No clear evidence of ACEi efficacy on the progression of chronic kidney disease in children with hypodysplastic nephropathy--report from the ItalKid Project database.

BACKGROUND: Chronic kidney diseases (CKD) tend to progress to end-stage renal failure (ESRF). As it has been demonstrated that angiotensin-converting enzyme inhibitors (ACEi) have a renoprotective effect in adults with proteinuric disease and may be effective in reducing hyperfiltration and proteinuria, they are also frequently used as anti-progression agents in paediatric patients with CKD despite the lack of data confirming their role in the nephropathies peculiar to children. The aim of this study was to investigate whether patients with hypodysplastic CKD (the most common cause of ESRF in children) treated with ACEi show a significantly slower decline in creatinine clearance (Ccr). METHODS: The analysis was based on the information available in the database of the ItalKid Project, a nationwide, population-based registry of chronic renal insufficiency (CRI) in children in Italy. Of the 822 patients with CRI due to hypodysplasia, we selected those who had been continuously treated with ACEi; the control patients were identified from the same diagnostic group and matched for gender, age and baseline Ccr. RESULTS: Progression was analysed as the slope of Ccr in a total of 164 patients: 41 cases and 123 matched controls. There were no significant between-group differences in blood pressure, duration of follow-up or pre-study slope of Ccr (-0.31+/-2.26 vs -0.33+/-3.58 ml/min/1.73 m2/year; P=NS). After an average of 4.9+/-2.3 years, the mean slope of Ccr was 40% lower in the ACEi-treated cases in comparison to controls (-1.08+/-2.08 vs -1.80+/-4.42 ml/min/1.73 m2/year), however, this difference was not statistically significant (P=0.31). CONCLUSIONS: We conclude that ACEi treatment does not significantly modify the naturally progressive course of hypodysplastic nephropathy in children and further studies are necessary before such treatment is routinely proposed for anti-progression purposes in children with CKD.     

Reproductive Health in Eastern Europe: A Collaborative Training Project in Romania

Since the fall of the Berlin Wall, fundamental political changes in eastern Europe have affected the Soviet-style health care systems that formerly provided basic care for everyone. Many of these systems have collapsed, and the new systems of social insurance that have replaced them often are inadequate. Advanced Training in Reproductive Health in Romania aimed to create an authority in family planning and reproductive health in selected Romanian university centers and to improve training and research capabilities. Initially, the project had 2 main goals: to provide advanced training in reproductive health and family planning to Romanian obstetrics-gynecology specialists from the main university centers-which would allow them to train other physicians (obstetricians, gynecologists, and general practitioners) and medical students-and to develop, test, and finalize specific training materials in Romanian to be used by the new trainers.     

Supernatants from Macrophages Stimulated with Microcystin‐LR Induce Electrogenic Intestinal Response in Rabbit Ileum

Microcystin‐LR is a cyclic heptapeptide hepatotoxin produced by the cyanobacterium Microcystis aeruginosa. This microorganism often forms toxic blooms in freshwater lakes and reservoirs for drinking water supply, producing serious disorders in humans and animals. Some have suggested that certain biological activities of microcystin may depend upon the stimulation of immune cells. Therefore, the aims of this research were to examine electrogenic intestinal secretion, in vitro, caused by the supernatants from macrophages stimulated with microcystin‐LR, as well as to investigate the presence of interleukin‐1β and tumour necrosis factor‐α in these supernatants. We found that the supernatants of macrophages stimulated with microcystin‐LR (0.1, 0.3 and 1.0 μg/ml) caused electrogenic intestinal effects (change in short‐circuit currents (Δ SCC)=57.6, 50.8 and 73.3, respectively, versus control=19.6 μA.cm^?2) in a time‐dependent way (microcystin‐LR (1.0 μg/ml)=63.2, 108.8, 120.4 and 132.3 μA.cm^?2 at time 0, 40, 50 and 60 min., respectively). In addition, the intestinal secretory activity present in these supernatants was blocked (57%) by the prior treatment of macrophages with dexamethasone. We also demonstrated that microcystin‐LR (0.1, 0.3 and 1.0 μg/ml) is capable of stimulating the synthesis of tumour necrosis factor‐α (375.4, 369.0 and 610.8 pg/ml, respectively, versus control=165.0 pg/ml) and interleukin‐1β (198.9, 189.3 and 522.1 pg/ml, respectively, versus control=39.7 pg/ml). These findings demonstrate that microcystin‐LR induces the release of interleukin‐1β and tumour necrosis factor‐α by peritoneal macrophages in vitro, and that the supernatants from these macrophages induce electrogenic secretion in rabbit ileal mucosa.     

Plasma levels of amyloid β 40 and 42 are independent from ApoE genotype and mental retardation in down syndrome

In Down syndrome (DS) brain an early, selective accumulation of amyloid β (Aβ) peptides ending at residue 42 (Aβ42) occurs. Whether this event depends on an altered processing of amyloid beta precursor protein (APP) or on defective clearance is uncertain. To investigate this issue, we measured Aβ species 40 and 42 in plasma from 61 patients with DS, 77 age‐matched normal controls, and 55 mentally retarded subjects without chromosomal abnormalities. The Aβ 40 and 42 plasma levels were then correlated with apolipoprotein E (apoE) genotypes in all groups of cases, and with I.Q. and Mini Mental Status Examination values in DS subjects. Both Aβ species were significantly elevated in DS compared to control groups, and the extent of their increase reflects that expected from APP gene overexpression. Plasma levels of Aβ 40 and 42 did not correlate with apoE genotypes in DS and control cases, and with the extent of mental retardation in DS subjects. The results indicate that accumulation and clearance of plasma and cerebral Aβ are regulated by different and independent factors. Am. J. Med. Genet. 95:224–228, 2000. © 2000 Wiley‐Liss, Inc.     

Palpatory Method Used to Identify the Recurrent Laryngeal Nerve during Thyroidectomy

The major complication of thyroid surgery, occurring in 1% to 6% of cases, is injury to the recurrent laryngeal nerve (RLN). A simple method to identify the RLN during thyroid surgery is described by the authors. It consists in palpation of the nerve caudally to the inferior pole of the thyroid, after the nerve has been made taut by the upward and medial traction of the thyroid gland. This method was used on 47 human cadavers and 45 patients with benign thyroid diseases. It made it possible to identify the RLN in all of the cadavers and 52 of the 55 identifications during 45 thyroidectomies (in 10 total thyroidectomies the identification was bilateral). Laryngeal motility was normal in all patients at postoperative laryngoscopy. Using the palpation before dissection in the region of the inferior thyroid artery, the traditional viewing method became easier and safer, reducing the risk of injury where it is most likely to occur to the nerve.     

Defining the role of TORC1/2 in multiple myeloma

Mammalian target of rapamycin (mTOR) is a downstream serine/threonine kinase of the PI3K/Akt pathway that integrates signals from the tumor microenvironment to regulate multiple cellular processes. Rapamycin and its analogs have not shown significant activity in multiple myeloma (MM), likely because of the lack of inhibition of TORC2. In the present study, we investigated the baseline activity of the PI3K/Akt/mTOR pathway TORC1/2 in MM cell lines with different genetic abnormalities. TORC1/2 knock-down led to significant inhibition of the proliferation of MM cells, even in the presence of BM stromal cells. We also tested INK128, a dual TORC1/2 inhibitor, as a new therapeutic agent against these MM cell lines. We showed that dual TORC1/2 inhibition is much more active than TORC1 inhibition alone (rapamycin), even in the presence of cytokines or stromal cells. In vitro and in vivo studies showed that p-4EBP1 and p-Akt inhibition could be predictive markers of TORC2 inhibition in MM cell lines. Dual TORC1/2 inhibition showed better inhibition of adhesion to BM microenvironmental cells and inhibition of homing in vivo. These studies form the basis for further clinical testing of TORC1/2 inhibitors in MM.     

Serum Vasopressin Response in Patients With Intradialytic Hypotension: A Pilot Study

Background and Objectives: Arginine vasopressin (AVP), an endogenous hormone with vasopressor properties, may be inadequately secreted during episodes of intradialytic hypotension (IDH).Design, Setting, Participants, and Measurements: To evaluate this, we performed a prospective, observational pilot study of 20 chronic hemodialysis patients assessing the baseline AVP level and trend of AVP with ultrafiltration in patients with a diagnosis of IDH compared with patients without IDH. Ten symptomatic IDH patients and 10 controls were enrolled and matched for age, gender, and dialysis vintage. AVP levels were obtained hourly throughout the dialysis session and during hypotensive episodes.Results: We observed that IDH patients experienced greater decreases in both systolic and diastolic blood pressure during the dialysis session despite equivalent ultrafiltration in both groups. AVP concentration did not increase in the IDH patients (5.0 ± 1.8) compared with controls (6.4 ± 6.0) (P = 0.5) despite hypotensive events.Conclusions: This study suggests that symptomatic IDH patients are unable to mount an appropriate increase in AVP secretion in the setting of hypotension. These findings support the possibility of AVP as a mechanism driven therapy for patients with symptomatic IDH.Intradialytic hypotension (IDH) is a major complication seen during hemodialysis, occurring in approximately 10% to 30% of treatments and is associated with significant morbidity and mortality (1). Cramps, nausea, vomiting, dizziness, and fatigue are common symptoms.Life-threatening events, such as cerebrovascular accident, syncope, myocardial ischemia, and arrhythmia, may also occur. The etiology of hypotension occurring during dialysis is thought to be multifactorial: 1) autonomic dysfunction in uremia, 2) acute decreases in plasma osmolality, 3) decreased vascular reactivity to vasopressor agents and overproduction of vasodilators, and 4) underlying cardiac disease (2,3). In addition, common comorbidities associated with end-stage renal disease (ESRD), such as diabetes mellitus, are strongly associated with autonomic dysfunction, contributing to an increased risk for IDH (4–6). Also, neurally mediated vasopressor syncope could contribute. Current therapeutic modalities for managing IDH include sodium modeling, intravenous mannitol, midodrine, and cool dialysate; however, these measures have been used with variable success and associated risks (7–13).Arginine vasopressin (AVP), an endogenous hormone synthesized in the hypothalamus and secreted by the posterior pituitary gland, is released in the setting of hyperosmolality or nonosmotic stimuli, including hypotension, hypovolemia, or nausea. AVP has been shown to increase in the setting of hypotension in septic or hypovolemic shock (14–16). In patients with autonomic insufficiency, however, AVP levels are inappropriately low to the level of hemodynamic compromise and likely related to baroreceptor dysfunction leading to decreased endogenous AVP synthesis and secretion (4,5,17). Thus, vasopressin insufficiency is thought to underlie or at the very least contribute to hypotension in these patients.The role of vasopressin insufficiency as a cause of hypotension has also been briefly considered in ESRD patients. A study in 23 hemodialysis patients published more than 10 yr ago demonstrated vasopressin insufficiency as a possible mechanism of IDH in ESRD patients (18). A recent study also demonstrated a hemodynamic benefit with subpressor doses of vasopressin in 22 hypertensive patients during hemodialysis with ultrafiltration (19). Both studies shed important insight into the role of vasopressin in hemodynamic stability. However, the older study did not use a matched normotensive control group that would allow comparison of serum AVP levels in response to reductions in blood pressure (BP). Also, the more recent publication did not study IDH patients when they measured AVP levels or examined the hemodynamic response to vasopressin infusion.This study was undertaken to evaluate the trend in AVP levels over the duration of hemodialysis in symptomatic patients with a diagnosis of IDH as compared with normotensive hemodialysis patients without IDH. In addition to verifying the data generated from the previously noted studies, we were particularly interested in the AVP response in IDH patients during frank hypotension. Understanding the serum AVP trend in symptomatic patients with IDH may assist with designing future clinical trials to treat this vexing problem.