Dealing with age discrimination in England: The merits of education vs. legislation

To improve the job prospects of older people, the Conservative government has chosen to educate employers rather than legislate against discriminatory practices. Has it made the right choice?     

HLA class I and class II antigens associated with multiple myeloma in southern Africa

While the exact aetiology of myeloma is unknown, genetic factors feature among the potential risk factors. The HLA phenotypes in African blacks with myeloma (the commonest haematopoietic malignancy in this group) have not been characterized. The purpose of this study was to determine the HLA class I and class II phenotypes of patients with multiple myeloma and to compare the findings to an ethnically matched control group of 100 individuals. Analysis of the HLA class I and class II phenotypes in 62 myeloma patients revealed: (i) a corresponding statistically significant association with HLA B18 [odds ratio (OR) 6.3; 95% confidence interval (CI) 1.013-39.727; P < 0.005]; (ii) no statistically significant association with HLA B13, Cw2, Cw6 or the DR and DQ antigens; and (iii) a statistically significant negative (protective) association with HLA Cw7 (OR 0.4; 95% CI 0.21-0.87; P < 0.005). This study suggests that although genetic factors may play a role in the multifactorial aetiology of multiple myeloma, with the exception of HLA B18, there is no specific association between HLA types and multiple myeloma in South African blacks.     

Expression of Plasmodium falciparum G6PD-6PGL in laboratory parasites and in patient isolates in G6PD-deficient and normal Nigerian children

As the production of NADPH in the pentose phosphate pathway is the main antioxidant defence mechanism available to the Plasmodium falciparum, we have studied the expression of P. falciparum glucose 6-phosphate dehydrogenase-6-phosphogluconolactonase (PfG6PD-6PGL) in G6PD-deficient and normal erythrocyte host cells. Both erythrocytes infected in vitro with a laboratory isolate and erythrocytes from natural human infections were used. Total RNA was prepared from parasites collected from five G6PD-deficient and nine G6PD-normal children in Ibadan, Nigeria, selected after screening 189 rural schoolchildren and 68 clinical malaria patients, and was subjected to Northern blot analysis. The probe was a cDNA fragment of the G6PD domain of the PfG6PD-6PGL gene, with an internal control probe of P. falciparum 18S ribosomal RNA. Quantification was performed using a phosphoimager. Relative to internal control, the abundance of PfG6PD-6PGL mRNA (mean +/- standard deviation) was lower in parasites from G6PD-deficient children (0.29 +/- 0.27) than in G6PD-normal control subjects (0.74 +/- 0.26) (P = 0.014, Mann-Whitney U-test). Although confirmation in a larger study is required, our results suggest a lower relative abundance of PfG6PD-6PGL, and presumably antioxidant activity, in malaria parasites from G6PD-deficient hosts, thus extending the current knowledge of the mechanism of G6PD-deficiency related host protection.     

Spotlight on Insulin Aspart in Type 1 and 2 Diabetes Mellitus

Insulin aspart (NovoLog, NovoRapid), a rapid-acting human insulin analog, provides more rapid absorption than regular human insulin after subcutaneous administration. In most randomized, nonblind clinical trials in patients with type 1 diabetes mellitus, insulin aspart administered immediately before meals resulted in significantly lower mean glycosylated hemoglobin (HbA1c) levels than regular human insulin (usually administered 30 minutes before a meal). Insulin aspart also significantly improved postprandial glycemic control compared with regular human insulin. The efficacy of insulin aspart was similar to that of insulin lispro when administered to patients with type 1 diabetes mellitus via continuous subcutaneous infusion in a randomized, nonblind trial. Preliminary data from randomized, nonblind trials suggest insulin aspart had a trend towards lower HbA1c levels compared with regular human insulin in patients with type 2,diabetes mellitus. Biphasic insulin aspart (30% soluble [rapid-acting] and 70% protamine-bound insulin aspart [BIAsp30]) [NovoLog Mix 70/30, NovoMix 30(2)] generally provided significantly better postprandial glucose control than a similar mixture of biphasic regular human insulin (BHI30) in a randomized, nonblind trial in patients with type 1 or 2 diabetes mellitus. However, the long-term efficacy of BIAsp30 was similar to that of BHI30 after 2 years in a randomized, nonblind trial in patients with type 2 diabetes mellitus. Patients with type 1 or 2 diabetes mellitus reported greater treatment satisfaction with insulin aspart or BIAsp30 than with regular human insulin or BHI30. The overall incidence of hypoglycemia with insulin aspart was lower than, or similar to, that of regular human insulin. Moreover, insulin aspart tended to be associated with a lower occurrence of nocturnal hypoglycemia and severe hypoglycemic events than regular human insulin. Conclusion: The standard preparation of insulin aspart has the potential to better mimic the physiological response to meals than regular human insulin. Insulin aspart when combined with a suitable basal insulin improved overall glycemic control and led to a similar or lower number of hypoglycemic episodes compared with a similar regular human insulin regimen. Insulin aspart was generally as effective and well tolerated as insulin lispro when administered by continuous subcutaneous infusion in a single comparative trial. The efficacy of biphasic insulin aspart has been documented in a small number of trials. Both insulin aspart and biphasic insulin aspart provide for flexible and convenient administration. Insulin aspart is now well established as an effective and convenient means of providing glycemic control which offers clinical and practical advantages over regular human insulin.     

The pancreatic islets in diabetes

Despite the fact that heterogeneity of diabetes in man has become more and more evident in recent years, its pancreatic pathology is still represented by two distinct entities, roughly corresponding to the classic juvenile-onset and maturity-onset types of the disease.In juvenile-onset, insulin-dependent diabetes, the pancreatic islets show severe and pathognomonic changes. B cells are greatly reduced in number already at clinical onset. Contrary to classic opinion they do not always disappear in the years to follow. Insulin's, a common finding in the pancreas of recent onset juvenile diabetic subjects, is compatible with a viral infection as well as with an autoimmune reaction as the cause of B cell destruction. In the pancreas of juvenile-onset diabetic subjects the islets, which in the past have been regarded as atrophic and inactive, are actually composed of cells containing glucagon and somatostatin. There is also a profound distortion of islet organization, and many endocrine cells are scattered as single cells in the exocrine tissue. These findings may well account for the abnormal secretory behavior of the glucagon-secreting A cells in insulin-dependent juvenile-onset diabetes.In maturity-onset, noninsulin-dependent diabetes, the pancreatic pathology is extremely variable and not pathognomonic. A numeric reduction of the B cells can be demonstrated in many maturity-onset diabetic subjects, but this reduction is much more moderate than in insulin-dependent juvenile-onset diabetic subjects and does not account for the disease. The same amount of B cell reduction can be found in many elderly subjects without clinical evidence of diabetes. In many maturity-onset diabetic subjects, the cytologic characteristics of the B cells suggest a decreased responsiveness to the stimulus of hyperglycemia. Islet fibrosis and hyalinosis (amyloidosis), although common, cannot explain this secretory dysfunction. The exact site of the defect in the B cells of maturity-onset diabetic subjects remains to be defined. Further investigations are necessary to assess the role of disturbed intraislet intercellular relationships in the pathogenesis of late-onset diabetes.The dual pattern of islet pathology in diabetes in man does not preclude a more profound heterogeneity in the etiology and pathogenesis of the disease.     

Neurotrophin-3 improves functional constipation

OBJECTIVE: Neurotrophin-3 (NT-3) is a neurotrophic factor involved in the growth, development, and function of the nervous system. In preliminary studies, s.c. recombinant methionyl-human NT-3 enhanced transit throughout the GI tract and increased stool frequency in normal and constipated subjects. Our aim was to assess 1) the dose-related effects of NT-3 on bowel function, colon transit, and symptoms of chronic constipation, and 2) its safety. METHODS: This was a double-blind, randomized, placebo-controlled phase II study. A total of 107 patients with a diagnosis of functional constipation (Rome II criteria) were randomized to receive 4 wk of double blind, s.c. injections of either placebo, 3 mg, or 9 mg NT-3 once per week (qW) or three times per week (TTW); or 9 mg NT-3 TTW for 1 wk, then qW. The primary endpoint was the change in number of spontaneous, complete bowel movements per week. Colon transit was assessed before and at end of treatment. RESULTS: Compared with placebo, patients who received 9 mg NT-3 TTW showed significant increases in frequency of spontaneous, complete bowel movements and total bowel movements, as well as dose-related softening of stool and improved ease of passage. The number of days per week without a bowel movement also decreased, colon transit improved, as did constipation-related symptoms. Weekly dosing was ineffective. Transient injection-site reactions, seen in one third of patients receiving NT-3 TTW, were the most frequent adverse event. CONCLUSIONS: NT-3, administered TTW, increased stool frequency, enhanced colon transit, and improved symptoms of chronic constipation. NT-3 seems to be a novel, safe, and effective agent for the treatment of functional constipation.     

Limitations of Barium Enema Performed as an Adjunct to Incomplete Colonoscopy

PURPOSE Colonoscopy is believed to be inadequate in 4 to 24 percent of procedures. Barium enema often is utilized to complete the examination. In radiology literature, a successful barium enema in this setting requires only that the cecum has been reached. In this study, completion barium enema was assessed for both completeness and quality of proximal visualization. METHODS The charts of 16,216 patients undergoing colonoscopy at Saint Vincent Health Center from July 1995 to July 2003 were reviewed to identify patients who underwent barium enema within six months of an incomplete colonoscopy. Incomplete colonoscopies were audited for history of previous abdominal/pelvic surgery, level of colon attained, and apparent reasons for failure. Corresponding barium enema reports were evaluated in a similar fashion. RESULTS In 485 patients (2.9 percent), colonoscopy was incomplete. One hundred eighteen patients underwent barium enema after incomplete colonoscopy. In these patients, sharp angulation (42 percent) or redundancy/looping (31 percent) most often limited endoscopy. Among the barium enema studies, 91 (77 percent) were technically adequate. Twenty-seven studies were suboptimal (poor preparation/intolerance = 7, redundancy = 6, poor filling = 6, stricture/narrowing = 6, severe diverticulosis = 2). Two patients demonstrated additional polyps. There was no correlation between reasons for endoscopic failure and inadequacy of barium enema. Completeness of barium enema was not affected by previous pelvic surgery. Immediate barium enema was no less complete than a delayed study. CONCLUSIONS The reliability of barium enema after incomplete colonoscopy is less than previously reported. Poster presentation at the meeting of The American Society of Colon and Rectal Surgeons, Dallas, Texas, May 8 to 13, 2004. Reprints are not available.     

Catheter Ablation of Inducible Atrial Flutter, in Combination with Atrial Pacing and Antiarrhythmic Drugs (“Hybrid Therapy”) Improves Rhythm Control in Patients with Refractory Atrial Fibrillation

Atrial flutter or tachycardia may coexist with atrial fibrillation [AF] and can be treated with ablation techniques in attempt to reduce the total AF burden. The role of ablation of latent atrial tachyarrhythmias elicited at electrophysiologic study in conjunction with atrial pacing and antiarrhythmic drugs in patients with refractory AF has not been evaluated. We evaluated the efficacy of catheter ablation of electrically induced atrial flutter or atrial tachycardia in improving rhythm control in patients with refractory AF. Methods: Consecutive patients with refractory AF, and spontaneous atrial flutter (Group 1) or without spontaneous atrial flutter (Group 2) underwent programmed stimulation in a baseline drug-free state. All patients had electrically induced atrial flutter or tachycardia. Radiofrequency ablation of the arrhythmia substrate was performed in all patients. Primary endpoints evaluated for patient outcome in both groups included maintenance of rhythm control and freedom from recurrent atrial tachyarrhythmias. Results: Forty-three patients, with a mean age of 66±13 years were studied. Group 1 consisted of 22 patients while Group 2 had 21 patients. Ablation of the tricuspid valve-inferior venacaval isthmus was performed in 41 patients who had common atrial flutter induced at electrophysiologic study. Ablation of other atrial sites was performed in 8 patients with induced atypical flutter and 4 patients with induced atrial tachycardia. Ten of these patients had ablation of more than one arrhythmia. 17 patients (40%) had atrial pacing instituted and 28 patients remained on a class 1/3 antiarrhythmic drug. During a mean follow-up of 26±14 months, 33 patients (82.5%) remained in rhythm control. Actuarial analysis showed 96% of patients in rhythm control at 6 months, 94% at 12 months, and 90% at 24 months. Freedom from symptomatic AF recurrence was 64% at 6 months, 58% at 12 months, and 42% at 24 months. The outcome for both of these endpoints was similar for Group 1 and Group 2 (p = NS). The AF free interval increased significantly from 7±9 days to 172±121 days (p < 0.01) after ablation. This increase was again similar in both the groups. In the 14 patients were who did not receive atrial pacing and who remained on the same class 1/3 antiarrhythmic drug, the AF free interval increased from 18±17 days to 212±102 days (p < 0.01). Conclusions: We conclude that electrophysiologic studies can elicit latent atrial flutter or tachycardia in patients with refractory AF without spontaneous monomorphic atrial tachyarrhythmias. Catheter ablation of electrically induced atrial flutter or tachycardia either alone, or with atrial pacing and with antiarrhythmic drug may improve rhythm control and reduce AF recurrences. This is similar in patients with and without spontaneous atrial flutter and refractory AF.     

Phannacokinetics of Intravenous Immunoglobulin in Neonates

Intravenous immunoglobulin (IVIG) may be a therapeutic adjunct to antibiotic treatment of neonatal infections. We examined the pharmacokinetics and safety of IVIG in human neonates. Thirty neonates with suspected sepsis were randomly assigned either to a treatment (receiving either 250, 500, or 1,000 mg/kg of IVIG plus antibiotics) or control (antibiotics alone) group. The 500 mg/kg dose produced a rise in total IgG for greater than 8 and in group B streptococcus (GBS) type-specific IgG for greater than 4-14 days. The type-specific antibody elevation varied with the amount of pathogen-specific antibody and dose of IVIG. Pharmacokinetic analysis suggests a Vdss of 42 ml/kg, Cl of 3.0 ml/kg/day, a biphasic elimination curve, and a terminal elimination half-life of 24.2 days. No toxicity was observed. These data may be valuable in determining optimal dosing schedules for IVIG in treating or preventing neonatal infections.