Diabetic cystopathy correlates with a long-term decrease in nerve growth factor levels in the bladder and lumbosacral dorsal root Ganglia

PURPOSE It has been proposed that a deficiency in the axonal transport of nerve growth factor (NGF) may have an important role in inducing diabetic neuropathy, which contributes to diabetic cystopathy. Therefore, in streptozotocin (Sigma Chemical Co., St. Louis, Missouri) induced diabetic rats we investigated the relationship of bladder function with NGF levels in the bladder and lumbosacral dorsal root ganglia, which contain afferent neurons innervating the bladder.MATERIALS AND METHODS At 6 and 12 weeks after the induction of diabetes with streptozotocin (65 mg./kg. intraperitoneally) the effects of diabetes on Adelta afferent fiber dependent, conscious voiding were evaluated by metabolic cage measurements and awake cystometry. The effects of diabetes on C-fiber mediated bladder nociceptive responses were also investigated by cystometry with intravesical instillation of 0.25% acetic acid in the rats under urethane anesthesia. NGF levels in the bladder and L6 to S1 dorsal root ganglia were measured by enzyme-linked immunosorbent assay 3, 6, 9 and 12 weeks after streptozotocin injection.RESULTS In diabetic rats NGF levels in the bladder and L6 to S1 dorsal root ganglia were significantly decreased 12 weeks after streptozotocin injection (p <0.01). In cystometry and metabolic cage studies bladder capacity and post-void residual volume were significantly increased 12 weeks after streptozotocin injection (p <0.01). Bladder nociceptive responses revealed by a reduction in inter-contraction intervals after acetic acid infusion were significantly decreased in a time dependent manner 12 weeks after streptozotocin injection.CONCLUSIONS Rats with streptozotocin induced diabetes mellitus showed a significant time dependent decrease in NGF levels in the bladder and L6 to S1 dorsal root ganglia that was associated with voiding dysfunction attributable to defects in Adelta and C-fiber bladder afferents. Therefore, reduced production of NGF in the bladder and/or impaired transport of NGF to L6 to S1 dorsal root ganglia, which contain bladder afferent neurons, may be an important mechanism inducing diabetic cystopathy.     

Herpes simplex virus mediated nerve growth factor expression in bladder and afferent neurons: potential treatment for diabetic bladder dysfunction

PURPOSE: Diabetic cystopathy resulting from sensory neuropathy may potentially be treated by direct gene therapy. It has been suggested that nerve growth factor (NGF) has an ameliorative effect in preventing the death in diabetes of afferent dorsal root ganglion neurons, which control bladder function. We investigated NGF gene transfer to the bladder and bladder afferent pathways for treating diabetic cystopathy. We used replication competent and replication defective herpes simplex virus type 1 (HSV-1) vectors that express a functionally active form of the beta-subunit of mouse NGF (beta-NGF) to examine the level and duration of therapeutic gene expression after administration of the vectors. MATERIALS AND METHODS: NGF expression during acute (3 days) and latent (21 days) infections was assessed by enzyme-linked immunosorbent assay (ELISA) and immunohistochemical testing after the injection of 1 x 106 to 1 x 108 pfu HSV-NGF expression vectors into the bladder wall of adult rats. RESULTS: HSV vectors with the strong human cytomegalovirus immediate early promoter used to drive beta-NGF gene expression exhibited increased NGF 3 days after infection in the bladder and L6 to S1 dorsal root ganglia, where bladder afferent neurons are located. ELISA analysis revealed that NGF in the bladder tissue and dorsal root ganglia was increased 7 to 9 and 2 to 4-fold, respectively, over the control vector. Increased NGF expression in L6 to S1 dorsal root ganglia neurons was also detected by immunohistochemical staining with antiNGF antibodies. Extended NGF expression was detected by ELISA 21 days after injection. Replication defective vectors containing HSV-1 latency promoter (LAP-2) driving NGF expressed NGF in the bladder and dorsal root ganglia 21 days after bladder injection. ELISA analysis confirmed an approximate 2 to 3-fold increase of NGF expression in the bladder and L6 to S1 dorsal root ganglia. CONCLUSIONS: The NGF gene may be transferred and expressed in the bladder and bladder afferent pathways using HSV vectors. To our knowledge our study represents the first demonstration of the effectiveness of gene therapy for altering neurotrophic expression in visceral sensory neurons. This technique of gene transfer may be useful for treating certain types of neurogenic bladder dysfunction, such as diabetic cystopathy, in which decreased NGF transport may be a causative factor.     

Nebulised fenoterol compared with metered aerosol.

The effect of nebulised fenoterol was compared with that of a similar dose administered by metered aerosol in 14 children, aged 7 to 17 years with moderately severe asthma. The initial response to fenoterol delivered by metered aerosol or nebuliser was the same, but a second dose by nebuliser after a dose by metered aerosol produced maximum potential bronchodilatation which was not seen when a second dose by metered aerosol was given after that by nebuliser. Administration of a bronchodilator by nebuliser does seem advantageous in the treatment of some children.     

Outcome of a trial of labor after prior cesarean delivery

In the United States over 90% of patients with a history of cesarean delivery in the prior pregnancy undergo repeat cesarean delivery in a subsequent pregnancy. The costs of the nearly universal approach to this issue are staggering and have been addressed by a recent National Institutes of Health consensus development conference. In 1979 at the Women's Hospital of Los Angeles County/University of Southern California Medical Center we initiated a policy of permitting a trial of spontaneous labor and vaginal delivery in selected patients with prior cesarean deliveries. Patients selected for a trial of labor (TOL) were those with a history of one prior uterine incision known to be low transverse. During 1980 there were 13,292 deliveries and 13,147 live births; 871 of these patients had a history of prior cesarean delivery. Of the 871 women, 308 (35%) were permitted a TOL. There were 240 vaginal deliveries, for a success rate of 78%. Twenty-two perinatal deaths occurred among the 871 patients, none directly attributable to the TOL. There were three ruptured uteri, one directly attributable to a TOL. Seven hysterectomies were performed in this group, none directly attributable to a TOL. This experience has encouraged us to expand the patient group offered a TOL after prior cesarean delivery under carefully controlled conditions.     

Four-quadrant assessment of amniotic fluid volume. Interobserver and intraobserver variation

While the use of the four-quadrant technique, or the amniotic fluid index (AFI), for amniotic fluid volume assessment has been shown to correlate with perinatal outcome, one concern among clinicians is the reliability of a single AFI measurement. The purpose of this investigation was to ascertain the margin of error using this technique among 23 term and postterm women. The AFI was obtained using linear array real-time B-scan ultrasound to measure the vertical diameter of the largest amniotic fluid pocket in each of the four quadrants. The sum of these measurements was expressed as the AFI. Eight women underwent ten consecutive AFI measurements by the same sonographer to determine intraobserver variation. Interobserver variation between five sonographers was measured by assessing the AFI in 15 additional patients. With the amniotic fluid volume in the low or normal range, our results demonstrated the intraobserver and interobserver variations in AFI to average 1.0 and 2.0 cm, respectively. With an above-normal amniotic fluid volume, a 2.5- to 3-fold greater variation was observed. A relatively small margin of error appears to exist between observers using the four-quadrant technique to assess amniotic fluid volume.     

Spinal cord dysfunction with quadriplegia complicating pneumococcal meningitis

A case of pneumococcal meningitis complicated by brain-stem herniation and flaccid quadriplegia is described, from which the patient, an 11 year old boy, made a partial recovery. The patient had suffered a head injury with skull fracture some years previously; this was his third episode of meningitis. The aetiology of the quadriplegia has not been fully established, but is presumed to be of vascular nature at spinal cord level, associated with an acute hypotensive episode. Preventative aspects of recurrent bacterial meningitis and brain-stem herniation following lumbar puncture are stressed.     

Vaginal birth after cesarean delivery in the twin gestation

The pregnancy outcomes of 56 women with a twin gestation and a prior cesarean birth were analyzed to determine whether a trial of labor was a reasonable consideration. Of these patients, 31 (55%) underwent an elective repeat cesarean delivery and 25 (45%) attempted vaginal delivery. Of those who attempted vaginal delivery, 18 (72%) were vaginally delivered of both infants. The dehiscence rate among women with twin pregnancies who attempted a trial of labor was 4% compared with 2% in women with singleton pregnancies. There were no significant differences in maternal or neonatal morbidity or mortality rates in trial of labor versus no trial of labor groups. We conclude in this limited population that a trial of labor in a twin gestation after a previous cesarean delivery appears to be a reasonable consideration. The usual safeguards for attempted vaginal delivery in the twin gestation should be followed.     

Urinary tract abnormalities in association with oesophageal atresia: frequency,significance, and influence on management

Urinary tract abnormalities occur in about 24% of infants with oesophageal atresia. It is important in the neonatal period to recognise those that may cause renal damage if untreated so that the long-term complications of renal disease, e. g., reflux-associated nephropathy, can be prevented. Our current practice is to obtain a renal ultrasound and micturating cystourethrogram during the first admission. If the infant has not been observed to pass urine, then renal ultrasound should be performed before repair of the oesophageal atresia, because there is inadequate functioning renal tissue for long-term survival in 3% of oesophageal atresia patients. The absence of Potter's syndrome in infants with both oesophageal atresia and bilateral renal agenesis means that these patients often cannot be identified pre-operatively on clinical grounds alone. Offprint requests to: Spencer W. Beasley     

Intussusception: recurrence following gas (oxygen) enema reduction

Over a 38-month period, prospective data were collected on all episodes of intussusception treated at the Royal Children's Hospital, Melbourne. There were 170 initial episodes for which a gas enema was performed, 127 of which were reduced successfully. Recurence occured in 10 patients following initial successful gas enema reduction, a recurrence rate of 7.9%, which compares with a recurrence rate of 8.9% with barium (P = 0.896). We conclude that the gas enema does not have a higher rate of recurrence than barium and that there is no evidence of a significant incidence of incomplete reduction unrecognised at the time of gas enema. Correspondence to: S. W. Beasley     

AOP2 (antioxidant protein 2): structure and function of a unique thiol-specific antioxidant

The accumulation of reactive oxygen species (ROS) in response to extracellular signals or intracellular biochemical processes can be regulated by the coordinate action of many antioxidant proteins. Because moderate levels of ROS can act as intracellular messengers in many of these processes, this modulation is critical for the transduction of specific signals. The thiol-specific antioxidant (TSA) family is a highly conserved group of enzymes that can reduce hydroperoxides in the presence of a thiol-containing electron donor. AOP2 (antioxidant protein 2) is a newly described member that shows significant evolutionary conservation between many different organisms. The protein contains three motifs that are highly conserved within the TSA family, including a cysteine residue that is the active site of oxidation for this class of proteins. Although AOP2 possesses TSA activity, it has several unique characteristics, including the absence of a second cysteine residue that is conserved in all other TSA proteins, the presence of a unique carboxy-terminal domain, and a demonstrated phospholipase activity. Furthermore, AOP2 shows conservation of several amino acids important in dimer formation and active site configuration that are not found in the other family members. Together, these data strongly suggest that AOP2 is a novel thiol-dependent antioxidant that functions to scavenge particular hydroperoxides in the cell and mediate specific signals. There is also evidence supporting a role for AOP2 in certain disease processes including atherosclerosis. Further evaluation of this protein and its substrate specificity will likely shed light on its precise role in cellular oxidant defense, signal transduction and pathogenesis.