Efficacy and safety of certolizumab pegol for Crohn's disease in clinical practice.

BACKGROUND: Certolizumab pegol (CZP) is Food and Drug Administration (FDA)-approved to treat Crohn's disease (CD). However, the efficacy and safety of CZP outside clinical trials are not well established. AIM: To report the efficacy, safety and predictors of response to CZP in CD patients treated during a 6-year period since FDA-approval at a tertiary care centre. METHODS: All CD patients who received CZP at our institution between 2008 and 2013 were evaluated through retrospective medical record-based review of steroid-free complete response (SCR), loss of response and safety. RESULTS: A total of 358 patients were included. One hundred twelve patients (31.3%) and 189 (52.8%) received CZP as their second and third biological agent, respectively. The probability of SCR at 26 week was 19.9% (95% CI, 15.9-24.5). The probability of survival free of loss of response at 2 year was 45.7% (95% CI, 32.5-59.5). A predictor of SCR was age at CD diagnosis of >40 years old (hazard ratio, HR relative to those <17, 4.69; 95% CI, 1.75-12.61). Negative predictors included present perianal fistula (HR, 0.39; 95% CI, 0.16-0.98) and prior primary nonresponse to adalimumab (ADA; HR relative to secondary loss of response, 0.18; 95% CI, 0.04-0.76). Twenty-three patients (6.4%) experienced serious adverse events and 19 patients (5.3%) discontinued CZP due to adverse events. CONCLUSIONS: Certolizumab pegol was both effective and well tolerated for the treatment of Crohn's disease in this large tertiary care centre enriched with biologics-exposed patients. It may be more effective in patients without early-aged Crohn's disease diagnosis, prior primary nonresponse to adalimumab and present perianal fistula.

Natalizumab for moderate to severe Crohn's disease in clinical practice: the Mayo Clinic Rochester experience.

BACKGROUND: Not all patients with Crohn's disease (CD) respond or maintain response to anti-tumor necrosis factor (TNF) agents and alternative treatment is necessary. Natalizumab, a monoclonal antibody to alpha-4 integrin approved for CD, has demonstrated efficacy in randomized clinical trials. We describe our experience with natalizumab in clinical practice at Mayo Clinic Rochester. METHODS: Consecutive patients prescribed natalizumab for active CD were invited to participate and were followed prospectively. Incidence of infection, hospitalization, neoplasm, or other adverse events were recorded. Clinical activity was assessed using the Harvey-Bradshaw Index at each 30-day infusion visit. RESULTS: Between April 2008 and September 2010, 36 patients were prescribed natalizumab and 30 (83.3%) agreed to participate. Median disease duration was 9 years (range, 3-43). Twenty-three patients had prior exposure to two anti-TNF agents, seven to one agent. All patients experienced at least one adverse event; none of the 13 patients in whom natalizumab was stopped (43%) discontinued due to adverse events. Five patients had infusions held for infection. No patient developed progressive multifocal leukoencephalopathy (PML). Fourteen patients (46%) had clinical response. The cumulative probability of achieving complete response within 1 year was 56% (28%-73%). Four of seven patients were weaned off corticosteroids. CONCLUSIONS: In our experience with natalizumab in clinical practice, adverse events were manageable and did not result in treatment cessation. No PML cases were seen and clinical response was similar to that in clinical trials. Natalizumab results in clinical benefit in patients who have active disease and have failed anti-TNF therapy.

Suicide methods in the elderly in South Australia 1981-2000.

The files of the Forensic Science Centre in Adelaide, Australia were examined over a 20-year period from 1981 to 2000 for cases of suicide in individuals aged 65 years and over. A total of 445 cases were found (13.8% of all suicides) with an age range of 65-94 years (average= 73.5 years). All cases had undergone full autopsies and police investigation. There were significantly more male than female victims; M:F = 330:115 (p < 0.001). Hangings accounted for the highest proportion of cases (107/445; 24%) followed by gunshot wounds (96/445; 21.6%), drug toxicity (82/435; 18.9%), drowning (66/445; 14.8%), and carbon monoxide toxicity (52/445; 11.7%). A miscellaneous group accounted for 42 of 445 cases (9.2%). No significant changes occurred in either the total suicide rate or in the rates in males and females, except for drowning deaths in males, which showed a significant decrease over time (p < 0.01). Female victims tended to avoid violent methods such as gunshot wounds in favour of drug overdose. Gunshot wound deaths were far less common than published data from other countries would indicate, with relative increases in deaths due to hanging, drug toxicity, drowning and carbon monoxide toxicity. An awareness of the considerable variability that occurs among populations in suicide methods and rates is important in determining local requirements for suicide prevention campaigns.

Death due to electrocution in childhood and early adolescence.

OBJECTIVES: To delineate the clinicopathological features of fatal childhood electrocutions and to identify specific risk factors. METHODS: Coronial files in Adelaide (Australia) were searched from 1967 to 2001 and Medical Examiners' files in San Diego (USA) were searched from 1988 to 2001, for cases of deaths of children and adolescents younger than 16 years attributed to electrocution. RESULTS: Sixteen cases were identified aged between 10 months and 15 years (mean 8.0 years) with a male : female ratio of 5 : 3. Deaths were due to accidents occurring while playing with or near faulty electrical equipment at home or at school (n = 8), electrical equipment while in the bath (n = 2), damaged outdoor electrical equipment (n = 1), overhead wires (n = 1), and a high voltage electricity substation (n = 1). In addition, one death was due to suicide involving an electrical appliance placed in a bath, and two other deaths occurred in older children who were moving equipment under overhead wires. No homicides were identified. CONCLUSIONS: Childhood deaths due to electrocution are rare and are more likely to occur when children are playing around electrical wires or equipment, and often result from either faulty apparatus, or a lack of understanding of the potential dangers involved. The majority of deaths (11/16; 69%) occur in the home environment. In contrast to adult electrical deaths, high-voltage electrocutions, suicides and workplace deaths are uncommon. Strategies for eliminating childhood electrocution should concentrate on ensuring safe domestic environments with properly maintained electrical devices.

Fatal unintentional traumatic asphyxia in childhood.

OBJECTIVE: The present study was undertaken to examine specific features of unintentional traumatic asphyxial deaths in childhood. METHODS: Coronial files and records at the Forensic Science Centre in Adelaide, South Australia, were examined over a 35-year period from 1966 to 2000 for all cases of traumatic asphyxial death occurring in children under the age of 17 years. RESULTS: Six cases of unintentional fatal traumatic asphyxia were identified. All of the victims were boys with an age range of 2-15 years (mean 6.8 years) and all were found dead at the scene. Fatal traumatic asphyxia resulted from entrapment beneath a chest of drawers, beneath a table tennis table, between a pile of wooden pallets and a metal fence, between a conveyor belt and its frame, and under a motor vehicle (in two cases). CONCLUSIONS: Fatal traumatic asphyxia in childhood is a rare event, with younger children commonly being trapped by furniture or by industrial equipment while playing, and older children being trapped under motor vehicles in similar circumstances to adult traumatic asphyxial deaths. Unsupervised play of young children around heavy and potentially unstable pieces of furniture may be dangerous, particularly if more than one child is present. Unsupervised play of young children in industrial yards should be avoided.

Upper airway occlusion by soil--an unusual cause of death in vehicle accidents.

Upper airway obstruction by soil is a rare cause of death in motor vehicle accidents. Four cases were found in a search of the records of the Forensic Science Centre in Adelaide, South Australia over a twenty-year period from January 1982 to December 2001. Case 1: A 68-year-old male driver died from sand inhalation after he was trapped in his vehicle following an accident. His mouth and upper airway were packed with sand. Case 2: A 33-year-old male pedestrian died from smothering after he had been knocked over and had his head pressed face down into sandy soil by a vehicle wheel. Case 3: A 12-year-old male passenger died from soil inhalation after the vehicle in which he was travelling rolled over and filled with soil. His mouth and upper airway were packed with soil. In these cases the victims had been trapped with the face covered in fine, or loose, soil or sand. In Case 4 a 41-year-old male passenger was ejected from a vehicle. He died from blunt chest trauma exacerbated by occlusion of the mouth and nose by soil. Careful scene descriptions are required in the assessment of such cases, in addition to evaluation of the relative contribution of injuries and asphyxia to the fatal episode.

Management of calcium oxalate stones.

This article discusses the incidence and prevalence of calcium oxalate renal stones. Etiology and risk factors for all renal stone formation are reviewed. The evaluation, diagnostic procedures, and management for new and recurrent stone formation are detailed. Management includes long-term pharmacologic and nonpharmacologic measures for successful prevention or reduction in the frequency of recurrent stones. Specific patient education factors, patient and family psychological aspects, and referral resources are discussed.

The hemodynamic effects of propofol in children with congenital heart disease.

UNLABELLED: We studied the hemodynamic effects of propofol during elective cardiac catheterization in 30 children with congenital heart disease. Sixteen patients were without cardiac shunt (Group I), six had left-to-right cardiac shunt (Group II), and eight had right-to-left cardiac shunt (Group III). The mean (+/-SD) ages were 3.8+/-3.1 yr (Group I), 3.2+/-3.7 yr (Group II), and 1.0+/-0.6 yr (Group III). After sedation and cardiac catheter insertion, hemodynamic data and oxygen consumption were measured before and after the administration of propofol (2-mg/kg bolus, 50- to 200-microg x kg(-1) x min(-1) infusion), and values were compared by using a paired t-test (significance: P < 0.05). After the propofol administration, systemic mean arterial pressure and systemic vascular resistance decreased significantly and systemic blood flow increased significantly in all patient groups; heart rate, pulmonary mean arterial pressure, and pulmonary vascular resistance were unchanged. Pulmonary to systemic resistance ratio increased (Group I, P = 0.005; Group II, P = 0.03; Group III, P = 0.10). In patients with cardiac shunt, propofol resulted in decreased left-to-right flow and increased right-to-left flow; the pulmonary to systemic flow ratio decreased significantly (Group II, P = 0.005; Group III, P = 0.01). Clinically relevant decreases in Pao2 (P = 0.008) and Sao2 (P = 0.01) occurred in Group III patients. We conclude that propofol can result in clinically important changes in cardiac shunt direction and flow. IMPLICATIONS: The principal hemodynamic effect of propofol in children with congenital heart defects is a decrease in systemic vascular resistance. In children with cardiac shunt, this results in a decrease in the ratio of pulmonary to systemic blood flow, and it can lead to arterial desaturation in patients with cyanotic heart disease.

Chronic pulmonary hypertension increases fetal lung cGMP phosphodiesterase activity.

An experimental ovine fetal model for perinatal pulmonary hypertension of the neonate (PPHN) was characterized by altered pulmonary vasoreactivity and structure. Because past studies had suggested impaired nitric oxide-cGMP cascade in this experimental model, we hypothesized that elevated phosphodiesterase (PDE) activity may contribute to altered vascular reactivity and structure in experimental PPHN. Therefore, we studied the effects of the PDE inhibitors zaprinast and dipyridamole on fetal pulmonary vascular resistance and PDE5 activity, protein, mRNA, and localization in normal and pulmonary hypertensive fetal lambs. Infusion of dipyridamole and zaprinast lowered pulmonary vascular resistance by 55 and 35%, respectively, in hypertensive animals. In comparison with control animals, lung cGMP PDE activity was elevated in hypertensive fetal lambs (150%). Increased PDE5 activity was not associated with either an increased PDE5 protein or mRNA level. Immunocytochemistry demonstrated that PDE5 was localized to vascular smooth muscle. We concluded that PDE5 activity was increased in experimental PPHN, possibly by posttranslational phosphorylation. We speculated that these increases in cGMP PDE activity contributed to altered pulmonary vasoreactivity in experimental perinatal pulmonary hypertension.

Developmental changes in lung cGMP phosphodiesterase-5 activity, protein, and message.

During transitional circulation, the pulmonary vascular bed undergoes a rapid and profound reduction in both tone and vascular smooth-muscle (VSM) content. 3',5'-Guanylate cyclic monophosphate (cGMP) is a crucial mediator in the regulation of pulmonary vascular resistance (PVR) and VSM proliferation. Hydrolysis of cGMP is achieved predominately by cGMP-specific phosphodiesterases (PDEs). Among the cGMP-specific PDEs, PDE5 is quantitatively prevalent in lung tissue. We have investigated the levels of pulmonary PDE5 enzymatic activity, protein, and messenger RNA (mRNA) in ovine and mouse lung during perinatal development. We report that within 1 h following birth, PDE5 activity, protein, and mRNA levels decrease in both species, in a manner that correlates with known decreases in PVR in early transition. However, from 4 to 7 d following birth, a secondary increase in PDE5 activity, protein, and mRNA occurs in both ovine and mouse lung, suggesting a complex regulation of PVR and VSM proliferation in late perinatal development. Our data imply that PDE5 may be an important mediator in the regulation of PVR in normal and possibly in pathologic states, and may ultimately provide a basis for PDE5 inhibitors as a treatment for pulmonary hypertension.

Current status of transurethral thermotherapy at the Mayo Clinic.

With the ever-expanding elderly population in the United States, benign prostatic hyperplasia (BPH) has become a widespread condition. Although surgical intervention (open prostatectomy and transurethral resection of the prostate) was the typical management approach for BPH in the past, other options currently include drug therapy and transurethral thermotherapy, a minimally invasive procedure that involves the targeting of heat deep within the prostate transition zone while cooling the surrounding anatomic structures with circulating water. Two thermo-therapy-devices--the Prostatron and the T3 transurethral thermoablation therapy catheter--have been studied in randomized controlled clinical trials at the Mayo Clinic. Both devices were shown to be effective in a substantial subset of patients with BPH: symptom scores decreased, peak urinary flow rates increased, and total serum prostate-specific antigen levels increased, an indication of destruction of adenomatous tissue. All patients were able to complete the treatment without the need for general or regional anesthesia, and thermotherapy was associated with few postprocedural events. Although this therapeutic strategy is currently used selectively in patients with lateral lobe prostatic adenoma, improvements in technology and understanding of the thermoregulatory properties of the prostate should broaden the application of thermotherapy devices in the management of BPH.

Correlation between prostate size estimated by digital rectal examination and measured by transrectal ultrasound.

OBJECTIVES: To correlate prostate size estimates performed by single or multiple examiners through digital rectal examination (DRE) with volume measured by transrectal ultrasound (TRUS) and to propose measures for predicting prostate volume using DRE estimates in clinical settings. METHODS: Data from four sources were analyzed: (1) the Olmsted County community study of 397 patients examined by a single urology nurse, with TRUS measurements done by multiple examiners; (2) a community study in Stirling, Scotland, involving 480 patients with DRE and TRUS performed by one urologist; (3) baseline data from the Veterans Affairs Cooperative Study No. 359 in 1222 patients with DRE and TRUS measurements by multiple personnel at 31 centers; and (4) a clinical series of 100 men with DRE and TRUS by a single urologist. RESULTS: DRE estimates and TRUS volumes were significantly correlated (r = 0.4 to 0.9), but prostate size was underestimated by 25% to 55% for men with a prostate volume over 40 mL, depending on the study, with greater variability for studies involving multiple examiners. In one study that assessed prostate dimensions by DRE, posterior surface area (SA) correlated with overall TRUS volume (r = 0.4). According to receiver operating characteristic curves, SA showed a 70% and 76% chance of correctly identifying men with prostate volume greater than 30 or 40 mL, respectively; those with larger prostates were best distinguished by SA greater than 7 cm2 (sensitivity greater than 0.74, specificity greater than 0.50). CONCLUSIONS: DRE underestimates prostate size, particularly if TRUS volume is greater than 30 mL. However, DRE estimates may help identify prostates likely to be larger than certain cutpoints by TRUS. Posterior SA may be useful as a preliminary assessment when prostate size is an important predictor of therapeutic response.

Role of a urology nurse in evaluating patients with prostatism.

Nurses play a prominent role in educating patients. This article presents experiences of one certified urology nurse collaborating with a urologist in the initial evaluation of 475 men randomly selected from the community for urinary symptoms or health status work-ups. Referrals to the urologist for further diagnosis and treatment were made for suspicion of prostate cancer, moderate to severe symptoms of prostatism, and microhematuria. The nurse also provided information about treatment options and watchful waiting. Participants showed a strong acceptance of the nurse in performing assessments.

Does the mode of questionnaire administration affect the reporting of urinary symptoms?

OBJECTIVES: To assess the effect of modes of administration (self-administered questionnaires, oral face-to-face interview, and telephone interview) on responses to the American Urological Association Symptom Index (AUASI) in randomly selected community men. METHODS: An age-stratified random sample of 475 white male residents of Olmsted County, Minnesota, aged 40 to 79 years, without prior prostate surgery or prostate cancer were queried about urinary symptom frequency twice at baseline and twice approximately 2 years later using questions with wording similar to the AUASI: At baseline and first follow-up, questionnaires were self-administered initially, followed by a structured interview by a female urology nurse within 2 to 28 weeks. A subset of 200 randomly selected men received a telephone interview by a female research assistant following the self-administered questionnaire given at a second follow-up approximately 4 years after baseline. RESULTS: Mean symptom scores obtained by oral interview were 1 to 2 points lower than those from self-administered questionnaires (P < 0.01). In a random subset (n = 200) interviewed by telephone, mean AUASI scores were as much as 4 points lower than those from self-completed questionnaires. CONCLUSIONS: Values of the AUASI obtained by interviewer administration may be lower than those obtained by self-administered questionnaires. When assessment of change in urinary symptoms over time is of interest, the same standardized method of questionnaire administration should be used at baseline and follow-up evaluations to avoid introducing artifactual differences related to the mode of administration.

Evaluation of a sexual assault prevention program.

The purpose of this investigation was to empirically evaluate a sexual assault prevention program. Of the 360 female college students who participated in the investigation, 181 students were in the treatment group and 165 students were in the control group. Although the program was not effective in decreasing the incidence of sexual assault for women with a sexual assault history, it was effective in decreasing the incidence of sexual assault for women without a sexual assault history. The program also led to a decrease in dating behaviors found to be associated with acquaintance rape and an increase in knowledge about sexual assault for the treatment group. The implications of these results for future preventive efforts are discussed.

Isoflurane partially preserves energy balance in isolated hepatocytes during in vitro anoxia.

We investigated whether a volatile anesthetic (1.5% isoflurane or 1.0% halothane) or an added anaerobic energy source (10 mM glucose or fructose) could act directly on liver cells to protect energy status during 20-30 min of anoxia. We used hepatocytes freshly isolated from fed rats or rats that had fasted, suspended them in Krebs' buffer, and incubated them in sealed flasks under O2/CO2 or N2/CO2 (95%:5%). The adenosine triphosphate (ATP) to adenosine diphosphate (ADP) ratio (ATP/ADP) measured cellular energy balance--the balance between overall ATP supply and demand. Lactate levels measured the extent to which ATP was supplied by the nonmitochondrial pathway, (anaerobic) glycolysis. Maximum values of energy balance were seen in cells from fed rats incubated in the presence of glucose and O2. When glucose was replaced by fructose, ATP/ADP decreased and lactate increased. During anoxia (O2 replaced by N2), increases in lactate were also seen with glucose; and ATP/ADP decreased to similarly low values with both substrates. In cells from fasted rats, ATP/ADP decreased significantly below the value for cells from fed rats only in the presence of glucose and O2. Compared with cells from fed rats, cells from fasted rats showed decreased lactate in the face of decreased ATP/ADP, suggesting that glycolysis was impaired. Isoflurane partially prevented anoxia-induced decreases in ATP/ADP. This protective effect on energy balance occurred equally with glucose and fructose, but was not seen in cells from fasted rats or with halothane. Thus, 1 MAC isoflurane and some factor(s) related to the fed state combined to protect partially the energy balance in anoxic liver cells through action(s) at the cellular level.(ABSTRACT TRUNCATED AT 250 WORDS)

Immunomodulatory action of levamisole--I. Structural analysis and immunomodulating activity of levamisole degradation products.

In our laboratory we observed that solutions of levamisole (LMS) stored at 4 degrees C consistently enhanced the lymphocyte proliferation response to concanavalin A (Con A) more than freshly prepared solutions did. To determine if the increased immunopotentiation observed with the stored solutions of LMS was due to products formed from LMS, we assessed the stability of LMS when stored at 4 or 37 degrees C at pH 6, 7, 7.5 and 8. Analysis of the various solutions by high pressure liquid chromatography demonstrated that LMS decomposes during storage in neutral and alkaline conditions to form three products. The formation of the products was accelerated by increasing the temperature from 4 to 37 degrees C. The three degradation products were purified by preparative high pressure liquid chromatography and their structures determined by mass spectrometry, infrared spectrometry and homo- and heteronuclear two dimensional nuclear magnetic resonance spectroscopy. The degradation products, denoted as No. 1, No. 2 and No. 3, based on their high pressure liquid chromatography retention times, were identified as: No. 1, 3-(2-mercaptoethyl)-5-phenylimidazolidine-2-one; No. 2, 6-phenyl-2,3-dihydroimidazo (2,1-b) thiazole and No. 3, bis [3-(2-oxo-5-phenylimidazolidin-1-yl) ethyl] disulfide. Product 2 significantly enhanced murine lymphocyte proliferation responses to concanavalin A (Con A) at concentrations between 0.5 and 10.0 micrograms/ml (whereas the optimum concentration of LMS is 10-100 fold higher (50-100 micrograms/ml)). Products 1, 2 and 3 significantly inhibited the lymphocyte proliferative response at concentrations greater than 2.2, 10.0 and 10.0 micrograms/ml, respectively. These studies indicate that under relatively mild conditions, including physiological conditions, LMS may decompose to products which inhibit or enhance lymphocyte responses to Con A.

Immunomodulatory action of levamisole--II. Enhancement of concanavalin A response by levamisole is associated with an oxidation degradation product of levamisole formed during lymphocyte culture.

Previously we determined that levamisole (LMS), when stored for a period of time, breaks down to three degradation products at neutral and alkaline pH. At low concentrations (10(-6) M), Product 1 inhibits the lymphocyte response to concanavalin A (Con A). Product 2 enhances the response and Product 3 has no effect. At higher concentrations (10(-5) M) all three products inhibit the response. To determine if these products are formed in culture media under culture conditions (e.g. in RPMI-1640 bicarbonate buffered medium, 37 degrees C, pH 7.0-7.5, during a 72 h culture period), we added freshly prepared LMS solutions to culture media with and without lymphocytes present and maintained the pH at 7.0, 7.25 or 7.5 by varying the amount of CO2 present. Periodically over a 72 h period, aliquots of the media were removed and analyzed for the presence of LMS and the three degradation products. Within 4 h, two of the degradation product began to form in culture media with or without lymphocytes present. Product No. 1, 3-(2-mercaptoethyl)-5-phenylimidazolidine-2-one or dl-2-oxy-3-(2-mercaptoethyl)-5-phenylimidazolidine (OMPI), which inhibits the lymphocyte response to concanavalin A (Con A) at concentrations above 0.4 micrograms/ml, was formed at pH 7.0, 7.25 and 7.5, but the compound did not reach inhibitory concentrations in the lymphocyte cultures during the 72 h culture period. Product No. 2, 6-phenyl-2,3-dihydroimidazo (2,1-b) thiazole, which enhances the Con A response between concentrations of 0.5 and 10 micrograms/ml, was detected at concentrations between 2.5 and 3.5 micrograms/ml at pH 7.25 and 7.5. Product 2 was not detected in cultures at pH 7.0 and subsequently when we cultured lymphocytes with freshly prepared LMS and maintained the pH at 7.0, no significant enhancement of the Con A response was observed.(ABSTRACT TRUNCATED AT 250 WORDS)