Targeting GRPR in urological cancers--from basic research to clinical application

Gastrin releasing peptide (GRP) is a regulatory peptide that acts through its receptor (GRPR) to regulate physiological functions in various organs. GRPR is overexpressed in neoplastic cells of most prostate cancers and some renal cell cancers and in the tumoral vessels of urinary tract cancers. Thus, targeting these tumours with specifically designed GRP analogues has potential clinical application. Potent and specific radioactive, cytotoxic or nonradioactive GRP analogues have been designed and tested in various animal tumour models with the aim of receptor targeting for tumour diagnosis or therapy. All three categories of compound were found suitable for tumour targeting in animal models. The cytotoxic and nonradioactive GRP analogues have not yet shown convincing tumour-reducing effects in human trials; however, the first clinical studies of radioactive GRP analogues--both agonists and antagonists--suggest promising opportunities for both diagnostic tumour imaging and radiotherapy of prostate and other GRPR-expressing cancers.

Physiologic and pathophysiologic fundamentals of proteinuria a review

The term proteinuria is taken to mean abnormally high protein excretion in the urine. Proteinuria is the consequence of glomerular filtration of plasma proteins, their subsequent reabsorption by the proximal tubular cells and secretion of protein by the tubular cells and distal urinary tract. In physiological conditions, the structural integry of the glomerular filtration barrier prevents the abnormal passage of albumin (molecular mass 66 kDa) and high-molecular-weight proteins (> 66 kDa), whereas the passage of low-molecular-weight proteins (< 66 kDa) is almost completely unrestricted. Proteins that arrive the tubular lumen are reabsorbed by endocytosis after binding to the megalin-cubilin complex. An increased load of proteins in the tubular lumen leads to the saturation of the reabsorptive mechanism and higher urinary protein excretion. Proteinuria can originate from prerenal, renal and postrenal causes. Elevated tubular protein concentrations have been recognized to be toxic to tubular cells and associated with the progression of chronic renal disease. Therefore, the quantitative and qualitative evaluation of proteinuria is important for the diagnosis of renal disease.

Designer aminoglycosides prevent cochlear hair cell loss and hearing loss.

Bacterial infections represent a rapidly growing challenge to human health. Aminoglycosides are widely used broad-spectrum antibiotics, but they inflict permanent hearing loss in up to ~50% of patients by causing selective sensory hair cell loss. Here, we hypothesized that reducing aminoglycoside entry into hair cells via mechanotransducer channels would reduce ototoxicity, and therefore we synthesized 9 aminoglycosides with modifications based on biophysical properties of the hair cell mechanotransducer channel and interactions between aminoglycosides and the bacterial ribosome. Compared with the parent aminoglycoside sisomicin, all 9 derivatives displayed no or reduced ototoxicity, with the lead compound N1MS 17 times less ototoxic and with reduced penetration of hair cell mechanotransducer channels in rat cochlear cultures. Both N1MS and sisomicin suppressed growth of E. coli and K. pneumoniae, with N1MS exhibiting superior activity against extended spectrum β lactamase producers, despite diminished activity against P. aeruginosa and S. aureus. Moreover, systemic sisomicin treatment of mice resulted in 75% to 85% hair cell loss and profound hearing loss, whereas N1MS treatment preserved both hair cells and hearing. Finally, in mice with E. coli-infected bladders, systemic N1MS treatment eliminated bacteria from urinary tract tissues and serially collected urine samples, without compromising auditory and kidney functions. Together, our findings establish N1MS as a nonototoxic aminoglycoside and support targeted modification as a promising approach to generating nonototoxic antibiotics.

Penetrability of the inner mucus layer: who is out there?

Large numbers of microorganisms colonise the skin and mucous membranes of animals, with their highest density in the lower gastrointestinal tract. The impact of these microbes on the host can be demonstrated by comparing animals (usually mice) housed under germ-free conditions, or colonised with different compositions of microbes. Inbreeding and embryo manipulation programs have generated a wide variety of mouse strains with a fixed germ-line (isogenic) and hygiene comparisons robustly show remarkably strong interactions between the microbiota and the host, which can be summarised in three axioms. (I) Live microbes are largely confined to their spaces at body surfaces, provided the animal is not suffering from an infection. (II) There is promiscuous molecular exchange throughout the host and its microbiota in both directions [1]. (III) Every host organ system is profoundly shaped by the presence of body surface microbes. It follows that one must draw a line between live microbial and host “spaces” (I) to understand the crosstalk (II and III) at this interesting interface of the host-microbial superorganism. Of course, since microbes can adapt to very different niches, there has to be more than one line. In this issue of EMBO Reports, Johansson and colleagues have studied mucus, which is the main physical frontier for most microbes in the intestinal tract: they report how different non-pathogenic microbiota compositions affect its permeability and the functional protection of the epithelial surface [2].

Pressure Ulcer-Related Pelvic Osteomyelitis: A Neglected Disease?

Background. Decubitus ulcers can become complicated by pelvic osteomyelitis. Little is known about the epidemiology of pressure ulcer-related pelvic osteomyelitis. Methods. We performed a retrospective cohort study of adult patients with pressure ulcer and pelvic osteomyelitis admitted to an academic center from 2006 to 2011. Data on clinical presentation, diagnostic evaluation, and treatment during the index admission were collected. Outcome measures included length of hospital stay and number of readmissions in the subsequent year. Results. Two hundred twenty patients were included: 163 (74%) were para/quadriplegic and 148 (67%) were male (148; 67%). Mean age was 50 (±18) years. Pelvic osteomyelitis was the primary admission diagnosis for 117 (53%). Fifty-six (26%) patients had concurrent febrile urinary tract infection. Wound cultures collected for 113 patients (51%) were notable for methicillin-resistant Staphylococcus aureus (37; 33%), Streptococci (19; 17%), and Pseudomonas spp (20; 18%). Plain films were obtained in 89 (40%) patients, computed tomography scans were obtained for 81 (37%) patients, and magnetic resonance images were obtained for 40 (18%) patients. Most patients received osteomyelitis-directed antibiotics (153; 70%), 134 of 153 (88%) of which were scheduled to receive ≥6 weeks of treatment. Fifty-five (25%) patients underwent surgery during the index admission; 48 (22%) patients received a combined medical-surgical approach. One third of patients had ≥2 readmissions during the subsequent year. Patients treated with a combined approach were less likely to be readmitted than those who received antibiotics alone (0 [range, 0-4] vs 1 [0-7] readmissions; P = .04). Conclusions. This is one of the largest cohort studies of pressure ulcer-related pelvic osteomyelitis to date. Significant variations existed in diagnostic approach. Most patients received antibiotics; those treated with a combined medical-surgical approach had fewer hospital readmissions.

An Insight Into Cervical Cancer Screening and Treatment Capacity in Sub Saharan Africa.

OBJECTIVE Approximately 85% of cervical cancer cases and deaths occur in resource-constrained countries where best practices for prevention, particularly for women with HIV infection, still need to be developed. The aim of this study was to assess cervical cancer prevention capacity in select HIV clinics located in resource-constrained countries. MATERIALS AND METHODS A cross-sectional survey of sub-Saharan African sites of 4 National Institutes of Health-funded HIV/AIDS networks was conducted. Sites were surveyed on the availability of cervical cancer screening and treatment among women with HIV infection and without HIV infection. Descriptive statistics and χ or Fisher exact test were used as appropriate. RESULTS Fifty-one (65%) of 78 sites responded. Access to cervical cancer screening was reported by 49 sites (96%). Of these sites, 39 (80%) performed screening on-site. Central African sites were less likely to have screening on-site (p = .02) versus other areas. Visual inspection with acetic acid and Pap testing were the most commonly available on-site screening methods at 31 (79%) and 26 (67%) sites, respectively. High-risk HPV testing was available at 29% of sites with visual inspection with acetic acid and 50% of sites with Pap testing. Cryotherapy and radical hysterectomy were the most commonly available on-site treatment methods for premalignant and malignant lesions at 29 (74%) and 18 (46%) sites, respectively. CONCLUSIONS Despite limited resources, most sites surveyed had the capacity to perform cervical cancer screening and treatment. The existing infrastructure of HIV clinical and research sites may provide the ideal framework for scale-up of cervical cancer prevention in resource-constrained countries with a high burden of cervical dysplasia.

Can urethrolysis resolve outlet obstruction related symptoms after Burch colposuspension for stress urinary incontinence?

OBJECTIVE Bladder outlet obstruction may occur after any incontinence surgery and may present as OAB, hesitancy and or the feeling of incomplete emptying. Aim of this study was to analyze the clinical and urodynamical outcome after urethrolysis in patients presenting with various clinical symptoms after Burch colposuspension for stress urinary incontinence. STUDY DESIGN Between January 2005 and December 2014, all patients who presented with symptoms and with bladder outlet obstruction were included. All patients had undergone Burch or Cowan colposuspension for stress urinary incontinence previously. Primary endpoint was the visual analogue scale (VAS) as measurement of patient perceived disease impact. Secondary endpoints were the various domains of the King's Health Questionnaire, urodynamic parameters as detrusor pressure at maximum flow, residual urine and sonographic bladder wall thickness before and six months after intervention. RESULTS Seventy-two female patients were included in this study whereof 42 suffered from urgency and urge incontinence, 20 from hesitancy and/or slow stream, seven from residual urine of more than 100ml and three from a combination of urgency and residual urine. VAS improved significantly (p<0.0001). Quality of life as determined by the King's Health Questionnaire improved for the domains general health, role limitations, emotions, physical limitations, personal limitations and incontinence impact significantly. Micturition pressure dropped significantly from 43cmH2O (95% CI 19-59cmH2O) to 18cmH2O (95% CI 16-23.5 H2O). Residual urine changed from 110ml (range 20-380ml) to 32ml (20-115ml). Bladder wall thickness decreased from 7mm (95% CI 6.235-7.152) to 5mm (95% CI 5.037-5.607; p<0.01). CONCLUSION Urethrolysis may resolve patients' symptoms and lower micturition pressure but irritative symptoms may persist.

Type IV delayed-type hypersensitivity of the respiratory tract due to budesonide use: report of two cases and a literature review

Respiratory type-IV hypersensitivity reactions due to corticosteroids is a rare phenomenon. We describe two such cases. The first is a 37- year-old atopic woman who developed labial angioedema and nasal itching after the use of budesonide nasal spray. A month later, after the first puffs of a formoterol/budesonide spray prescribed for asthma, she noticed symptoms of tongue and oropharyngeal itching and redness with subsequent dysphagia, labial and tongue angioedema, and facial oedema. The second is a 15-year-old non-atopic woman who reported pruritic eruptions around the nostrils after using a budesonide nasal spray. A year later she presented with nasal pruritus with intense congestion and labial and facial oedema after using the same spray. Both patients were evaluated with patch-tests using the commercial T.R.U.E. test, a budesonide solution, and corticosteroid creams. Test evaluation was performed at 48 and 96 hours. In both patients, patch tests were positive to budesonide (++) on the second day. The first patient also had a positive (+) reaction to tixocortol-21-pivalate. All the other patch tests were negative. Clinicians should be aware that hypersensitivity reactions may occur during the use of nasal or inhaled corticosteroids.

[Right-sided lower abdominal pain and diarrhea of a young diabetic woman]

We report the case of a 24-years old diabetic women hospitalised because of right-sided lower abdominal pain and diarrhea. She fulminantly developed shock before appendectomy could be performed and was transferred to intensive care unit. Hypotension remained and laparoscopy revealed primary peritonitis and toxic shock syndrome by Group A Streptococcus which was cultivated in blood and ascites. Therapy with penicilline and clindamycine resolved symptoms. During hospitalisation Clostridium difficile colitis occurred. This complication leaded to prolonged hospitalisation.

Smoothelin is a specific and robust marker for distinction of muscularis propria and muscularis mucosae in the gastrointestinal tract

As tumour specimens and biopsy specimens become smaller, recognition of anatomical structures relevant for staging is increasingly challenging. So far no marker is known that reliably discriminates between muscularis propria (MP) and muscularis mucosae (MM) of the gastrointestinal tract. Recently, smoothelin expression has been shown to differ in MP and MM of the urinary bladder. We aimed to analyse the expression of smoothelin in the gastrointestinal tract in MP and MM in order to define a novel diagnostic tool to identify MM bundles.

Use of modern and traditional products to self-treat symptoms of sexually transmitted infections in South African women

The objective of the study is to investigate products used by women self-treating symptoms of reproductive tract infections (RTIs), including sexually transmitted infections (STIs), and their methods of administration. A household survey using a multi-stage cluster sample design was undertaken in KwaZulu-Natal, South Africa. Women aged 18-60 years were interviewed (n = 867) and information was collected on demographics, reproductive health and sexual behaviours. A fifth of women reported having RTI/STI symptoms (20.5%), of whom 41.9% were treating these symptoms (mostly discharge [79.1%], ulcers [6.8%] and itching [7.7%]). Only three women were using medication prescribed by a health provider, while the remainder were self-treating using traditional medicines and modern products, including antiseptics, soaps, petroleum jelly, menthol creams and alum. Products were administered in various ways. Although RTI/STI treatment is widely available and free in public health facilities, many women are still self-treating. Potential harm of products for self-treatment requires further investigation and efforts should be made to improve STI service uptake.

Urinary soluble HLA-DR is a potential biomarker for acute renal transplant rejection

BACKGROUND.: Urine is a potentially rich source of biomarkers for monitoring kidney dysfunction. In this study, we have investigated the potential of soluble human leukocyte antigen (sHLA)-DR in the urine for noninvasive monitoring of renal transplant patients. METHODS.: Urinary soluble HLA-DR levels were measured by sandwich enzyme-linked immunosorbent assay in 103 patients with renal diseases or after renal transplantation. sHLA-DR in urine was characterized by Western blotting and mass spectrometry. RESULTS.: Acute graft rejection was associated with a significantly elevated level of urinary sHLA-DR (P<0.0001), compared with recipients with stable graft function or healthy individuals. A receiver operating characteristic curve analysis showed the area under the curve to be 0.88 (P<0.001). At a selected threshold, the sensitivity was 80% and specificity was 98% for detection of acute renal transplant rejection. sHLA-DR was not exosomally associated and was of lower molecular weight compared with the HLA-DR expressed as heterodimer on the plasma membrane of antigen-presenting cells. CONCLUSIONS.: sHLA-DR excreted into urine is a promising indicator of renal transplant rejection.

DW-MRI of the urogenital tract: applications in oncology

Diffusion-weighted magnetic resonance imaging (DW-MRI) appears to hold promise as a non-invasive imaging modality in the detection of early microstructural and functional changes of different organs. DW-MRI is an imaging technique with a high sensitivity for the detection of a large variety of diseases in the urogenital tract. In kidneys, DW-MRI has shown promise for the characterization of solid lesions. Also in focal T1 hyperintense lesions DW-MRI was able to differentiate hemorrhagic cysts from tumours according to the lower apparent diffusion coefficient (ADC) values reported for renal cell carcinomas. Promising results were also published for the detection of prostate cancer. DW-MRI applied in addition to conventional T2-weighted imaging has been found to improve tumour detection. On a 3 T magnetic resonance unit ADC values were reported to be lower for tumours compared with the normal-appearing peripheral zone. The combined approach of T2-weighted imaging and DW-MRI also showed promising results for the detection of recurrent tumour in patients after radiation therapy. DW-MRI may improve the performance of conventional T2-weighted and contrast-enhanced MRI in the preoperative work-up of bladder cancer, as it may help in distinguishing superficial from muscle invasive bladder cancer, which is critical for patient management. Another challenging application of DW-MRI in the urogenital tract is the detection of pelvic lymph node metastases. As the ADC is generally reduced in malignant tumours and increased under inflammatory conditions, reduced ADC values were expected in patients with lymph node metastases.

Compression hosiery for occupational leg symptoms and leg volume: a randomized crossover trial in a cohort of hairdressers

OBJECTIVE: Occupational leg symptoms are highly prevalent in the general population and impair the psychic state of health. We investigated hairdressers, a cohort exposed to prolonged standing during work, in a randomized crossover trial. We hypothesized that hairdressers wearing low-strength compression hosiery would benefit from less leg volume increase and discomfort. METHODS: One hundred and eight hairdressers were randomized to wear medical compression stockings (MCS; 15-20 mmHg) in a crossover study. The effect of MCS on symptoms and on lower leg volume was compared with no compression treatment. Symptoms were assessed with a comprehensive questionnaire, categorized using factor analysis with varimax rotation and correlated with leg volume changes. RESULTS: Wearing MCS reduced the symptom score for pain and feelings of swelling (range 0-4) by an average of 0.22 (12%, P < 0.001). Sleep disturbance, feeling of unattractive legs and depressiveness improved with MCS compared with no MCS. Subjects initially obliged to refrain from wearing stockings showed a significant decrease of pain and feelings of swelling as well (by 0.10 [6%], P = 0.015). Wearing MCS was associated with a decrease of lower leg volume by an average of 19 mL (P < 0.001), with preference in older hairdressers (P < 0.001). The effects of wearing MCS on symptoms and on leg volume were not correlated with each other. CONCLUSIONS: Individuals working in a standing profession experience leg pain, feelings of swelling, heaviness and various other disturbing feelings. These symptoms can be alleviated by wearing low-strength MCS.

Urothelial neoplasms of the urinary bladder occurring in young adult and pediatric patients: a comprehensive review of literature with implications for patient management

Bladder urothelial carcinoma is typically a disease of older individuals and rarely occurs below the age of 40 years. There is debate and uncertainty in the literature regarding the clinicopathologic characteristics of bladder urothelial neoplasms in younger patients compared with older patients, although no consistent age criteria have been used to define "younger" age group categories. Use of the World Health Organization 2004/International Society of Urological Pathology 1998 grading nomenclature and recent molecular studies highlight certain unique features of bladder urothelial neoplasms in young patients, particularly in patients below 20 years of age. In this meta-analysis and review, the clinical, pathologic, and molecular features and risk factors of bladder urothelial neoplasms in patients 40 years or less are presented and analyzed according to decades of presentation. Similar to older patients, bladder urothelial neoplasms in patients 40 years or younger occur more common in male patients, present mainly with gross painless hematuria, and are more commonly located at bladder trigone/ureteral orifices, but in contrast have a greater chance for unifocality. Delay in diagnosis of bladder urothelial neoplasms seems not to be uncommon in younger patients probably because of its relative rarity and the predominance of benign causes of hematuria in this age group causing hesitancy for an aggressive work-up. Most tumors in patients younger than 40 years were low grade. The incidence of low-grade tumors was the lowest in the first 2 decades of life, with incremental increase of the percentage of high-grade tumors with increasing age decades. Classification according to the World Health Organization 2004/International Society of Urological Pathology grading system identified papillary urothelial neoplasms of low malignant potential to be relatively frequent among bladder tumors of young patients particularly in the teenage years. Similar to grade, there was marked predominance of low stage tumors in the first 2 decades of life with gradual inclusion of few higher stage and metastatic tumors in the 2 older decades. Bladder urothelial neoplasms occurring in patients <20 years of age lack or have a much lower incidence of aberrations in chromosome 9, FGFR3, p53, and microsatellite instability and have fewer epigenetic alterations. Tumor recurrence and deaths were infrequent in the first 2 decades and increased gradually in each successive decade, likely influenced by the increased proportion of higher grade and higher stage tumors. Our review of the literature shows that urothelial neoplasms of the bladder occurring in young patients exhibit unique pathologic and molecular features that translate to its more indolent behavior; this distinction is most pronounced in patients <20 years. Our overall inferences have potential implications for choosing appropriate noninvasive diagnostic and surveillance modalities, whenever feasible, and for selecting suitable treatment strategies that factor in quality of life issues vital to younger patients.