Clinical significance of small airway obstruction markers in patients with asthma.

BACKGROUND: The role of small airway obstruction in the clinical expression of asthma is incompletely understood. OBJECTIVE: We tested the hypotheses that markers of small airway obstruction are associated with (i) increased asthma severity, (ii) impaired asthma control and quality of life and (iii) frequent exacerbations. METHODS: Seventy-four adults with asthma and 18 healthy control subjects underwent impulse oscillometry (IOS), multiple breath inert gas washout (MBW), body plethysmography, single-breath determination of carbon monoxide uptake and spirometry. Patients completed the six-point Asthma Control Questionnaire (ACQ-6) and standardized Asthma Quality of Life Questionnaire [AQLQ(S)]. Asthma severity was classified according to the Global Initiative for Asthma (GINA) treatment steps. RESULTS: The putative small airway obstruction markers Sacin , resistance at 5 Hz minus resistance at 20 Hz (R5-R20) and reactance area (AX) were not independently associated with asthma severity, control, quality of life or exacerbations. In contrast, markers of total (R5) and mean airway resistance of large and small airways (R20) were significantly higher in the severe asthma group compared with the mild-moderate group (0.47 vs. 0.37, P < 0.05 for R5; 0.39 vs. 0.31, P < 0.01 for R20). The strongest independent contributors to ACQ-6 score were R20 and forced expiratory volume in one second (% pred.), and the strongest independent contributors to AQLQ(S) score were R20 and forced vital capacity (% pred.). A history of one or more exacerbations within the previous year was independently associated with R20. CONCLUSIONS AND CLINICAL RELEVANCE: Previously reported markers of small airway obstruction do not appear to be independently associated with asthma disease expression. In contrast, the IOS parameter R20, a marker of mean airway resistance of both large and small airways, appears to have independent clinical significance. These observations require confirmation in prospective longitudinal studies.

Gelastic syncope: an unusual condition.

Gelastic syncope or laughter-induced syncope is a rare disease often misdiagnosed as narcolepsy or cataplexy. We report a 54-year-old man with syncopal episodes. Each episode started after laughter, leading to light-headedness with blurring of vision and loss of consciousness for a few seconds. The episodes resolved spontaneously. The treatment of gelastic syncope is the same as that for neurally mediated syncope.

SABRE-B: an evaluation of paclitaxel and bevacizumab with or without sunitinib as first-line treatment of metastatic breast cancer.

BACKGROUND: The vascular endothelial growth factor (VEGF) pathway can be targeted through VEGF neutralization or VEGF receptor (VEGFR) blockade using tyrosine kinase inhibition. Because laboratory models suggest that combining these approaches might be synergistic, we sought to evaluate the feasibility and efficacy of combining sunitinib with paclitaxel + bevacizumab (PB). METHODS: Patients with human epidermal growth factor receptor 2 (HER2)-negative, metastatic breast cancer receiving first-line chemotherapy were randomized to PB or PB with sunitinib (PBS), with planned escalation of the sunitinib dose. RESULTS: Forty-six patients were randomized to PB or PBS with sunitinib dosed at 25 mg p.o. daily. Patients receiving PBS encountered substantial toxicity that precluded adequate treatment. The percentage of patients with grade ≥3 adverse events was greater in the PBS arm than the PB arm (83% versus 57%), and sunitinib dosing was modified in 78% of patients, most often due to neutropenia, febrile neutropenia, and fatigue. In addition, 44% of patients had sunitinib dose reduction to 12.5 mg, and 39% required discontinuation. Patients receiving PBS had more bevacizumab treatment interruptions and discontinuations because of toxicity. Median treatment duration was longer in the PB arm compared with the PBS arm (14.1 versus 11.1 weeks), reflecting early treatment discontinuation of PBS. Because of poor tolerability of the addition of sunitinib to PB, the planned sunitinib dose escalation was halted and the study accrual was terminated. CONCLUSION: Adding sunitinib to standard doses of bevacizumab plus paclitaxel for metastatic breast cancer is not feasible. Different strategies will be required to evaluate whether there is additional clinical benefit to combining VEGF/VEGFR-targeted agents.

Safety and Diagnostic Efficacy of Gadobenate Dimeglumine in MRI of the Brain and Spine of Neonates and Infants.

BACKGROUND AND PURPOSE: Contrast-enhanced MR imaging provides essential information for pediatric imaging applications. We evaluated gadobenate dimeglumine for contrast-enhanced MR imaging of infants younger than 2 years of age. MATERIALS AND METHODS: Ninety children younger than 2 years of age (including 55 children younger than 1 year) who underwent enhanced MR imaging of the CNS with gadobenate dimeglumine at 0.1 mmol/kg body weight ± 25% by volume were retrospectively enrolled at 2 imaging centers. Safety data were assessed for adverse events and, when available, vital signs and electrocardiogram and clinical laboratory values obtained from 48 hours before until 48 hours after the MR imaging examination. The efficacy of gadobenate dimeglumine-enhanced MR imaging was evaluated prospectively by 3 blinded, unaffiliated readers in terms of the accuracy of combined pre- and postcontrast images relative to precontrast images alone for differentiation of tumor from non-neoplastic disease and the correct diagnosis of specific disease. Differences were tested using the McNemar test. A possible effect of dose on diagnostic accuracy was assessed using the Fisher exact test. RESULTS: Nine nonserious adverse events were reported for 8 (8.8%) patients. Five adverse events occurred in patients 12 months of age or older. All events occurred at least 24 hours after gadobenate dimeglumine administration, and in each case, the investigating radiologist considered that there was no reasonable possibility of a relationship to gadobenate dimeglumine. No clinically meaningful changes in vital signs, electrocardiogram results, or laboratory parameters were reported. Accurate differentiation of tumor from non-neoplastic disease and exact matching of each specific MR imaging-determined diagnosis with the on-site final diagnosis were achieved in significantly more patients by each reader following evaluation of combined pre- and postcontrast images relative to precontrast images alone (91.0%-94.4% versus 75.3%-87.6%, P < .04, and 66.3%-73.0% versus 52.8%-58.4%, P < .02, respectively). No significant differences (P > .133) in diagnostic accuracy were noted between patients receiving ≤0.08 mmol/kg of gadobenate dimeglumine and patients receiving >0.08 mmol/kg of gadobenate dimeglumine. CONCLUSIONS: Gadobenate dimeglumine is safe and effective for pediatric MR imaging.

Antiperoxidative, antithyroidal, antihyperglycemic and cardioprotective role of Citrus sinensis peel extract in male mice.

An extract of Citrus sinensis (CS) peel was evaluated for its efficacy in ameliorating L-thyroxine (L-T(4)) induced tissue lipid peroxidation (LPO), hyperthyroidism and hyperglycemia in mice. In a preliminary investigation, of the three different doses of CS (12.5 mg/kg, 25 mg/kg and 50.0 mg/kg) peel extract, 25 mg/kg was found to be the most effective and antiperoxidative, while 50 mg/kg was proved to be hepatotoxic. Therefore in the pilot experiment the effects of 25 mg/kg/day of CS for 10 days were studied in L-T(4) induced hyperthyroid animals. L-T(4) (500 microg/kg/day for 10 days) increased the levels of thyroxine (T(4)) and triiodothyronine (T(3)) with a concomitant increase in serum glucose concentration, alpha-amylase activity, heart/body weight ratio (HW/BW), kidney/body weight ratio (KW/BW) and cardiac as well as hepatic LPO. However, it decreased the concentration of different serum lipids such as total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and very low-density lipoprotein cholesterol (VLDL-C). Administration of CS extract (25 mg/kg/day) in hyperthyroid animals reversed most of these observations revealing the ameliorating potential of CS extract against various adverse effects of hyperthyroidism. It appears that the test extract primarily acts through its antioxidative/free radical-scavenging, antithyroidal and HDL-C stimulating properties.

Mechanochemical synthesis of high coercivity Nd2(Fe,Co)14B magnetic particles.

With increasing demand for magnets in energy conversion systems, the quest for the development and understanding of novel processing routes to produce permanent magnets has become urgent. We report a novel mechanochemical process for the synthesis of Nd2(Fe,Co)14B magnetic particles with a high coercivity of 12.4 kOe. This process involves the reduction of neodymium oxide, iron oxide, cobalt oxide and boron anhydride in the presence of a calcium reducing agent and a CaO diluent. The formation mechanism of Nd2(Fe,Co)14B changed with increasing CaO content, and the average crystal size of the Nd2(Fe,Co)14B particles also increased, resulting in an increase in the coercivity values. The reaction mechanism during milling was revealed through a study of the phase transformations as a function of milling time. It was found that unlike self-propagating reactions, this reduction reaction during milling requires continuous input of mechanical energy to reach a steady state.

Early experiences with diffusion tensor imaging and magnetic resonance tractography in stroke patients.

INTRODUCTION: Recent advances in magnetic resonance (MR) diffusion tensor imaging technique enable evaluation of the anisotropy of white matter tracts in-vivo, as well as the integrity of fibre tracts and their orientation. We describe our initial experiences with diffusion tensor imaging and MR tractography techniques to evaluate the structural degeneration of white matter tracts following stroke. METHODS: Diffusion tensor imaging data were acquired in 11 cases with stroke on a 3T MR imaging scanner, with three-dimensional diffusion tensor imaging-based colour maps and MR tractography performed offline. We evaluated the spatial relationships of the eloquent white matter tracts to the infarcts and areas of haemorrhage, and classified therewith the tracts as either disrupted or displaced. We compared these with the clinical severity of the neurological deficits and prognosis. RESULTS: A good correlation was found between tractography findings and patient's clinical recovery. All the patients with disruption of white matter tracts had residual deficits on clinical follow-up, whereas the patients with displaced tracts had near complete neurological recovery. CONCLUSION: Diffusion tensor imaging and MR tractography provide a novel and useful method to directly visualise changes in the white matter tracts in stroke. This can potentially allow clinical-imaging correlation with prognostic potential.

Cardio-protective role of Terminalia arjuna bark extract is possibly mediated through alterations in thyroid hormones.

Terminalia arjuna bark extract is believed to exhibit cardio-protective effects. In the present study we investigated the possible involvement of thyroid hormones in the amelioration of cardiac and hepatic lipid peroxidation (LPO) by a bark extract of the plant in albino rats. While L-thyroxine (L-T4) treatment increased the level of thyroid hormones, heart/body weight ratio as well as cardiac and hepatic lipid peroxidation, simultaneous administration of 21.42 and 42.84 mg/kg of the plant extract decreased the level of thyroid hormones and also the cardiac LPO, suggesting the possible mediation of the drug action through an inhibition in thyroid function. These effects were comparable to a standard antithyroid drug, propyl thiouracil (PTU). When the drug was administered to euthyroid animals, serum concentrations of thyroid hormones were decreased, whereas the hepatic LPO increased indicating a drug induced toxicity in euthyroid subjects. Although a suboptimal dose of the drug was found to be non-toxic to the liver, it appeared to be of no use, as it could neither affect the thyroid functions nor the cardiac lipid peroxidation. Since in euthyroid animals, thyroid hormones were decreased and hepatic LPO was increased, it is suggested that high amounts of this plant extract should not be consumed, as hepatotoxicity as well as hypothyroidism may be caused.

Activity-regulated, cytoskeleton-associated protein (Arc) is essential for visceral endoderm organization during early embryogenesis.

Activity-regulated, cytoskeleton-associated protein (Arc) was first identified as an immediate-early gene regulated by synaptic activity. We have studied its functional role in vivo using a gene-targeting approach. We found that Arc is encoded by a single exon, and Arc mRNA is ubiquitously expressed in early mouse embryos. Homozygous Arc mutants are severely growth-retarded, fail to gastrulate and subsequently die before day 8.5 of embryogenesis. Further analysis revealed severe disorganization of visceral endoderm formation, and total separation and ectopic location of embryonic and extraembryonic structure. These findings demonstrate that Arc function is essential for early embryo development and patterning in mice, and support the hypothesis that signaling from visceral endoderm is essential for normal patterning of the extraembryonic and embryonic structure.

Phase I trial of subcutaneous recombinant human interleukin-12 in patients with advanced renal cell carcinoma.

Patients with advanced renal cell carcinoma were treated in a Phase I trial with escalating doses of recombinant human interleukin-12 (rHuIL-12) given on days 1, 8, and 15 of each 28-day cycle. Treatment in the initial dose scheme consisted of a fixed dose with dose levels of 0.1, 0.5, and 1.0 microg/kg given to cohorts composed of three or six patients. On the basis of the toxicity profile, a second scheme (up-titration) was undertaken wherein rHuIL-12 was escalated for each patient from week 1 to week 2, to a target dose given week 3 and thereafter; cohort target dose levels were 0.5, 0.75, 1.0, 1.25, and 1.5 microg/kg. Fifty-one patients were treated: 32 (63%) had prior cytokine therapy and 19 (37%) had received no prior systemic therapy. The maximum tolerated dose for the fixed dose scheme was 1.0 microg/kg. Dose-limiting toxicities included increase in transaminase concentration, pulmonary toxicity, and leukopenia. The most severe toxicities occurred with the first injection and were milder upon further treatment. With the up-titration dose scheme, the maximum tolerated dose was reached at 1.5 microg/kg, and dose-limiting toxicity consisted of an increase in serum transaminase levels. At the maximum tolerated dose of 1.5 microg/kg, serum IL-12 levels increased to a mean peak level of 706 pg/ml. Serum levels of IFN-gamma increased to a mean peak level of about 200 pg/ml at 24 h after the first maintenance dose of 1.5 microg/kg. The best responses were as follows: one patient had complete response, 34 patients were stable, 14 patients showed progression, and 1 patient was inevaluable. In conclusion, rHuIL-12 was relatively well tolerated when administered by s.c. injection. The recommended dose according to the up-titration schedule of rHuIL-12 (microg/kg) for Phase II trials was as follows: cycle 1, 0.1 (day 1), 0.5 (day 8), 1.25 (day 15); cycle 2 onwards, 1.25. Phase II trials of rHuIL-12 were initiated in previously untreated patients with renal cell carcinoma and in patients with melanoma.

Normal variants of the intracranial circulation demonstrated by MR angiography at 3T.

Magnetic resonance angiography (MRA) at 3T offers increased signal to noise ratio with better background suppression, leading to exquisite depiction of the intracranial circulation. We present a pictorial review of the normal variations and anomalies of the intracranial circulation detected on MRA performed on a high field 3T clinical scanner using parallel imaging techniques. The salient imaging features of these anomalies and normal variations are discussed with relevance to clinical practice.

The role of the IPSS (International Prostate Symptoms Score) in predicting acute retention of urine in patients undergoing major joint arthroplasty.

BACKGROUND: Acute urinary retention following major joint arthroplasty is common. It does necessitate instrumentation, puts patients at risk of complications, and causes discomfort and embarrassment. The aim of the study was to find a test to help the surgeon to predict the possibility of acute retention of urine. METHODS: Male patients admitted for elective major joint arthroplasty filled in an IPSS (International Prostate Symptoms Score) during the pre-operative visit. They were observed post-operatively to document if they passed urine spontaneously or went into acute retention. RESULTS: There was a strong correlation between the IPSS and the likelihood of developing acute retention. Patients with moderate to high IPSS had a 55% to 100% chance of developing acute retention of urine, respectively. CONCLUSION: The IPSS proved to be a simple and reliable test to help the surgeon in predicting the possibility of developing acute retention. It might be a good addition to the pre-admission clinic investigations in patients undergoing major surgery. It could consolidate the decision to pre-emptive catheterisation in patients at risk.

Therapeutic response to somatostatin analogue, BIM 23014, in metastatic prostatic cancer.

Metastatic prostate cancer is well known to respond to hormonal manipulations, but once progression occurs new treatment modalities are required. Specific and systemic antitumour therapy is preferable to local treatments such as radiotherapy in such patients. The finding that somatostatin analogue, BIM 23014, inhibits prostatic tumour growth in animal models is of great interest. We treated 25 poor risk patients with progressive metastatic prostate cancer. Sixteen had also failed to respond to 'total androgen blockade'. Two patients have achieved a partial remission, one of which is maintained at over 30 months, and three had stable disease for over 6 months. Side effects have consisted of mild diarrhoea and abdominal cramp in the first few days of treatment in a minority of the patients. These results are encouraging and further randomized studies are in progress.

Prednimustine (Sterecyt) versus cyclophosphamide both in combination with methotrexate and 5-fluorouracil in the treatment of advanced breast cancer.

153 women with advanced breast cancer were randomly allocated for treatment with SMF [prednimustine (Sterecyt) + methotrexate + 5-fluorouracil, 83 patients] or CMF (cyclophosphamide+methotrexate+5-fluorouracil, 70 patients). Prednimustine was administered orally 100 mg/m2 daily, for 5 days, and cyclophosphamide was administered orally 100 mg/m2, for 14 days, each, every 4 weeks. Methotrexate was given at a dose of 40 mg/m2 and 5-fluorouracil at 600 mg/m2 on day 1 and 8, every 4 weeks. Leucovorin was used in 39 patients to alleviate mucositis. The two treatment groups were balanced in terms of age, performance status, lymph node status, histology, menopausal status and previous therapy. Response was evaluated in 140 patients. Of 76 patients treated with SMF, 4 had a complete and 21 a partial response (CR+PR = 33%), 40 had no change (NC) and 11 had progressive disease (PD). Of 64 patients treated with CMF, 3 had a complete and 18 a partial response (CR+PR = 33%), 30 had no change (NC) and 13 had progressive disease (PD). Time to treatment failure and survival were similar in both groups. A relationship between haematological and gastrointestinal toxicity and therapeutic efficacy was demonstrated with a superior survival and response rate recorded for patients with such toxicity than in patients without. Haematological toxicity was, in general, mild to moderate with no difference between the two groups. Alopecia (P = 0.008), nausea/vomiting (P = 0.02) and euphoria (P = 0.03) were more common in the CMF-treated group. Diarrhoea was more common in the SMF group (P = 0.03). In conclusion, SMF seems to be as efficient as CMF with regard to response rate, time to treatment failure and survival. However, SMF was tolerated better than CMF.

Imaging findings in rabies encephalitis.

SUMMARY: Rabies encephalitis is perhaps one of the few infectious diseases that command attention and fear not only from the layman but also from physicians. The unique mode of transmission, the virtually exclusive neurotransmission shown by the agent, and the complete hopelessness of the established disease sets rabies apart from other zoonoses transmitted to man. Rabies encephalitis is a fatal disease and its diagnosis is usually based on the clinical presentations and findings. Hence, imaging in rabies is seldom done, and imaging findings in rabies encephalitis have rarely been described. We present the imaging findings in two confirmed cases of rabies encephalitis in which antemortem diagnosis was obtained by corneal impression smears showing the presence of viral antigens. The differential diagnosis of the imaging findings as well as the role and the relevance of imaging in the diagnosis of this disease are discussed. The current literature on the subject is also reviewed.

Therapy of advanced ovarian cancer with D-Trp-6-LH-RH (decapeptyl) microcapsules.

Forty-one patients with advanced ovarian cancer (FIGO stage III or IV) who had relapsed following conventional treatment were treated with long acting depot preparation of D-Trp-6-LH-RH once a month. There were no exclusion criteria and patients of any age or performance status were eligible. Thirty patients continued to progress following therapy. Twenty-six patients died within the first 16 weeks from onset of therapy. Five patients remained stable (SD) on D-Trp-6-LH-RH with no change in tumor size. Six patients had evidence of clinical and/or radiological partial remission (PR) where the tumor size decreased by more than 50%. The remissions in the responding patients were maintained for a mean duration of 10 months (range 6-18 months). Thus 11 patients (6 PR + 5 SD) have had remission or stabilization of disease which has been clinically worthwhile. Clinical benefit of therapy with microcapsules of slow-release D-Trp-6-LH-RH in about 26% of patients is highly encouraging. Treatment with D-Trp-6-LH-RH offers an important non-toxic alternative in patients who do not tolerate chemotherapy or who have progressive disease following chemotherapy.

How would you like to have an orchidectomy for advanced prostatic cancer?

One hundred thirteen patients were randomized for the study. There was no significant difference between the groups for response or survival. The incidence of side effects related to the reduction of testosterone was similar in both groups. Disease "flare" was seen in three patients treated with long-acting D-Trp-6 LH-RH. All symptoms resolved by the end of 8 weeks. There was less psychological morbidity in the D-Trp-6 LH-RH group but the difference did not reach statistical significance. Our results indicate that long-acting D-Trp-6 LH-RH offers a safe and effective alternative to surgical orchidectomy.

Female genital tuberculosis: hysterosalpingographic appearances.

Genital tuberculosis is an important cause of infertility in developing countries and hysterosalpingography (HSG) is the initial procedure performed for the evaluation. Reviewing 37 cases of female genital tuberculosis, we encountered various appearances on HSG. Of 579 HSGs performed over a period of 4 years, 492 (85%) were performed as part of infertility work up. Genital tuberculosis was found in 6.3% of all the patients who underwent HSGs and 7.5% of all patients investigated for infertility. The various features of proven tuberculosis cases are illustrated in this pictorial review. We briefly discuss the pathology and these appearances along with radiopathological correlation.

Intra-articular fractures of the calcaneum treated operatively or conservatively. A prospective study.

We report a prospective trial of 66 patients with intraarticular fractures of the calcaneum. All fractures were assessed by CT. Patients with displaced fractures were randomised to receive either conservative (n = 31) or operative treatment (n = 25). Undisplaced fractures (n = 10) were treated conservatively. Operation involved open reduction of the posterior subtalar joint, and fixation with Kirschner wires. All 66 patients were reviewed at a minimum of one year (mean 23 months). After conservative treatment the undisplaced fractures had slightly better results than the displaced fractures. There was no significant difference in outcome between the operatively and the conservatively treated displaced fractures. We have also documented prospectively the natural history of the injury, which is of use in assessing prognosis for both clinical and medicolegal purposes.