Elevated preoperative recipient neutrophil-lymphocyte ratio is associated with delayed graft function following kidney transplantation.

INTRODUCTION: The neutrophil-lymphocyte ratio (NLR) is an indicator of inflammatory status. We studied the effect of preoperative elevated NLR in the recipient in relation to the risk of developing delayed graft function (DGF) after kidney transplantation. METHODS: We retrospectively analysed the preoperative white blood cell count of renal transplant recipients between 2003 and 2005. An NLR >3.5 was considered elevated. There were 398 kidney transplant recipients of whom 249 received organs from donors after brain death (DBD), 61 from donors after circulatory death (DCD), and 88 from living donors. RESULTS: One hundred three patients (26%) developed DGF, of which 67 (65%) had NLRs >3.5. Of 295 recipients with primary graft function, only 44 (15%) had elevated NLR. Univariate analysis revealed three factors that significantly influenced graft function: NLR >3.5, cold ischemic time (CIT) >15 hours, and donor type. On multivariate analysis, both donor type (DCD: hazard ratio [HR] = 2.421, confidence interval [CI] = 1.195-4.905, P = .014; LD: HR = 0.289, CI = 0.099-0.846, P = .024) and NLR (HR = 10.673, CI = 6.151-18.518, P < .0001) remained significant. CONCLUSIONS: Elevated recipient preoperative NLR could contribute to increase the risk of developing DGF, which appears to be more pronounced in patients receiving grafts from living donors.

Acute lower limb ischemia following pediatric renal transplantation.

Live donor renal transplantation remains the best treatment option for end stage renal failure in pediatric patients (1-3). Better understanding of the hemodynamics of donor-recipient size discrepancy and advances in interventional techniques with improved surgical techniques have decreased the incidence and severity of surgical complications and enhanced graft survival (1, 2). We describe a rare complication occurring intra-operatively in a pediatric renal transplant resulting in acute limb ischemia and the surgical option taken.

Pilot study of local hyperthermia, radiation therapy, etanidazole, and cisplatin for advanced superficial tumours.

Five patients (six hyperthermia sites) with advanced superficial tumours were treated with combined etanidazole, cisplatin, local hyperthermia, and radiation therapy as part of a Phase I pilot study. Treatment was given once weekly and consisted of etanidazole 3 gm/m2 IV bolus, cisplatin 50 mg/m2 IV bolus, hyperthermia for 60 min with a target temperature of 43 degrees C, and radiation therapy 500 cGy/fraction (median total dose 3000 cGy) for a total of six weeks. Blood levels of etanidazole were taken during treatment at week 1 and week 4. Etanidazole drug exposure was calculated using the trapezoidal rule and expressed as the area under the curve (AUC) of plasma concentration x time. Five of six treatment sites had received prior irradiation. Prior chemotherapy had been given in three patients and tamoxifen therapy given in the other two patients. The median follow-up time is 34 months; 3/5 patients have died of disease. The most significant toxicity was grade I or II nausea and vomiting associated with 19/32 treatments (59%) and a second degree burn in 2/6 fields. None of the five patients experienced peripheral neuropathy, skin ulceration, or needed surgical repair. In addition, there was mild renal toxicity; pharmacokinetic analysis showed a 28-75% increase in the week 1 to week 4 AUC in three patients, all of whom had a decrease in creatinine clearance over the same time of 15-47%. This pilot study suggests this combined modality therapy can be delivered without major complications and that renal function, determined by creatinine clearance, affects clearance of etanidazole and alters the AUC. Therefore, monitoring renal function is important in patients receiving etanidazole in addition to other nephrotoxic agents such as cisplatin. The impact of etanidazole on the therapeutic index of hyperthermia, radiation therapy and cisplatin may be worth of study, especially since a positive interaction between these modalities is found in laboratory models.

Sulphasalazine in the management of psoriatic arthritis.

There are few 'second-line' drugs available for the treatment of PSA and their use is often limited by toxicity. Thirty-nine patients with active PSA recruited from two rheumatology units were randomly allocated to either enteric-coated sulphasalazine (SASP) or placebo and followed for 24 wk. Six patients in the SASP group and 11 on placebo discontinued therapy before 24 wk. Evaluation of effect of treatment revealed significant improvements in articular index in both groups at 12 wk. By 24 wk the articular index in placebo group was still showing benefit. In addition to articular index the SASP group improved significantly in terms of visual analogue scale, duration of morning stiffness and ESR. SASP is effective in PSA but the partial clinical response to placebo indicates the importance of placebo-controlled studies in this variable disease.

Local hyperthermia, radiation therapy, and chemotherapy in patients with local-regional recurrence of breast carcinoma.

We retrospectively reviewed the response rate and the acute and long-term toxicity of combined treatment using radiation therapy, hyperthermia, and chemotherapy in 29 patients with locally or regionally recurrent or advanced adenocarcinoma of the breast who completed at least 4 of the 6 prescribed hyperthermia treatments as part of a Phase I-II trial. Thirty-nine separate hyperthermia treatment fields were evaluated. Cisplatin alone or cisplatin with etanidazole or bleomycin was delivered just prior to hyperthermia once weekly. Hyperthermia was delivered to a target minimum tumor temperature of 43 degrees C +/- 0.5 for 60 min. Following hyperthermia, a 400 cGy fraction of radiation was given. The radiation fraction size on other days was 200 cGy. Twenty-two fields had previously been irradiated and 17 fields had not. Prior chemotherapy had been given in 24 of 29 patients (83%) and hormonal therapy given in 21 (72%). The median follow-up time is 10 months; 16/29 patients (55%) have died of disease. The overall complete response rate for all fields was 53%. Response rate was not related to any clinical factor, radiation dose, microwave or ultrasound technique, type of chemotherapy, or tumor temperatures, but the number of patients in the study population was small. A statistically significant association between the likelihood of complications and the total radiation therapy dose (previous radiation and present radiation) was found. Persistent ulceration lasting greater than 1 month after completing treatment was seen in 67% of previously irradiated fields compared to 21% of fields that had not been previously treated (p = 0.015). Surgical wound repair was needed for 38% of fields with a history of prior irradiation versus 6% of those without prior treatment (p = 0.050). A statistically significant radiation therapy dose response was found for the likelihood of these complications. None of the hyperthermia temperature parameters studied correlated with an increased risk of complication. We conclude that the combination of radiation therapy, hyperthermia, and chemotherapy results in a high rate of complete response. However, in patients who have been treated with prior radiation therapy, this combination may be more locally toxic than treatment with hyperthermia and radiation therapy alone. The precise impact of chemotherapy on the therapeutic index of hyperthermia and radiation therapy remains to be determined in randomized clinical trials.

Articular cartilage defects of the knee: correlation between magnetic resonance imaging and gross pathology.

Magnetic resonance imaging (MRI) of the knee articular cartilage is possible owing to the contrast provided by different signal intensities of adjacent menisci and subchondral bone. The objective of this study was to determine the accuracy of MRI in quantitatively detecting thinning and focal defects of articular cartilage in vivo. High resolution MRI was performed followed by dissection of the knee within one hour of amputations above the knee of eight patients (62-89 years) with peripheral vascular disease. Articular cartilage was examined for erosions, surface irregularities, and appearance. Mean thicknesses of femoral and tibial articular cartilage sagittal sections from MRI were statistically indistinguishable from matched gross thicknesses. In those joints in which cartilage erosions, thinning, or irregularities were detected by MRI the same defects were apparent by gross examination. Cartilage that appeared normal by MRI had a normal gross appearance by gross examination. Thus high resolution MRI can accurately predict gross articular cartilage appearance and thickness, allowing an objective, quantitative, noninvasive assessment of eroded cartilage.

Evaluation of sulphasalazine in ankylosing spondylitis--an interventional study.

Sulphasalazine has recently been shown to have an effect in ankylosing spondylitis but the clinical indication for its use is controversial. We have used an 'interventional' study design to investigate the clinical and laboratory effects of sulphasalazine in a group of 20 patients with active ankylosing spondylitis and peripheral joint disease. Following an initial assessment period, patients were treated with sulphasalazine for 24 weeks and the drug was then withdrawn and the patients monitored for a further 12 weeks. Significant improvements were observed in chest expansion, number of active joints, ESR and CRP which deteriorated after withdrawal of sulphasalazine. No change in spinal mobility was demonstrated. The 'interventional' design may be a useful screening procedure for identifying potential second line drugs in ankylosing spondylitis.

A phase I-II trial of cisplatin, hyperthermia and radiation in patients with locally advanced malignancies.

A Phase I-II trial testing the addition of systemic cisplatin (CDDP) to local hyperthermia and radiation was conducted to determine the dose of cisplatin that is tolerable once weekly for 6 weeks and to estimate the therapeutic potential of this trimodality combination in patients with locally advanced malignancies. Cisplatin at 20 mg/m2 (4 patients), 30 mg/m2 (8 patients), and 40 mg/m2 (12 patients) was given rapidly (over 5-10 min) i.v. after prehydration with 1 liter of normal saline. After approximately two-thirds of the cisplatin dose had been delivered, microwave hyperthermia was begun and continued for 60 min; the target minimum tumor temperature was 43 degrees C. Following hyperthermia, a 400 cGy fraction of radiation was delivered to the tumor. On other days during the treatment weeks, additional 200 cGy fractions were given to total doses of 6,000-6600 cGy in patients with full radiation tolerance or 2400-3600 cGy in patients with limited radiation tolerance. The 24 patients in this trial had a median age of 57 years and the predominant sites/tumor types were head and neck/squamous cell carcinoma (9) and chest wall/breast adenocarcinoma (9). Seventeen of the 24 treated tumors (70%) had previously been irradiated. Eighteen patients (75%) had received prior chemotherapy and nine patients (38%) had previously been treated with cisplatin. Bone marrow suppression was dose limiting in patients heavily pretreated with chemotherapy and chest wall radiation. No significant toxicities were observed at the 20 and 30 mg/m2 dose levels, but 5 of the 12 patients (42%) treated at 40 mg/m2 required modification of the cisplatin dose because of blood count suppression in four patients and mild renal dysfunction in one patient. Each of the patients with bone marrow suppression, however, had been heavily pretreated except for one patient with thrombocytopenia due to hypersplenism. Nausea and vomiting were mild with use of a standard, multiagent antiemetic regimen. Twelve patients (50%) attained a complete regression (CR) and 12 patients (50%) a partial regression (PR). Complete regression appeared to correlate with small tumor volumes (115 cc for CR versus 199 cc for PR patients) and higher tumor temperatures (4.6 average minimum equivalent minutes at 43 degrees C in CR versus 2.0 min in PR patients). Local toxicities included second degree burns in 12 patients (50%) and third degree burns in 6 (25%), but all burns healed in 4-12 weeks without surgical intervention.(ABSTRACT TRUNCATED AT 400 WORDS)

A survey of renal function in outpatients with rheumatoid arthritis.

The acute renal side-effects of nonsteroidal anti-inflammatory drugs are well documented. These include interstitial nephritis, hyperkalaemia, renal tubular acidosis, fluid retention, hypertension and nephrotic syndrome. The long-term effects are less well known. We have carried out a cross-sectional survey of an unselected out-patient population with definite or classical rheumatoid arthritis to determine the prevalence of renal problems in this group. Thirty-four patients (20%) were shown to have an abnormality as defined by our criteria but in the majority this was transient or had been previously recognised. Thirteen patients (8%) had a persistent unexplained abnormality but only 1 had merited renal biopsy using established criteria (Patient 1). We conclude that the long-term use of NSAID's is associated with relatively few renal side-effects.

Raised titres of anti-klebsiella IgA in ankylosing spondylitis, rheumatoid arthritis, and inflammatory bowel disease.

Serum titres of IgA are raised in ankylosing spondylitis and increased titres of antibodies to klebsiella have also been reported. The humoral response was investigated in ankylosing spondylitis and other inflammatory disorders. IgA antibodies to klebsiella pneumoniae K43 were measured in patients with ankylosing spondylitis, Crohn's disease, ulcerative colitis, and rheumatoid arthritis and in controls. Significantly raised median titres of anti-klebsiella IgA, measured as optical density at 405 nm with an enzyme linked immunosorbent assay (ELISA), were seen among the patients with ankylosing spondylitis (0.7), Crohn's disease (0.8), rheumatoid arthritis (0.6), and ulcerative colitis (0.8) compared with controls (0.4). Activity of disease in ankylosing spondylitis and titres of anti-klebsiella IgA were not correlated. In contrast, titres of anti-klebsiella IgM were significantly lower in patients with ankylosing spondylitis and ulcerative colitis. The increase in the titres of anti-klebsiella IgA may be due to increased permeability of the gut to bacterial antigens, leading to an increased IgA response in the gut mucosa and permitting the release of IgA into the circulation. As the increased antibody titres were seen in Crohn's disease and rheumatoid arthritis as well as in ankylosing spondylitis the response may be nonspecific, occurring because of possible underlying inflammatory bowel disease in these conditions.

Comparison of phenytoin and gold as second line drugs in rheumatoid arthritis.

Phenytoin has known immunosuppressive properties, and a recent pilot study has indicated that it may have a second line effect in rheumatoid arthritis (RA). To evaluate this role 60 patients with active RA were randomly allocated to receive either oral phenytoin or intramuscular gold. The two treatment groups were comparable at the outset (Mann-Whitney U test). Twenty four patients completed 24 weeks of therapy in each group and no unexpected side effects were encountered. All variables except haemoglobin (Hb) improved significantly in the gold group while in the phenytoin group significant improvement was limited to articular index, erythrocyte sedimentation rate (ESR), and Hb. Between group comparison (Mann-Whitney) at week 24 showed a significant advantage of gold over phenytoin for pain score and morning stiffness. Thus phenytoin appears to exert a less potent second line effect than gold and is unusual in influencing laboratory indicators of disease activity more than clinical variables. This is likely to limit its usefulness as a second line drug in RA.

Drug treatment of pain in rheumatoid disorders.

The relief of pain remains a delicate balance between the potential toxicity and desired effect of currently available compounds. Physician and patient need to make the optimum use of such therapies. Control of pain and stiffness in rheumatic diseases is a dynamic process. There is a constant need for re-appraisal of aims and objectives and adjustment of treatment according to variations in disease and response. Where 'specific' therapy is available, it is clearly preferable to use it rather than employ large doses of purely symptom-relieving drugs. At present toxicity is inextricably linked to efficacy, and dissociation of these two factors seems unlikely to be achieved in the near future. More efficient 'targeting' of drugs at the site of desired action should help to minimize the adverse effects of therapy. Ultimately the most efficient way of relieving pain and stiffness will be to prevent or suppress the inflammatory disorders which give rise to the symptoms. Unfortunately this is an elusive goal at present.

The pharmacology of hippocampal theta cells: evidence that the sensory processing correlate is cholinergic.

The firing repertoires of theta cells in the CA1 and dentate layers of the hippocampal formation of the freely moving rabbit were analyzed during 3 behavioral conditions: (1) voluntary motor patterns, termed type 1 theta behaviors; (2) automatic motor patterns, termed type 2LIA behaviors; (3) alert immobility with presentation of sensory stimuli, termed type 2 theta behavior. Cholinergic manipulations were shown to effect the firing repertoires of theta cells during the type 2 theta behavior condition (sensory processing) and not the other two behavioral conditions. A hypothesis of a sensorimotor processing function of the hippocampal formation is presented and discussed.

Dr William Johnston (1846-1900) of Leicester--an unknown Victorian general practitioner.

The famous names of medical history are well documented, but facts about the little-known have to be sought after. The author was curious about the founder member of the practice he works in. By a painstaking search of local and national records, he learned that his Dr Johnston was an Irishman who practised in Derbyshire before arriving in Leicester in 1876. He was much concerned about the zymotic diseases, and his greatest achievement was in persuading the council to pass a Notification of Infectious Diseases bye-law in 1879, making Leicester one of the first towns to have such a regulation.