Risk factors for repeat hernia repair in women of childbearing age.

PURPOSE: Herniorrhaphy is a source of substantial cost and morbidity. Although women are a substantial proportion of patients seeking repair, gender-specific data, including the influence of childbirth on hernia recurrence, are lacking. Our objective was to estimate the rate and identify risk factors for repeat herniorrhaphy in reproductive-aged women. METHODS: Retrospective cohort study of women who underwent herniorrhaphy during June 2000-December 2014 in the United States. Women aged 18-50 who underwent umbilical, incisional/ventral, or inguinal/femoral herniorrhaphy in the Truven Health Analytics MarketScan® Commercial Claims and Encounters database were included. Women without a hernia diagnosis or multiple/concurrent index herniorrhaphy types were excluded. Primary outcome of interest was second herniorrhaphy. RESULTS: Of 123,674 women, 13% had a second herniorrhaphy within 10 years; increasing age, comorbidities, childbirth, smoking, obesity, and inpatient procedure were independently associated with increased risk. Cesarean delivery before umbilical herniorrhaphy (HR 1.61, 95% CI 1.34, 1.92) and both vaginal (HR 2.57, 95% CI 1.98, 3.34) and cesarean delivery (HR 2.95, 95% CI 2.25, 3.87) after umbilical herniorrhaphy were associated with increased risk of second herniorrhaphy. Both vaginal (HR 1.66, 95% CI 1.13, 2.43) and cesarean delivery (HR 2.72, 95% CI 2.09, 3.53) after incisional/ventral herniorrhaphy and vaginal delivery after inguinal/femoral herniorrhaphy (HR 1.75, 95% CI 1.22, 2.51) were associated with increased risk of second herniorrhaphy. CONCLUSIONS: Among reproductive-aged women, childbirth, increasing age, comorbidities, smoking, and obesity increase risk of subsequent herniorrhaphy. Risk of second herniorrhaphy is higher with cesarean delivery compared to vaginal delivery, and higher for delivery occurring after initial hernia repair compared to before.

Mitigating effect of EUK-207 on radiation-induced cognitive impairments.

The brain could be exposed to irradiation as part of a nuclear accident, radiological terrorism (dirty bomb scenario) or a medical radiological procedure. In the context of accidents or terrorism, there is considerable interest in compounds that can mitigate radiation-induced injury when treatment is initiated a day or more after the radiation exposure. As it will be challenging to determine the radiation exposure an individual has received within a relatively short time frame, it is also critical that the mitigating agent does not negatively affect individuals, including emergency workers, who might be treated, but who were not exposed. Alterations in hippocampus-dependent cognition often characterize radiation-induced cognitive injury. The catalytic ROS scavenger EUK-207 is a member of the class of metal-containing salen manganese (Mn) complexes that suppress oxidative stress, including in the mitochondria, and have been shown to mitigate radiation dermatitis, promote wound healing in irradiated skin, and mitigate vascular injuries in irradiated lungs. As the effects of EUK-207 against radiation injury in the brain are not known, we assessed the effects of EUK-207 on sham-irradiated animals and the ability of EUK-207 to mitigate radiation-induced cognitive injury. The day following irradiation or sham-irradiation, the mice started to receive EUK-207 and were cognitively tested 3 months following exposure. Mice irradiated at a dose of 15Gy showed cognitive impairments in the water maze probe trial. EUK-207 mitigated these impairments while not affecting cognitive performance of sham-irradiated mice in the water maze probe trial. Thus, EUK-207 has attractive properties and should be considered an ideal candidate to mitigate radiation-induced cognitive injury.

Laminin 332 deposition is diminished in irradiated skin in an animal model of combined radiation and wound skin injury.

Skin exposure to ionizing radiation affects the normal wound healing process and greatly impacts the prognosis of affected individuals. We investigated the effect of ionizing radiation on wound healing in a rat model of combined radiation and wound skin injury. Using a soft X-ray beam, a single dose of ionizing radiation (10-40 Gy) was delivered to the skin without significant exposure to internal organs. At 1 h postirradiation, two skin wounds were made on the back of each rat. Control and experimental animals were euthanized at 3, 7, 14, 21 and 30 days postirradiation. The wound areas were measured, and tissue samples were evaluated for laminin 332 and matrix metalloproteinase (MMP) 2 expression. Our results clearly demonstrate that radiation exposure significantly delayed wound healing in a dose-related manner. Evaluation of irradiated and wounded skin showed decreased deposition of laminin 332 protein in the epidermal basement membrane together with an elevated expression of all three laminin 332 genes within 3 days postirradiation. The elevated laminin 332 gene expression was paralleled by an elevated gene and protein expression of MMP2, suggesting that the reduced amount of laminin 332 in irradiated skin is due to an imbalance between laminin 332 secretion and its accelerated processing by elevated tissue metalloproteinases. Western blot analysis of cultured rat keratinocytes showed decreased laminin 332 deposition by irradiated cells, and incubation of irradiated keratinocytes with MMP inhibitor significantly increased the amount of deposited laminin 332. Furthermore, irradiated keratinocytes exhibited a longer time to close an artificial wound, and this delay was partially corrected by seeding keratinocytes on laminin 332-coated plates. These data strongly suggest that laminin 332 deposition is inhibited by ionizing radiation and, in combination with slower keratinocyte migration, can contribute to the delayed wound healing of irradiated skin.

Mitigation of radiation injuries via suppression of the renin-angiotensin system: emphasis on radiation nephropathy.

Radiation nephropathy and other normal tissue radiation injuries can be successfully mitigated, and also treated, by antagonists of the renin-angiotensin system (RAS). This implies a mechanistic role for that system in radiation nephropathy, yet no evidence exists to date of activation of the RAS by irradiation. RAS antagonists, including angiotensin converting enzyme inhibitors and angiotensin receptor blockers, are the standard of care in the treatment of subjects with other chronic progressive kidney diseases, in which they exert benefit by reducing both glomerular and tubulo-interstitial injury. These drugs are likely to act in a similar way to mitigate radiation nephropathy.

Propagation of giant migrating contractions between the small intestine, cecum and colon during radiation.

BACKGROUND: Radiation increases the frequency of small intestinal and colonic giant migrating contractions (GMCs). These contractions contribute to the diarrhea and cramping after radiation therapy and are coordinated with one another across the ileocolonic (IC) junction. METHODS: We investigated the coordination of contractile activity between the small intestine, cecum and colon in five canines following circumferential myotomy on the ileum at the IC junction and compared it to intact animals. Studies were performed before and during a radiation schedule. KEY RESULTS: Myotomy increased the frequency of small intestinal GMCs prior to irradiation. In intact animals, the duration and amplitude of cecal GMCs decreased when multiple contractions occurred in rapid succession. This is in contrast to small intestinal and colonic GMCs and suggests a different mechanism of propagation for GMCs within the cecum. Ileal myotomy dramatically decreased the frequency of propagating radiation-induced colonic GMCs. The total number of colonic GMCs was not altered. Colonic contractile activity was disrupted in intact animals during irradiation. However, after ileal myotomy, irradiation did not affect the pattern of colonic contractile states. Diarrhea in irradiated animals with myotomy started earlier than intact animals. This may be related to the frequency of small intestinal GMCs. CONCLUSIONS & INFERENCES: Our findings suggest importance of the enteric neural connections at the IC region to contractile disorders of both the small and large intestine. The anatomic relationship between the canine IC junction is similar to the human ileo-appendiceal-colonic region and surgical manipulations of this area may likewise affect human contractile activity.

Vascular injury after whole thoracic x-ray irradiation in the rat.

PURPOSE: To study vascular injury after whole thoracic irradiation with single sublethal doses of X-rays in the rat and to develop markers that might predict the severity of injury. METHODS AND MATERIALS: Rats that received 5- or 10-Gy thorax-only irradiation and age-matched controls were studied at 3 days, 2 weeks, and 1, 2, 5, and 12 months. Several pulmonary vascular parameters were evaluated, including hemodynamics, vessel density, total lung angiotensin-converting enzyme activity, and right ventricular hypertrophy. RESULTS: By 1 month, the rats in the 10-Gy group had pulmonary vascular dropout, right ventricular hypertrophy, increased pulmonary vascular resistance, increased dry lung weights, and decreases in total lung angiotensin-converting enzyme activity, as well as pulmonary artery distensibility. In contrast, irradiation with 5 Gy resulted in only a modest increase in right ventricular weight and a reduction in lung angiotensin-converting enzyme activity. CONCLUSION: In a previous investigation using the same model, we observed that recovery from radiation-induced attenuation of pulmonary vascular reactivity occurred. In the present study, we report that deterioration results in several vascular parameters for

Plateau waveform shape allows a much higher patient shock energy tolerance in AF patients.

OBJECTIVES: To evaluate the possible pain reduction of the plateau waveform in atrial fibrillation (AF) patients. BACKGROUND: Previous studies have indicated that reduced amplitude waveforms would be less painful than a conventional (65/65% tilt) biphasic waveform. Computer modeling suggested that a moderately long (10-12 msec) plateau (flat topped) shock waveform would deliver equivalent effectiveness with the lowest possible peak amplitude. METHODS: We enrolled 27 patients at two sites with persistent AF with a total of 220 shocks delivered during internal atrial cardioversion using an interleaved crossover design. Patient response was scored in three ways: (1) a verbally reported discomfort score, (2) visual analog scale (VAS), and (3) a blinded observer reporting a contraction score. RESULTS: All scores were significantly reduced (P < 0.0001) by the plateau waveform with impressive statistics: Verbal discomfort (3.51 +/- 0.13 to 2.89 +/- 0.12), VAS (7.00 +/- 0.56 to 5.91 +/- 0.36), and contraction scores (1.94 +/- 0.12 to 1.62 +/- 0.12). The average pain threshold shift (TS) for the Verbal score was 2.34, while that for the VAS score was 2.30. (This means that the patient typically could tolerate 2.34 times as much energy with the plateau waveform for the same level of verbally reported discomfort.) The contraction TS was less at 1.57. Response scores were also corrected for the shock sequence number to control for the sensitization effect from multiple shocks. This increased the TS for the Verbal score to 3.58, but the shock number was not significant for the VAS. A pulmonary artery electrode return was associated with lower pain compared with a coronary sinus position. CONCLUSION: A plateau shaped biphasic waveform resulted in significantly increased shock energy pain tolerances. Controlling for session sensitization, patients tolerated over three times as much energy for the same verbally reported discomfort score.

Treatment of radiation nephropathy with ACE inhibitors and AII type-1 and type-2 receptor antagonists.

Radiation nephropathy has emerged as a significant complication of bone marrow transplantation and radionuclide radiotherapy, and is a potential sequela of radiological terrorism and radiation accidents. In the early 1990's, it was demonstrated that experimental radiation nephropathy could be treated with a thiol-containing ACE inhibitor, captopril. Further studies have shown that enalapril (a non-thiol ACE inhibitor) is also effective in the treatment of experimental radiation nephropathy, as are both AII type-1 (AT(1)) and type-2 (AT(2)) receptor antagonists. ACE inhibitors and AII receptor antagonists are also effective in the mitigation (prevention) of radiation nephropathy. Other types of antihypertensive drugs are ineffective in mitigation, but brief use of a high-salt diet in the immediate post-irradiation period significantly decreases renal injury. There are differences between mitigation and treatment of radiation nephropathy that imply that different mechanisms are operating. First, a high-salt diet is effective in the mitigation of radiation nephropathy, but deleterious on the treatment of established disease. Second, AT(1) blockade is more effective than ACE inhibition for mitigation of radiation nephropathy, but equally effective for treatment. Third, the efficacy of AT(1) blockade and ACE inhibition is highly dependent on drug dose in mitigation of radiation nephropathy, but not so in treatment. Finally, while AT(2) blockade augments the benefit of AT(1) blockade in mitigation of radiation nephropathy, it does not do so in treatment. We hypothesize that while mitigation of radiation nephropathy works by suppression of the renin-angiotensin system, treatment of established radiation nephropathy requires blood pressure control in addition to (or possibly instead of) suppression of the renin-angiotensin system.

Stepped defibrillation waveform is substantially more efficient than the 50/50% tilt biphasic.

BACKGROUND: Even with biphasic waveforms, patients with high defibrillation thresholds (DFTs) still are seen; thus, improved defibrillation waveforms may be of clinical utility. The stepped waveform has three parts: the first portion is positive with two capacitors in parallel, the second is positive with the capacitors in series, and the last portion is negative, also with the capacitors in series. OBJECTIVES: The purpose of this study was to assess the clinical utility of improved defibrillation waveforms. METHODS: We measured the delivered energy DFT in 20 patients in a dual-site study using the stepped waveform and a 50/50% tilt biphasic truncated exponential as the control. All shocks were delivered using an arbitrary waveform defibrillator, which was programmed to mimic two 220-microF capacitors (110 microF in series and 440 microF in parallel). RESULTS: The peak voltage at DFT was reduced in 19 of the 20 patients. The median peak voltage was reduced by 32.0%, from 472 V to 321 V (P <.001). The median energy DFT was reduced by 33%, from 11.7 J to 7.8 J (P = .008). The mean voltage and energy were reduced by 25.3% and 20.2%, respectively. On average, the stepped waveform was able to defibrillate as well as the 50/50% tilt biphasic, with 33% more energy. The benefit was more pronounced in patients with either a lower ejection fraction or a superior vena cava coil. The benefit of the stepped waveform had an inverse quadratic correlation with the resistance (r(2) = 0.47), suggesting that the capacitance values chosen for the stepped waveform were close to optimal for a 35-Omega resistance. CONCLUSION: The stepped waveform reduced the DFT compared to the 50/50% tilt waveform in this preliminary study.

Mobile phones, mobile phone base stations and cancer: a review.

There have been reports in the media and claims in the courts that radiofrequency (RF) emissions from mobile phones are a cause of cancer, and there have been numerous public objections to the siting of mobile phone base antennas because of a fear of cancer. This review summarizes the current state of evidence concerning whether the RF energy used for wireless communication might be carcinogenic. Relevant studies were identified by searching MedLine with a combination of exposure and endpoint terms. This was supplemented by a review of the over 1700 citations assembled by the Institute of Electrical and Electronics Engineers (IEEE) International Committee on Electromagnetic Safety as part of their updating of the IEEE C95.1 RF energy safety guidelines. Where there were multiple studies, preference was given to recent reports, to positive reports of effects and to attempts to confirm such positive reports. Biophysical considerations indicate that there is little theoretical basis for anticipating that RF energy would have significant biological effects at the power levels used by modern mobile phones and their base station antennas. The epidemiological evidence for a causal association between cancer and RF energy is weak and limited. Animal studies have provided no consistent evidence that exposure to RF energy at non-thermal intensities causes or promotes cancer. Extensive in vitro studies have found no consistent evidence of genotoxic potential, but in vitro studies assessing the epigenetic potential of RF energy are limited. Overall, a weight-of-evidence evaluation shows that the current evidence for a causal association between cancer and exposure to RF energy is weak and unconvincing. However, the existing epidemiology is limited and the possibility of epigenetic effects has not been thoroughly evaluated, so that additional research in those areas will be required for a more thorough assessment of the possibility of a causal connection between cancer and the RF energy from mobile telecommunications.

Post-irradiation approaches to treatment of radiation injuries in the context of radiological terrorism and radiation accidents: a review.

PURPOSE: Events of the recent past have focused attention on the possibility of radiological (nuclear) terrorism and on the implications of such terrorist threats for radiation accident preparedness. This review discusses recent advances in the knowledge about how radiation injuries from such events might be treated pharmacologically, and the practical barriers to clinical utilization of these approaches. CONCLUSIONS: A wide range of pharmacological approaches are being developed in the laboratory that could greatly expand the ability to treat acute and chronic radiation injuries. However, there are currently a variety of practical and legal barriers that would prevent the actual clinical use of most of the approaches. There are also the potential weaknesses in most of the current programmes for dealing with the consequences of radiation accidents or nuclear terrorism, including the absence of widespread radiation biodosimetry capabilities and the resulting inability to triage. If a major radiation accident or terrorist event occurs, the lack of biodosimetry and treatment capabilities will be compounded by widespread public fear of 'radiation'.

ACE inhibitors and AII receptor antagonists in the treatment and prevention of bone marrow transplant nephropathy.

Radiation nephropathy has emerged as a major complication of bone marrow transplantation (BMT) when total body irradiation (TBI) is used as part of the regimen. Classically, radiation nephropathy has been assumed to be inevitable, progressive, and untreatable. However, in the early 1990's, it was demonstrated that experimental radiation nephropathy could be treated with a thiol-containing ACE inhibitor, captopril. Further studies showed that enalapril (a non-thiol ACE inhibitor) was also effective in the treatment of experimental radiation nephropathy, as was an AII receptor antagonist. Studies also showed that ACE inhibitors and AII receptor antagonists were effective in the prophylaxis of radiation nephropathy. Interestingly, other types of antihypertensive drugs were ineffective in prophylaxis, but brief use of a high-salt diet in the immediate post-irradiation period decreased renal injury. A placebo-controlled trial of captopril to prevent BMT nephropathy in adults is now underway. Since excess activity of the renin-angiotensin system (RAS) causes hypertension, and hypertension is a major feature of radiation nephropathy; an explanation for the efficacy of RAS antagonism in the prophylaxis of radiation nephropathy would be that radiation leads to RAS activation. However, current studies favor an alternative explanation, namely that the normal activity of the RAS is deleterious in the presence of radiation injury. On-going studies suggest that efficacy of RAS antagonists may involve interactions with a radiation-induced decrease in renal nitric oxide activity or with radiation-induced tubular cell proliferation. We hypothesize that while prevention (prophylaxis) of radiation nephropathy with ACE inhibitors, AII receptor antagonists, or a high-salt diet work by suppression of the RAS, the efficacy of ACE inhibitors and AII receptor antagonists in treatment of established radiation nephropathy depends on blood pressure control.

Dietary sodium modification and experimental radiation nephropathy.

PURPOSE: To determine whether suppression of the renin-angiotensin system (RAS) with high dietary sodium (salt) has the same beneficial effect on radiation nephropathy as suppression of the RAS with angiotensin-converting-enzyme (ACE) inhibitors or angiotensin II (AII) receptor antagonists. MATERIALS AND METHODS: Normal and irradiated rats were placed on high- or low-salt diets and assessed for effects on blood pressure, on AII levels and on the development of radiation nephropathy. RESULTS: In unirradiated animals, a high-salt diet suppressed AII and caused hypertension, while a low-salt diet produced no detectable effects. Use of a high-salt diet 3-9 weeks after irradiation exacerbated radiation-induced hypertension but attenuated the development of radiation nephropathy. Continuous use of a high-salt diet slowed the progression of radiation nephropathy, but eventually exacerbated radiation-induced hypertension and accelerated renal failure. Use of a high-salt diet in animals with established radiation nephropathy was deleterious. A low-salt diet had no effect on the development of radiation nephropathy. CONCLUSIONS: These studies provide further support for the hypothesis that the beneficial effect of AII receptor antagonists, ACE inhibitors and high dietary sodium in the prophylaxis of radiation nephropathy is due to their suppression of the RAS, not to their anti-hypertensive effects.

Prevention of radiation-induced nephropathy and fibrosis in a model of bone marrow transplant by an angiotensin II receptor blocker.

Nephropathy, interstitial pneumopathy, and renal and lung fibrosis are major complications of bone marrow transplantation (BMT). This study evaluated the antifibrotic property of an angiotensin II (A2) type-1 receptor blocker (L-159,809) and compared it with those of Captopril and Enalapril, two angiotensin-converting enzyme (ACE) inhibitors, in a rat model of BMT. Male WAG/Rij/MCW rats received a preparative regimen of 60 mg/kg body wt of cytoxan (i.p., Days 9 and 8) and 18.5 Gy of total body irradiation (TBI) in six twice daily fractions (Days 2, 1, and 0) followed immediately (Day 0) by BMT. Modifiers were given in drinking water from Day 10 until autopsy, 8 weeks after BMT. Rats treated with TBI plus cytoxan alone developed severe nephropathy. Trichrome staining showed marked collagen deposition in glomeruli, renal interstitium, and renal arteries and arterioles (especially in their adventitia). Collagen deposition and renal damage were markedly reduced by the three modifiers. Of the three, L-158,809-treated rats had slightly thinner vessels and slightly less collagen than nonirradiated normal controls. The study shows the effectiveness of these drugs in the protection of the renal parenchyma from the development of radiation-induced fibrosis. It also indicates a role for angiotensin II in the modulation of collagen synthesis.