A mouse model of the slow channel myasthenic syndrome: Neuromuscular physiology and effects of ephedrine treatment.

In the slow channel congenital myasthenic syndrome mutations in genes encoding the muscle acetylcholine receptor give rise to prolonged ion channel activations. The resulting cation overload in the postsynaptic region leads to damage of synaptic structures, impaired neuromuscular transmission and fatigable muscle weakness. Previously we identified and characterised in detail the properties of the slow channel syndrome mutation εL221F. Here, using this mutation, we generate a transgenic mouse model for the slow channel syndrome that expresses mutant human ε-subunits harbouring an EGFP tag within the M3-M4 cytoplasmic region, driven by a ~1500 bp region of the CHRNB promoter. Fluorescent mutant acetylcholine receptors are assembled, cluster at the motor endplates and give rise to a disease model that mirrors the human condition. Mice demonstrate mild fatigable muscle weakness, prolonged endplate and miniature endplate potentials, and variable degeneration of the postsynaptic membrane. We use our model to investigate ephedrine as a potential treatment. Mice were assessed before and after six weeks on oral ephedrine (serum ephedrine concentration 89 ± 3 ng/ml) using an inverted screen test and in vivo electromyography. Treated mice demonstrated modest benefit for screen hang time, and in measures of compound muscle action potentials and mean jitter that did not reach statistical significance. Ephedrine and salbutamol show clear benefit when used in the treatment of DOK7 or COLQ congenital myasthenic syndromes. Our results highlight only a modest potential benefit of these ß2-adrenergic receptor agonists for the treatment of the slow channel syndrome.

Congenital fibre type disproportion associated with mutations in the tropomyosin 3 (TPM3) gene mimicking congenital myasthenia.

Congenital myopathy with fibre type disproportion (CFTD) has been associated with mutations in ACTA1, SEPN1, RYR1 and TPM3 genes. We report the clinico-pathological and electrophysiological features of 2 unrelated cases with heterozygous TPM3 mutation. Case 1 is a 19-year-old lady who presented with motor delay in infancy, respiratory failure in early teens requiring non-invasive ventilation despite being ambulant, ptosis, axial more than proximal weakness and scoliosis. Case 2 is a 7-year-old boy with hypotonia, feeding difficulties, motor delay and scoliosis, also requiring non-invasive ventilation while ambulant. Muscle biopsies in both cases showed fibre type disproportion. Muscle MRI (Case 1) showed mild uniformly increased interstitial tissue in and around the muscles. Sequencing of TPM3 in case 1 revealed a previously described heterozygous c.503G > A(pArg168His) missense variant in exon 5 and a novel heterozygous missense mutation c.521A > C(pGlu174Ala), also in exon 5, in case 2. A mild abnormality in the single fibre EMG was documented on electrophysiology in both cases. These cases highlight the neuromuscular transmission defect in CFTD secondary to TPM3 mutations.

Ephedrine treatment in congenital myasthenic syndrome due to mutations in DOK7.

BACKGROUND: Mutations in the postsynaptic adaptor protein Dok-7 underlie congenital myasthenic syndrome (CMS) with a characteristic limb girdle pattern of muscle weakness. Patients usually do not respond to or worsen with the standard CMS treatments: cholinesterase inhibitors and 3,4-diaminopyridine. However, anecdotal reports suggest they may improve with ephedrine. METHODS: This was an open prospective follow-up study to determine muscle strength in response to ephedrine in Dok-7 CMS. Patients were first evaluated as inpatients for suitability for a trial of treatment with ephedrine. The response was assessed at 2 and 6 to 8 months follow-up clinic visits using a quantitative myasthenia gravis (severity) score (QMG) and mobility measures. RESULTS: Ten out of 12 of the cohort with DOK7 mutations tolerated ephedrine. We noted a progressive response to treatment over the 6 to 8 months assessment period with a significant improvement at the final QMG score (p = 0.009). Mobility scores also improved (p = 0.0006). Improvements in the subcomponents of the QMG score that measured proximal muscle function (those muscle groups most severely affected) were most marked, and in some cases were dramatic. All patients reported enhanced activities of daily living at 6-8 months. CONCLUSION: Ephedrine appears to be an effective treatment for Dok-7 CMS. It is well-tolerated by most patients and improvement in strength can be profound. Determining the long-term response and the most effective dosing regimen will require further research. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that ephedrine given at doses between 15 and 90 mg/day improves muscle strength in patients with documented mutations in DOK7.

Ipsilateral ureteroureterostomy for the treatment of vesicoureteral reflux or obstruction associated with complete ureteral duplication.

PURPOSE: We reviewed our experience with ureteroureterostomy as definitive treatment for vesicoureteral reflux or obstruction associated with ureteral duplication to determine the efficacy and morbidity of this procedure and identify factors that affect outcome. MATERIALS AND METHODS: We performed a total of 100 ureteroureterostomies in 94 children with an average age of 28 months during the 23-year period ending May 1999. Four patients (4 kidneys) failed to return for postoperative evaluation. Followup was 2.5 to 206 months (mean 33). Indications for surgery were vesicoureteral reflux in 53 cases, obstructing ureterocele in 19, ureterocele with upper pole reflux in 4, an ectopic obstructed upper pole ureter in 18 and other in 2. In 23 kidneys ureteroureterostomy was combined with reimplantation of the recipient ureter. Surgery was considered successful when postoperative imaging revealed no reflux or obstruction and a patent ureteroureterostomy anastomosis. RESULTS: Ureteroureterostomy with or without ureteroneocystostomy was successful for treating 94% of kidneys, including 51 of 53 with reflux, 21 of 23 (91%) with ureterocele and 17 of 18 (94%) with an ectopic obstructed upper pole ureter. Significant ureteral size disparity, defined as a donor ureter diameter greater than 2-fold that of the recipient ureter, was noted in 69 kidneys. The most common complication (13 patients) was prolonged output from the Penrose drain. However, this complication did not result in a failed procedure in any case. CONCLUSIONS: Ipsilateral ureteroureterostomy is safe and efficacious for treating abnormalities associated with ureteral duplication. A significant discrepancy in ureteral size does not preclude ureteroureterostomy.

Megacystis microcolon intestinal hypoperistalsis syndrome: bladder distension and pyelectasis in the fetus without anatomic outflow obstruction.

We report a case of a 46,XY male infant with a history of normal amniotic fluid levels who was delivered by elective cesarean section at 38.5 weeks' gestation because of progressive bladder distension, hydroureteronephrosis, and what was thought to be a dilated posterior urethra. The child died at 19 days of age of cardiovascular complications. The autopsy revealed megacystis, bilateral megaureters and pyelocaliectasis, congenital absence of ganglion cells in the bladder wall, renal dysplasia, and a microcolon. No dilation or anatomic obstruction of the posterior urethra was found. These findings strongly suggest the diagnosis of megacystis microcolon intestinal hypoperistalsis syndrome. We discuss the ultrasound findings of in utero bladder distension with hydronephrosis and one of its rare etiologies.

Unenhanced computerized axial tomography to detect retained calculi after percutaneous ultrasonic lithotripsy.

PURPOSE: We report our experience with unenhanced computerized axial tomography (CT) after percutaneous ultrasonic lithotripsy in patients thought to be at high risk for retained calculi. MATERIALS AND METHODS: CT was obtained in 121 patients (124 kidneys) within 12 to 36 hours of percutaneous ultrasonic lithotripsy for staghorn or large nonstaghorn renal calculi. Cases were grouped according to the CT findings as no retained calculi, insignificant retained calculi (fragments 1 to 3 mm.), retained calculi amenable to shock wave lithotripsy and retained fragments requiring second look percutaneous ultrasonic lithotripsy or flexible nephroscopy. RESULTS: No calculi were seen in 73 kidneys (59%) and retained calculi were identified in 51 (41%). Shock wave lithotripsy was used to treat 8 patients and another percutaneous ultrasonic lithotripsy or flexible nephroscopy was performed in 23 to remove retained stones. Insignificant calculi were noted in the remaining 21 patients. CONCLUSIONS: We believe that postoperative unenhanced CT is superior to plain renal tomography and is the best method to determine if a patient is stone-free after percutaneous ultrasonic lithotripsy. It helps to locate precisely those stones requiring a second percutaneous ultrasonic lithotripsy or nephroscopic extraction. An unenhanced renal CT devoid of calculi obviates routine postoperative second look flexible nephroscopy. We encourage others to consider this technique to define more accurately kidney stone status after percutaneous ultrasonic lithotripsy for large staghorn calculi or in any patient at high risk for retained calculi after percutaneous ultrasonic lithotripsy.

Kidney transplantation in children: a single center experience.

PURPOSE: We reviewed our most recent 10-year experience with kidney transplantation in children to determine the morbidity and mortality of the procedure, and to identify factors that affected outcome. MATERIALS AND METHODS: A total of 107 renal transplants were done in 95 children 1 to 17 years old (mean age 10.9) during the 10-year period ending January 1, 1997. The 4 most common causes of end stage renal disease were renal dysplasia, reflux nephropathy, obstructive uropathy and systemic immunological diseases. Cyclosporine based immunosuppression was used in all but 2 recipients. After April 1991 antilymphocyte antibody induction, coagulopathy screening, systemic anticoagulation and cytomegalovirus prophylaxis were incorporated into the protocols. The effects of kidney source, recipient gender, recipient age, preformed anti-HLA antibody level, preemptive renal transplantation, cytomegalovirus risk, antilymphocyte antibody induction therapy and date of renal transplantation on kidney graft survival were examined with the log rank test. RESULTS: The 1-year graft and patient survival rates were 91 and 99%, respectively. The most common causes of graft failure were rejection and recurrence of primary renal disease. The only factors that significantly (p < 0.05) influenced graft survival were antilymphocyte antibody induction immunosuppression and kidney transplantation after April 1991. Three urological complications required surgical correction. Medical morbidity included hypertension in 48.6% of the cases, short stature in 46.6% and obesity in 58.9%. CONCLUSIONS: Pediatric renal transplantation can be done with acceptable morbidity, a low rate of technical complications and low mortality. Hypertension, chronic rejection and abnormal body habitus continue to be problematic.

Examining the immune response in sentinel lymph nodes of mice and men.

Recently, it was recognized that an immune response develops along one of two major pathways. One leads to a destructive immune response (type 1), while the alternative leads to a nondestructive immune response (type 2). Our studies in animal models suggest that therapeutic vaccines induce a tumor-specific type 1 immune response while ineffective vaccines induce a type 2 response. These results have led us to examine the immune response in sentinel lymph nodes draining tumor vaccines of patients entered onto clinical trials for melanoma, breast and renal cell cancer.

A rational approach to managing stage I nonseminomatous germ cell cancer.

Regardless of the treatment option selected for management of low-stage germ cell cancer, ultimate survival is nearly identical. Treatment-related morbidity is very low regardless of management modality and the individual patient can expect similar physical limitations owing to therapy. The overall difference in loss of productivity between treatment programs varies by little more than 1 week. The cost of treatment is similar for all methods, although there is a definite financial advantage to surveillance, less so for selective surveillance, when compared with other forms of management. Socioeconomic factors are of importance when managing limited resources for a large population, but are of less concern to an individual, especially when the mean differences in per patient costs vary by only $5000. Because of these close similarities in efficacy, morbidity, and costs treatment decisions should be individualized. A responsible and reliable patient can be managed safely by selective surveillance. Those individuals considered to be less self-motivated to pursue intensive care should be managed by primary therapy. Without more information regarding the long-term outcomes associated with primary adjuvant chemotherapy, primary adjuvant RPLND, where experienced surgical support is available, is the preferred management for low-stage germ cell cancer in patients selected for, or electing, active treatment rather than surveillance. Active investigations examining the role of medical management in this population should be continued. Our preferred choice of initial management is to offer selective surveillance to appropriate patients and modified RPLND to the remainder.

Urologist-acquired renal access for percutaneous renal surgery.

OBJECTIVES: In most endourology programs an interventional radiologist is employed to acquire renal access for percutaneous renal surgery. Over the last 13 years the senior endourologist at Oregon Health Sciences University has acquired access without employing a radiologist. We report our experience with urologist-acquired renal access for percutaneous renal surgery in 522 cases. METHODS: We reviewed the records of all patients at our hospital who underwent percutaneous renal surgery between August 1983 and December 1996 with renal access being obtained in the operating room by a urologist. RESULTS: Four hundred fifty-six patients underwent 522 procedures. Indications for percutaneous renal surgery were renal and proximal ureteral calculi (n = 516), retained ureteral stent (n = 3), and intrarenal collecting system tumor (n = 3). We were successful in gaining access to 513 of 522 kidneys (98.3%). Access was obtained via a subcostal approach in 344 procedures, over the 12th rib in 152 procedures, over the 11th rib in 15 procedures, and transabdominally in 2 procedures. Sixty-five patients (12.7%) required a second or multiple sites to facilitate complete removal of calculi. Our overall complication rate was 15.3%. Blood transfusion was required in 5.4% of the cases, ileus developed in 1.9%, pneumothorax in 1.1%, intraoperative hydrothorax in 1.1%, postoperative pleural effusion requiring aspiration in 0.9%, and septic shock in 0.9%. Our overall success rate for stone removal was 94.5%. CONCLUSIONS: In our experience, the urologist is able to safely and effectively obtain percutaneous access to the collecting system for percutaneous renal surgery as a one-stage procedure without the aid of interventional radiologists.

Bleeding ileal conduit stomal varices: diagnosis and management using transjugular transhepatic angiography and embolization.

An uncommon complication of ileal conduit urinary diversion is bleeding varices at the stoma site. Variceal formation is a complication of portal hypertension, which is most commonly due to intrinsic liver disease. Problematic recurrent bleeding is usually managed locally or by portosystemic shunt. We report a case of recurrent, massive ileal conduit variceal hemorrhage in a patient without a significantly elevated portosystemic gradient. Therefore, this patient was not a candidate for a shunt procedure. Using a transjugular transhepatic approach to the portal vein, the varices were embolized to stasis without any complications. The patient has subsequently experienced no further bleeding episodes.

Recruiting the occupational and environmental medicine physicians of the future: results of a survey of current residents.

In July 1994, current occupational and environmental medicine (OEM) residents (n = 180) were surveyed about their motivation for decisions to enter OEM residencies, near-term and long-term career goals, and their opinions on various strategies for recruitment to the field. A total of 151 persons responded (84%), representing all 40 accredited OEM residencies in the United States and Canada. A total of 16% first learned about OEM in medical school, and 11% were first exposed during residency training. Most respondents (62%) decided to enter OEM residency training after beginning their professional working careers. Only 11% of respondents decided to enter OEM residency training before (2%) or during (9%) medical school, whereas 24% made their decision during internship or residency. Respondents were attracted to several aspects of OEM, but the prevention focus of the field (64%), lifestyle (56%), and worker and labor issues (53%) were most commonly cited. Although only 25% of respondents stated that a role model had a significant impact on their decision to pursue training in OEM, persons influenced by a role model were more likely to have made the decision to pursue a career in OEM during medical school or clinical residency training (odds ratio = 2.4; 95% CI, 1.0-5.4; Fisher's exact two-tailed P value = 0.04). In the short term, residents were most often interested in working for industry (32%), whereas over the long term, careers in consulting were most often preferred (39%). The data have important implications for strategies to increase recruitment to residency training programs in OEM and to increase staffing in the field.

Dietary calcium and iron: effects on blood pressure and hematocrit in young spontaneously hypertensive rats.

Supplemental dietary calcium in spontaneously hypertensive rats (SHRs) aged 21-28 d produces a decrease in blood pressure and hematocrit. The simultaneous fall in hematocrit and blood pressure suggests that the changes in blood pressure may be, in part, a consequence of the decrease in hematocrit and reduction in viscosity. To examine this possibility, SHRs aged 21 d were placed on one of four diets varying in iron content. At age 28, the animals showed iron-induced variations in hematocrit (P less than 0.001) but no difference in blood pressure. Subsequent manipulation of the ratio of calcium and iron in the diets of additional groups of animals resulted in variations in hematocrit that were independent of the calcium-induced alterations in blood pressure. We conclude that the effects of calcium on blood pressure are relatively independent of its effects on hematocrit.