Amphotericin B colloidal dispersion combined with flucytosine with or without fluconazole for treatment of murine cryptococcal meningitis

Junctional epidermolysis bullosa is a heritable, heterogeneous blistering skin disease with mechanically induced dermal-epidermal separation, mild skin atrophy, nail dystrophy, and alopecia. Four unrelated junctional epidermolysis bullosa families with different phenotypes were investigated here and four novel mutations associated with the disease were identified. Patients 1, 2, and 3 had generalized atrophic benign epidermolysis bullosa, with nonscarring blistering and varying degree of alopecia. Patient 4 had the localisata variant of junctional epidermolysis bullosa, with predominantly acral blistering and normal hair. All patients had mutations in the COL17A1 gene encoding collagen XVII, a hemidesmosomal transmembrane protein. Patients 1 and 2 carried homozygous deletions 520delAG and 2965delG, respectively. Patient 3 was compound heterozygous for a missense and a deletion mutation (G539E and 2666delTT), and patient 4 was heterozygous for a known mutation R1226X. The deletions led to premature termination codons and to drastically reduced collagen XVII mRNA and protein levels, consistent with the absence of the collagen in generalized atrophic benign epidermolysis bullosa skin. The missense mutation G539E allowed synthesis of immunoreactive collagen XVII in keratinocytes, but prevented its secretion, thus causing lack of the protein in the skin. The data suggest that different COL17A1 mutations and their combinations can result in a spectrum of biologic and clinical phenotypes of not only generalized atrophic benign epidermolysis bullosa, but also localized junctional epidermolysis bullosa.     

Altered expression of a new antigen of the dermal-epidermal junction (NU-T2 DEJ Ag) in junctional epidermolysis bullosa

NU-T2 antigen (Ag) is a new and recently described antigen of the dermal-epidermal junction, recognized by an anti-CD1b monoclonal antibody denominated NU-T2. We studied NU-T2 Ag expression in junctional epidermolysis bullosa (13 patients) and in other forms of hereditary epidermolysis bullosa (23 patients), comparing the results with nicein expression. In junctional epidermolysis bullosa gravis type no differences were found between the expression of NU-T2 and nicein, both being negative in bullous as well as in non-bullous skin. Interestingly, in mitis type junctional epidermolysis bullosa, NU-T2 Ag was found to be absent or reduced in five of six patients both in lesional and in uncleaved skin. When compared with nicein expression, clearcut differences were found, further suggesting that these two antigens are different. These data confirm that NU-T2 Ag is a novel epitope of the dermal-epidermal junction, probably relevant in dermal-epidermal cohesion, and it could be responsible, together with nicein, 19-DEJ-1 and other adhesion molecules, for the different subtypes of junctional epidermolysis bullosa. Finally, NU-T2 monoclonal antibody is a new relevant tool for the diagnosis, classification, and prenatal diagnosis of junctional epidermolysis bullosa.     

Corneal involvement in epidermolysis bullosa simplex

A 17-year-old boy and his mother represent the first reported cases of ocular (corneal) involvement of the simplex form of epidermolysis bullosa. Both had a ring-like configuration of fine bullous lesions in the midperiphery bilaterally at the level of deep corneal epithelium superficial to Bowman's membrane (basal cell layer), with the son manifesting symptoms when some of his bullae ruptured through to the corneal epithelial surface. Nonscarring blistering was present in three generations of this family, suggestive of dominantly inherited epidermolysis bullosa simplex, and was confirmed by electron microscopy of a skin specimen from the son. Thus, ocular involvement has now been observed in all of the major types of epidermolysis bullosa.     

180-kDa bullous pemphigoid antigen defective generalized atrophic benign epidermolysis bullosa: report of four cases with an unusually mild phenotype

Generalized atrophic benign epidermolysis bullosa (GABEB) is a rare variant of non-lethal junctional epidermolysis bullosa characterized by generalized skin blistering healing with atrophy and by atrophic alopecia with onset in childhood. Other features include mild mucosal blistering, dental abnormalities and nail dystrophy. We report four additional cases of GABEB from two families originating from the same isolated village. The patients shared an unusually mild clinical phenotype with cutaneous blisters strictly limited to trauma sites and rare occurrence of oral mucosal lesions. Scalp, eyelash and eyebrow alopecia was present in only two cases. Immunofluorescence studies showed a markedly reduced expression of the 180-kDa bullous pemphigoid antigen (BP180), and northern analysis of cultured keratinocytes indicated that the gene encoding for BP180 is affected in these GABEB patients.     

Tetravinyl-tetramethylcyclo-tetrasiloxane (tetravinyl D4) is a mutagen in Rat2lambda lacI fibroblasts

We describe a patient with sporadic dystrophic epidermolysis bullosa associated with well-documented atopic dermatitis. We discuss this case in relation to a newly described clinical subtype of epidermolysis bullosa known as epidermolysis bullosa pruriginosa, a dystrophic variant associated with prominent pruritus. The relations of this case of sporadic dystrophic epidermolysis bullosa with other dominantly inherited forms of dystrophic epidermolysis bullosa such as the Pasini variant, the pretibial variant, and Bart's syndrome are also discussed. The role of atopic dermatitis in exacerbating dystrophic epidermolysis bullosa in this patient raises an important consideration in the care of this group of patients.     

Maternal uniparental meroisodisomy in the LAMB3 region of chromosome 1 results in lethal junctional epidermolysis bullosa

Herlitz junctional epidermolysis bullosa (OMIM#226700) is a lethal, autosomal recessive blistering disorder caused by mutations in one of the three genes LAMA3, LAMB3, or LAMC2, encoding the constitutive polypeptide subunits of laminin 5. In this study, we describe a patient homozygous for a novel nonsense mutation Q936X in exon 19 of LAMB3, which has been mapped to chromosome 1q32. The patient was born with extensive blistering and demonstrated negative immunofluorescence staining for laminin 5, and transmission electron microscopy revealed tissue separation within lamina lucida of the dermal-epidermal junction, diagnostic of Herlitz junctional epidermolysis bullosa. The mother of the proband was found to be a heterozygous carrier for this mutation, whereas the father demonstrated the wild-type LAMB3 allele only. Nonpaternity was excluded by 13 microsatellite markers in six different chromosomes. Genotype analysis using 28 microsatellite markers spanning chromosome 1 revealed that the patient had maternal primary heterodisomy, as well as meroisodisomy within two regions of chromosome 1, one on 1p and the other one on 1q, the latter region containing the maternal LAMB3 mutation. These results suggest that Herlitz junctional epidermolysis bullosa in this patient developed as a result of reduction to homozygosity of the maternal LAMB3 mutation on chromosome 1q32.     

Congenital bllbar urethral stenosis and its therapy by means of internal urethrotomy under direct vision (according to Sachse) (author's transl)

Congenital bulbar urethral stenosis arises from incomplete opening of the urogenital membrane. The etiology may possibly be genetic or else a disturbance in the maternal hormones during the embryonic phase. The diagnosis from other types of stenosis is made by urethroscopy. The urodynamic consequences are a compensatory hypertrophy of bladder muscle, in extreme cases finally followed by hydronephrosis. Symptoms of stenosis include dysuria, polyuria, enuresis, and recurrent urinary tract infection. The whole urinary tract should be investigated. At present, the operation of choice for dealing with this type of stenosis, is internal urethrotomy under direct vision (Sachse's operation). Short-term indwelling catheterization, prophylaxis against infection, and hydraulic auto-bougination (raising the internal urethral pressure by compressing the penis during micturition) help to ensure success. The percentage of complications is low. The risk of recurrence is less than with the use of electrocautery.     

Esophageal stenosis in epidermolysis bullosa hereditaria]

Benign esophageal strictures in the upper esophagus may be caused by systemic diseases. A rare reason for esophageal strictures are the mechanobullous disorders marked by blister formation following relatively minor trauma, e.g. epidermolysis bullosa. In this report we present a 63-year-old patient who had suffered from epidermolysis bullosa simplex since birth. The epicutaneous symptoms were no longer present but an esophageal stricture had developed. The stricture was treated by X-ray-controlled balloon dilation twice, with a functionally good result. We suggest managing a recurrence recidiv of stricture with balloon dilation to minimize trauma and prevent further lesions.     

One-stage anterior urethroplasty

PURPOSE: A deficient urethral segment was replaced with penile skin during a 1-stage procedure in patients with a long, tight urethral stricture, multiple attempts at hypospadias repair or severe hypospadias and circumcision. MATERIALS AND METHODS: In 29 patients a pedicled circumferential strip of distal penile skin was used to construct a neourethral floor. The roof was formed by regeneration of the epithelium from the edges of the floor over Buck's fascia. In our series the urethra was reconstructed because of an anterior urethral stricture in 11 patients, multiple failed hypospadias repairs in 6 and severe hypospadias with circumcision in 12. RESULTS: A neourethra of sufficient caliber and length was constructed with minimal postoperative complications in all patients. There were 2 cases of urethrocutaneous fistula at the subcoronal region, 1 meatal stenosis, 1 persistent chordee and 1 small distal penile skin patch slough that required only prolonged dressings. Mean followup was 19 months. CONCLUSIONS: Our urethroplasty technique can be used to correct various types of anterior urethral stricture or hypospadias associated with insufficient penile or preputial skin.     

Anatomical anterior exenteration with urethral and vaginal preservation: illustrated surgical method

PURPOSE: We describe in detail a method for urethral and vaginal preservation in women considering orthotopic urinary tract reconstruction after bladder removal. MATERIALS AND METHODS: We retrospectively reviewed the pathological reports of patients treated with anterior exenteration at our hospital between 1984 and 1997 for specific evidence of urethral, vaginal, cervical or uterine involvement by the primary bladder tumor. Based on our findings we describe our approach to anterior exenteration in 6 patients. RESULTS: A total of 46 patients were treated at our center with en bloc anterior exenteration and pelvic lymphadenectomy for primary bladder cancer between 1984 and 1997. In 7 patients (15%) pathological review of the surgical specimen documented urethral involvement by the primary tumor. In 1 patient (2%) microscopic evidence of tumor was identified in the cervix and 1 (2%) had tumor extension to the vagina documented in the final pathology report. CONCLUSIONS: The observed rates of vaginal and urethral involvement agree with those reported by others, and suggest that in the majority of women treated with anterior exenteration sacrifice of the urethra and vagina is usually not necessary from an oncological perspective. This procedure is particularly appropriate in women concerned with postoperative sexual function and those considering orthotopic reconstruction of the lower urinary tract after exenterative bladder cancer surgery.     

Molecular biological aspects of acquired bullous diseases

Bullous diseases of the oral mucosa and skin were originally classified on the basis of clinical and histological criteria. The discovery of autoantibodies in some of these patients and the introduction of molecular biology have resulted in a new understanding of the pathological mechanisms of many of the bullous lesions. In this article, updated topics of the immune-mediated bullous lesions which involve oral mucosa and skin are reviewed. Pemphigus antigens, which are desmosomal-associated proteins and belong to the cadherin superfamily of cell adhesion proteins, have been isolated, and their genes have been cloned. The antigens which react with autoantibodies from patients with bullous pemphigoid, cicatricial pemphigoid, acquired epidermolysis bullosa, and linear IgA disease are all proteins of the hemidesmosome basement membrane complex. Interestingly, most of the antigens also appear to be the target for mutations seen in patients with the inherited type of epidermolysis bullosa in which bullous lesions are a prominent clinical feature.     

Epidermolysis bullosa junctionalis progressiva in three siblings

Three siblings of Swiss origin with epidermolysis bullosa junctionalis progressiva are described. The following clinical features were present from school age: dystrophy of the nails, non-scarring blistering of the skin, mild skin atrophy, hypodontia and dental caries. Light microscopy showed subepidermal blistering. Direct immunofluorescence was negative. On indirect immunofluorescence staining of a fresh spontaneous blister, bullous pemphigoid antigen and laminin were localized to the blister roof, and collagen IV and collagen VII to the blister base, indicating junctional splitting. Electron microscopy revealed a normal dermo-epidermal junction zone, including normal hemidesmosomes. There were no deposits of electron-dense amorphous material.     

Lack of resistance to erythromycin, rifampicin and ciprofloxacin in 98 clinical isolates of Legionella pneumophila

Epidermolysis bullosa simplex Dowling-Meara (MIM# 1317600) is the most severe of the three common epidermolysis bullosa simplex subtypes. In addition to the palmoplantar distribution seen in other epidermolysis bullosa simplex subtypes, extensive herpetiform blistering spontaneously develops on the trunk and limbs and may lead to scarring or milia formation. The keratin 5 and keratin 14 genes encode proteins that form the primary structural components of the basal epidermal keratinocytes, mutations in either of these genes can cause epidermolysis bullosa simplex. In this study we sequenced these genes in a family with epidermolysis bullosa simplex Dowling-Meara. We report a novel T to C transition in the helix termination peptide of K5 that causes a nonconservative substitution of a highly conserved amino acid within this critical region (I466T). This mutation adds to those previously reported and provides further evidence of phenotype-genotype correlation in epidermolysis bullosa simplex.     

Surgical repair of urethral circumcision injuries

PURPOSE: The 2 types of urethral injury that can occur during circumcision are urethrocutaneous fistula and urethral distortion secondary to partial glans amputation. We report the surgical repair of these rare injuries. MATERIALS AND METHODS: In 8 patients urethrocutaneous fistulas located on the distal penile shaft or at the coronal margin were managed by splitting the glans and using a Mathieu style skin flap in 4 or vascularized penile skin flap in 4 to bridge the urethral defect. Three patients underwent repair of a hypospadiac deviated urethra secondary to partial glans amputation by 1 cm. of urethral mobilization and repositioning the meatus into a terminal position within the remaining glans tissue. RESULTS: The 8 patients with urethrocutaneous fistulas voided via a terminal meatus without fistula recurrence at a mean followup of 3.2 years (range 1 to 6). The 3 patients with partial glans amputation and urethral deviation repaired by short urethral advancement had functionally acceptable results, defined as a normal urinary stream, although 1 required meatal dilation postoperatively. CONCLUSIONS: The 2 types of urethral injuries that can occur during circumcision are a subcoronal urethrocutaneous fistula and scarred abnormal urethra from partial glans amputation. The urethrocutaneous fistula can be successfully repaired by splitting the glans and forming a neourethra from a vascularized pedicle flap of penile skin. The abnormal urethra after partial glans amputation is more difficult to repair but repositioning the urethra in a more cosmetic location has restored function.     

Lower urinary tract symptoms in lumbar root compression syndromes: a prospective survey

STUDY DESIGN: A prospective, observational survey. OBJECTIVES: To describe lower urinary tract symptoms in uncomplicated lumbar root compression syndromes with special reference to prevalence, nature, and severity, and to analyze whether the occurrence of lower urinary tract symptoms correlates with age, pain, analgesic intake, or the type and level of compression. SUMMARY OF BACKGROUND DATA: Lower urinary tract symptoms with lumbar root compression are well known in the classic but rather rare cauda equina syndrome. However, micturition difficulties seem to be far more frequent in lumbar root compression syndromes. METHODS: One hundred eight male patients admitted for surgery for lumbar disc herniation or spinal stenosis were investigated with an extensive questionnaire about their micturition. RESULTS: Fifty-five percent had significant lower urinary tract symptoms. Eighty percent of the patients with spinal stenosis had symptoms. Thirty-three patients had irritative symptoms, 36 had obstructive symptoms, and 23 had retention symptoms. Twenty-four had severe symptoms. Median compression resulted in more symptoms than paramedian compression. There was no correlation between age, level of compression, drug intake, or pain score and lower urinary tract symptoms. CONCLUSIONS: Lower urinary tract symptoms of mixed type occur with a high prevalence in male patients with lumbar root compression syndromes referred for neurosurgical evaluation and treatment.     

Diagnosis and surgical treatment of distal urethral stenosis caused by fibrous periurethritis in women. Our experience

OBJECTIVE: To report on our experience in the diagnosis and surgical treatment of distal urethral stenosis arising from fibrous periurethritis in women. METHODS: 9 patients who had undergone surgery for distal urethral stenosis caused by fibrous periurethritis are described. Patient history, clinical symptoms, the surgical technique employed, complications and post-operative course are presented. RESULTS: All 9 patients had a history of recurrent urinary infection and alteration of the urinary stream. The results obtained by surgery were satisfactory in all cases. CONCLUSIONS: Distal urethral stenosis arising from fibrous periurethritis is uncommon, but not rare. Diagnosis is principally based on the clinical symptoms, characterized by low urinary obstructive symptoms, and the finding at physical examination of a narrow meatus and periurethral enlargement caused by fibrous tissue surrounding the distal urethra. The Richardson urethrolysis technique achieved satisfactory results in these patients.     

Pitfalls in the diagnosis and management of Lyme disease

Absence of plectin, a large cytoskeleton-associated protein expressed in the skin and muscle, has been shown to underlie epidermolysis bullosa with muscular dystrophy (EB-MD), an autosomal recessive disorder (OMIM No. 226670). In the present study, we report the case of a patient who presented with neonatal blistering and late-onset muscular dystrophy with nail and tooth abnormalities, as well as severe mucocutaneous involvement including laryngeal webs and urethral strictures, features not previously reported in this syndrome. Mutation detection, based on the use of heteroduplex analysis, revealed that the proband was a compound heterozygote for two plectin mutations, 4416delC/4359ins13, both resulting in premature termination codons in the plectin rod domain. Because these mutations, and the majority of those previously reported, reside within exon 32 of the plectin gene (PLEC1), we applied the protein truncation test (PTT) to screen for mutations in the two large 3' exons (nos. 32 and 33) of PLEC1, which together comprise approximately 75% of the coding region of the gene. PTT readily detected truncated polypeptides in the proband profiled in this study, as well as in a patient in whom we have previously identified premature termination codon mutations in exon 32. Thus, PTT provides a rapid and reliable strategy to identify premature termination codon mutations from genomic DNA within PLEC1.     

Responses of natural killer cell activity to acute laboratory stressors in healthy men at different times of day

BACKGROUND: Five renal recipients with neurovesical dysfunction (NVD) were retrospectively reviewed focusing on anatomical and urodynamic abnormalities of the lower urinary tract and their management prior to kidney transplantation. METHODS: The underlying anomalies in these 5 patients were a posterior urethral valve (1 with an imperforate anus; n = 2), meningomyelocele (n = 2) and a congenital short urethra with an imperforate anus (n = 1). Their urinary tracts were evaluated prior to transplantation with voiding cystourethrography, urethrocystoscopy, cystometrography and electromyography of the external urethral sphincter to identify a possible focus of urinary tract infection, urine storage and voiding function. RESULTS: All 5 patients had NVD proven by urodynamic studies or by documentation of urinary retention in the absence of mechanical outlet obstruction. Bilateral high grade vesicoureteral reflux was noted in all patients, requiring ureteroneocystostomy. Clean intermittent catheterization (CIC) was ultimately employed for bladder emptying in all patients. Two patients with poor bladder compliance underwent augmentation cystoplasty before transplantation. The Mitrofanoff procedure was used in 2 patients with structural urethral abnormalities to access the bladder for catheterization. After eradication of possible sources of infection and establishment of a low-pressure urine storage system with bladder emptying by CIC, kidney transplantation was performed. Following kidney transplantation, all of the recipients were asymptomatic for urinary tract infections using CIC. Although 1 patient lost his graft due to chronic rejection, the other 4 other patients have good renal function. CONCLUSION: Kidney transplantation in patients with NVD can be performed provided that their urinary tract problems are properly resolved.     

The contribution of urethrocystoscopy to evaluation of lower urinary tract dysfunction in women

The aim of this study was to determine whether the evaluation of lower urinary dysfunction with urodynamics and urethrocystoscopy provides unique information that is missed by urodynamics alone. Eighty-four women underwent multichannel urodynamics and urethrocystoscopy. Retrospective analysis included evaluation of the relationships between lower urinary tract lesions and risk factors using chi2 and Fisher's exact tests. Urethrocystoscopic findings changed the diagnosis and management in 6 patients. New urethrocystoscopic findings included papillary transitional-cell carcinoma, cystitis glandularis, an intravesical suture and a urethral diverticulum. Clinical parameters were not predictive of these findings. Urethrocystoscopic findings also contributed to the final diagnosis in 10 patients with intrinsic sphincter deficiency. Considered alone, maximum urethral closure pressure < or =20 cmH2O had a sensitivity of only 20% and a positive predictive value of 40% for this diagnosis. Urodynamics without urethrocystoscopy would have missed important diagnoses in 19% of women. Urethrocystoscopy and urodynamics complement one another, and both have a role in the evaluation of women with lower urinary tract dysfunction.     

Transitional carcinomas of the urinary tract: synchronous and metachronous lesions

OBJECTIVE: The urothelium is a pseudostratified cylindrical epithelium that lines the calices, renal pelvis, urethers, bladder, part of the urethra and part of the prostate ducts. Transitional cell carcinoma (TCC) is a malignant neoplasia that can appear in any site where urothelium is present, being the bladder the most frequently affected organ. We performed an analysis of our experience and conducted a literature-based metanalysis to evaluate the coexistence of tumoral lesions at different locations in the urinary tract. MATERIAL AND METHODS: Between 1983 and 1993, 397 patients with TCC lesions involving the upper urinary tract (UUT), bladder, urethra or prostate, were diagnosed and treated. Coexistence, either synchronic or metachronic, of several lesions in different sites of the urinary tract was considered as a multiple tumor. RESULTS: Overall, 440 tumors were diagnosed in 397 patients. A single lesion appeared in 360 patients, while 37 presented multiple locations with a total of 79 tumors. The lesions were located at the following levels: 17 renal, 21 uretheral, 372 vesical, 13 in the urethra and 17 in the prostate ducts. According to the location, the frequency of single lesions was: UUT 58%, bladder 91%, urethra 8% and prostate ducts 35%. Synchronic UUT and intravesical tract tumors develops in 1% and 4% of patients with bladder TCC, respectively. Two percent of vesical tumors showed metachronic relationship with UUT tumors and the same rate was seen for intravesical lesions. CONCLUSIONS: Urothelial UUT tumors have a typical nosologic entity with specific features. Their coexistence with vesical tumors is frequent. When tumors of the bladder occur after a UUT tumor the interval of highest incidence between diagnoses is 2-3 years, and there are no histological risk factors among them for prognosis. Transitional cell prostatic urethral tumors are most often secondary to histologically similar, poor prognosis, bladder tumors, and usually synchronic.