Management of iatrogenic cystoscopic urethral lesion associated with sequela of cuff erosion in a patient after previous AMS 800 implantation. One-step technique with revision, without cuff explantation. / Tratamiento de la lesión uretral cistoscópica iatrogénica asociada a secuela de la erosión del manguito en un paciente después de la implantación previa de AMS 800. Técnica de un solo paso con revisión, sin explantación del manguito.

INTRODUCTION: Iatrogenic urethral lesion with subsequent cuff erosion during cystoscopy is a rare complication. The alternative surgical strategy with in situ urethroplasty while maintaining the open cuff left in situ will be presented. MATERIALS AND METHODS: The authors report 3cases of iatrogenic urethral lesion with cuff erosion during cystoscopic evaluation to exclude stricture or cuff erosion due to new onset of obstructive lower urinary tract symptoms. All patients had a history of a AMS 800 implantation due to posprostatectomy incontinence. Rigid cystoscopy was performed, which revelaed no pathologies; however, iatrogenic small urethral lesion was identified during the removal of the cystoscope at the projection of the cuff. RESULTS: In situ urethroplasty was performed, and the cuff was left open in situ. Additionally a protection fat flap was placed around the urethra from the dorsolateral aspect, separating the cuff and urethra from the direct contact with each other. After 6 weeks the urethral defect was completely healed and via a primary perineal incision the cuff was readapted and closed. The device was fully functioning without any additional adjustments. CONCLUSION: Our modification should be considered in select cases with absence of infection as part of management strategy for cases of iatrogenic urethral lesions with subsequent cuff erosion. Thereby the original cuff can be spared and the possibly difficult preparation of the urethra during reoperation can be avoided. However, additional more cases should be presented in the world-wide literature, to confirm the utility of this surgical principle.

Constitutively activated PI3K accelerates tumor initiation and modifies histopathology of breast cancer.

The gene encoding phosphatidylinositol 3-kinase catalytic subunit α-isoform (PIK3CA, p110α) is frequently activated by mutation in human cancers. Based on detection in some breast cancer precursors, PIK3CA mutations have been proposed to have a role in tumor initiation. To investigate this hypothesis, we generated a novel mouse model with a Cre-recombinase regulated allele of p110α (myristoylated-p110α, myr-p110α) along with p53fl/fl deletion and KrasG12D also regulated by Cre-recombinase. After instillation of adenovirus-expressing Cre-recombinase into mammary ducts, we found that myr-p110α accelerated breast tumor initiation in a copy number-dependent manner. Breast tumors induced by p53fl/fl;KrasG12D with no or one copy of myr-p110α had predominantly sarcomatoid features, whereas two copies of myr-p110α resulted in tumors with a carcinoma phenotype. This novel model provides experimental support for importance of active p110α in breast tumor initiation, and shows that the amount of PI3K activity can affect the rate of tumor initiation and modify the histological phenotype of breast cancer.

The role of the N-methyl-D-aspartate receptor NR1 subunit in peripheral nerve injury-induced mechanical allodynia, glial activation and chemokine expression in the mouse.

The N-methyl-d-aspartate receptor (NMDAR) has been strongly implicated in mechanisms of persistent pain states. The purpose of the present study was to determine whether the NMDAR NR-1, a key subunit in regulation of NMDAR channel complex is directly contributing to the onset and propagation of peripheral nerve injury-induced allodynia and whether N-methyl-d-aspartate (NMDA) signaling interacts with spinal chemokine (chemotactic cytokines) expression and glial activation. We used genetically engineered male mice that had their normal NR1 gene knocked out and expressed a modified NR1 gene at either normal level (NR1 +/+, wild type) or at a low level (NR1+/-, knock down). Each mouse underwent a peripheral nerve injury in which the lumbar 5 spinal segment (L5) nerve was transected. Mechanical allodynia was assessed using 0.008 and 0.015 g von Frey filaments on days 1, 3, 5, 7, 10, 14, 17 and 21 post-surgery. Mice were killed on day 21 and the harvested L5 spinal cord was analyzed for chemokine expression using RNAse protection assay. In a separate study, glial expression using immunohistochemistry was assessed in both groups 7 days following peripheral nerve injury. The NR1+/- mice displayed decreased mechanical allodynia in comparison to their wild type counterparts. However, even with dramatically impaired NMDA receptor signaling, there was still evidence of tactile hypersensitivity. Using the RPA analysis, we found decreases in mRNA chemokine expression in the NR1+/- mice as compared with NR1+/+ mice. There were no apparent differences in microglial or astrocytic expression between the wild type and knock down mice. These data provide important insights into the cascade of events involving the dynamic interaction between NMDAR function and spinal chemokine and glial production in neuropathic pain states. The results support the findings that chemokine signaling releases glutamate in the spinal cord.

Repeated injury to the lumbar nerve roots produces enhanced mechanical allodynia and persistent spinal neuroinflammation.

STUDY DESIGN: A lumbar radiculopathy model investigated pain behavioral responses after nerve root reinjury. OBJECTIVES: To gain a further understanding of central sensitization and neuroinflammation associated with chronic lumbar radiculopathy after repeated nerve root injury. SUMMARY OF BACKGROUND DATA: The pathophysiologic mechanisms associated with chronic radicular pain remain obscure. It has been hypothesized that lumbar root injury produces neuroimmunologic and neurochemical changes, sensitizing the spinal cord and causing pain responses to manifest with greater intensity and longer duration after reinjury. However, this remains untested experimentally. METHODS: Male Holtzman rats were divided into two groups: a sham group having only nerve root exposure, and a chromic group in which the nerve root was ligated loosely with chromic gut suture. Animals underwent a second procedure at 42 days. The chromic group was further divided into a reinjury group and a chromic-sham group, in which the lumbar roots were only re-exposed. Bilateral mechanical allodynia was continuously assessed throughout the study. Qualitative assessment of spinal cord glial activation and IL-beta expression was performed. RESULTS: Mechanical allodynia was significantly greater on both the ipsilateral and contralateral sides after reinjury (P < 0.001), and the response did not return to baseline after reinjury, as it did with the initial injury. There were also persistent spinal astrocytic and microglial activation and interleukin-1beta expression. CONCLUSIONS: The bilateral responses support central modulation of radicular pain after nerve root injury. An exaggerated and more prolonged response bilaterally after reinjury suggests central sensitization after initial injury. Neuroinflammatory activation in the spinal cord further supports the hypothesis that central neuroinflammation plays an important role in chronic radicular pain.

Nerve injury proximal or distal to the DRG induces similar spinal glial activation and selective cytokine expression but differential behavioral responses to pharmacologic treatment.

The specific mechanisms by which nervous system injury becomes a chronic pain state remain undetermined. Historically, it has been believed that injuries proximal or distal to the dorsal root ganglion (DRG) produce distinct pathologies that manifest in different severity of symptoms. This study investigated the role of injury site relative to the DRG in (1) eliciting behavioral responses, (2) inducing spinal neuroimmune activation, and (3) responding to pharmacologic interventions. Rats received either an L5 spinal nerve transection distal to the DRG or an L5 nerve root injury proximal to the DRG. Comparative studies assessed behavioral nociceptive responses, spinal cytokine mRNA and protein expression, and glial activation after injury. In separate studies, intrathecal pharmacologic interventions by using selective cytokine antagonists (interleukin-1 [IL-1] receptor antagonist and soluble tumor necrosis factor [TNF] receptor) and a global immunosuppressant (leflunomide) were performed to determine their relative effectiveness in these injury paradigms. Behavioral responses assessed by mechanical allodynia and thermal hyperalgesia were almost identical in the two models of persistent pain, suggesting that behavioral testing may not be a sensitive measure of injury. Spinal IL-1beta, IL-6, IL-10, and TNF mRNA and IL-6 protein were significantly elevated in both injuries. The overall magnitude of expression and temporal patterns were similar in both models of injury. The degree of microglial and astrocytic activation in the L5 spinal cord was also similar for both injuries. In contrast, the pharmacologic treatments were more effective in alleviating mechanical allodynia for peripheral nerve injury than nerve root injury, suggesting that nerve root injury elicits a more robust, centrally mediated response than peripheral nerve injury. Overall, these data implicate alternate nociceptive mechanisms in these anatomically different injuries that are not distinguished by behavioral testing or the neuroimmune markers used in this study.

The New York University Pediatric Heart Failure Index: a new method of quantifying chronic heart failure severity in children.

OBJECTIVE: The assessment of the severity of heart failure in pediatric patients is handicapped by the subjectivity of diagnostic parameters. This study evaluated the feasibility of a new standardized heart failure index, the New York University Pediatric Heart Failure Index (NYU PHFI), to quantify the degree of heart failure in a selected pediatric population. METHODS AND RESULTS: The index is a weighted, linear combination of scores based on symptoms, physical signs, and medical regimen. Overall, healthy children (n = 12) scored very low (0 to 2) on this index. Mean scores of children (<2 years; mean age, 4.8 months; n = 12) with a left-to-right shunt lesion declined from 11.4 (SD +/- 4.1, P <.001, 2-tailed test) before surgery to 1.8 (SD +/- 1.3) after surgical correction of their cardiac defects. The average inter-observer correlation coefficient was 0.95 (P <.001), despite a wide range of scores. CONCLUSIONS: The NYU PHFI appears to be a reliable and convenient instrument for measuring heart failure severity in children. These initial results support further testing in broader diagnostic and age groups and over longer periods.

Intrathecal anti-IL-6 antibody and IgG attenuates peripheral nerve injury-induced mechanical allodynia in the rat: possible immune modulation in neuropathic pain.

Interleukin-6 (IL-6) is a pleiotrophic cytokine with a diverse range of actions including the modulation of the peripheral and central nervous system. We have previously shown significant IL-6 protein and messenger RNA elevation in rat spinal cord following peripheral nerve injury that results in pain behaviors suggestive of neuropathic pain. These spinal IL-6 levels correlated directly with the mechanical allodynia intensity following nerve injury. In the current study, we sought to determine whether it is possible to attenuate mechanical allodynia and/or alter spinal glial activation resulting from peripheral nerve injury by specific manipulation of IL-6 with neutralizing antibodies or by global immune modulation utilizing immunogamma-globulin (IgG). Effects of peripheral administration of normal goat IgG and intrathecal (i.t.) administration of IL-6 neutralizing antibody, normal goat or normal rat IgG on mechanical allodynia associated with L5 spinal nerve transection were compared. Spinal glial activation was assessed at day 10 post surgery by immunohistochemistry. Low dose (0.01-0.001 microg) goat anti-rat IL-6 i.t. administration (P=0.025) significantly decreased allodynia and trended towards significance at the higher dose (0.08 microg to 0.008 microg, P=0.062). Low doses (0.01-0.001 microg) i.t. normal goat and rat IgG significantly attenuated mechanical allodynia, but not at higher doses (0.08-0.008 microg; P=0.001 for both goat and rat IgG). Peripherally administered normal goat IgG (30 or 100 mg/kg) did not attenuate mechanical allodynia. Spinal glial activation was unaltered by any treatment. These data provide further evidence for the role of central IL-6 and neuroimmune modulation in the etiology of mechanical allodynia following peripheral nerve injury.

Intraoperative myocardial ischemia recognized by transesophageal echocardiography monitoring in the pediatric population: a report of 3 cases.

We used continuous intraoperative transesophageal echocardiography (TEE) monitoring to detect intraoperative myocardial ischemia in children after they had been weaned from cardiopulmonary bypass for cardiac surgery. Three pediatric patients are described here to illustrate the usefulness of such TEE monitoring in surgical procedures involving coronary arteries. The indications for intraoperative TEE monitoring and a simplified scheme for immediate qualitative interpretation are discussed.

Left ventricular volume after correction of isolated aortic coarctation in neonates.

To determine the capacity of the left ventricle to expand after biventricular repair of left ventricular (LV) outflow tract obstruction, we studied pre- and postoperative echocardiographic variables from 14 infants (< 2 months old) who underwent successful repair of isolated aortic coarctation. We show that in this lesion, LV volume is a dynamic entity, and that the left ventricle achieves a larger cavity size once surgery relieves compression and normalizes loading conditions.

Gender differences in rat neuropathic pain sensitivity is dependent on strain.

It is well recognized that gender differences play a major role in pain sensitivity, pain report, analgesic efficacy and prevalence of certain chronic pain disorders. In the present study we sought to determine whether male or female rats of two different outbred strains (Sprague-Dawley and Holtzman) experienced differential pain sensitivity after the same mononeuropathy lesion. Following baseline mechanical allodynia testing, rats of each sex and strain underwent an L5 spinal nerve transection. Mechanical allodynia using 2 and 12 g von Frey filaments was assessed at days 1, 3, 5, 7, and 10 post surgery. There were no statistically significant differences in allodynia between gender in the Holtzman strain or between strains. However, mechanical allodynia was significantly greater in female Sprague-Dawley rats as compared with males following a spinal nerve transection. These data suggest that the choice of rat gender and strain should be considered in experimental neuropathic pain studies, especially in the assessment of potential analgesics.

Transgenic expression of TNF by astrocytes increases mechanical allodynia in a mouse neuropathy model.

It has been hypothesized that increased expression of proinflammatory cytokines mediate a variety of central nervous system disorders such as multiple sclerosis, Alzheimer's disease, cerebral ischemia, spinal cord injury, HIV encephalopathy and chronic pain. In order to further examine the central role of TNF in neuropathic pain, transgenic mice were used in which expression of murine TNF was targeted to astrocytes using a glial fibrillary acidic protein (GFAP)-TNF fusion gene. Spinal nerve (L5) transection was performed in either the GFAP-TNF transgenic or wild type mice. Mechanical allodynia was significantly enhanced in the GFAP-TNF transgenic mice compared with the wild type mice. These data support a central role of glial expression of TNF in the generation of neuropathic pain.

Cyclooxygenase-2 inhibitor SC-236 attenuates mechanical allodynia following nerve root injury in rats.

Low back pain is a common problem, affecting approximately two-thirds of the adult population. Of these individuals, a significant percentage will exhibit symptoms of radicular pain or sciatica. The purpose of this study was to determine the effect of one systemic (2 mg/kg) or intrathecal (0.2 mg/kg) dose of a selective cyclooxygenase-2 inhibitor (SC-236) in decreasing existing mechanical allodynia in a rat model of radiculopathy. Gait disturbance and mechanical allodynia (increased response to non-noxious von Frey monofilament stimuli) were assessed daily until the rats were killed 7 days after surgery. Robust mechanical allodynia developed in the rats in all groups except for those in the sham group by day 1 after surgery. Mechanical allodynia was significantly lower in the rats that received the systemic or the intrathecal dose of SC-236 than in those in the vehicle control group (analysis of variance followed by Bonferroni multiple comparison test, p = 0.002). The intrathecal drug route of administration produced greater attenuation in allodynia than the systemic dose, supporting a central mechanism of action of the cyclooxygenase-2 inhibitor (p = 0.002). The hypothesis that cyclooxygenase-2 is involved in spinal nociceptive processing after a nerve root injury was supported by this study. In addition, these data support continued basic science research to further elucidate central inflammatory processes that follow nerve root injury.

Limited role of macrophages in generation of nerve injury-induced mechanical allodynia.

The purpose of this study was to investigate the role of peripheral macrophages in the generation of mechanical allodynia utilizing a modification of the Chung rat model of neuropathy. Three distinct methods were used: (1) systemic and perineural macrophage inhibition utilizing CNI-1493; (2) depletion of the peripheral macrophage population by liposome-encapsulated clodronate; and (3) perineural administration of activated or inactivated bone marrow-derived macrophages (BMDM) in sham-surgery rats. Mechanical allodynia was tested on days 1, 3, 5, 7, and 10 post-intervention or surgery using von Frey monofilaments. In order to assess the role of spinal glia following these interventions, microglial (CNS macrophages) and astrocytic activation was assessed using immunohistochemistry. CNI-1493 did not attenuate mechanical allodynia, or spinal glial expression as compared to the saline control group. Similarly, the clodronate depletion of peripheral macrophages prior to nerve injury did not have any effect on the resultant mechanical allodynia or spinal glial activation. Perineural administration of activated or inactivated BMDM did not evoke mechanical allodynia in sham surgery rats. Of interest, we observed an ipsilateral, dorsal horn increase in microglial expression following perineural administration of activated macrophages. In summary, these data suggest a limited role of activated macrophages in the onset of mechanical allodynia in an animal model of neuropathy.

Increase of interleukin-6 mRNA in the spinal cord following peripheral nerve injury in the rat: potential role of IL-6 in neuropathic pain.

Interleukin-6 (IL-6) is a multifunctional cytokine whose actions include modulation of proliferation, differentiation, and maturation of hemapoietic progenitors and other cell lineages; growth regulation of certain carcinoma cell lines; and control of cellular metabolic activities. Initially described in terms of its activities in the immune system and inflammation, accumulating evidence supports an essential role of IL-6 in the development, differentiation, regeneration and degeneration of neurons in the peripheral and central nervous system. We have previously demonstrated that immunoreactive-like IL-6 protein is significantly elevated in the spinal cord in response to peripheral nerve injury that results in neuropathic pain behaviors in the rat. In the current study, our objective was to determine if the source of IL-6 protein was endogenous to the central nervous system by measuring any detectable increases in spinal IL-6 mRNA expression following established mononeuropathy procedures associated with neuropathic pain: spinal nerve cryoneurolysis (SPCN) or spinal nerve tight ligation (SPTL). Using in situ hybridization and a digoxigenin-labeled oligonucleotide, IL-6 mRNA in neurons was significantly elevated at 3 and 7 days post SPCN and 7 days post SPTL in both dorsal and ventral horns. The cellular localization of the IL-6 mRNA expression was predominately neuronal as confirmed by NeuN serial staining. For example, in the SPCN 7 day group, IL-6 mRNA cell profiles in the ipsilateral dorsal horn were significantly different from the normal group (38.7+/-12.8 vs. 4.89+/-1.6, p<0.001). These data demonstrate the central, spinal production of a proinflammatory cytokine in response to a peripheral nerve injury. In addition, these results add to the growing body of literature implicating these immune products, cytokines, as potential neuromodulators/neurotransmitters and provides further evidence for their role in the nociceptive processing which leads to chronic pain.

Unusual case of prominent Chiari network trapped in the left atrium.

We describe a case of an unusually prominent Chiari network in a premature neonate who was evaluated with echocardiography. The network, which is an embryologic remnant, was extensive, mobile, and moved in and out of the right ventricle. Later, tissue strands passed the foramen ovale and ultimately became trapped in the left atrium. The differential diagnosis included thrombus, tumor, vegetation, and ruptured chordae.

Loss of protein kinase C inhibition in the beta-T594M variant of the amiloride-sensitive Na+ channel.

We previously reported the presence of a novel variant (beta-T594M) of the amiloride-sensitive Na+ channel (ASSC) in which the threonine residue at position 594 in the beta-subunit has been replaced by a methionine residue. Electrophysiological studies of the ASSC on Epstein-Barr virus (EBV)-transformed lymphocytes carrying this variant showed that the 8-(4-chlorophenylthio) adenosine 3':5'-cyclic monophosphate (8cpt-cAMP)-induced responses were enhanced when compared to wild-type EBV-transformed lymphocytes. Furthermore, in wild-type EBV-transformed cells, the 8cpt-cAMP-induced response was totally blocked by the phorbol ester, phorbol 12-myristate 13-acetate (PMA). This inhibitory effect of PMA was blocked by a protein kinase C inhibitor, chelerythrine. We now have identified individuals who are homozygous for this variant, and showed that PMA had no effect on the 8cpt-cAMP-induced responses in the EBV-transformed lymphocytes from such individuals. Cells heterozygous for this variant showed mixed responses to PMA, with the majority of cells partially inhibited by PMA. Our results demonstrate that an alteration in a single amino acid residue in the beta-subunit of the ASSC can lead to a total loss of inhibition to PMA, and establish the beta-subunit as having an important role in conferring a regulatory effect on the ASSC of lymphocytes.

Clinical trials of the CytoRich specimen-preparation device for cervical cytology. Preliminary results.

OBJECTIVE: To obtain preliminary data on the Roche CytoRich thin-layer system for the preparation of gynecologic cytology specimens, derived from a preclinical startup evaluation of the instrument and comparing the CytoRich method to conventional smears. STUDY DESIGN: At six different clinical sites, 286 pairs of conventional and CytoRich slides derived from the same patient sample were compared for the following: final Bethesda classification diagnosis, specimen adequacy and presence of microorganisms. RESULTS: The study showed agreement between the methods for an exact Bethesda diagnosis in 78% and agreement within one Bethesda diagnosis category in 95%. The CytoRich method diagnosed more cases of squamous intraepithelial lesion (SIL) than did the conventional method, and the differences in SIL detection were statistically significant. The CytoRich method identified similar numbers of cases with microorganisms as did the conventional smears, and the CytoRich system improved overall specimen adequacy as compared to the conventional method, with fewer cases of unsatisfactory and less-than-optimal smears. CONCLUSION: The CytoRich method may improve the overall sensitivity and specificity of the cervical cytology procedure. Clinical trials to verify these preliminary data are ongoing.

The effects of endocervical canal topography, tubal metaplasia, and high canal sampling on the cytologic presentation of nonneoplastic endocervical cells.

Use of new endocervical cytologic sampling devices has correlated with increased numbers of cases showing endocervical "atypia." To ascertain the potential causes, a cytologic and histologic correlative study of the normal endocervical canal was undertaken. Hysterectomy specimens from 25 patients with no history of cervical disease were used. The anterior and posterior endocervical canals were divided into three equal sections. Each of the sections of the anterior canal were sampled cytologically, with the corresponding posterior canal processed for histology. Endocervical gland number, depth, and cellular crowding were most pronounced in the middle third of the canal. Tubal metaplasia (present in 100% of cases) was most prominent in the upper third. The most cellular cytologic samples were obtained from the middle third. "Atypical" endocervical groups were most commonly identified in the upper third. The normal topography of the endocervical canal, with sampling of the upper regions by newly utilized devices, may account for the increase in samples showing cytologic patterns that mimic endocervical neoplasia.

The influence of alkoxymethyl purine and pyrimidine acyclonucleosides on growth inhibition of Kirkman-Robbins hepatoma and possible mechanism of their cytostatic activity.

Newly synthesized allyloxymethyl purine and pyrimidine acyclonucleosides [Fig. 1, comp. 1-6] were tested in Syrian hamster, six days after heterotransplantations of Kirkman-Robbins hepatoma and compared with Th5, Th5P and PMT [Fig. 1, comp. 7-9]. 48 hours after intraperitoneal (i.p.) administration of AMT and Th5 in a dose of 80 mg per kg body weight, these compounds reduced tumor weight by 42%, while AMU (in the same dose) by 30%. The inhibition of tumor weight is accompanied by a decrease in dThd and dGuo kinase activities in tumor cytosol by AMU (36% and 33%, respectively) by AMT (59% and 53%, respectively) and by Th5 (58% and 55%, respectively). AMU, AMT and Th5 are phosphorylated in vivo by kinases present in cytosol of growing hepatoma to mono, di and triphosphates, but allyloxymethyl residue of AMU and AMT is first hydrated to hydroxypropoxymethyl residue, having CH2OH group. The lack of phosphorylation of PMT in vivo (having saturated propoxymethyl residue) and phosphorylation of Th5P (when used as a substrate for dNMP kinase) only to Th5 diphosphate suggested that AMU, AMT and Th5 triphosphates are responsible for the inhibition of dTMP and dGMP synthesis.