Intravenous Lidocaine Relieves Spinal Cord Injury Pain: A Randomized Controlled Trial

Background: Neuropathic pain in spinal cord injury is a common challenging therapeutic condition. The current study examines the analgesic effect of the sodium channel blocker lidocaine on neuropathic pain in patients with spinal cord injury and the predictive role of concomitant evoked pain on pain relief with lidocaine.

Methods: Twenty-four spinal cord injury patients with neuropathic pain at or below the level of injury were randomized and completed a double-blind crossover trial of 5 mg/kg lidocaine and placebo infused over 30 min. Twelve patients reported evoked pain, and 12 patients had no evoked pain. Spontaneous and evoked pains were assessed using a visual analog scale and quantitative sensory testing.

Results: Lidocaine significantly reduced spontaneous pain in all patients (P < 0.01) and in each of the two groups with (P < 0.01) and without (P = 0.048) evoked pain, with no difference in number of responders (pain reduction >= 33%) between the patients with (n = 6) and without (n = 5) evoked pain. Lidocaine significantly relieved both at-level and below-level neuropathic pain and decreased brush-evoked dysesthesia but not cold allodynia, pinprick hyperalgesia, or pain evoked by repetitive pinprick.     

Fibroepithelial polyps of the vagina: are they old granulation tissue polyps?

AIMS: To study the nature of fibroepithelial polyps of the vagina. METHODS: Sixty five fibroepithelial polyps of the vagina and 64 granulation tissue polyps diagnosed over 15 years were reviewed histologically. RESULTS: Cytologically benign multinucleated stromal cells were present in large numbers in 19 of the fibroepithelial polyps of the vagina (FEPV). Only one polyp contained atypical stromal cells, a high mitotic count, and abnormal mitoses and was indistinguishable from a malignant tumour. Immunostaining showed the presence of vimentin and desmin positive mono- and multinucleated stromal cells in FEPV and occasional oestrogen receptor positive nuclei. Desmin positive cells could not be shown in granulation tissue polyps. CONCLUSIONS: FEPV are common lesions with benign mono- and multinucleated fibroblastic stromal cells in which myoid differentiation is often present. FEPV may develop as a result of a granulation tissue reaction after some local injury of the vaginal mucosa. Hormonal factors may modulate the growth of FEPVs. Delayed differentiation of myofibroblastic cells may explain why granulation tissue sometimes does not contract properly but turns into polyps.     

Identification of a type 1 diabetes-associated CD4 promoter haplotype with high constitutive activity

CD4 is a candidate gene in autoimmune diseases, including Type 1 diabetes mellitus (T1DM), because the CD4 receptor is crucial for appropriate antigen responses of CD4(+) T cells. We previously found linkage between a CD4-1188(TTTTC)(5-14) promoter polymorphism and T1DM. In the present study, we screened the human CD4 promoter for mutations and identified three frequent single nucleotide polymorphisms (SNPs): CD4-181C/G, CD4-521C/G and CD4-1050T/C. The SNPs are in strong linkage disequilibrium (LD) and association with the CD4-1188(TTTTC)(5-14) alleles, and we observed nine CD4 promoter haplotypes, of which four are frequent. We genotyped the SNPs in 253 Danish T1DM families (1129 individuals) and found evidence for linkage and association of a CD4 (A4(-1188)T(-1050)G(-521)C(-181)) haplotype to T1DM. In reporter studies, we show that (1) the T1DM-associated CD4 haplotype encodes high constitutive promoter activity and (2) the CD4-181G variant encodes higher stimulated promoter activity than the CD4-181C variant. This difference is in part neutralized in the frequently occurring CD4 promoter haplotypes by the more upstream genetic variants. Thus, we report functional impact of a novel CD4-181C/G SNP on stimulated CD4 promoter activity and the identification of a novel CD4 haplotype with high constitutive promoter activity that is linked and associated with T1DM.     

Effect of cyanide on renal metabolic rate and glomerulotubular balance.

Measurements of anesthetized dogs by the heat-accumulation technique showed that cyanide reduced equally the metabolic rates of outer medulla and cortex, whereas combined infusion of ethacrynic acid and chlorothiazide reduced mainly the metabolic rate of the outer medulla. During ethacrynic acid and chlorothiazide infusion, cyanide reduced the remaining sodium reabsorption by an average of 19% and the remaining cortical metabolic rate by 43%, but had no additional effect on the outer medullary metabolism. Metabolic rates remained essentially constant when glomerular filtration rate (GFR) was raised during cyanide infusion from 63 plus or minus 3 to 135 plus or minus 7% of control by carotid constriction or intravenous infusion of angiotensin. Glomerulotubular balance, defined as proportional relationship between sodium reabsorption and GFR during infusion of ethacrynic acid and chlorothiazide, was present only at GFR less than 80% of control in experiments with and without cyanide infusion. We conclude that cyanide inhibits proximal energy-requiring sodium transport which cannot be inhibited by ethacrynic acid and chlorothiazide, but does not alter the range of GFR over which glomerulotubular balance applies.     

DNA ploidy, tumour site, and prognosis in colorectal cancer. A flow cytometric study of paraffin-embedded tissue

DNA ploidy patterns were studied by flow cytometry in nuclear suspensions from 149 paraffin-embedded colorectal adenocarcinomas. The DNA ploidy of rectal tumours was not significantly different from that of colonic tumours. Patients with DNA diploid tumours had a significant survival advantage compared with patients with non-diploid tumours, but DNA ploidy did not confer any significant additional prognostic information when tumour site, Dukes's stage, the invasiveness of the tumour, and the number of lymph node metastases were adjusted for in a proportional hazards regression analysis (Cox). It is concluded that DNA ploidy does not contribute significantly to the explanation of why patients with rectal cancer have a poorer prognosis than those with colonic cancer.     

The IQ‐CSRC Prospective Clinical Phase 1 Study: “Can Early QT Assessment Using Exposure Response Analysis Replace the Thorough QT Study?”

A collaboration between the Consortium for Innovation and Quality in Pharmaceutical Development and the Cardiac Safety Research Consortium has been formed to design a clinical study in healthy subjects demonstrating that the thorough QT (TQT) study can be replaced by robust ECG monitoring and exposure–response (ER) analysis of data generated from First‐in‐Man single ascending dose (SAD) studies. Six marketed drugs with well‐characterized QTc effects were identified in discussions with FDA; five have caused QT prolongation above the threshold of regulatory concern. Twenty healthy subjects will be enrolled in a randomized, placebo‐controlled study designed with the intent to have similar power to exclude small QTc effects as a SAD study. Two doses (low and high) of each drug will be given on separate, consecutive days to 9 subjects. Six subjects will receive placebo. Data will be analyzed using linear mixed‐effects ER models. Criteria for QT‐positive drugs will be the demonstration of an upper bound (UB) of the 2?sided 90% confidence interval (CI) of the projected QTc effect at the peak plasma level of the lower dose above the threshold of regulatory concern (currently 10 ms) and a positive slope of ER relationship. The criterion for QT‐negative drug will be an UB of the CI of the projected QTc effect of the higher dose <10 ms. It is expected that a successful outcome in this study will provide evidence supporting replacement of the TQT study with ECG assessments in standard early clinical development studies for a new chemical entity.     

Age‐time risk patterns of solid cancers in 60 901 non‐Hodgkin lymphoma survivors from Finland,Norway and Sweden

Survival after non‐Hodgkin lymphoma (NHL) has increased thanks to improved treatment but NHL survivors have an increased risk of second neoplasms. The assessment of cancer risk patterns after NHL may help to quantify the late side‐effects of therapy. Poisson regression was used to estimate relative risks (RRs) and absolute incidence rates for nine solid tumours based on a nationwide cohort of 60 901 NHL survivors from Finland, Norway and Sweden. Patients were diagnosed between 1980 and 2006 and developed 6815 s neoplasms. NHL patients showed an increased risk of each of the nine investigated cancer sites: prostate and pancreas (both RRs 1·28), breast (1·37), colorectum (1·48), urinary bladder (1·52), stomach and lung (both RRs 1·87), skin (melanoma 2·27) and kidney (2·56). The RRs showed a U‐shaped relationship with time after NHL for all nine‐second cancer types. NHL diagnosis early in life was a risk factor for the development of second cancers with the exception of melanoma, but a risk excess was even observed in patients diagnosed with NHL at age 80+ years. The present study provides accurate estimates on the adverse late effects of NHL therapy, which should guide the establishment of cancer prevention strategies in NHL survivors.