leads to a decrease in the D(3)R mRNA concentration in the lesioned SI 7 days after the lesion, whereas the D(3)R binding is little affected. Fourteen days after the neonatal thalamic lesion, the D(3)R binding and mRNA are drastically reduced and the barrel-like pattern of the D(3)R is absent. Elevation of the D(3) binding normally seen between the first and second postnatal weeks does not occur. Thalamic lesion on P6 differentially affects the D(3)R expression. One day after the lesion, the D(3) binding and mRNA are down-regulated, but the effect is transient. Five days after the lesion the concentration of D(3) mRNA in the lesioned hemisphere returns to the control level. The typical barrel-like pattern of D(3)R expression is evident in the lesioned SI, although TCAs are completely absent. Quantitative analysis demonstrated elevated cellular levels of the D(3) mRNA in barrel neurons 5 days after the lesion. These higher levels are needed, perhaps, to support the increased production of the D(3)R protein appropriate for this age. Age-related dynamics of the D(3)R binding is retained in the lesioned SI, although the concentration of D(3)R sites remains reduced. These data demonstrate that intact thalamic input is essential for the formation of mechanisms responsible for developmental regulation of the D(3)R expression in the SI.     

The anti-glycolytic action of (S)-α-chlorohydrin on epididymal bovine spermatozoa in vitro

(S)-alpha-Chlorohydrin interferes with glycolysis in bovine spermatozoa whereas the (R)-isomer is ineffective. The action of the (S)-isomer, which involves inhibition of the reaction catalysed by glyceraldehyde 3-phosphate dehydrogenase, is not immediate but is evident only after a brief period of incubation with the spermatozoa. This inhibitory action is prevented when glycerol is present suggesting that the mechanism of action of (S)-alpha-chlorohydrin requires its oxidation to (S)-3-chlorolactaldehyde which is the active metabolite. Addition of racemic 3-chlorolactaldehyde to bovine spermatozoa caused immediate inhibition of glycolysis. It is proposed that the action of (S)-alpha-chlorohydrin in bovine spermatozoa is similar to that observed in the spermatozoa of other species in being a two-stage process; first, its oxidation to (S)-3-chlorolactaldehyde, and then inhibition of the glycolytic enzyme by this metabolite.     

1,25-Dihydroxyvitamin D3 stimulates vascular smooth muscle cell proliferation through a VEGF-mediated pathway

Atherosclerosis is a complex process characterized by an increase in the wall thickness owing to the accumulation of cells and extracellular matrix between the endothelium and the smooth muscle cell wall. This process is associated with different pathologies and it is accelerated in patients with chronic renal failure. In these patients, decreased synthesis of 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) leads to secondary complications, like hyperparathyroidism, and treatment with 1,25(OH)(2)D(3) is a common practice. The effect of 1,25(OH)(2)D(3) on vascular smooth muscle cells (VSMCs) calcification has been widely studied, but the role of 1,25(OH)(2)D(3) on VSMC proliferation remains obscure. We have analyzed the effects of 1,25(OH)(2)D(3) in the proliferation of VSMC. We found that 1,25(OH)(2)D(3) (5-100 nM) induces a dose-dependent increase in VSMC proliferation in quiescent cells and in cells stimulated to grow. This increase in proliferation is achieved by shortening the G1 phase. The effect of 1,25(OH)(2)D(3) on VSMC proliferation is mediated by an increase of the expression of vascular endothelial growth factor A (VEGF), as the inhibition of VEGF activity totally blunted the 1,25(OH)(2) D(3)-induced VSMC proliferation. We found this increase in proliferation in vitro, ex vivo in aortic rings incubated with 1,25(OH)(2)D(3), and in vivo in animals with a model of chronic renal failure (5/6 nephrectomy) treated with 1,25(OH)(2)D(3) (1 mug/kg three times a week for 8 weeks). Thus, we conclude that 1,25(OH)(2)D(3) induces increases in VSMC proliferation through an increase on VEGF expression.     

Handling of cysteine S-conjugates of methylmercury in MDCK cells expressing human OAT1

BACKGROUND: The activity of the organic anion transporter 1 (OAT1) has been implicated recently in the basolateral uptake of thiol conjugates of inorganic mercury in renal proximal tubular cells. However, very little is known about the role of OAT1 in the renal epithelial transport of organic forms of mercury, such as methylmercury (CH(3)Hg(+)), especially when it is in the form of the cysteine (Cys) S-conjugate of methylmercury (CH(3)Hg-Cys), which is believed to be a biologically relevant form of mercury. METHODS: Accordingly, the present study, was designed to characterize the transport of CH(3)Hg-Cys in Madin-Darby canine kidney (MDCK) cells transfected stably with the human isoform of OAT1 (hOAT1) and in proximal tubular-derived NRK-52E cells. RESULTS: Data on saturation kinetics, time dependency, substrate specificity, and temperature dependency demonstrate that CH(3)Hg-Cys is transported by hOAT1. Substrate-specificity data from the control cells also show that CH(3)Hg-Cys is a substrate of one or more transporter(s) that is/are not hOAT1. Additional findings indicate that at least one amino acid transport system is involved in the uptake of CH(3)Hg-Cys in MDCK cells. Furthermore, in the presence of cytotoxic concentrations of CH(3)Hg-Cys, rates of survival were lower in hOAT1-transfected cells than in wild-type control cells. CONCLUSION: The present data demonstrate clearly that CH(3)Hg-Cys is indeed a transportable substrate of OAT1. Moreover, the collective findings from the MDCK cells and NRK-52E cells infer that CH(3)Hg-Cys is a likely transportable mercuric species in proximal tubular epithelial cells that is taken up in vivo by both OAT1 and amino acid transporters.     

ANCA-associated vasculitis: report from Korea

We investigated the clinical features of Korean patients with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) by reviewing the literature. The characteristics of AAV in Korean patients were as follows: (1) granulomatous and limited disease is prevalent in granulomatosis with polyangiitis (Wegener’s) (GPA), (2) ANCA positivity is lower in GPA (56.6–68.9 %) and eosinophilic granulomatosis with polyangiitis (EGPA) (5.9–8.3 %), whereas it is higher in microscopic polyangiitis (MPA) (69–94 %), (3) C-ANCA/proteinase 3 (PR3)-ANCA positivity is 71.5–100 % in GPA and P-ANCA/myeloperoxidase (MPO)-ANCA positivity reached 94–100 % in patients with MPA, (4) renal involvement or progression to end-stage renal disease was lower in Korean patients with GPA and EGPA than in Caucasians with GPA and EGPA (according to data provided in reports). The data provided here may need to be confirmed in large-scale studies.     

Evaluation of tissue oxygen measurements for flap monitoring in an animal model

Tissue oxygen tension (p (ti)O (2)) measurements are common in neurosurgery but uncommon in plastic surgery. We examined this technique as a monitoring method with probe placement in the subcutaneous tissue and addressed the importance of probe placement. Myocutaneous flaps were raised in an animal model and p (ti)O (2) measurements performed at different levels in the subcutaneous fat. Flap artery and vein were occluded until a 50% p (ti)O (2) reduction had occurred (T (1/2)). We found no significant effect of depth ( P > 0.10) on the level of p (ti)O (2). T (1/2)(arterial) was 7.2 minutes and T (1/2)(venous) was 18 minutes. We found no significant relation between intitial levels of p (ti)O (2) and T (1/2). Location of the probe and absolute p (ti)O (2) value is of little relevance for flap monitoring. It is the relative change in p (ti)O (2) that is important. The p (ti)O (2) technique is well suited for monitoring in the subcutaneous tissue and is highly sensitive to changes in both arterial and venous blood flow.     

Open rhinoplasty

Open rhinoplasty provides visualization, which for many is essential for the best sculpturing. The indications for its use include every primary and secondary rhinoplasty candidate unless tip grafts are going to be under tension or if the deformity is minor. The technique of opening the nose has been described. Emphasis is placed on (1) suturing the medial crura together, (2) suturing the medial crura to the septum, (3) resecting a portion of the lateral crus, and (4) leaving as much cartilage in the supratip and cephalic parts of the lateral crus as possible. The result is (1) greater tip projection with fewer tip grafts, (2) improved correction of tip convexity, (3) fewer supratip deformities, and (4) fewer Weir excisions. The columella scar is usually inconspicuous and has not been a significant problem in any case.     

Current Status of Palliative and Terminal Care for Patients with Primary Malignant Brain Tumors in Japan

Palliative care and advance care planning (ACP) from the first diagnosis of glioblastoma are important. This questionnaire survey was conducted to understand the current status of palliative care for brain tumors in Japan. Representative characteristics of Japan in comparison with Western countries (P <0.01) are described below: (1) Gender ratio of male in physicians who treat brain tumors in Europe and the United States/Canada are about 70%, but 94% in Japan. (2) The specialty is predominantly neurosurgeon (93%) in Japan. The ratio of neurologists is predominantly 40% in Europe. In the United States/Canada, neurologist (27%) and neurosurgeon (29%) are main parts. (3) Years of medical experience over 15 in physicians is 73% in Japan. Proportions of those with over 15 years are 45% in Europe and 30% in the United States/Canada. (4) In practicing setting, the rate of academic medical centers is about 80% in Europe and the United States/Canada, and ~60% in Japan. Representative differences compared with past domestic data (2007) (P <0.01): (1) In glioblastoma, the rate of explaining about median survival time increases from 39% (2007) to 80% (2018). Explanation about medical conditions to the patient himself with his family increases from 20% (2007) to 39% (2018). (2) Place of death: The rate at hospital is decreasing from 96% (2007) to 79% (2018) and at home is increasing from 3% (2007) to 10% (2018) (3) The rate of ventilator in adult has decreased from 74% (2007) to 54% (2018), but nasal tube feeding has remained unchanged from 62% (2007) to 60% (2018). These results will be shared with physicians to make better care systems for patients with brain tumors.     

Rapidly progressive glomerulonephritis: analysis of prevalence and clinical course

Over a period of 68 months we observed 33 patients with biopsy-confirmed severe crescentic glomerulonephritis (GN) and another 5 patients who fulfilled the clinical criteria of rapidly progressive glomerulonephritis (RPGN; no biopsy confirmation) in a region comprising approximately 930,000 inhabitants. Additional 7 patients with Wegener's granulomatosis (WG)/microscopic polyarteritis (MP) from the same region were not seen by nephrologists. The calculated annual incidence of crescentic GN/RPGN is 0.7/100,000. Of the 38 patients 13 had classical WG, 7 MP, 3 systemic lupus erythematosus, 5 Sch?nlein-Henoch purpura, 3 Goodpasture's syndrome, 2 IgA glomerulonephritis. Of note is the high prevalence of WG/MP and the relative frequency of Sch?nlein-Henoch purpura. At the last follow-up, 3 patients were dead (8%), 7 patients were on dialysis (18%), 7 patients had elevated serum creatinine (18%) and 21 patients had normal serum creatinine (55%). We conclude that: (i) RPGN is more frequent than reported; (ii) WG and MP account for more than 50% of cases of RPGN; (iii) renal functional prognosis is good in WG/MP, but less favorable in RPGN of other causes; (iv) severe hypertension is not a feature of RPGN; (v) WG/MP, and not Goodpasture's syndrome, is the most common cause of pulmonary hemorrhage in association with RPGN; (vi) death from infection or malignoma is uncommon (not observed in this series); (vii) de novo IgA GN may occur in patients in remission from WG (2 observations).     

Emigration from the British Isles to Southeastern Spain: A Study of Attitudes Toward Organ Donation

Southeastern Spain is a cosmopolitan area where there is a growing British and Irish population. The objective is to analyze the attitude toward organ donation among British and Irish citizens living in southeastern Spain. A sample was taken stratified according to a respondent's country of origin (n = 1700) between November 2005 and April 2006. Attitude was evaluated using a validated questionnaire, which was self-administered and completed anonymously. A sample of 2000 Spanish citizens was used as a control group. The survey completion rate was 95% (n = 1611). Attitude toward donation is favorable in 72% (n = 1155) of respondents with 8% (n = 122) against and 20% (n = 334) undecided. Attitude is more favorable than in the control group (72% vs. 63%; p < 0.0001). The following factors influence this attitude: (1) attitude toward the donation of a family member's organs (OR = 4.891); (2) having discussed the matter of organ donation within the family (OR = 2.513); (3) a willingness to accept an autopsy if it were necessary (OR = 1.706); (4) having no concern about the mutilation of the deceased donor (OR = 3.294); (5) having a partner who is in favor of donation (OR = 2.786) and (6) a respondent's belief that he or she might need a transplant in the future (OR = 2.243). The attitude of this population is more positive than in the native Spanish population and is determined by many psychosocial factors.     

Mechanical strain stimulates osteoblast proliferation through the estrogen receptor in males as well as females.

Mechanical strain, testosterone, and estrogen all stimulate proliferation of primary cultures of male rat long bone (LOB)-derived osteoblast-like cells as determined by [3H]thymidine incorporation. The maximum proliferative effect of a single period of mechanical strain (3400 microepsilon, 1 Hz, and 600 cycles) is additional to that of testosterone (10(-8) M) or estrogen (10(-8) M). The cells' proliferative response to strain is abolished both by concentrations of tamoxifen that cause proliferation (10(-8) M) and by those that have no effect (10(-6) M). Strain-related proliferation also is reduced by the estrogen antagonist ICI 182,780 (10(-8) M) but is unaffected by the androgen receptor antagonist hydroxyflutamide (10(-7) M). Tamoxifen, ICI 182,780, and the aromatase inhibitor 4-dihydroandrostenedione, at concentrations that have no effect on basal proliferation, significantly reduce the proliferative effect of the aromatizable androgen testosterone but not that of the nonaromatizable androgen 5alpha-dihydrotestosterone. Hydroxyflutamide, at a concentration that has no effect on basal proliferation (10(-7) M), eliminates the proliferative effect of 5alpha-dihydro-testosterone but had no significant effect on that caused by testosterone. Proliferation associated with strain is blocked by neutralizing antibody to insulin-like growth factor II (IGF-II) but not by antibody to IGF-I. Proliferation associated with testosterone is blocked by neutralizing antibody to IGF-I but is unaffected by antibody to IGF-II. These data suggest that in rat osteoblast-like cells from males, as from females, strain-related proliferation is mediated through the estrogen receptor (ER) in a manner that does not compete with estrogen but that can be blocked by ER modulators. Proliferation associated with testosterone appears to follow its aromatization to estrogen and is mediated through the ER, whereas proliferation associated with 5alpha-dihydrotestosterone is mediated by the androgen receptor. Strain-related proliferation in males, as in females, is mediated by IGF-II, whereas proliferation associated with estrogen and testosterone is mediated by IGF-I.     

SAMMA induces premature human acrosomal loss by Ca2+ signaling dysregulation

SAMMA is licensed for development as a contraceptive microbicide. Understanding mechanisms of its biological activity is prerequisite to designing more active second generation products. This study examined Ca(2+) involvement in SAMMA-induced premature acrosomal loss (SAL) in noncapacitated human spermatozoa. SAMMA causes acrosomal loss (AL) in a dose-dependent manner (ED(50) = 0.25 microg/mL). SAL requires extracellular Ca(2+) (ED(50) = 85 microM). SAL is inhibited by verapamil (nonspecific voltage-dependent Ca(2+) channel blocker; IC(50) = 0.4 microM), diphenylhydantoin and NiCl(2) (T-type [Ca(v)3.x] channel blockers; IC(50) 210 microM and 75 microM, respectively). Verapamil blockade of L-type (Ca(v)1.x) channels is use-dependent; activated channels are more sensitive to inhibition. However, verapamil inhibition of SAL does not increase after repeated SAMMA stimulation. SAL is unaffected by 10 microM nifedipine (selective L-type channel blocker). This contrasts to 40% inhibition (P < .001) of AL induced by 1 microM thapsigargin (Ca(2+)-ATPase inhibitor; releases intracellular Ca(2+) stores, promotes capacitative Ca(2+) entry). SAL is unaffected by 1 microM BAPTA-AM (intracellular Ca(2+) chelator), and 50 microM 2-APB (blocks InsP3 receptors and store-operated channels). This contrasts with thapsigargin-induced AL, inhibited nearly 65% by BAPTA-AM (P < .005) and 91% by 2-APB (P, .001). The results suggest that SAL is mediated by Ca(2+) entry through channels pharmacologically similar to the T-type (Ca(v)3.2) class. This process appears distinct from that caused by physiological stimuli such as progesterone or zona pellucida-derived proteins. SAMMA's contraceptive activity may be caused by induction of premature AL through dysregulation of Ca(2+) signaling.     

Effect of premedication on the induction dose of thiopentone in children

The effective dose of thiopentone in 90% ( ED90 ) of unpremedicated children is 10.5 mg/kg. This is significantly greater (p less than 0.01) than in premedicated children. The ED90 in children premedicated with TDP (a mixture of trimeprazine , droperidol and physeptone with atropine) is 4.2 mg/kg which is significantly less (p less than 0.05) than with trimeprazine and atropine ( ED90 5.2 mg/kg) or papaveretum and hyoscine ( ED90 5.0 mg/kg).     

Neonatal hypercalcemia

The causes of hypercalcemia during the neonatal period are varied. Diagnosis is based on the plasma levels of parathyroid hormone (PTH). (a) PTH in plasma is diminished; exogenous o r endogenous calcium overloading is suspected. (b) PTH in plasma is increased; hyperparathyroidism caused by homozygous or heterozygousloss-of-function mutations in the CaR gene is suspected. (c) PTH i n plasma is normal; low or normal urinary calcium excretion (i.e.relative hypocalciuria) and normal PTH plasma levelsare relevant findings of familial hypocalciuric hypercalcemia (FHH) syndrome.     

A decision for the strategy of treatment of patients with chronic calculous cholecystitis in the elderly and senile age

The article presents the material on treatment of 515 elderly patients with chronic calculous cholecystitis. According to the developed strategy of planned surgical treatment the patients were divided into five groups: (1) The operation is contraindicated due to high operative risk; (2) Laparoscopic cholecystectomy is possible; (3) Combined operation is possible; (4) Transition from laparoscopic to laparotomic access is indicated due to intraoperative problems; (5) By the data of preoperative examination only laparotomic access is possible.     

Correlation of oxygen delivery with central venous oxygen saturation, mean arterial pressure and heart rate in piglets

BACKGROUND: Accurate assessment and monitoring of the cardiocirculatory function is essential during major pediatric and pediatric cardiac surgery. Invasive monitoring of cardiac output and oxygen delivery (DO(2)) is expensive and sometimes associated with adverse events. Measurement of central venous oxygen saturation (ScvO(2)) is less invasive and may reflect the DO(2). Therefore, we investigated the correlation of ScvO(2) with cardiac index (CI) and DO(2) and in comparison the more common monitored parameters heart rate (HR) and mean arterial pressure (MAP) with DO(2) in an animal experimental setting. METHODS: In five fasted, anesthetized and mechanically ventilated piglets CI (transpulmonary thermodilution), venous and arterial blood gases, HR and MAP was measured during normal conditions, volume loading, inotropic support, and exsanguination. RESULTS: In the five piglets 168 measurements could be performed. In a wide hemodynamic range (CI 22-335 ml x kg(-1) min(-1)) we found significant correlations of ScvO(2) with DO(2)) (r(2) = 0.91, P < 0.0001) and CI (r(2) = 0.88, P < 0.0001) and also between DO(2) and MAP (r = 0.86, P < 0.0001) and HR (r = 0.19, P < 0.05). CONCLUSIONS: ScvO(2) is a better parameter for indirect estimation of DO(2) than MAP and heart rate. Measurement of ScvO(2) is simple and does not necessitate additional invasive techniques. In the clinical setting ScvO(2) should be used in combination with other standard vital parameters, i.e. MAP, central venous pressure, lactate, base excess, and urine output.     

Fasting uric acid and phosphate in urine and plasma of renal calcium-stone formers.

Clearance experiments in calcium-stone patients (n = 60) and controls (n = 60) demonstrated significantly higher urinary uric acid (UA) in younger (less 40 years) stone patients than controls (median: 480 vs. 351 mug/min) but not in older (greater than 40 years) patients. Serum UA and urinary oxypurines were comparable in health and stone disease. Conversely urinary phosphate was significantly lower in younger patients than matched controls (males: 224 vs. 304 mug) and presumably is responsible for the more alkaline pH. It is suggested that calcium-stone formation in humans is represented by two different populations.