HCV genotype 4, 5 and 6: Distribution of viral subtypes and sustained virologic response rates in clinical trials of approved direct-acting antiviral regimens.

Multiple direct-acting antiviral (DAA)-based regimens are now available for all hepatitis C virus (HCV) genotypes (GTs). Because HCV GT 4, 5 and 6 are less common in the United States (US) and worldwide, relatively small numbers of participants with these GTs were evaluated in individual clinical trials. To provide a comprehensive description of subtype diversity and treatment outcomes in clinical trials for these less common GTs, we analysed data from 744 participants with HCV GT4 (n = 573), GT5 (n = 81), or GT6 (n = 90) across 18 clinical trials of DAA regimens. These data are from US New Drug Applications submitted between 2014 and 2017, and our analyses included only approved regimens. Excluding unresolved or mixed subtypes, the distribution of reported GT4 subtypes was 49% 4a, 31% 4d and 16% for one of 14 other subtypes. The distribution of GT6 subtypes was 39% 6a, 27% 6e, 8% 6 L and 23% for one of 11 other subtypes. Across approved regimens, sustained virologic response rates 12 weeks post-treatment (SVR12) for GT 4, 5 and 6 ranged from 91% to 100%, 93% to 97% and 96% to 100%, respectively. SVR12 by GT4 subtype ranged from 96% to 100% for 4a and 81% to 100% for 4d. Virologic failures occurred in GT 4a, 4b, 4d and 4r. For GT6, SVR12 was 100% for all subtypes except 6 L, for which 1 of 7 participants experienced virologic failure. To our knowledge, this is the largest compilation of HCV GT 4, 5 or 6 clinical trial data. These analyses may be useful for clinicians treating HCV GT 4, 5 or 6.

An intact HDM2 RING-finger domain is required for nuclear exclusion of p53.

The p53 tumour-suppressor protein is negatively regulated by HDM2. Recent reports indicate that the leucine-rich nuclear-export sequence (NES) of HDM2 enables it to shuttle to the cytoplasm, and that this activity is required for degradation of p53. However, it is unclear whether HDM2 is involved in nuclear export of p53, partly because p53 has itself been shown to contain a functional NES within its tetramerization domain. Here we show that co-expression of HDM2 with green fluorescent protein (GFP)-tagged p53 causes redistribution of p53 from the nucleus to the cytoplasm of the cell. This activity is dependent on binding of p53 to HDM2, and requires an intact p53 NES, but is independent of the HDM2 NES. A mutant of the HDM2 RING-finger domain that is unable to ubiquitinate p53 does not cause relocalization of p53, indicating that ubiquitin ligation or other activities of this region of HDM2 may be necessary for its regulation of p53 localization.

High-fat diet induces systemic B-cell repertoire changes associated with insulin resistance.

The development of obesity-associated insulin resistance is associated with B-lymphocyte accumulation in visceral adipose tissue (VAT) and is prevented by B-cell ablation. To characterize potentially pathogenic B-cell repertoires in this disorder, we performed high-throughput immunoglobulin (Ig) sequencing from multiple tissues of mice fed high-fat diet (HFD) and regular diet (RD). HFD significantly changed the biochemical properties of Ig heavy-chain complementarity-determining region-3 (CDRH3) sequences, selecting for IgA antibodies with shorter and more hydrophobic CDRH3 in multiple tissues. A set of convergent antibodies of highly similar sequences found in the VAT of HFD mice but not RD mice showed significant somatic mutation, suggesting a response shared between mice to a common antigen or antigens. These findings indicate that a simple high-fat dietary intervention has a major impact on mouse B-cell repertoires, particularly in adipose tissues.

Inner-city older blacks have high levels of functional disability.

OBJECTIVES: To describe the frequency and severity of functional problems in two groups of noninstitutionalized inner-city blacks aged 70 years and older contrasted with results from appropriate groups of white and black older adults and with the goals of the Healthy People 2000 program. DESIGN: Cross-sectional descriptive study. SETTING: Community-based samples. PARTICIPANTS: A population-based sample of 416 older adults living in a 3.5-square mile catchment area in north St. Louis (NSL), Missouri, and a sample of 197 older residents living in public housing in East St. Louis (ESL), Illinois. MEASUREMENTS: Health status, preventive health activities, health services utilization, and risks for progressive frailty were assessed by self report and observation using well validated, standardized instruments. Whenever possible, comparison data were derived from national datasets, original samples used to validate the measures, and other useful comparison groups. RESULTS: The NSL sample had somewhat better health status and risk for progressive disability than the ESL sample. However, compared with national or regional reference groups using age-gender adjustments, both study groups demonstrated increased levels of dependence in intermediate activities of daily living, restricted activity days, inability to walk one-half mile without assistance, reported poor vision, living alone, and limited income compared with both older whites and blacks, and increased levels of worsening health, inability to perform heavy work around the house, never walking a mile or more, and currently unmarried versus whites with variable decrements versus blacks. Contrasted with other comparison groups, the two samples had increased body fat; consistent decrements in gait speed, timed chair stands, timed one-leg balance, and frequency of preventive exercise; and lower levels of dental care; results relative to physician visits and hospital days were mixed. They also had high levels of measured visual and hearing impairments, unmet needs for home delivered meals, and problems with false teeth. Deficiencies compared with the goals of Healthy People 2000 were large. CONCLUSIONS: The special attributes of inner-city blacks, including poverty and access to and acceptance of remedial programs, will have to be considered if the goals of Healthy People 2000 are to be met in this important and growing segment of older Americans. 44:0000-0000, 1996.

A chemosterilized antigen-extracted autodigested alloimplant for bone banks.

Limited chemical extraction of hydrophobic glycopeptides and subtotal autodigestion of the donor's cells and plasma membranes in undemineralized cortical bone in vitro reduces the putative quantity of haptenic substances absorbed by the recipient. Iodoacetic acid and sodium azide or other sulfhydryl group enzyme inhibitors added to the buffer solutions during in vitro autodigestion and estraction of intracellular alloantigens protects the bone matrix morphogenetic property against enzymatic degradation. The delayed hypersensitivity reaction induced by aseptically collected freeze-dried bone and the destruction of the bone morphogenetic property caused by radiation-sterilization is avoidable by sequential chemodigestion and chemosterilization of bone that preserves the maximum morphogenetic potential while transferring a minimum quantity of alloantigen.

Role of urethral reconstruction and artificial sphincter in complicated salvage radical prostatectomy.

Patients undergoing radical prostatectomy following failed definitive radiation therapy for adenocarcinoma of the prostate run a substantial risk of refractory bladder neck contractures and urinary incontinence developing. A combined reconstructive technique utilizing a urethral pull-through procedure and implantation of an artificial urinary sphincter to treat these complications is described. When a patient can truly be cured by radical prostatectomy, this relatively straightforward reconstruction can salvage what otherwise would be considered a surgical failure.

Two-stage technique for implantation of inflatable penile prosthesis in pelvic cancer surgery.

A two-stage technique for implantation of an inflatable penile prosthesis has been developed for patients undergoing radical pelvic cancer surgery. Over the past five years, this method has been utilized in 147 men undergoing radical cystectomies or prostatectomies. The technique involves implanting the reservoir and pump of the prosthesis at the time of the radical cancer operation when the lateral neurovascular bundles of erection are being sacrificed. The reservoir and pump are permanently connected, and the cylinder tubings from the pump are temporarily connected and placed in the subcutaneous tissue overlying the pubis. During a second procedure, usually six to twelve weeks later, the cylinders are implanted infrapubically and connected to the easily located pump tubing. The advantages are several. (1) The pump and reservoir are easily implanted during the pelvic surgery while importantly not adding significantly to the operative time or morbidity of the primary procedure. (2) The reservoir is easily positioned in the pelvis. (3) The scrotum with its contained pump already will be healed when the entire prosthesis is connected, bypassing the initial scrotal pain and edema. (4) Psychologically the patients feel relieved that their erectile dysfunction is being treated immediately. This two-stage technique appears to maximize the gain of early and easy implantation while minimizing the potential problems of concomitant surgery.

Ectopic ureter presenting in midline urethral diverticulum.

A rare case of an ectopic ureter terminating in a urethral diverticulum is presented. While numerous cases of extravesical ectopic ureters draining directly into the urethra or uterovaginal canal have been reported, the termination of a ureter as a diverticular sac is extremely unusual. Moreover, only rarely has a urethral diverticulum been documented to arise congenitally due to any cause. The history and management of this new case are detailed, and the general subjects of ectopic ureter and urethral diverticulum are discussed with particular reference to etiology and continence.

Diabetes insipidus and nonobstructive dilation of urinary tract.

Two cases of diabetes insipidus (hypothalamic and nephrogenic) with massive nonobstructive trabeculation and dilation of the bladder and hydroureteronephrosis are reported. The cases are evaluated thoroughly--radiologically and urodynamically. Treatment options are discussed, including the use of an important new drug, dDAVP. The general subject of diabetes insipidus and its urologic implications is reviewed.

Successful use of transureteroureterostomy to salvage ureterosigmoidostomy after anastomotic failure.

Four cases are presented of patients who had undergone ureterosigmoidostomy and in whom a unilateral ureteral anastomotic complication developed that was salvaged subsequently by a transureteroureterostomy. Although other forms of urinary diversion are now being utilized routinely in many centers, the ureterosigmoidostomy is still being employed worldwide, and urologic surgeons need to be versed in its potential problems and how to correct them.

Ventral penile curvature following radical pelvic surgery: a variant of urethral manipulation syndrome.

OBJECTIVES: Urethral manipulation syndrome (UMS) describes ventral penile curvature and urethral stricture disease that develop following repeated episodes of urethral manipulation. We describe a variant of this syndrome, in which the presence of an indwelling catheter following radical pelvic surgery led to a marked penile curvature without clinically apparent urethral stricture disease. METHODS: We identified 4 patients in whom ventral penile curvature developed following radical pelvic surgery. Three patients underwent radical retropubic prostatectomy and the fourth patient underwent radical cystoprostatectomy with creation of a neobladder to the urethra. All were treated with 3 weeks of catheter drainage postoperatively. Each patient reported straight erections prior to surgery. RESULTS: These patients came to prosthesis surgery between 7 months and 3 years after their pelvic procedure. Each patient was noted to have ventral penile curvature when artificial erection was induced. Curvature was secondary to scarring between the anterior corpus spongiosum and the overlying ventral tunica albuginea in the mid- to proximal penile shaft. It was necessary to mobilize the urethra off the corpora and to incise the scarred tunica to obtain a satisfactory result at the time of prosthesis placement. In 3 cases, GoreTex was needed to bridge the corporeal defect. CONCLUSIONS: These cases represent a variant of UMS in which catheter drainage leads to scarring of the ventral tunica albuginea, resulting in ventral penile curvature. In view of the increasing number of radical pelvic procedures being performed, this potential complication must be recognized, as aggressive corporeal reconstruction with urethral mobilization is needed if subsequent prosthesis surgery is undertaken.

Study of antireflux nipple valves of Kock ileal urinary reservoir. Experimental investigation in dogs.

To better assess the construction, maintenance, and function of the Kock ileal urinary reservoir with its continent antirefluxing nipple valves, laboratory investigations in dogs were done simultaneously with clinical trials in humans in 1983. Fifteen dogs underwent creation of hemi-Kock ileal reservoirs (without the efferent valve and limb) that were anastomosed to their bladders as enterocystoplasties. The afferent antirefluxing nipple valves were intussuscepted after 7 cm of underlying mesentery had been removed. The nipples were further stabilized with metal and absorbable (Polysorb) staples and Marlex collars. The right ureters were anastomosed to the afferent limb of the reservoirs with the contralateral systems left intact as controls. Ten dogs were able to be followed at the vivaria for twelve to thirty-six months and then studied. All nipple valves remained intact, viable, and nonrefluxing without revision. All kidneys remained histologically normal except those in dogs with dilated ureters secondary to ureteroileal stenosis with concurrent calculi formation. Calculi formed on exposed metal staples and Marlex. The absorbable staples were found to promote appropriate healing and were never the nidus for stone formation. It appears that the intussuscepted nipple valve (with its mesentery removed) is reproducible and functionally reliable in preventing reflux. It also appears these valves can histologically preserve diverted kidneys if the upper urinary tract drainage is normal and calculi are minimized. The proper placement of staples and the elimination of Marlex-anchoring collars are indicated to minimize calculi.

Prospective study of metabolic abnormalities in patient with continent Kock pouch urinary diversion.

Metabolic alterations as a result of bowel being employed in the urinary tract are well documented. To investigate this phenomenon in the continent ileal reservoir urinary diversion, 106 patients who had undergone Kock pouch surgery were followed in a prospective study at the University of Southern California between 1985 and 1987. Serum chemistries and urine osmolality determinations were performed approximately every three months for a year. Mean patient values for each time period were then compiled and compared with the norms and with the preoperative values. The mean serum electrolyte values were found to be within normal limits during all follow-up periods. Fourteen patients were identified, however, as having values falling intermittently outside of the normal range. These patients were investigated and found to be abnormal during episodes of acute renal failure usually secondary to dehydration or obstruction at which time they usually became acidotic and occasionally hyperchloremic. These problems disappeared when the renal failure was corrected. This study corroborated our previously reported findings that hyperchloremic acidosis or other metabolic alterations requiring replacement therapy do not routinely occur in this population.

Lower urinary tract reconstruction in the female using the Kock ileal reservoir with bilateral ureteroileal urethrostomy: update of continence results and fluorourodynamic findings.

OBJECTIVES: To update continence results and present fluorourodynamic data in 17 female patients undergoing orthotopic lower urinary tract reconstruction with the Kock ileal urethrostomy following cystectomy. METHODS: Continence results, voiding pattern, and overall patient satisfaction were evaluated by means of patient survey. Fluorourodynamic data and abdominal leak point pressures were obtained in 6 patients. RESULTS: Complete daytime urinary continence was reported in 93% of patients, whereas complete nighttime continence was reported by 87% of patients. Fluorourodynamic studies demonstrated excellent neobladder capacity with low reservoir pressure in all cases. Abdominal leak point pressure measurements confirmed normal urethral sphincter function. CONCLUSIONS: Excellent results with respect to urinary continence, voiding pattern, patient satisfaction, and reservoir function can be expected in women undergoing orthotopic lower urinary tract reconstruction.

Prospective pathologic analysis of female cystectomy specimens: risk factors for orthotopic diversion in women.

OBJECTIVES: To prospectively evaluate our previously established pathologic risk factors in women undergoing cystectomy for bladder cancer and to determine if these criteria identify appropriate female candidates for orthotopic diversion. METHODS: Prospective pathologic evaluation was performed on 71 consecutive female cystectomy specimens removed for primary transitional cell carcinoma of the bladder. The histologic grade, pathologic stage, presence of carcinoma in situ, number, and location of tumors were determined. In addition, final pathologic analysis of the bladder neck and proximal urethra was performed and compared with the intraoperative frozen-section analysis of the distal margin (proximal urethra). RESULTS: Tumor at the bladder neck and proximal urethra was seen in 14 (19%) and 5 (7%) cystectomy specimens, respectively. Bladder neck tumor involvement was found to be the most significant risk factor for tumor involving the urethra (P <0.001). All patients with urethral tumors demonstrated concomitant bladder neck tumors. However, more than 60% of patients with bladder neck tumors had a normal (tumor-free) proximal urethra. Furthermore, no patient with a normal bladder neck demonstrated tumor involvement of the urethra. Intraoperative frozen-section analysis of the distal surgical margin was performed on 47 patients: 45 without evidence of tumor and 2 patients with urethral tumor involvement. In all cases, the intraoperative frozen-section analysis was correctly confirmed by final permanent section. CONCLUSIONS: We prospectively demonstrate that bladder neck tumor involvement is a significant risk factor for urethral tumor involvement in women. However, despite bladder neck tumor involvement, a number of women undergoing cystectomy for bladder cancer have a normal urethra and may be candidates for orthotopic diversion. Furthermore, our data demonstrate that intraoperative frozen-section analysis of the distal surgical margin accurately and reliably evaluates the proximal urethra and currently determines which patients undergo orthotopic diversion at our institution.

Needle bladder neck suspension for female stress incontinence.

A highly successful transvaginal bladder neck suspension for female stress urinary incontinence is described and illustrated. Precise lateral placement of sutures, maximum mobilization of the anterior vaginal wall and bladder neck, and ease of approach are keys to the technique. The procedure can be utilized in any setting with minimal complications and with neither obesity nor multiple previous surgeries as contraindications.

Complications of the Kock pouch.

Over the past 41/2 years, 395 consecutive Kock pouch procedures have been performed by the urology faculty at the University of Southern California School of Medicine as an alternative to conventional cutaneous urinary diversion. This article reviews the early and late complications experienced in the 386 patients surviving the operation and describes in detail modifications in surgical technique designed to reduce the complication rate and the subsequent need for re-operation. We remain convinced that construction from ileum of a low-pressure, high-capacity internal reservoir with continent and nonrefluxing valves as originally described by Kock remains the ultimate technique for patients requiring permanent urinary diversion or for those requiring conversion from a pre-existing form of diversion.

An update on the Kock pouch for continent urinary diversion.

The authors continue to feel, based on a 4 1/2 year clinical experience in more than 400 patients, that the Kock continent urostomy offers an important alternative to noncontinent forms of diversion. Not only can it provide an improved body image, but the Kock pouch can also help to salvage, both physically and emotionally, those patients with unsatisfactory results from conduit diversion.

Kock pouch bladder replacement.

Between May 1986 and February 1990, 126 consecutive male patients have undergone lower urinary-tract reconstruction by means of Kock bladder replacement at our institution. The early and late complication rates have been minimal. Good continence has been achieved in 94% of patients during the day and in 84% at night. Our experience with bladder replacement has yielded extraordinary results in terms of patients acceptance. It is anticipated that our experience as well as the experience of others with this surgery will encourage patients afflicted with high-grade bladder cancer and their physicians toward an earlier decision for aggressive therapy by cystectomy while cure is still possible.

Technique of creation of a continent internal ileal reservoir (Kock pouch) for urinary diversion.

Kock and associates have made a major contribution to the urologic surgical armamentarium by developing a method to create a continent internal urinary reservoir out of ileum. This innovative procedure now offers patients requiring cystectomy for bladder cancer or cutaneous urinary diversion for any reason a real alternative to the standard ileal conduit, which requires wearing an external appliance. Operative technique, including some modifications developed by the authors, is presented.