High rates of advanced disease,complications, and decline of renal function after radical nephroureterectomy

ObjectivesRecurrences remain common following radical nephroureterectomy (RNU) for locally advanced upper-tract urothelial carcinoma (UTUC). We review a cohort of RNU patients to identify the incidence of locally advanced disease, decline in renal function, complications, and utilization of adjuvant chemotherapy (AC).MethodsInstitutional databases from 7 academic medical centers identified 414 RNU patients treated between 2003 and 2012 who had not received neoadjuvant chemotherapy. Glomerular filtration rate was estimated using the Modification of Diet in Renal Disease equation. Complications were classified according to the modified Clavien system. Cox proportional hazard modeling and Kaplan-Meier analysis determined factors associated with cancer-specific survival.ResultsOf 414 patients, 177 (43%) had locally advanced disease, including 118 pT3N0/Nx, 13 pT4N0/Nx, and 46 pTanyN+. Estimated 3- and 5-year cancer-specific survival was 47% and 34%, respectively. Only 31% of patients with locally advanced UTUC received AC. Mean estimated glomerular filtration rate declined from 59 to 51 ml/min/1.73 m² following RNU, including a new-onset decline below 60 and 45 ml/min/1.73 m² in 25% and 15% of patients, respectively (P<0.001 for both). Complications occurred in 46 of 177 (26%) patients, of which one-quarter were grade III or IV. Increasing age (Hazard Ratio (HR) 1.4, P = 0.03), positive surgical margins (HR 2.1, P = 0.01), and positive lymph nodes (HR 4.3, P<0.001) were associated with an increased risk of death from UTUC, whereas receipt of AC (HR 0.85, P = 0.05) was associated with a decrease in UTUC mortality.ConclusionsUnder one-third of RNU patients with locally advanced UTUC cancers received AC. Perioperative complications and decline in renal function may have contributed to this low rate. Such data further underscore the need for continued discussion regarding the use of chemotherapy in a neoadjuvant setting for appropriately selected patients with UTUC.     

Effect of a Cooling Vest on Core Temperature in Athletes With and Without Spinal Cord Injury

Background:

It is well accepted that persons with spinal cord injury (SCI) have impaired ability to regulate core temperature due to impaired vasomotor and sudomotor activity below their level of injury. Impaired heat dissipation puts SCI athletes at great risk of exercise-induced hyperthermia (EIH) (>37.8°C). There is minimal evidence for efficacy of any specific cooling method in SCI athletes in a thermoneutral sport-specific setting.

Objective:

To evaluate the extent of EIH in persons with and without SCI and subsequently examine the effect of a cooling vest to attenuate rise in core body temperature (T_c).

Methods:

SCI (n = 17) and able-bodied (AB; n = 19) athletes participated in a 60-minute intermittent sprinting exercise in a thermoneutral (21.1°C-23.9°C) environment. Participants were separated according to their level of injury: tetraplegia defined as above T1 (TP; n = 6), high paraplegia defined as T5 through T1 (HP; n = 5), low paraplegia defined as T6 and below (LP; n = 6), and AB (n = 19). T_c was recorded at 15-minute intervals using an ingestible thermometer pill. This protocol was completed with a cooling vest (V) and without a cooling vest (NV).

Results:

All SCI and most AB athletes experienced EIH. After 60 minutes, T_c of TP athletes was significantly increased compared to HP (P = .03) and AB athletes (P = .007). There was no significant effect of the vest on T_c over time for any group.

Conclusions:

TP athletes have the highest risk of exercise-induced hyperthermia. The cooling vest does not significantly attenuate rise in T_c in SCI or AB athletes.Key words: body temperature, hyperthermia, spinal cord injury, thermoregulationInjury to the spinal cord results in impairment of vasomotor and sudomotor function at and below the level of injury (LOI).¹ In non–spinal-cord-injured individuals, internal heat gain from metabolically active muscles (eg, during exercise) and external heat gain from the ambient air is mitigated through processes regulated by the hypothalamus. The afferent input of heat gain results in neurological efferent signals that regulate vasomotor tone (convective cooling) and sudomotor activation (evaporative cooling). In persons with spinal cord injury (SCI), the output from the hypothalamus is blocked due to lesions within the spinal cord. Furthermore, the loss of skeletal muscle pump activity from the paralyzed limbs further impairs blood circulation and thus core temperature regulation. As a result, persons with SCI have difficulty dissipating heat during exercise compared to their able-bodied (AB) counterparts.^1–3 The extent of such thermal impairment has been shown to be directly related to level and completeness of injury, with higher and complete lesions having more impairment than lower, incomplete lesions.^4,5 Specifically, the vessels of the face and neck are sympathetically mediated from levels T1-4, upper extremity vessels mediated from T5-7, and vessels of the lower extremity from T10 to L3.⁶ Therefore, persons with complete tetraplegia have essentially no vasomotor control, whereas persons with high paraplegia have vasomotor control of face and neck and persons with low paraplegia have control of upper limbs and potentially some control of lower limb vessels depending on the LOI.In the AB athlete, is it well accepted that elevated core temperature (T_c) due to internal and external heat gain during exercise can impair endurance and performance.^7,8 Extreme elevations in T_c can result in exercise-induced hyperthermia (EIH) (>37.8°C-38.3°C) that that can lead to heat exhaustion (<40°C) or heat stroke (>40°C) as defined by American College of Sports Medicine (ACSM).⁹ For this reason, cooling methods such as whole body cooling, cooling vests, and hand/foot cooling are utilized before and during exercise in AB athletes.^10–13 These devices have been shown to reduce thermal strain, increase endurance capacity, and improve performance.^14–17Due to the increased risk of EIH and heat-related illness from thermoregulatory dysfunction in persons with SCI, a number of commercially available cooling devices have been tested in a controlled laboratory setting in attempts to attenuate rise in T_c. Foot cooling garments, hand cooling garments, head and neck cooling garments, misting devices, and a cooling vest have been tested in SCI populations.^18–22 This study sought to test the efficacy of the cooling device in a sport-specific environment. The cooling vest interferes minimally with wheelchair propulsion during sporting activities and was thus chosen for this study.While the efficacy of the cooling vest in normalizing T_c in the AB population has been clearly documented, the efficacy of the vest in SCI populations has variable results from 3 small studies.^14,23,24 Armstrong et al¹⁸ found that cooling (ice) vests worn during 30 minutes of wheelchair roller exercise in a hot-humid environment (~33°C and ~75% relative humidity) did not significantly decrease T_c in an SCI group (4 with paraplegia, 1 with tetraplegia). Webborn et al evaluated the effect of cooling vests in 2 studies of 8 persons with tetraplegia during an arm crank ergometry intermittent sprint protocol (defined as 14 two-minute exercise periods each consisting of 10 seconds passive rest, 5 seconds maximum sprint, and 105 seconds of active recovery). The first study reported a significant decrease in T_c and rate of perceived exertion when vests were used before (pre-cooling) or during 28 minutes of exercise in the heat.¹⁹ The second study also reported a significant decrease in T_c and time to exhaustion during 60 minutes in the heat when wearing the vest.²⁵ Webborn recommended that tetraplegic athletes performing intermittent sprint exercise in hot conditions should wear a cooling vest before or during exercise to attenuate rise in T_c. This study tested Webborn’s recommendation to examine whether these findings translate to a nonlaboratory field-based environment of athletes engaging in intermittent sprint exercise during play of wheelchair basketball and rugby. This concept of testing has recently been recommended, as testing of athletes in their normal sports wheelchair and their natural environment may yield results that are more relevant than laboratory testing.²⁶The objectives of this study are 2-fold: (1) to evaluate the extent of EIH in persons with and without SCI, and (2) to examine the ability of a cooling vest to attenuate the rise in T_c of SCI and AB athletes during intermittent sprinting exercise.     

Nephropathy and Elevated BP in Mice with Podocyte-Specific NADPH Oxidase 5 Expression

NADPH oxidase (Nox) enzymes are a significant source of reactive oxygen species, which contribute to glomerular podocyte dysfunction. Although studies have implicated Nox1, -2, and -4 in several glomerulopathies, including diabetic nephropathy, little is known regarding the role of Nox5 in this context. We examined Nox5 expression and regulation in kidney biopsies from diabetic patients, cultured human podocytes, and a novel mouse model. Nox5 expression increased in human diabetic glomeruli compared with nondiabetic glomeruli. Stimulation with angiotensin II upregulated Nox5 expression in human podocyte cultures and increased reactive oxygen species generation. siRNA-mediated Nox5 knockdown inhibited angiotensin II–stimulated production of reactive oxygen species and altered podocyte cytoskeletal dynamics, resulting in an Rac-mediated motile phenotype. Because the Nox5 gene is absent in rodents, we generated transgenic mice expressing human Nox5 in a podocyte-specific manner (Nox5^pod+). Nox5^pod+ mice exhibited early onset albuminuria, podocyte foot process effacement, and elevated systolic BP. Subjecting Nox5^pod+ mice to streptozotocin-induced diabetes further exacerbated these changes. Our data show that renal Nox5 is upregulated in human diabetic nephropathy and may alter filtration barrier function and systolic BP through the production of reactive oxygen species. These findings provide the first evidence that podocyte Nox5 has an important role in impaired renal function and hypertension.Albuminuria is a clinical marker of kidney dysfunction that arises in most glomerulopathies and is associated with poor prognoses for ESRD, hypertension, and cardiovascular mortality. Changes to the podocyte (e.g., foot process effacement, hypertrophy, detachment, and loss) underlie the development and progression of albuminuria and thereby highlight the critical role for these cells in upholding the glomerular filtration barrier.^1,2 Therefore, identifying factors that induce podocyte injury and loss is essential to understanding the mechanisms of filtration barrier dysfunction.Of the many factors implicated in podocyte dysfunction, excessive production of reactive oxygen species (ROS; oxidative stress) may be particularly important.^3–6 Although sources of ROS are numerous, the NADPH oxidase (Nox) family of enzymes yields significant superoxide production in the kidney.^7–10 Nox-induced ROS production has been closely linked to various glomerular pathologies. In animal models of minimal change disease, membranous nephropathy, and FSGS, inhibition of Nox activity is associated with decreased podocyte effacement and amelioration of albuminuria.^11–14 In models of diabetic nephropathy, treatment with the Nox inhibitor apocynin, as well the antioxidant vitamin E, reduces oxidative stress, podocyte effacement and loss, and albuminuria.^6,15,16 Noxs are regulated by many factors, including the renin angiotensin aldosterone system.^5,9 Several studies have linked increased renin angiotensin aldosterone system activity to enhanced renal Nox activity and ROS generation.^5,17 Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers slow progression of proteinuria in models of diabetes, and these effects may be, in part, independent of their effects on systemic BP,^17–20 because direct activation of Nox enzymes through the angiotensin II (AngII)/AT1 receptor (AT1R) pathway leads to oxidative stress. In vitro studies in both human and rodent cell lines have also shown that Nox family member expression and activity are regulated by disease-associated factors, including AngII, ET-1, TGF-β, high glucose, mechanical stretch, and PDGF (factors that are upregulated in the diabetic milieu).^3,21–23The roles of Nox4, and to a lesser extent, Nox1 and -2, in the kidney have been examined, but nothing is known regarding the role of the most recently identified member of the Nox family, Nox5. The Nox5 gene is absent from the mouse and rat genomes, making the use of conventional animal models unfeasible. Unlike other Nox family members, Nox5 does not require membrane-bound or cytosolic components, such as p22phox or p47phox, for its activity, but is tightly regulated by changes in intracellular calcium levels.^24,25 Nox5 has a large amino terminal EF hand-containing domain that plays a critical role in its calcium-dependent activation along with several phosphorylation sites that alter the sensitivity of Nox5 to intracellular calcium.^26–29 Because AngII increases intracellular calcium concentrations, it seems to induce renal Nox5-dependent ROS generation, which was shown in human endothelial cells.²³ Here, we show that (1) Nox5 is upregulated in human diabetic glomeruli; (2) AngII stimulates ROS generation in human podocytes in a Nox5-dependent manner, a process associated with actin cytoskeletal reorganization and activation of Rac GTPase, which promotes podocyte motility in vitro; (3) mice that express human Nox5 in a podocyte-specific manner (Nox5β^pod+ mice) exhibit renal dysfunction, including albuminuria, podocyte effacement, glomerular basement membrane (GBM) thickening, interstitial fibrosis, and hypertension; and (4) Nox5^pod+ mice subjected to streptozotocin (STZ)-induced diabetes develop a more severe kidney phenotype than nontransgenic littermates. These novel data indicate the potential importance of podocyte Nox5 in human renal pathologies, such as diabetic nephropathy.     

Pathologic Grade and Tumor Size are Associated with Recurrence-Free Survival in Patients with Duodenal Neuroendocrine Tumors

Background

Duodenal neuroendocrine tumors are rare and few studies exist to guide surgical management. This study identifies factors associated with recurrence after resection.

Methods

A retrospective, single institution review was performed between 1983 and 2011 on patients with a pathologic diagnosis of duodenal neuroendocrine tumor. Tumor grade was assigned based on WHO 2010 criteria (Ki-67 and mitotic rate).

Results

Seventy-five patients were identified that underwent curative resection. This included 12 patients with endoscopic mucosal resection, 34 that had local resection, and 29 that underwent pancreaticoduodenectomy. Two-year and 5-year recurrence-free survival was 84 and 81 %, respectively. There were 11 tumor recurrences (either local or distant), and four patients died of their disease (3/4 had high-grade lesions) with an overall median follow-up of 27 months. On univariate analysis, tumor size and tumor grade were identified as being associated with recurrence, but not intervention type, lymph node metastases, ampullary location, or margin status.

Conclusions

Tumor grade and size are associated with recurrence-free survival in duodenal neuroendocrine tumors. When feasible, a less aggressive surgical approach to treat low-grade and low-stage duodenal NETs should be considered.     

Lateral unicompartmental knee replacements: early results from a District General Hospital

Lateral unicompartment knee replacements are performed infrequently in the United Kingdom. This study evaluates the experience of two knee surgeons in a District General Hospital for all lateral unicompartmental arthroplasties performed between October 2007 and August 2011. Two different implants were used in this time period, the Oxford domed and the Zimmer fixed-bearing system. Twenty-seven procedures were completed in this time span (15 Oxford domed and 12 Zimmer fixed bearing), all of which once completed were followed up and 21 patients completed an Oxford knee score. Average Oxford knee scores were 36.6 (95 % CI 29.0–44.2) for the Oxford domed prosthesis and 28.6 (19.8–37.5) for the Zimmer fixed-bearing prosthesis (p = 0.15). One patient with an Oxford domed prosthesis required revision for bearing dislocation. The follow-up Oxford knee scores support the use of this technique as an alternative to total knee replacement but with no significant difference in functional outcome. Our results, however, may encourage a more cautious approach to the use of a mobile-bearing prosthesis in favour of a fixed-bearing prosthesis.     

Fewer intensive care unit refusals and a higher capacity utilization by using a cyclic surgical case schedule

PURPOSE: Mounting health care costs force hospital managers to maximize utilization of scarce resources and simultaneously improve access to hospital services. This article assesses the benefits of a cyclic case scheduling approach that exploits a master surgical schedule (MSS). An MSS maximizes operating room (OR) capacity and simultaneously levels the outflow of patients toward the intensive care unit (ICU) to reduce surgery cancellation. MATERIALS AND METHODS: Relevant data for Erasmus MC have been electronically collected since 1994. These data are used to construct an MSS that consisted of a set of surgical case types scheduled for a period or cycle. This cycle was executed repetitively. During such a cycle, surgical cases for each surgical department were scheduled on a specific day and OR. The experiments were performed for the Erasmus University Medical Center and for a virtual hospital. RESULTS: Unused OR capacity can be reduced by up to 6.3% for a cycle length of 4 weeks, with simultaneous optimal leveling of the ICU workload. CONCLUSIONS: Our findings show that the proposed cyclic OR planning policy may benefit OR utilization and reduce surgical case cancellation and peak demands on the ICU.     

Fear of falling does not alter the kinematics of recovery from an induced trip: a preliminary study

Marone JR, Rosenblatt NJ, Troy KL, Grabiner MD. Fear of falling does not alter the kinematics of recovery from an induced trip: a preliminary study.

Objective

To provide preliminary information about the relationships between self-reported fear of falling (FOF) in healthy community-dwelling women, number of falls, and recovery kinematics in response to a laboratory-induced trip.

Design

Cohort study.

Setting

Clinical research laboratory.

Participants

A subset of community-dwelling older women (N=33) recruited from studies of laboratory-induced trips and fall prevention.

Intervention

A laboratory-induced trip.

Main Outcome Measures

Number of fallers in the FOF group versus the control group. Recovery kinematics of FOF group falls versus control group falls, and FOF group recoveries versus control group recoveries were compared. Degree of FOF was assessed by using the Activities-Specific Balance Confidence (ABC) Scale.

Results

Falls occurred in 6 of 14 (43%) FOF and 4 of 16 (25%) control subjects (P=.26). The kinematics of FOF group falls were similar to those of control group falls. At completion of the initial recovery step, the FOF group showed significantly greater trunk extension velocity than controls (−82.1°/s±−66.1°/s vs −25.0°/s±−53.0°/s, respectively; P=.05). All other variables were not significantly different. ABC Scale scores of FOF subjects did not differ significantly between fallers and those who recovered (mean, 75.2±5.6, 71.1±11.8, respectively; P=.84).

Conclusion

Healthy community-dwelling older adults would benefit from fall prevention regardless of the presence of self-reported FOF.