Pelvic inflammatory disease: diagnosis and treatment in the emergency department.

Pelvic inflammatory disease is associated with complications that include infertility, chronic pelvic pain, ruptured tubo-ovarian abscess, and ectopic pregnancy. The diagnosis may be delayed when the presentation has nonspecific signs and symptoms. Even when properly diagnosed, pelvic inflammatory disease is often treated suboptimally. This review provides evidence-based recommendations for the diagnosis, treatment, disposition, and follow-up of patients with pelvic inflammatory disease. Arranging follow-up of patients within 48 to 72 hours and providing clear patient education are fundamental to ensuring good patient outcomes. Emerging issues, including new pathogens and\ evolving resistance patterns among pelvic inflammatory disease pathogens, are reviewed.

Pelvic Inflammatory Disease: Diagnosis And Treatment In The Emergency Department.

Pelvic inflammatory disease is a common disease that is associated with significant complications including infertility, chronic pelvic pain, ruptured tubo-ovarian abscess, and ectopic pregnancy. The diagnosis may be delayed when the presentation has nonspecific signs and symptoms. Even when it is properly identified, pelvic inflammatory disease is often treated suboptimally. This review provides evidence-based recommendations for the diagnosis, treatment, disposition, and follow-up of patients with pelvic inflammatory disease. Arranging follow-up of patients within 48 to 72 hours and providing clear patient education are fundamental to ensuring good patient outcomes. Emerging issues, including new pathogens and evolving resistance patterns among pelvic inflammatory disease pathogens are reviewed.

Pelvic inflammatory disease: diagnosis and treatment in the emergency department [digest].

Pelvic inflammatory disease is a common disease that is associated with significant complications including infertility, chronic pelvic pain, ruptured tubo-ovarian abscess, and ectopic pregnancy. The diagnosis may be delayed when the presentation has nonspecific signs and symptoms. Even when it is properly identified, pelvic inflammatory disease is often treated suboptimally. This review provides evidence-based recommendations for the diagnosis, treatment, disposition, and follow-up of patients with pelvic inflammatory disease. Arranging follow-up of patients within 48 to 72 hours and providing clear patient education are fundamental to ensuring good patient outcomes. Emerging issues, including new pathogens and evolving resistance patterns among pelvic inflammatory disease pathogens are reviewed. [Points & Pearls is a digest of Emergency Medicine Practice].

Structural features and domain organization of huntingtin fibrils.

Misfolding and aggregation of huntingtin is one of the hallmarks of Huntington disease, but the overall structure of these aggregates and the mechanisms by which huntingtin misfolds remain poorly understood. Here we used site-directed spin labeling and electron paramagnetic resonance (EPR) spectroscopy to study the structural features of huntingtin exon 1 (HDx1) containing 46 glutamine residues in its polyglutamine (polyQ) region. Despite some residual structuring in the N terminus, we find that soluble HDx1 is highly dynamic. Upon aggregation, the polyQ domain becomes strongly immobilized indicating significant tertiary or quaternary packing interactions. Analysis of spin-spin interactions does not show the close contact between same residues that is characteristic of the parallel, in-register structure commonly found in amyloids. Nevertheless, the same residues are still within 20 Å of each other, suggesting that polyQ domains from different molecules come into proximity in the fibrils. The N terminus has previously been found to take up a helical structure in fibrils. We find that this domain not only becomes structured, but that it also engages in tertiary or quaternary packing interactions. The existence of spin-spin interactions in this region suggests that such contacts could be made between N-terminal domains from different molecules. In contrast, the C-terminal domain is dynamic, contains polyproline II structure, and lacks pronounced packing interactions. This region must be facing away from the core of the fibrils. Collectively, these data provide new constraints for building structural models of HDx1 fibrils.

Perturbation with intrabodies reveals that calpain cleavage is required for degradation of huntingtin exon 1.

BACKGROUND: Proteolytic processing of mutant huntingtin (mHtt), the protein that causes Huntington's disease (HD), is critical for mHtt toxicity and disease progression. mHtt contains several caspase and calpain cleavage sites that generate N-terminal fragments that are more toxic than full-length mHtt. Further processing is then required for the degradation of these fragments, which in turn, reduces toxicity. This unknown, secondary degradative process represents a promising therapeutic target for HD. METHODOLOGY/PRINCIPAL FINDINGS: We have used intrabodies, intracellularly expressed antibody fragments, to gain insight into the mechanism of mutant huntingtin exon 1 (mHDx-1) clearance. Happ1, an intrabody recognizing the proline-rich region of mHDx-1, reduces the level of soluble mHDx-1 by increasing clearance. While proteasome and macroautophagy inhibitors reduce turnover of mHDx-1, Happ1 is still able to reduce mHDx-1 under these conditions, indicating Happ1-accelerated mHDx-1 clearance does not rely on these processes. In contrast, a calpain inhibitor or an inhibitor of lysosomal pH block Happ1-mediated acceleration of mHDx-1 clearance. These results suggest that mHDx-1 is cleaved by calpain, likely followed by lysosomal degradation and this process regulates the turnover rate of mHDx-1. Sequence analysis identifies amino acid (AA) 15 as a potential calpain cleavage site. Calpain cleavage of recombinant mHDx-1 in vitro yields fragments of sizes corresponding to this prediction. Moreover, when the site is blocked by binding of another intrabody, V(L)12.3, turnover of soluble mHDx-1 in living cells is blocked. CONCLUSIONS/SIGNIFICANCE: These results indicate that calpain-mediated removal of the 15 N-terminal AAs is required for the degradation of mHDx-1, a finding that may have therapeutic implications.

Intrabodies binding the proline-rich domains of mutant huntingtin increase its turnover and reduce neurotoxicity.

Although expanded polyglutamine (polyQ) repeats are inherently toxic, causing at least nine neurodegenerative diseases, the protein context determines which neurons are affected. The polyQ expansion that causes Huntington's disease (HD) is in the first exon (HDx-1) of huntingtin (Htt). However, other parts of the protein, including the 17 N-terminal amino acids and two proline (polyP) repeat domains, regulate the toxicity of mutant Htt. The role of the P-rich domain that is flanked by the polyP domains has not been explored. Using highly specific intracellular antibodies (intrabodies), we tested various epitopes for their roles in HDx-1 toxicity, aggregation, localization, and turnover. Three domains in the P-rich region (PRR) of HDx-1 are defined by intrabodies: MW7 binds the two polyP domains, and Happ1 and Happ3, two new intrabodies, bind the unique, P-rich epitope located between the two polyP epitopes. We find that the PRR-binding intrabodies, as well as V(L)12.3, which binds the N-terminal 17 aa, decrease the toxicity and aggregation of HDx-1, but they do so by different mechanisms. The PRR-binding intrabodies have no effect on Htt localization, but they cause a significant increase in the turnover rate of mutant Htt, which V(L)12.3 does not change. In contrast, expression of V(L)12.3 increases nuclear Htt. We propose that the PRR of mutant Htt regulates its stability, and that compromising this pathogenic epitope by intrabody binding represents a novel therapeutic strategy for treating HD. We also note that intrabody binding represents a powerful tool for determining the function of protein epitopes in living cells.

Outcomes for live donor renal transplantation using kidneys with medial fibroplasia.

OBJECTIVES: To review the outcomes for live donor renal transplantation using kidneys with fibromuscular dysplasia. METHODS: We performed a retrospective review and searched a departmental database to identify all renal donors with fibromuscular dysplasia from 1995 through 2001. These donors were then paired with the recipient using the institution's renal transplant database. A single radiologist reviewed the original arteriographic studies. Mild disease was defined as mild irregularity of the artery without significant stenosis. Moderate disease was defined as arterial irregularity with less than 50% stenosis. Severe disease was defined as irregularity with greater than 50% stenosis or with aneurysms. RESULTS: Thirty-six donor/recipient pairs were identified. Twenty-six donors had unilateral and 10 bilateral disease. Twenty-eight had mild and eight moderate disease. Four grafts were lost during the follow-up period (three acute rejection and one chronic rejection) for an overall graft survival rate of 89%. The median graft survival/follow-up was 37.1 months (range 0.5 to 82). The median serum creatinine was 1.6 mg/dL. The median systolic and diastolic blood pressure was 155 and 82 mm Hg, respectively. Six recipients required no antihypertensive agents. All but 9 of the remaining patients required two or fewer antihypertensive agents. CONCLUSIONS: Selected patients with medial fibroplasia can be used as renal donors, and satisfactory functional outcomes can be achieved. Renal donors with mild anatomic abnormalities such as medial fibroplasia could be used to increase the potential donor pool and decrease the waiting time for renal transplantation.

Bladder neck cinch for pediatric neurogenic outlet deficiency.

PURPOSE: The fascial bladder neck sling achieves continence in 50% to 90% of children with neurogenic outlet deficiency. Most slings apply only partial pressure around the bladder neck. We evaluated the effectiveness of a rectus fascia bladder neck cinch which applies circumferential pressure around the bladder neck and elevation as a means of increasing outlet resistance. MATERIALS AND METHODS: Fifteen children with spina bifida underwent a fascial bladder neck cinch procedure at the time of augmentation cystoplasty. A 1 to 1.5 cm width of variable length rectus fascia was harvested and a vertical slit was made in 1 end. The fascia was "cinched" tightly around the bladder neck and secured to the symphysis or rectus fascia. RESULTS: The 14 girls and 1 boy ranged in age range from 4 to 17 years. All children had neurogenic intrinsic sphincter deficiency and a poorly compliant and/or small capacity bladder. Followup ranged from 10 to 36 months (followup in 12 greater than 1 year). Postoperatively, all children perform clean intermittent catheterization. At the last followup 8 girls and the boy (60%) were dry (no leak and no pads at 4 hours from the last catheterization and dry throughout the night). CONCLUSIONS: Rectus fascia used as a bladder neck cinch is effective but no better than other bladder neck slings for decreasing urinary incontinence. The bladder neck cinch appears to be an acceptable addition to the technique of fascial slings. However, we have subsequently changed our technique because these results did not meet our expectations.

Follow-up functional radiographic studies are not mandatory for all patients after ureteroscopy.

OBJECTIVES: To evaluate the usefulness of follow-up radiographic studies after ureteroscopy by retrospective chart review. METHODS: We reviewed the charts of 118 patients who underwent 134 ureteroscopic procedures from January 1998 to November 1999. RESULTS: Follow-up was obtained at our institution for 87 patients. The follow-up period ranged from 3 to 34 weeks (mean 7, SE +/- 0.75). Of 10 patients who underwent ureteroscopy for diagnostic purposes, none had postoperative pain or obstruction on follow-up radiographic studies. Of 77 patients who underwent ureteroscopy for calculi, 12 (16%) had postoperative obstruction. One third of patients with residual obstruction (4 of 12) complained of persistent pain versus 6% of patients without evidence of obstruction (4 of 65) (P = 0.02). Twelve patients had residual stone fragments on their follow-up radiographic studies; 5 (42%) of these patients complained of pain versus 3 (5%) of 65 patients who were stone free after surgery (P = 0.002). The use of pain to predict either obstruction or residual fragments had a negative and positive predictive value of 83% and 75%, respectively. Preoperative obstruction and postoperative pain were combined as one indicator for the presence of residual fragments and postoperative obstruction. Patients who had preoperative obstruction and presented with postoperative pain had a 67% chance of having residual fragments and a 50% chance of residual obstruction, and 96% of patients without preoperative obstruction and no postoperative pain had no persistent obstruction or residual fragments (P = 0.001). CONCLUSIONS: For patients who present for ureteroscopy with no obstruction and report no pain at follow-up, a plain radiograph may be sufficient. For patients who present with obstruction and report pain during follow-up, functional imaging studies are recommended.

Polaris, a protein disrupted in orpk mutant mice, is required for assembly of renal cilium.

Cilia are organelles that play diverse roles, from fluid movement to sensory reception. Polaris, a protein associated with cystic kidney disease in Tg737(o)(rpk) mice, functions in a ciliogenic pathway. Here, we explore the role of polaris in primary cilia on Madin-Darby canine kidney cells. The results indicate that polaris localization and solubility change dramatically during cilia formation. These changes correlate with the formation of basal bodies and large protein rafts at the apical surface of the epithelia. A cortical collecting duct cell line has been derived from mice with a mutation in the Tg737 gene. These cells do not develop normal cilia, which can be corrected by reexpression of the wild-type Tg737 gene. These data suggest that the primary cilia are important for normal renal function and/or development and that the ciliary defect may be a contributing factor to the cystic disease in Tg737(o)(rpk) mice. Further characterization of these cells will be important in elucidating the physiological role of renal cilia and in determining their relationship to cystic disease.