Intravenous Alfacalcidol Once Versus Twice or Thrice Weekly in Hemodialysis Patients

Secondary hyperparathyroidism remains a serious problem in hemodialysis patients. The use of vitamin D analogs still constitutes a basis for its treatment. This study was carried out to evaluate the efficacy of intravenous administration of alfacalcidol once versus twice or thrice weekly in hemodialysis patients with secondary hyperparathyroidism. Twenty‐nine end‐stage renal disease patients maintained on hemodialysis for more than one year were included in this prospective study after signing the consent. These patients with secondary hyperparathyroidism had been on intravenous alfacalcidol twice or thrice per week and were followed up to 4 months (stage 1). Then they were shifted to intravenous alfacalcidol once weekly starting with the last total weekly intravenous dose for another 4 months (stage 2). The dose of alfacalcidol was adjusted according to intact parathyroid hormone, serum calcium and phosphorus levels, and calcium‐phosphorus product. Intact parathyroid hormone, calcium, phosphorus, calcium‐phosphorus product were measured monthly. Parathyroid ultrasound was done as a baseline and then repeated at the end of stage 1 and stage 2. The intact parathyroid hormone was reduced from 49.72 ± 2.72 pmol/L (mean ± standard error of the mean [SEM] during stage 1 to 42.13 ± 2.15 pmol/L during stage 2 (P = 0.005). Dose of alfacalcidol was reduced from 18.80 ± 1.15 µg/month (mean ± SEM) in stage 1 to 15.18 ± 1.27 µg/month in stage 2 (P = 0.008), and consequently the cost of alfacalcidol was reduced from 21.05 ± 1.25 US$/month (mean ± SEM) during stage 1 to 16.87 ± 1.40 US$/month during stage 2 (P = 0.008). Although the phosphorus level increased from 1.56 ± 0.36 mmol/L (mean ± SD) in stage 1 to 1.70 ± 0.46 mmol/ L in stage 2 (P = 0.003), and calcium‐phosphorus product increased from 3.48 ± 0.82 mmol²/L² (mean ± SD) in stage 1 to 3.76 ± 1.00 mmol²/L² in stage 2 (P = 0.017), they remained in the target levels recommended by the Kidney Disease Outcomes Quality Initiative guidelines. No serious effects were observed during stage 1 and stage 2, respectively. Intravenous alfacalcidol once weekly is effective, safe and less costly in suppressing intact parathyroid hormone compared to twice or thrice weekly administration in chronic hemodialysis patients.     

Organometallic‐Mediated Radical Polymerization: Developing Well‐Defined Complexes for Reversible Transition Metal‐Alkyl Bond Homolysis

Organometallic‐mediated radical polymerization (OMRP) has emerged as a powerful new class of living controlled radical polymerization. In order to fulfill its potential in the polymerization of vinyl acetate (VOAc) and other challenging monomers, the effects of ancillary ligands on the metal‐alkyl bond dissociation energy in OMRP reagents must be thoroughly explored. Recent results investigating structure‐activity relationships in well‐defined cobalt, iron and chromium complexes will be discussed. The involvement of radical intermediates in oxidative addition of secondary alkyls for catalytic cross‐coupling reactions catalyzed by first row transition metals will also be examined for relevant design concepts.

     

GLUT-1 is preferentially expressed in atypical endometrial hyperplasia and endometrial adenocarcinoma.

The facilitative transport of monosaccharides in human cells is accomplished by a family of transmembrane proteins, GLUT-1 to GLUT-7, that differ in their tissue distribution, affinities for specific monosaccharides, and physiologic regulation. GLUT-1, a high-affinity glucose transporter, is normally expressed in erythrocytes, the perineurium of peripheral nerves, and capillary endothelial cells of the blood-brain barrier. Although the aberrant expression of GLUT-1 has been reported in a wide spectrum of epithelial malignancies, its possible correlation with the malignant transformation of endometrial epithelium has not been clearly established. The purpose of this study was to evaluate the extent to which benign, hyperplastic, atypical, and malignant endometrial epithelia express GLUT-1. The authors examined the IHC expression of GLUT-1 in cases of proliferative endometrium (n=12), secretory endometrium (n=10), endometrial polyps (n=10), adenomyosis (n=18), simple hyperplasia (n=14), complex hyperplasia without atypia (n=17), complex hyperplasia with atypia (n=17), and adenocarcinoma (n=31). Positive staining was defined as distinct, linear membrane staining, particularly at cell-cell borders. Cells that showed only cytoplasmic staining were considered negative. The percentages of positive cells and staining intensity were assessed in a semiquantitative fashion and scored (1+ to 3+). All cases from proliferative endometrium, secretory endometrium, adenomyosis, and simple hyperplasia and 90% (9/10 cases) of the endometrial polyps were negative for GLUT-1. GLUT-1 was expressed in 24% (4/17 cases) of complex hyperplasia without atypia, 71% (12/17 cases) of complex hyperplasia with atypia, and 90% (28/31 cases) of adenocarcinomas. The extent of staining ranged from occasional positive foci to extensive multifocal staining. GLUT-1 positivity increased in intensity as the distance of tumor cells to stroma increased. The authors conclude that GLUT-1 is preferentially expressed in complex hyperplasia with atypia and in adenocarcinoma and that GLUT-1 immunostaining is useful in distinguishing benign hyperplasia from hyperplasia strongly associated with malignancy. GLUT-1-mediated glucose transport may allow hypoxic tumor cells distant from stromal blood vessels to survive through glycolysis. These data suggest that the expression of GLUT-1 transporter may be closely related to the malignant transformation of epithelial endometrial tumors by supporting their increased need for glucose metabolism.     

Molecular-based diagnosis of <Emphasis Type="Italic">Clostridium difficile</Emphasis> infection is associated with reduced mortality

Polymerase chain reaction (PCR) for the diagnosis of Clostridium difficile infection (CDI) might result in overdiagnosis. The clinical outcomes of symptomatic CDI patients diagnosed by PCR remain uncertain. We aimed to determine whether patients whose diagnosis of CDI was based on PCR had different characteristics and clinical outcomes than those diagnosed by toxin immunoassay. Consecutive CDI patients, hospitalized at Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel, between January 2013 and January 2016, were identified retrospectively and included in the study. Diagnosis of CDI was based on PCR or diagnosis by immunoassay for C. difficile toxin. The main outcome was 30- and 90-day all-cause mortality. The PCR group included 165 patients and the immunoassay group included 157 patients. In comparison to the immunoassay group, patients in the PCR group were more likely to be younger, to be independent, to undergo previous abdominal surgery, and to use laxatives. The 30-day mortality rate in the PCR group was significantly lower than that in the immunoassay group, 29/165 (18%) vs 49/157 (31%), respectively; p?=?0.028. On multivariate analysis, PCR diagnosis was associated with reduced mortality, OR 0.48 (95% CI 0.26–0.88). PCR-based diagnosis of CDI is associated with reduced all-cause mortality rates. Further studies are needed to determine the management of patients with discrepant immunoassay and PCR diagnosis of CDI.     

Stem cell implantation in the treatment of peripheral vascular disease

Treatment options of ischemic vascular disease of the lower limbs are a challenged field that necessitates new therapeutic modalities. Stem cell transplantation offers a promising achievement of therapeutic angiogenesis in patients with ischemic limbs. Our study investigated the efficacy and safety of the implantation of autologous peripheral blood mononuclear cells (PBMNCs) mobilized by granulocyte colony-stimulating factor (G-CSF) in patients with chronic limb ischemia. Twenty-four patients with chronic lower limb ischemia were enrolled and divided randomly into two groups: the implanted group (n?=?12) and the control group (n?=?12). In the implanted group, the patients received subcutaneous injections of recombinant human G-CSF (300 μg/day) for 5 days to mobilize stem/progenitor cells, and their PBMNCs were harvested using a blood cell separator and were implanted by multiple intramuscular injections into the ischemic limbs, while the control group was injected with sterile saline and received conventional medical treatment. All patients were followed up after 12 weeks. At the end of the follow-up period, the main manifestations significantly improved in patients of the implanted group compared with the control group. The mean of rest pain decreased from the baseline level of 6.42?±?2.15 to 1.67?±?0.389 (P?<?0.001). The mean of pain-free walking distance increased from 25.00?±?8.90 to 409.00?±?104.00 (P?<?0.001). The mean ankle–brachial pressure index increased from 0.45?±?0.12 to 0.79?±?0.38 (P?=?0.005). Seven out of nine limb ulcers and wounds (77.8 %) of implanted patients healed after cell implantation. Two lower limb amputations (16.67 %) occurred in the implanted patients. In contrast, eight control patients (66.67 %) had to receive lower limb amputation. Implantation of stem/progenitor cells is a feasible and readily available effective strategy for therapeutic angiogenesis in patients with chronic limb ischemia.     

Prognostic significance of alterations in KRAS isoforms KRAS‐4A/4B and KRAS mutations in colorectal carcinoma

Somatic KRAS mutation is an early well‐known event in colorectal carcinogenesis but a complete understanding of RAS function and dysfunction in colorectal cancer is still to come. Our aim was to study the incidence of KRAS mutation; KRAS splice variants: KRAS4A and KRAS4B; and their relationships with various clinico‐pathological characteristics in colorectal cancer (CRC).In this study, 285 CRC cases were analysed for KRAS mutation by direct DNA sequencing followed by immunohistochemical analysis after validation with real‐time PCR assay, to study the protein expression of KRAS4A and ‐4B isoforms. KRAS gene mutations were seen in 80/285 CRCs (28.1%) and of the mutated cases, the majority of the mutations were seen in codon 12 (81.2%) as opposed to codon 13 (18.8%). CRCs with KRAS mutations were associated with a poor overall survival (p = 0 . 0009). Furthermore, KRAS mutations at codon 12 were associated with a poor overall survival of 64.4% at 5 years compared with a 5‐year overall survival of 75.8% and 78.2% with codon 13 mutation and absence of KRAS mutations, respectively (p = 0 . 0025). KRAS4A protein expression was predominantly seen in the cytoplasm, while KRAS4B protein was nuclear. KRAS4A overexpression was significantly associated with left colon, histology subtype of adenocarcinoma, p27kip1, and cleaved caspase3 expression. Interestingly, KRAS4A overexpression was associated with a better overall survival (p = 0 . 0053). On the other hand, KRAS4B overexpression (33.2%) was significantly associated with larger tumour size (p = 0 . 0234) and inversely correlated with p27kip1 protein (p = 0 . 0159). Both KRAS mutation and KRAS4A were independent prognostic markers in a multivariate analysis with age, gender, stage, differentiation, and MSI status. Our results highlight the differential role of KRAS isoforms in CRC, their utility as a prognostic biomarker, and underline the importance of KRAS alterations as a potential therapeutic target for CRC. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Congenital esophageal stenosis associated with esophageal atresia: new concepts

Congenital esophageal stenosis (CES) is suspected by a fixed intrinsic narrowing of the esophagus that affects the normal swallowing mechanism. The diagnosis is only confirmed by histopathologic picture, which may show fibromuscular disease (FMD) or tracheobronchial remnants (TBR). The latter involves ciliated pseudo stratified columnar epithelium, seromucous glands or cartilage each alone or in combination. The aim of this study is to document the usefulness of histologic picture of surgical specimens obtained from the lower esophageal pouch (LEP) during primary repair in detecting cases of CES associated with esophageal atresia (EA) with or without tracheoesophageal fistula (TEF). Over an 8-year period, 57 consecutive cases operated upon for EA with or without TEF were subjected for histologic examination of surgical specimens obtained from the tip of the LEP. Cases that histologically showed FMD or TBR were included. The usefulness of this histologic picture as a diagnostic and therapeutic aid is assessed. Methods of treatment and outcome were also reviewed. Eight patients out of 57 (14%) had a histologic picture suggestive of CES, two with FMD, four with TBR without cartilage and two with cartilage. Out of 57 patients, 23 developed strictures, six of them had positive biopsies suggestive of CES. One patient with TBR without cartilage did not have stricture. Another case of pure atresia had LEP resection and gastric pull up showed cartilage involving the whole lower esophagus. Excluding the case of pure EA with gastric pull up, all patients suffered from feeding problems and recurrent aspiration. Fluoroscopic barium studies showed late onset minor dysmotility in five patients and late onset major dysmotility in two. All cases studied showed significant gastro-esophageal reflux (GER). Stricture was seen at the anastomotic site extending distally in the two fibromuscular cases and one case with cartilage, at the anastomotic site in three cases with TBR without cartilage. Anti reflux surgical procedures were performed in four patients without benefit in two patients with major dysmotility. Dilatation was successful in the three patients with TBR without cartilage. One patient with cartilage had resection of the anastomotic site and required frequent dilatations and is now doing well. A case of FMD did not improve after frequent dilatations and myotomy together with Nissen’s fundoplication and required resection while the other case of FMD responded partially to dilatations. Cartilage in cases of CES requires surgical resection. Those with TBR without cartilage may not develop stricture. If stricture develops, it responds well to dilatation and patients have good clinical outcomes. Unlike isolated CES, GER is a significant feature in CES with EA. Anti reflux procedures should be avoided before definitive surgery for the stricture and if necessary a partial wrap with gastrostomy is recommended. CES should be considered in the etiology of anastomotic stricture. Taking a surgical specimen routinely from the tip of the LEP during primary esophageal repair for histologic studies is highly recommended.     

“Inorganic and Organometallic Clusters and Polymers: Syntheses and Applications” Symposium

Conference Reports: This section contains reports on topical conferences. Reports are usually written at the request of the editorial office, but unsolicited contributions are also welcome. Suggestions should be sent to the editorial office of the Macromolecular journals, preferably by E‐mail to macromol@wiley‐vch.de.     

HCV associated glomerulopathy in Egyptian patients: clinicopathological analysis

BACKGROUND: Hepatitis C virus (HCV) infection in Egypt has reached an epidemic proportion and is associated with many extra hepatic manifestations; Glomerulonephritis (GN) is one of the most consequences of HCV infection often resulting in end stage renal disease in some cases. Detection of viral genome or particles within the kidney biopsies from HCV-infected patients has proven to be difficult. Histological characterization of renal lesions still represents a major challenge. The aim of our work was to describe the histological pattern of HCV-associated nephropathy. METHODS: Fifty Patients--out of 233--presented to Mansoura Urology and Nephrology clinic with manifestations of glomerular disease were screened for HCV antibodies by a 3rd generation ELISA test. Those tested positive for HCV antibodies were confirmed by PCR for HCV-RNA and subjected to more detailed clinical, biochemical and histological study. Kidney biopsies and in appropriate cases liver biopsies were examined by LM and electron microscopy (EM). RESULTS: Histological study of renal biopsies revealed membranoproliferative (MPGN) type 1 to be the most common lesion encountered (54%), followed by focal segmental glomerulosclerosis (FSGS) (24%), mesangioproliferative GN (18%), membranous nephropathy (MN) (4%) in that order. EM examinations of renal biopsies were successful in identifying HCV like particles in frozen renal tissue. CONCLUSION: HCV-associated glomerulopathy is a distinct category of glomerulonephritis. Results of LM showed some peculiar features. In addition, we were successful in location and detection of HCV particles in renal tissues by EM.