Harvest of large fascia lata autograft: Outcomes in 108 patients.

PURPOSE: Due to the reclassification of transvaginal mesh as a high-risk device, there has been renewed interest in the use of fascia lata in pelvic floor reconstruction. Here we report our experience in 108 patients who underwent large fascia lata harvest for pelvic organ prolapse (POP) repair. Our primary objective was to highlight the postoperative morbidity of the large fascia lata harvest in patients who underwent POP repair using fascia lata autograft. METHODS: Surgery involved harvesting a fascia lata graft through a small lateral upper thigh incision and was used for either autologous transvaginal POP repair or autologous sacrocolpopexy. To prevent seroma, a temporary Jackson-Pratt drain was intraoperatively placed and a mild compression wrap was applied to the area for 4-6 weeks postoperatively. Patient demographics were obtained preoperatively, while physical exam findings and postoperative outcomes related to the fascia lata harvest were collected at sequential follow up visits. RESULTS: One-hundred eight patients underwent 111 large fascia lata harvests for either transvaginal or abdominal/robotic POP repair from July 2016 to January 2022. Mean follow-up was 19.6 months (range: 1-65) with 38 patients having 24 months or more of follow-up. Mean Visual Analog Pain (VAP) score was 1 (range: 0-10). Sixteen patients developed asymptomatic thigh bulges, 16 patients developed harvest site seromas (of which 14 resolved), and 59 patients experienced mild, non-bothersome paresthesia near the incision. CONCLUSION: Large fascia lata harvest offers a robust autograft for transvaginal or transabdominal POP repair with minimal morbidity. Harvest site complications are minor and typically resolve with expectant management. This technique can be safely utilized in patients who desire graft-augmented repair of POP without the use of synthetic mesh, allograft, or xenograft.

Total Autologous Fascia Lata Sacrocolpopexy for Treatment of Pelvic Organ Prolapse: Experience in Thirty-Four Patients.

OBJECTIVE: To develop a technique for open/robotic sacrocolpopexy using autologous fascia lata autograft. We report our experience in our first 34 patients. METHODS: The operation utilizes a 4-5-cm x 15-18-cm piece of fascia lata harvested through a 3-4-inch lateral upper thigh incision. The graft is configured into a traditional Y-shaped configuration using CV-2 Goretex sutures and is used to perform sacrocolpopexy. Patients were followed by history and physical, POP-Q scores, and symptoms related to thigh harvest including visual analog pain (VAP) scores. Treatment failure was defined as symptomatic pelvic organ prolapse (POP) involving apical descent. RESULTS: Autologous fascia lata sacrocolpopexy was performed on 34 patients with a mean age of 62. Mean follow-up was 13 months (range 2-42). Thirteen cases were open sacrocolpopexies, and 21 were robotic. Concurrent procedures included hysterectomy (9), vaginal mesh excision (7), bowel resection and rectopexy (5), and autologous sling (5). POP symptoms resolved in all 34 patients, and there were no treatment failures. The overwhelming majority of harvest site issues were minor and managed expectantly. Mean VAP score at the harvest site was 0.4 (range 0-3). Three patients developed non-bothersome thigh bulges. One patient developed a harvest site seroma. Twelve patients reported mild, non-bothersome harvest site paresthesias. No thromboembolic events occurred. CONCLUSION: Autologous fascia lata sacrocolpopexy is an efficacious treatment for patients who desire non-mesh POP repair. Most harvest site issues are minor and typically resolve with expectant management alone. Continued follow-up of this series is ongoing to determine long-term success of this operation.

Symptom Resolution and Recurrent Urinary Incontinence Following Removal of Painful Midurethral Slings.

OBJECTIVE: To evaluate pain improvement and recurrent stress incontinence (SUI) following painful synthetic midurethral sling (MUS) removal. METHODS: We conducted a retrospective review of patients who underwent synthetic MUS removal at our institution from 2009-2016 for the indication of pain. We recorded sling type (transobturator vs retropubic), complete vs partial removal, and presenting symptoms. Postoperative pain improvement was categorized as resolved (pain resolved, requiring no further therapy), improved (pain less bothersome, may require further therapy), or unresolved (no/minimal improvement, requiring further management). Recurrent incontinence and further reconstructive procedures were assessed. RESULTS: 87 patients (49 complete and 38 partial removal) with pain as the primary indication for removal were included. Median age at intervention was 54 years with median follow-up of 8 months. Overall, pain improved or resolved in 78.1% of cases. Complete removal was associated with significantly greater percentage of pain resolution (63.3%) compared to partial removal (26.3%) (P = 0.002) regardless of sling type. No significant differences in recurrent SUI were noted in complete vs partial removal. Additional reconstructive procedures were performed in 28 patients, most commonly sling placement, with no significant difference in complete (20.4%) vs partial (28.9%) removal groups (P = 0.36). The overall complication rate was low (5.7%), a majority of which were transfusions (4.6%). CONCLUSION: Following MUS removal, most patients experienced resolution or improvement of pain. Complete sling removal was associated with significantly greater percentage of pain resolution compared to partial removal in both retropubic and transobturator slings. Rates of recurrent SUI and reintervention for SUI were not related to the extent of sling removal.

Comparison of magnetic resonance defecography grading with POP-Q staging and Baden-Walker grading in the evaluation of female pelvic organ prolapse.

PURPOSE: The physical examination and pelvic imaging with MRI are often used in the pre-operative evaluation of pelvic organ prolapse. The objective of this study was to compare grading of prolapse on defecography phase of dynamic magnetic resonance imaging (dMRI) with physical examination (PE) grading using both the Pelvic Organ Prolapse Quantification (POP-Q) staging and Baden-Walker (BW) grading systems in the evaluation of pelvic organ prolapse (POP). METHODS: We retrospectively reviewed the charts of 170 patients who underwent dMRI at our institution. BW grading and POP-Q staging were collected for anterior, apical, and posterior compartments, along with absolute dMRI values and overall grading of dMRI. For the overall grading/staging from dMRI, BW, and POP-Q, Spearman rho (ρ) was used to assess the correlation. The correlations between dMRI grading and POP-Q staging were compared to the correlations between dMRI grading and BW grading using Fisher's Z transformation. RESULTS: A total of 54 patients were included. dMRI grading was not significantly correlated with BW grading for anterior, apical, and posterior compartment prolapse (p > 0.15). However, overall dMRI grading demonstrated a significant (p = 0.025) and positive correlation (ρ = 0.305) with the POP-Q staging system. dMRI grading for anterior compartment prolapse also demonstrated a positive correlation (p = 0.001, ρ = 0.436) with the POP-Q staging derived from measurement locations Aa and Ba. The overall dMRI grade is better correlated with POP-Q stage than with BW grade (p = 0.024). CONCLUSION: Overall and anterior compartment grading from dMRI demonstrated a significant and positive correlation with the overall POP-Q staging and anterior compartment POP-Q staging, respectively. The overall dMRI grade is better correlated with POP-Q staging than with BW grading.

Pain Resolution and Recurrent Prolapse Rates Following Vaginal Mesh Removal.

OBJECTIVE: To evaluate pain resolution and recurrent prolapse following removal of painful pelvic organ prolapse (POP) mesh. METHODS: This was an IRB-approved retrospective review of patients who underwent POP mesh removal from 2009 to 2018 for the primary indication of pain and/or dyspareunia. Factors of interest included mesh type, complete versus partial removal, presenting symptom(s), and recurrent prolapse. Complete removal was defined as complete excision of all possible mesh, including arms, and partial removal was anything less. Postoperative symptom improvement was categorized as resolved, improved, or unresolved. RESULTS: Ninety-two mesh removal patients were identified, 78 of whom underwent mesh removal for pain or dyspareunia, with mean follow-up of 17.25 months (range: 0.46-60.25). Overall, presenting symptoms resolved or improved in 85.9%. In the 45 complete removal patients, 46.7% resolved, 40.0% improved, and 11.1% unresolved compared to 51.5% resolved, 33.3% improved, and 12.1% unresolved in the 33 partial removal patients (P = .82). Recurrent symptomatic POP developed in 31.1% of patients after complete removal compared to 15.2% after partial removal (P = .12). Overall, 23 (30.3%) patients required additional reconstructive procedures. CONCLUSION: Most patients experienced resolution or improvement in painful symptoms after any degree of mesh removal. Complete removal was not significantly associated with greater symptom improvement compared to partial removal. Complete removal was associated with a higher percentage of recurrent POP, but this association was not statistically significant. Less than one-third of patients required additional surgery.

Holmium Laser Enucleation of the Prostate Is Safe and Feasible as a Same Day Surgery.

OBJECTIVE: To assess the safety, feasibility and treatment outcomes of holmium laser enucleation of the prostate (HoLEP) as a same day surgery (SDS). METHODS: HoLEPs performed from November 2013 to December 2018 at our institution were reviewed retrospectively. Inclusion criteria for same day surgery (SDS) included living in the local metropolitan area with access to local hospital and Eastern Cooperative Oncology Group (ECOG) 0-2, regardless of prostate size and anticoagulation status. Those patients who were discharged directly from the postoperative care unit were identified as SDS cases. Patients admitted overnight after HoLEP during the same period were used as a matched cohort. Patient demographics, disease characteristics and treatment outcomes were compared. RESULTS: A total of 377 patients were identified, including 199 SDS and 178 non-SDS patients. No statistical difference was present between the 2 groups regarding the post-op complication and readmission rates. The non-SDS group had a significantly higher percentage of patients with history of urinary retention, lower pre-op Qmax, and larger prostate volume. The SDS group had shorter operative time, length of stay (LOS), and catherization time (all P <.05). At 1-year follow-up, no statistically different change in Qmax, PVR, or IPSS score was noted between the 2 groups. CONCLUSION: Same day outpatient surgery for HoLEP is safe in patients who live in close proximity and have ECOG status 0-2. Our readmission rate and complication rate are comparable to those reported in the literature with markedly decreased LOS. Long-term functional outcome is not compromised by SDS.

Total Autologous Fascia Lata Anterior and Apical Pelvic Organ Prolapse Repair: A New Technique and Initial Experience.

OBJECTIVE: To address renewed interest in nonmesh transvaginal Pelvic Organ Prolapse (POP) repair since the FDA reclassification of transvaginal mesh, our goal was to develop a transvaginal sacrospinous fixation for anterior and apical POP using only autologous fascia lata. We report our experience in 33 patients. METHODS: Autologous Anterior and Apical Pelvic Organ Prolapse (AAA-POP) repair utilizes a 4 × 14 cm piece of fascia lata harvested through a 3-4-inch upper thigh incision. The graft is reconfigured to provide apical fixation to the sacrospinous ligaments and distal fixation to the obturator fascia. Patients were followed by history, SEAPI scores, POP-Q scores, and Visual Analogue Pain Score. Treatment success was defined as absence of symptomatic anterior or apical POP. RESULTS: Thirty-three patients (mean age 63, mean follow-up 12 months) underwent AAA-POP. Treatment was successful in 31 patients (94%), and 2 failures were due to uterine prolapse. Mean harvest site Visual Analog Pain score was 0.27. Five and 7 patients developed nonbothersome thigh bulges and wound paresthesias, respectively. All 4 harvest-site seromas resolved, with 2 requiring simple aspiration. Eleven patients developed urinary retention, 10 (91%) of them after concurrent pubovaginal sling. All resolved after sling loosening (6 patients) or sling lysis (4 patients). CONCLUSION: AAA-POP is an efficacious treatment for patients desiring nonmesh POP repair. Postoperative harvest site issues are minor and typically resolve with expectant management. Patients should be counseled about the potential risk of failure with a uterine-sparing approach and the risk of urinary retention with concurrent pubovaginal sling.

Management of vaginal mesh exposure: A systematic review.

Objectives: To identify various predisposing factors, the clinical presentation, and the management of vaginal mesh-related complications, with special emphasis on mesh exposure and the indications for and results of vaginal mesh removal. Methods: A systematic literature review was performed using a search strategy based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses criteria. PubMed was queried for studies regarding aetiology, risk factors, and management of vaginal mesh exposure from 1 January 2008 to June 2018. Full-text articles were obtained for eligible abstracts. Relevant articles were included, and the cited references were used to identify relevant articles not previously included. Results: A total of 102 abstracts were identified from the PubMed search criteria. An additional 45 studies were identified based on review of the cited references. After applying eligibility criteria and excluding impertinent articles, 58 studies were included in the final analysis. Conclusion: Numerous studies have found at least some degree of symptomatic improvement regardless of the amount of mesh removed. Focal areas of exposure or pain can be successfully managed with partial mesh removal with low rates of complications. With partial mesh removal, many patients will ultimately require subsequent mesh removal procedures. For this reason, complete mesh excision is an alternative for patients with diffuse vaginal pain, large mesh exposure, and extrusion of mesh into adjacent viscera. However, when considering complete mesh removal, it is important to counsel patients regarding possible complications of removal and the increased risk of recurrent stress urinary incontinence and pelvic organ prolapse postoperatively. Abbreviations: MUS: midurethral sling; OR: odds ratio; POP: pelvic organ prolapse; PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-analyses; SUI: stress urinary incontinence; TOT: transobturator; TVT: tension-free vaginal tape.

Improved Detection of Pelvic Organ Prolapse: Comparative Utility of Defecography Phase Sequence to Nondefecography Valsalva Maneuvers in Dynamic Pelvic Floor Magnetic Resonance Imaging.

PURPOSE: To evaluate the utility of a defecography phase (DP) sequence in dynamic pelvic floor MRI (DPMRI), in comparison to DPMRI utilizing only non-defecography Valsalva maneuvers (VM). MATERIALS AND METHODS: Inclusion criteria identified 237 female patients with symptoms and/or physical exam findings of pelvic floor prolapse. All DPMRI exams were obtained following insertion of ultrasound gel into the rectum and vagina. Steady-state free-precession sequences in sagittal plane were acquired in the resting state, followed by dynamic cine acquisitions during VM and DP. In all phases, two experienced radiologists performed blinded review using the H-line, M-line, Organ prolapse (HMO) system. The presence of a rectocele, enterocele and inferior descent of the anorectal junction, bladder base, and vaginal vault were recorded in all patients using the pubococcygeal line as a fixed landmark. RESULTS: DPMRI with DP detected significantly more number of patients than VM (p<0.0001) with vaginal prolapse (231/237, 97.5% vs. 177/237, 74.7%), anorectal prolapse (227/237, 95.8% vs. 197/237, 83.1%), cystocele (197/237, 83.1% vs. 108/237, 45.6%), and rectocele (154/237, 65% vs. 93/237, 39.2%). The median cycstocele (3.2cm vs. 1cm), vaginal prolapse (3cm vs. 1.5cm), anorectal prolapse (5.4cm vs. 4.2cm), H-line (8cm vs. 7.2cm) and M-line (5.3cm vs. 3.9cm) were significantly higher with DP than VM (p<0.0001). CONCLUSIONS: Addition of DP to DPMRI demonstrates a greater degree of pelvic floor instability as compared to imaging performed during VM alone. Pelvic floor structures may show mild descent or appear normal during VM, with marked prolapse on subsequent DP images.

Surgery for Posterior Compartment Vaginal Prolapse: Graft Augmented Repair.

Posterior compartment vaginal prolapse can be approached with multiple surgical techniques, including transvaginally, transperineally, and transanally, repaired with either native tissue or with the addition of an augment. Augment material for posterior compartment prolapse includes biologic graft (dermal, porcine submucosal), absorbable mesh (Vicryl polyglactin), or nonabsorbable synthetic mesh (polypropylene). Anatomic success rates for posterior compartment repair with augment has ranged from 54% to 92%. Augmented posterior compartment repair has not been shown to have superior outcome to native tissue repair. The focus of this article is on the transvaginal approach comparing native tissue repair with graft or mesh augmented repair.

Dynamic Pelvic Magnetic Resonance Imaging Evaluation of Pelvic Organ Prolapse Compared to Physical Examination Findings.

OBJECTIVE: To compare dynamic magnetic resonance imaging (dMRI) defecography phase findings with physical examination (PE) grading in the evaluation of pelvic organ prolapse (POP). METHODS: We retrospectively reviewed 274 consecutive patients who underwent dMRI with defecography. Baden-Walker grading of POP, absolute dMRI values, and grading by dMRI were collected for anterior, apical, and posterior compartments. Anatomically significant POP on PE was defined as Baden-Walker Grade ≥3 and on dMRI by dMRI Grade ≥2. A Spearman's Rank correlation was performed between absolute dMRI values and respective POP grades. RESULTS: A total of 178 female patients were included. Anatomically insignificant and significant cystoceles had a 26.4% (19/72) and 84.6% (66/78) agreement respectively. Anatomically insignificant and significant apical prolapse had a 2.0% (2/100) and 62.9% (17/27) agreement respectively. Anatomically insignificant and significant posterior prolapse had a 49.5% (51/103) and 78.7% (59/75) agreement respectively. PE detected only 30% (9/30) of total dMRI detected enteroceles and misdiagnosed 10% (3/30) of these patients with a rectocele. CONCLUSION: The dMRI defecography phase correlated well for anatomically significant prolapse in anterior and posterior compartments. dMRI was superior to PE for enterocele detection and was better able to distinguish an enterocele from a rectocele. Thus, dMRI may have the greatest diagnostic value in cases where the presence of an enterocele is unclear in apical and/or posterior compartments.

Review Article: Preoperative Evaluation and Optimization of the Geriatric Urological Patient.

INTRODUCTION: Geriatric urological patients are at higher risk for postoperative morbidity and mortality compared to their younger counterparts because of an increased prevalence of comorbidities and functional impairments. A comprehensive preoperative evaluation is necessary to identify and address these issues, as well as to optimize perioperative physiological and functional status. METHODS: The presence of frailty in geriatric patients is an especially important indicator of increased perioperative surgical risk but frailty screening is poorly addressed in the majority of guidelines on preoperative screening. Geriatric patients are categorized as frail, pre-frail or nonfrail. Preoperative evaluation of these patients should include nutritional status, a psychosocial assessment, and assessment of aftercare and social support. RESULTS: Routine preoperative laboratory and radiographic evaluations are not recommended based solely on age. Rather, an individualized, pragmatic approach founded on the preoperative assessment, evidence-based guidelines, and the nature and extent of the surgery is advised. CONCLUSIONS: Following these recommendations will provide the urologist a thorough and practical approach to the preoperative evaluation of geriatric urological patients, with the ultimate goal of reducing perioperative morbidity and mortality.

Pressure flow studies in men and women.

There are well established pressure flow criteria and nomograms for urinary obstruction in men. The pressure flow criteria for female urinary obstruction are not well established due to differences in female voiding dynamics as compared to men. Typically, other information such as radiographic data and clinical symptoms are needed to facilitate the diagnosis. Detrusor underactivity remains a poorly studied clinical condition without definitive urodynamic diagnostic criteria. Modalities proposed for objective analysis of detrusor function such as power (watt) factor, linear passive urethral resistance relation and BCI nomogram were all developed to analyze male voiding dysfunction. Overall, further investigation is needed to establish acceptable urodynamic criteria for defining detrusor underactivity in women.

Painful bladder syndrome: an update and review of current management strategies.

Interstitial cystitis/painful bladder syndrome (IC/PBS) remains a prevalent, but untreated disease with a poorly understood pathophysiology. Nonetheless, four main processes currently appear to be involved in producing IC/PBS symptoms: (1) disruption of the bladder GAG/proteoglycan layer, (2) upregulated immune/inflammatory response, (3) neural upregulation, and (4) pelvic floor dysfunction. Current and emerging therapies aimed at these potential targets will be the focus of this review with an update on IC/PBS therapy.

Increased expression of histone deacetylaces (HDACs) and inhibition of prostate cancer growth and invasion by HDAC inhibitor SAHA.

Histone deacetetylases (HDACs) are a group of corepressors of transcriptional activators and their levels of expression are potentially dysregulated in prostate cancer. Certain inhibitors of histone deacetylases show anti-tumor activity in prostate cancer cell lines. Here, we systemically studied the expression of HDACs in human prostate cancer and the suppression of prostate cancer growth and invasion by HDAC inhibitor SAHA. HDAC1-5 showed increased expression using a combination of DNA microarray, in-situ hybridization, and immunohistochemistry in benign and malignant human prostate tissue as well as RT-PCR and Western blot analysis on various PCa cell lines. Importantly, HDAC inhibitor SAHA suppressed, in particular, prostate cancer cell growth and invasion determined using cell proliferation and Matrigel invasion assays. The findings of this study show that the expression of HDACs and their associated corepressors are increased in prostate cancer in humans and HDAC inhibitor SAHA could serve as a potential therapeutic agent in prostate cancer in addition to anti-androgens.

Validating the incontinence symptom severity index: a self-assessment instrument for voiding symptom severity in women.

PURPOSE: Most voiding symptom self-assessment instruments assess either symptom bother or effect on quality of life. The Incontinence Symptom Severity Index is an instrument for self-assessment of severity of female urinary storage and voiding symptoms, rather than symptom bother or effects of symptoms on quality of life. We assessed the validity of the Incontinence Symptom Severity Index for female voiding symptom self-assessment. MATERIALS AND METHODS: The Incontinence Symptom Severity Index assesses 8 symptom domains, including emptying, urgency, urge incontinence, nocturia, daytime frequency, stress incontinence, leakage with physical activity and pad use. Three separate cohorts of women with a mean age of 59, 60 and 63 years, respectively, who underwent evaluation for urinary complaints associated with incontinence and vaginal prolapse were analyzed. Internal consistency was assessed via item-total correlations and Cronbach's alpha. Concurrent validity against the Urogenital Distress Inventory and Pelvic Floor Distress Inventory-Short Form were studied by correlating similar symptom domains of the Incontinence Symptom Severity Index with both instruments. We assessed criterion validity by comparison with the objective measures of post-void residual urine, voiding logs and self-reported pad use. Response to change was assessed by comparing pretreatment and posttreatment Incontinence Symptom Severity Index scores. RESULTS: Significant item total correlations were seen for each Incontinence Symptom Severity Index item and Cronbach's alpha was 0.69. All Incontinence Symptom Severity Index items significantly correlated with similar items of the Urogenital Distress Inventory and Pelvic Floor Distress Inventory-Short Form. Significant posttreatment reductions were also observed for all 8 Incontinence Symptom Severity Index items. Progressively higher post-void residual urine was noted for the 4 severity scores of Incontinence Symptom Severity Index item 1 (emptying) (p = 0.07). Incontinence Symptom Severity Index items 3 (nocturia) and 4 (daytime frequency) showed significantly increasing nighttime and daytime voids with worsening severity scores for each (p <0.0001 and <0.0041, respectively). Incontinence Symptom Severity Index items 5 to 8 (stress incontinence, urge incontinence, leakage with activity and pad use) showed significantly increasing trends in mean daily pad use (p <0.0001, 0.022, <0.0001 and <0.0001, respectively) among the 4 severity scores for each. CONCLUSIONS: The Incontinence Symptom Severity Index demonstrates good reliability and validity. It is a useful instrument for assessment of female incontinence and voiding symptom severity in clinical and research settings.

Increased startle responses in interstitial cystitis: evidence for central hyperresponsiveness to visceral related threat.

PURPOSE: Hypersensitivity to visceral stimuli in interstitial cystitis/painful bladder syndrome may result from enhanced responsiveness of affective circuits (including the amygdala complex) and associated central pain amplification. Potentiation of the eyeblink startle reflex under threat is mediated by output from the amygdala complex and, therefore, represents a noninvasive marker to study group differences in responsiveness in this brain circuit. MATERIALS AND METHODS: Acoustic startle responses were examined in female patients with interstitial cystitis/painful bladder syndrome (13) and healthy controls (16) during context threat (application of muscle stimulation electrodes to the lower abdomen overlying the bladder), and cued conditions for safety (no stimulation possible), anticipation and imminent threat of aversive abdominal stimulation over the bladder. RESULTS: Patients showed significantly greater startle responses during nonimminent threat conditions (baseline, safe and anticipation periods) while both groups showed similar robust startle potentiation during the imminent threat condition. Higher rates of anxiety and depression symptoms in the patient group did not account for the group differences in startle reflex magnitude. CONCLUSIONS: Compared to controls, female patients with interstitial cystitis/painful bladder syndrome showed increased activation of a defensive emotional circuit in the context of a threat of abdominal pain. This pattern is similar to that previously reported in patients with anxiety disorders as well as those with irritable bowel syndrome. Since these circuits have an important role in central pain amplification related to affective and cognitive processes, these results support the hypothesis that the observed abnormality may be involved in the enhanced perception of bladder signals associated with interstitial cystitis/painful bladder syndrome.

Dietary methionine effects on plasma homocysteine and HDL metabolism in mice.

The effects of dietary manipulation of folate and methionine on plasma homocysteine (Hcy) and high-density lipoprotein cholesterol (HDL-C) levels in wild-type and apolipoprotein-E-deficient mice were determined. A low-folate diet with or without folate and/or methionine supplementation in drinking water was administered for 7 weeks. Fasted Hcy rose to 23 microM on a low-folate/high-methionine diet, but high folate ameliorated the effect of high methionine on fasted plasma Hcy to approximately 10 microM. Determination of nonfasted plasma Hcy levels at 6-h intervals revealed a large diurnal variation in Hcy consistent with a nocturnal lifestyle. The daily average of nonfasted Hcy levels was higher than fasted values for high-methionine diets but lower than fasted values for low-methionine diets. An acute methionine load by gavage of fasted mice increased plasma Hcy 2.5 h later, but mice that had been on high-methionine diets had a lower fold induction. Mice fed high-methionine diets weighed less than mice fed low-methionine diets. Based on these results, two solid-food diets were developed: one containing 2% added methionine and the other containing 2% added glycine. The methionine diet led to fasted plasma Hcy levels of >60 microM, higher than those with methionine supplementation in drinking water. Mice on methionine diets had >20% decreased body weights and decreased HDL-C levels. An HDL turnover study demonstrated that the HDL-C production rate was significantly reduced in mice fed the methionine diet.