Education and evidence are needed to improve neonatal parenteral nutrition practice

BACKGROUND: Parenteral nutrition (PN) is an essential component of neonatal care for those infants who are unable to tolerate adequate enteral feeding. Its use is not without complications such as biochemical derangements, sepsis, thrombosis, extravasation of fluid, and death. Such complications can be reduced by meticulous management of PN in response to biochemical abnormalities, nutrition teams, policies to reduce sepsis, and staff training to be more aware of pericardial and pleural effusions. We ascertained the current practices in PN administration and management of complications in all neonatal units with 6 or more intensive care cots in England, Scotland, and Wales. METHODS: Telephone survey of middle grade doctors (Specialist Registrars) working in all 57 neonatal units was conducted using a standard questionnaire. The questions were focused around practical issues and problems that are commonly encountered with PN practice, including composition, complications, and nutrition support. RESULTS: A response was obtained from 95% of the units contacted and a wide range of practices observed. Thirty-three percent of units delay protein (nitrogen) until > 48 hours after birth. Lipid infusions are stopped in proven or suspected sepsis in just over half of all units. In hyperglycemic preterm infants, 25 units decrease their glucose infusion, 21 commence insulin, and 8 have no policy. Two thirds of middle grade doctors had no idea of the amount of protein or nitrogen to prescribe for these infants, and only one-third involve a pharmacist in the PN prescribing. CONCLUSIONS: There is a diverse practice and knowledge with a concerning lack of education in nutrition among the middle grade doctors in England, Scotland, and Wales. The management of common complications such as sepsis and hyperglycemia are highly variable. Improved staff training and production of unified evidence-based guidelines need urgent consideration.     

Interaction of nucleoside analogues with nucleoside transporters in rat brain endothelial cells

A number of nucleoside analogues, consisting of antiviral compounds and agents designed as adenosine A1 receptor agonists, were examined for nucleoside transporter affinity using an in vitro model of the blood-brain barrier (BBB), the rat brain endothelial cell line, RBE4. Structure-activity relationships (SAR) were also performed to identify the key structural requirements for transporter recognition and the suitability of these systems for carrier-mediated strategies to deliver therapeutics across the BBB. Adenosine receptor agonists did not show transport affinity for concentrative nucleoside carriers, but exhibited affinity for equilibrative systems (Ki=10.8-97.9 microM) within the range of Kms for natural substrates. However, none of the antiviral compounds tested in this study showed affinity for either class of nucleoside transporter. SAR studies suggest that the hydroxyl group located at the 3'-position of the ribose moiety is an essential requirement for transporter recognition. This may explain the inability of nucleoside derived anti-viral compounds to use these systems despite the significant structural homology with naturally occurring nucleosides. Sites have also been identified which accommodate structural additions with retention of carrier affinity, suggesting that compounds which fail to penetrate the BBB could be attached to these sites for carrier-mediated delivery using a prodrug strategy.     

Pioglitazone is effective therapy for elderly patients with type 2 diabetes mellitus

BACKGROUND: Pioglitazone as monotherapy and in combination with sulfonylurea, metformin, or insulin has consistently demonstrated improved glycaemic and lipid parameters in patients with type 2 diabetes mellitus. OBJECTIVE: We performed a subanalysis to examine the effect of pioglitazone on glycaemia and lipids in patients <65 and > or =65 years of age in two double-blind, placebo-controlled monotherapy studies and in three separate multi-centre trials. METHOD: In Study 1, 197 patients were randomised to receive pioglitazone 30 mg/day or placebo for 16 weeks. Study 2 was a forced dose-titration trial in patients randomised to receive pioglitazone 7.5/15/30 mg/day, pioglitazone 15/30/45 mg/day, or placebo daily for 26 weeks. Each of the lower dosages was given for at least 4 weeks and the highest dosage for 16 weeks. The three combination studies evaluated efficacy of pioglitazone 30 or 45 mg/day over a 24-week period in combination with sulfonylureas, metformin, or insulin. RESULTS: In both placebo-controlled monotherapy studies, at 16 weeks, and at maximum pioglitazone dosage, 0.53-0.55% and 0.57-1.27% mean reductions from baseline in glycosylated haemoglobin (HbA(1c)) were seen in patients aged <65 (n = 225) and > or =65 (n = 45) years, respectively. There were statistically significant differences between the placebo and pioglitazone groups in each age cohort. Similar effects were observed in fasting plasma glucose (FPG) levels, with 2.03-2.59 mmol/L and 3.20-4.44 mmol/L mean reductions from baseline, respectively, which were significantly different from the changes in the placebo group, but there was no difference between pioglitazone groups. At treatment endpoint in combination trials, pioglitazone added to sulfonylurea produced a mean decrease in HbA(1c) of 0.78-1.61%, and 1.64-1.96% in patients aged <65 (n = 557) and > or =65 (n = 115) years, respectively. Pioglitazone added to metformin produced a mean decrease in HbA(1c) of 0.78-1.03% and 0.78-0.98% in patients aged <65 (n = 686) and > or =65 (n = 112) years, respectively. Pioglitazone added to insulin produced a mean decrease in HbA(1c) of 1.13-1.37% and 1.39-1.66% in patients aged <65 (n = 500) and > or =65 (n = 156) years, respectively. In patients aged > or =65 years, hypoglycaemia was observed in 1 of 14 patients and in 0 of 13 patients in the two monotherapy studies. In the combination studies, the incidence of hypoglycaemia among patients aged > or =65 years was as follows: 26.7-28.8% combined with sulfonylurea; 0-4.4% combined with metformin; and 53.4-56.4% combined with insulin. CONCLUSION: Pioglitazone monotherapy, or added to a sulfonylurea, metformin, or insulin demonstrated no significant differences in effectiveness while exhibiting similar adverse events in patients aged > or =65 years compared with patients aged <65 years. Well-controlled randomised clinical trials are recommended to confirm the impact of pioglitazone therapy on the glycaemic and lipid control in elderly patients with type 2 diabetes.     

Waldenstrom macroglobulinemia involving extramedullary sites: morphologic and immunophenotypic findings in 44 patients

Waldenstrom macroglobulinemia (WM) is a clinicopathologic syndrome in which a B-cell neoplasm involving the bone marrow, usually lymphoplasmacytic lymphoma (LPL), is associated with immunoglobulin M paraprotein in the serum. Extramedullary involvement occurs in a subset of patients and is infrequently examined histologically. The files of M.D. Anderson Cancer Center were searched for patients with WM who underwent biopsy of one or more extramedullary sites during the course of disease. Each biopsy specimen was classified using the criteria of the World Health Organization classification. The study group consisted of 44 patients (26 men and 18 women), with a total of 51 specimens obtained from lymph nodes (n = 36), soft tissue (n = 4), spleen (n = 3), skin (n = 2), lung (n = 2), tonsils (n = 1), colon (n = 1), liver (n = 1), and gallbladder (n = 1). Lymphoplasmacytic lymphoma was the most common histologic type, in 40 (78%) samples. This category was morphologically heterogeneous and was further subclassified as lymphoplasmacytic (n = 21), lymphoplasmacytoid (n = 18), and polymorphous (n = 1). Four of these LPL cases morphologically resembled marginal zone B-cell lymphoma. Four additional samples were involved by diffuse large B-cell lymphoma, probably transformed from LPL. Three more samples were involved by LPL with unusual features: two were CD5-positive and one was a composite tumor with classical Hodgkin's disease. Other categories of lymphoma in this group of patients with WM included small lymphocytic lymphoma/chronic lymphocytic leukemia (n = 2), mantle cell lymphoma (n = 1), and follicular lymphoma (n = 1). Waldenstrom macroglobulinemia is most commonly associated with LPL but can rarely occur with other types of B-cell lymphoma. Lymphoplasmacytic lymphoma in patients with WM is morphologically heterogeneous and can be indistinguishable from marginal zone B-cell lymphoma. CD5+ B-cell lymphomas with features otherwise typical of LPL are rare, and we think these tumors are part of the spectrum of LPL.     

Measurement of Surgical Dexterity Using Motion Analysis of Simple Bench Tasks

Abstract The possibility of using quantitative motion analysis for objective assessment of simple surgical dexterity is investigated using the Imperial College Surgical Assessment Device (ICSAD) with qualitative analysis undertaken by inspection. Bench-top knot tying and suturing skills were performed and examined for the ability to discriminate between surgeons of varying experience. These exercises were found to discriminate significantly between junior and senior surgeons in terms of both time taken and the number of movements required. The relation between time and motion was found to be variable depending on what skill was being undertaken: simple suturing, suturing at depth, or knot tying (1.71 vs. 1.86 vs. 2.36; p = 0.002 for 1 vs. 2; p < 0.001 for others). When the number of movements in a minute (standardized movements per minute) were considered, both groups were found to work at a similar rate, depending on the task, implying that the more experienced surgeon is more economical, performing the same exercise with fewer moves rather than with higher speed. Motion analysis exhibits face and construct validity and is a reliable assessment of simple surgical dexterity. Its use for objective assessment of dexterity and competence should be encouraged.     

Development of a HPLC method for the determination of cyclosporin-A in rat blood and plasma using naproxen as an internal standard

An isocratic reversed phase high-performance liquid chromatographic (HPLC) method with ultraviolet detection at 205 nm has been developed for the determination of cyclosporin-A (CyA) in rat blood and plasma. Naproxen was successfully used as an internal standard. Blood or plasma samples were pretreated by liquid–liquid extraction with diethyl ether. The ether extract was evaporated and the residue was reconstituted in acetonitrile–0.04 M monobasic potassium phosphate buffer (pH 2.5) solvent mixture. After washing with n-hexane, 30 μl of the reconstituted solution was injected into HPLC system. Good chromatographic separation between CyA and internal standard peaks was achieved by using a stainless steel analytical column packed with 4 μm Nova-Pak Phenyl material. The system was operated at 75 °C using a mobile phase consisting of acetonitrile–0.04 M monobasic potassium phosphate (pH 2.5) (65:35 v/v) at a flow rate of 1 ml/min. The calibration curve for CyA in rat blood was linear over the tested concentration range of 0.0033–0.0166 M with a correlation coefficient of 0.989. For rat plasma, the range of the concentrations tested were between 0.002 and 0.0166 M and showed linearity with a correlation coefficient of 0.953. The intra- and inter-run precision and accuracy results were 1.24–21.87 and 3.1–12.23%, respectively. The low volume of blood or plasma needed (200 μl), simplicity of the extraction process, short run time (5 min) and low injection volume (30 μl) make this method suitable for quick and routine analysis.     

Salbutamol sulfate suppositories: influence of formulation on physical parameters and stability

PURPOSE: To prepare and evaluate a suppository dosage form of salbutamol sulfate. The prepared formulae with and without different concentrations of gels were tested for hardness, melting time, content uniformity, and drug release. The stability of some of the selected formulae was assessed. METHODS: Salbutamol sulfate was formulated as a rectal suppository with emulsifying fatty bases (suppocire and witepsol) and water-soluble bases (PEG) adopting the molding from a melt technique. Physical characteristics and dissolution profiles of the prepared formulations were determined as the responses. The effects of adding gels, methyl cellulose (MC), and Eudispert (Eud) and their concentrations (1, 3, and 6%) on these responses were also investigated. Formulations showing high rank order were scaled up for shelf-life stability study for one year. RESULTS: The results showed that all the investigated formulae have acceptable physical characteristics with respect to hardness, melting time (except F7), and uniformity of drug content. The amount of drug dissolved in 100 min of dissolution time was inversely affected by the melting point of the fatty base. The release from PEG bases was found to be molecular weight dependent. Addition of 1% MC or Eud gel increased the release from all the investigated formulae. Increasing gel concentration to 3% then to 6% showed different effects on the release. The degradation of salbutamol sulfate in the investigated formulae was found to be a first-order reaction. CONCLUSIONS: Rectal suppository of salbutamol sulfate could be prepared as an alternative to the oral dosage form to circumvent the first-pass metabolism.     

Orbital and periorbital myofibromas in childhood: two case reports

PURPOSE: Infantile myofibromatosis is an uncommon tumor that occurs rarely in the periorbit and orbit. This article reports two cases of infantile myofibromatosis of the orbital adnexa and describes the associated clinical, histopathologic, and immunohistochemical findings. DESIGN: Two retrospective, interventional case reports with clinicopathologic correlation. INTERVENTION: Treatment consisted of excision of the tumors. MAIN OUTCOME MEASURES: Histologic and immunohistochemical evaluation and clinical evaluation for tumor recurrence. RESULTS: The first patient was a newborn male with a large tumor extending from his eyelid that was excised at day 2 of life. Histologic and immunohistochemistry analyses were used to make a diagnosis of infantile myofibromatosis. He remains disease free at age 7 years. The second case was a 6-year-old boy with a 1-month history of proptosis resulting from an orbital mass. Incisional biopsy revealed a tumor consistent with infantile myofibromatosis. He remains tumor free 12 months after complete gross surgical resection. CONCLUSIONS: Infantile myofibromatosis is an uncommon tumor that is rare in the orbit. Differential diagnosis can be difficult based solely on histologic analysis. Immunohistochemistry evaluation demonstrating cytoplasmic actin filaments within neoplastic spindle cells confirms the diagnosis. As soon as the diagnosis is made, chest and abdominal imaging is of value to define the prognosis and to direct further treatment. After the diagnosis of nonvisceral infantile myofibromatosis, complete gross resection, if possible, is the treatment of choice.     

Genetics and biochemistry of primary congenital glaucoma

Several observations noted by early investigators supported the supposition that in most cases, congenital glaucoma is determined by genetic factors. The genetic heterogeneity of PCG was confirmed by genetic linkage studies conducted in the 1990s when the authors determined that CYP1B1 is the congenital glaucoma gene at the GLC3A locus. The coding sequence of CYP1B1 has been subjected to extensive screening in familial and sporadic cases of glaucoma from numerous countries and from a large number of ethnic groups. These studies have provided evidence for extensive allelic heterogeneity at the GLC3A locus. This article also discusses the molecular evidence for reduced penetrance in congenital glaucoma and the phenotypic heterogeneity of CYP1B1 mutations, mouse models of CYP1B1, and the biochemistry of CYP1B1.