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OBJECTIVE: To analyze reasons for low enrollment in a randomized controlled trial (RCT) of the effect of hydrocortisone for cardiovascular insufficiency on survival without neurodevelopmental impairment (NDI) in term/late preterm newborns. STUDY DESIGN: The original study was a multicenter RCT. Eligibility: ⩾34 weeks' gestation, <72 h old, mechanically ventilated, receiving inotrope. Primary outcome was NDI at 2 years; infants with diagnoses at high risk for NDI were excluded. This paper presents an analysis of reasons for low patient enrollment. RESULTS: Two hundred and fifty-seven of the 932 otherwise eligible infants received inotropes; however, 207 (81%) had exclusionary diagnoses. Only 12 infants were randomized over 10 months; therefore, the study was terminated. Contributing factors included few eligible infants after exclusions, open-label steroid therapy and a narrow enrollment window. CONCLUSION: Despite an observational study to estimate the population, very few infants were enrolled. Successful RCTs of emergent therapy may require fewer exclusions, a short-term primary outcome, waiver of consent and/or other alternatives.

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OBJECTIVE: We conducted a post-hoc analysis of early inhaled nitric oxide (iNO)-randomized controlled trial data to identify associations pertinent to the management of moderate hypoxic respiratory failure in term/late preterm infants. STUDY DESIGN: Univariate and multivariate logistic regression analyses were used to determine risk factors for the progression of respiratory failure and extracorporeal membrane oxygenation (ECMO)/death. RESULT: Among the 299 enrolled infants, oxygenation index (OI) <20 at enrollment (odds ratio 0.52, confidence interval (CI) 0.27 to 0.97) and surfactant use before randomization (odds ratio 0.47, CI 0.24 to 0.91) were associated with decreased ECMO/death rates. Early surfactant use for respiratory distress syndrome, perinatal aspiration syndrome and pneumonia/sepsis was associated with lower risk of ECMO/death (P<0.001). Early iNO (OI 15 to 25) decreased the progression of respiratory failure to OI >30 (P=0.002) and to composite outcome of OI >30 or ECMO/death (P=0.02). CONCLUSION: This post-hoc analysis suggests that early use of surfactant and iNO in moderate respiratory failure is associated with improved outcomes.

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BACKGROUND: Accelerated bone loss in patients with cancer is a frequent problem that may result from invasion of the cancer to bone, paraneoplastic tumor proteins, and/or hormonal therapies utilized for cancer treatment. Patients with osteolytic bone disease from multiple myeloma and bone metastases from solid tumors may develop a vicious cycle of bone destruction involving both osteolytic and osteoblastic effects. Consequently, a variety of skeletal-related events (SREs) may occur, including pathological fractures, hypercalcemia, spinal cord compression, and the need for surgical intervention and radiation therapy. METHODS: This article reviews the results of trials that investigated the safety and efficacy of pharmacologic agents, including bisphosphonates and denosumab, for treatment of bone metastases. This analysis is derived from an assessment of the medical literature. RESULTS: Beneficial systemic therapies for bone metastases have been developed to decrease SREs. Possible antitumor effects of the bisphosphonates are explored. In addition, the utility of markers of bone turnover in relation to response to therapy and survival, the safety and toxicity of bone-targeted therapies, treatment guidelines, and economic considerations are also discussed. CONCLUSIONS: Effective systemic therapies for metastatic bone disease are available. Ongoing and future research projects in this field are also presented.

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BACKGROUND: Topiramate was approved for the treatment of epilepsy in 1999 and has since been approved for the prevention of migraine headache. It is structurally different from the majority of antiepileptic medications and is pharmacodynamically unique in its ability to inhibit the enzyme carbonic anhydrase. Postmarketing reports of topiramate-associated hypothermia have occurred but this adverse event has not been well characterized. Data mining of an adverse event database was used to assist in the identification of hypothermia. OBJECTIVE: We sought to explore a possible association between the concomitant use of topiramate and valproic acid and the induction of hypothermia. METHODS: This was a pharmacovigilance case series survey of spontaneous hypothermia, a reported adverse event in patients treated with topiramate and valproic acid, alone and in combination. The U.S. Food and Drug Administration's Adverse Events Reporting System (AERS) database was searched for reports of hypothermia in association with the use of topiramate. A data mining algorithm was used on the AERS to identify scores for hypothermia associated with antiepileptic drugs. RESULTS: We identified 22 unduplicated reports of hypothermia in patients exposed to topiramate. Three of the 22 were confounded by patient overdoses with multiple drugs and not considered. Use of more than one antiepileptic drug was reported in most of the remaining 19 reports. Of these 19 reports, valproic acid was mentioned in 7. Two of the 19 reports mentioned topiramate only. Eleven of the 19 patients were men. The median age of the 19 patients was 40 years (range, 3(1/2)-82 years). Body temperatures ranged from 29.5 degrees C (moderate hypothermia) to 35 degrees C (mild hypothermia) with a median of 34 degrees C. Eleven of 18 reports of hypothermia occurred during the cooler months (one report did not indicate the time of year in which hypothermia occurred). Comorbid conditions included hypothyroidism in six reports, five in patients who received valproic acid concomitantly with topiramate and five reports of hyperammonemia in similarly treated patients. Data mining scores (empirical Bayes geometric mean) for antiepileptic drugs ranged from a high of 5.845 for phenobarbital to 2.956 for gabapentin. Hypothermia was reported 4.7 times more frequently when topiramate was used than was statistically expected. CONCLUSION: We have found hypothermia, defined as an unintentional drop in body core temperature to <35 degrees C, to be associated with concomitant administration of topiramate (a carbonic anhydrase inhibitor) and valproic acid in patients who have tolerated either drug alone. Data mining analysis for topiramate showed a signal of hypothermia. Topiramate was reported 4.72 times more frequently in the database than would be statistically expected when considering all other drugs. Topiramate may act pharmacodynamically to potentiate the effects of valproic acid as a result of its ability to decrease blood HCO(3) (-) and increase blood ammonia levels.

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The aim of this prospective 4-yr study was to analyse changes in mean plantar pressure (PP) over time and local shifts of maximal PP in Type 2 diabetic patients. One-hundred fifty-five Type 2 diabetic patients (age 58.9 +/- 7.5 yr, diabetes duration 11.0 +/- 7.6 yr, baseline HbA1c 9.6 +/- 1.6%) were examined with regard to foot abnormalities, neuropathy and measurement of PP during walking (pedobarography). They were assigned to two subgroups, namely normal PP (n=94) and elevated PP (n=57). Patients with an abnormal mean PP did not significantly differ from subjects with a normal PP with regard to sex, age, duration of diabetes and HbA1c. With the exception of the hallux, the mean PP was significantly increased in both groups at all other plantar sites. Maximum PP was located below the metatarsal heads (MTH) 2-5 and significantly increased from baseline (median, lower/upper quartile: 475, 355/715 kPa) to the end of the study (540, 435/749; p<0.0001). On the other hand, PP was normalized in 17 subjects (29.8%) who had an elevated PP at baseline. Furthermore, we observed a local shift in maximal PP towards the MTH 2-5 region. The percentage of patients who had their highest PP under MTH 2-5 was increased from 54.0% at baseline to 61.1% at the end of the study. In general, we registered an elevation of PP over time and a centralization towards sites which are generally prone to ulceration.

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AIMS/HYPOTHESIS: To re-evaluate the use of Granulocyte-Colony Stimulating Factor (G-CSF) in the treatment of infected diabetic foot ulcers. METHODS: Thirty-seven diabetic subjects were randomised to Granulocyte-Colony Stimulating Factor (G-CSF) (n=20) or placebo (n=17). The primary endpoint was resolution of cellulitis, which was evaluated clinically and with an infection summary score. Patients were hospitalised for 10 days and received subcutaneously either 5 microg/kg G-CSF or placebo daily. Ulcers were treated with a standard wound protocol and the patients were instructed to stay in bed. All subjects received antibiotics (clindamycin and ciprofloxacin) intravenously until the inflammation had subsided. RESULTS: Patients who received G-CSF did not have an earlier resolution of clinically defined cellulitis (p=0.57). The infection summary score declined, but comparably, in both groups (G-CSF: 29.5+/-18.4 to 6.7+/-6.3 p<0.001, placebo: 24.2+/-16.9 to 8.9+/-7.2 p<0.001). The ulcer volume, which was not greater among placebo patients, was reduced by 59% in G-CSF and by 35% in placebo patients. CONCLUSION/INTERPRETATION: We conclude that antibiotic and non weight-bearing therapy (bed rest) accelerated the resolution of cellulitis in infected foot ulcers. Additional treatment with G-CSF had no further beneficial effect.

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One hundred eighty-seven type 2 diabetic patients without a history of foot ulceration were followed for a mean period of 3.6 years to investigate the incidence of foot ulceration in a diabetes cohort and to analyze risk factors for foot ulceration by multivariate means. During the study, 10 subjects developed 18 forefoot ulcerations. In multivariate logistic regression, significant predictors for foot ulceration were an elevated vibration perception threshold (VPT) (relative risk [RR] = 25.4), an increased plantar pressure (RR = 6.3), and daily alcohol intake (RR = 5.1). This is the first prospective study to demonstrate plantar pressure and daily alcohol intake as predictors of foot ulceration among patients without previous ulceration. Further, VPT could be confirmed as the strongest predictor for foot ulceration, and it was clearly demonstrated that the more pronounced severity of complications occurred among subjects with elevated VPT.

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We set out to evaluate changes in arterial oxygen tension (PaO(2)) when weaning neonates from inhaled nitric oxide (INO). We reviewed the records of 505 prospectively collected INO weaning attempts on 84 neonates with hypoxic respiratory failure. PaO(2) values before and 30 min after weaning attempts were recorded. Relationships between change in PaO(2) and decreases in INO concentrations were investigated using regression analysis and ANOVA. PaO(2) decreased (-18.7 +/- 1.8 torr; P < 0.001); when weaning INO. A stepwise decline in PaO(2) was observed weaning INO from 40 ppm. The greatest decline occurred when INO was discontinued (-42.1 +/- 4.1 torr). Forward stepwise multiple regression using variables with significant relationships to the decline in PaO(2) identified the specific dose reduction 7(P < 0.001), the prewean PaO(2) (P < 0.001), and surfactant therapy (P = 0.018) as the variables best describing the change in PaO(2)(P = 0.004, r = 0.51). In conclusion, a graded decline in PaO(2) occurs when reducing INO. INO should be weaned to less than 1 ppm before discontinuing its use. Prior surfactant treatment appears to enhance the oxygenation reserve when weaning INO.

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The main risk factors for plantar forefoot ulcers are loss of protective sensation due to sensory neuropathy and increased mechanical stress on the sole of the foot. The aim of this study was to find a better parameter than the plantar pressure to explain the occurrence of plantar ulcers under the metatarsalheads (MTHs). Twenty diabetic patients (3 Type 1 and 17 Type 2) each with 1 plantar ulcer and 23 Type 2 diabetic patients without plantar ulceration (controls), were investigated. The parameters of plantar pressure, length of contact time and pressure-time integral (PTI) were determined by pedography at defined foot regions. PTI represents the duration of mechanical stress on the foot. Based on the distribution of ulcers, the ratio of stress on the MTHs to that on the big toe was calculated. In diabetic patients with ulcers the difference of PTI between MTHs and hallux was higher at 153% and hence 3.2 times greater than the difference in plantar pressure between MTHs and hallux of 47.3%. In the control group the ratio of difference had a factor of 2 only because the corresponding difference in PTI was 85.1% and the difference in plantar pressure was 43.1%. These results may indicate that increased stress at the MTHs is responsible for the occurrence of planar ulcers compared with other regions of the sole. Diabetic patients with elevated PTI ratio are at risk of developing foot ulcers and therefore have to be provided with orthopaedic shoes to prevent foot ulceration.

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BACKGROUND: Nitrogen dioxide (NO2) is a toxic by-product of inhalation therapy with nitric oxide (NO). The rate of NO2 formation during NO therapy is controversial. METHODS: The formation of NO2 was studied under dynamic flows emulating a base case NO ventilator mixture containing 80 ppm NO in a 90% oxygen matrix. The difficulty in measuring NO2 concentrations below 2 ppm accurately was overcome by the use of tunable diode laser absorption spectroscopy. RESULTS: Using a second-order model, the rate constant, k, for NO2 formation was determined to be (1.19 +/- 0.11) x 10(-11) ppm-2s-1, which is in basic agreement with evaluated data from atmospheric literature. CONCLUSIONS: Inhaled NO can be delivered safely in a well-designed, continuous flow neonatal ventilatory circuit, and NO2 formation can be calculated reliably using the rate constant and circuit dwell time.

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There is a causal relationship between diabetic foot ulceration, elevated plantar pressure, and severe sensory neuropathy. Cushioned footwear intended to relieve plantar pressure is well established for prevention and healing of plantar ulcers. The aim of the present study was to investigate whether pressure relief by means of a running shoe with optimized forefoot pressure damping is comparable to that of a custom-made soft insole placed into an in-depth shoe. The in-shoe pressures were compared to an in-depth shoe with the original cork insole and with a leather-soled Oxford shoe. The maximum reduction of plantar pressure in the running shoe was 47% under the 2nd and 3rd metatarsal heads, 29% at the first metatarsal head, and 32% at the great toe in comparison to the Oxford shoe. This was surpassed only by the custom-made insole, which reduced pressures at the metatarsal heads by 50%. The specially designed running shoe yielded the same pressure relief at the central metatarsal heads as the custom-made insole. Such shoes are likely to be very useful in preventing diabetic foot ulceration in high-risk patients as a comparatively affordable and immediately available device.

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OBJECTIVE: Our purpose was to measure umbilical blood flow continuously by use of a transit time ultrasonic flow transducer and to compare the blood flow measurements with the steady-state diffusion method in the chronic fetal sheep preparation. STUDY DESIGN: We compared umbilical blood flow measurements calculated by the steady-state diffusion method with ethanol as the diffusing substance and with the transit time ultrasonic flow transducer placed on the common umbilical artery in five chronically prepared fetal sheep. RESULTS: There was no statistical difference between measurements of umbilical blood flow measured by the flow transducer versus the steady-state diffusion method, 600 +/- 22 versus 664 +/- 56 ml per minute (mean +/- SEM) (p = 0.23). The mean coefficient of variation within each study was 13.6% for the steady-state diffusion method versus 4.1% for the transit time flow transducer. Umbilical blood flow variance was significantly lower as measured by the flow transducer compared with the diffusion method (p < 0.0001). There were no differences in umbilical blood flow per kilogram or fetal oxygen uptake between the two methods. CONCLUSION: We conclude that umbilical blood flow can be measured continuously under steady-state conditions by use of a transit time flow transducer. Because of the lower variability in the flow transducer-obtained measurements, we speculate that the flow transducer may differentiate alterations in umbilical blood flow with greater precision in chronic preparations. This may be advantageous for measuring absolute changes in fetal substrate uptake, especially under non-steady-state conditions.

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Immunological response against myocardial antigens was assessed in 12 patients (pts) (9 males, 3 females, aged 24-62 years) with aortic homografts (AH) and 36 pts (29 males, 7 females, aged 26-61 years) with aortic valve prostheses (AVP). In all pts a titre of anti-myocardial antibodies, a concentration of free-circulating immune complexes and leucocytes migration inhibition test with myocardial antigen were assessed before operation and 1, 12, 24 months after operation. In 20 pts with AH immunological humoral response against HLA antigens was evaluated. After the operation pathological indexes of immunological response against myocardial antigens were observed both in pts with AH as in pts with AVP. The mean titre of anti-myocardial antibodies before operation was in both groups between 1:4 and 1:8, and 1 month after operation between 1:32 and 1:64. In 12 and 24 months after operation the mean titre in AH and AVP group was respectively 1:8 and 1:4. Before operation pathological concentration of immune complexes (> 0.084 mg/ml) was observed in 17% AH and 11% AVP pts. Pathological elevation of immune complexes 1, 12 and 24 months after operation was observed respectively in AH and AVP group in 58%, 42%, 33% and 67%, 50%, 42%. Leucocyte migration inhibition index was pathological (< 0.8) before operation in 58% in both groups, and 1, 12, 24 months after operation was pathological in AH and AVP group respectively in 67%, 17%, 17% and 61%, 33%, 31%. In most pts of both groups immunological response against myocardial antigens was transient and was terminated up to 12-24 months after operation.(ABSTRACT TRUNCATED AT 250 WORDS)

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The results of surgical treatment of 220 patients with acquired aortic valve malformations using two different methods were evaluated 5 years postoperatively. In 130 patients the aortic valve was replaced with "fresh" allograft and in the remaining 90 with prosthetic valve. In the group with allograft compared to patients after prosthetic valve implantation we have found: lower early mortality of 3% (p less than or equal to 0.01) (vs. 15.5%) higher probability of 5 years survival of 91.5% (p less than or equal to 0.001) (vs. 74.6%) low incidence of thromboembolic events of 1.7% (p less than or equal to 0.05) (vs. 8.8%) Allografts appear to be especially advisable and well tolerated in patients with active endocarditis. No statistically significant difference was found between both groups in relation to: probability of late death (5 years postoperatively), frequency of bacterial endocarditis during the postoperative course, frequency of valve failure. Slow increase of degenerative alterations during the succeeding postoperative years was distinctive for allografts, and the dysfunction of the implants appeared from the third postoperative year with the risk of 1.5% to 0.8% annually. Dysfunction of the prosthetic valve (perivalvular leak, thrombosis) was observed with the frequency of 5% to 1.3% annually. It developed quickly and usually was the cause of an urgent operation. The study demonstrates the advantages of allografts and their superiority over the prosthetic valves. Allograft implantation produces better life comfort for patients and diminishes or excludes the risk of thromboembolic complications.

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A new method known as pedography enables the measurement of plantar pressure while walking. Different areas on the sole can be separately analyzed by means of a personal computer. We studied plantar pressure in 20 patients walking normally on a horizontal platform. Four different stages of weight bearing were investigated, namely 0, 10, 20, and 30 kg, in the ten diabetics and ten non-diabetics. All diabetic suffered from peripheral neuropathy, which was clinically proven as well as a reduction in nerve conduction velocity in the peroneal nerve. Non-diabetics showed no abnormal clinical findings on the lower extremities and nerve conduction velocity was within the normal range. The mean age and size differed between the diabetics and non-diabetics 52 +/- 5 versus 37 +/- 7 and 178 +/- 5 versus 185 +/- 4. Body weight was equal (84 +/- 6 versus 85 +/- 5 kg). We found no significant difference in maximum pressure on the heel, though there were differences on the fore-foot. Diabetics showed a higher maximum pressure already without weight bearing and reached a plateau at the 10 kg level, which was not exceeded at the higher stages of weight bearing. In summary, diabetic patients with neuropathy are subjected to very high plantar pressures at relatively low stages of weight bearing. Pedography enables preventive measures to be undertaken in time, e.g. prescription of orthopaedic insoles.

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The absorption of oral digoxin and of desmethyldiazepam, from its precursor clorazepate, was studied in seven patients who had received abdominal and/or pelvic radiation therapy for neoplastic disease. All patients were in remission and had normal renal function and no evidence of malabsorption. Single 0.5-mg doses of digoxin tablets and 15-mg doses of clorazepate were administered in the fasting state. Concentrations of digoxin (by radioimmunoassay) and desmethyldiazepam (by gas chromatography) were determined in multiple plasma samples and all urine collected during 24 hours after dosage. The mean (+/- S.E.) weight-normalized area under the 24-hour plasma digoxin concentration curve (WtN-AUC-24) in the patients (722 +/- 40 ng/ml-hr-kg) was similar to that in five normal controls (713 +/- 57 ng/ml-hr-kg), but 24-hour urinary excretion of digoxin in patients (54.5 +/- 4.4 microgram) was significantly less (P less than 0.025) than in controls (83.4 +/- 11.4 microgram). Neither age, sex, nor renal function explained the difference. In the clorazepate study, WtN-AUC-24 for desmethyldiazepam in the patients (187 +/- 19 microgram/ml-hr-kg) was significantly less (P less than 0.01) than in 15 normal control subjects (230 +/- 5 microgram/ml-hr-kg). Age and sex did not explain the difference. Thus, radiation therapy, or the underlying disease, is associated with malabsorption of these two drugs, possibly because of damage to gastric acid-secreting cells.

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The case records of 81 patients over the age of 60 were reviewed with respect to complications following lymphangiography. Adverse prognostic factors and complications were studied. Of the 81 patients, 48 were 60-69 years old and 33 were 70 or older; 19 patients had mild risk factors and 16 had severe risk factors. There were only six complications secondary to lymphangiography--two moderate and four mild. No severe complications were noted. This study suggests that age in itself is not a contraindication to lymphangiography.

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Biotransformation of chlordiazepoxide was studied in mice following a single 1000-rad dose of hepatic irradiation. Meabolic N-demethylation of chlordiazepoxide in irradiated mice was impaired when tested 3 days after irradiation. No such effect was observed in mice tested 3 weeks or 6 weeks after irradiation. Thus, hepatic irradiation appeared to produce short-lived, reversible impairment of drug-metabolizing function. The effect was small and of uncertain biological significance.

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