Differential expression of proopiomelanocortin (POMC) transcriptional variants in human skin cells.

The aims of this study were to examine content and expression level of proopiomelanocortin (POMC) mRNA variants in human dermal fibroblasts (HDF) as compared to primary keratinocytes and HaCaT cells of keratinocyte origin. Primary fibroblasts and keratinocytes were obtained from normal human foreskin. Full-length and total (i.e. the full-length, truncated and/or alternatively spliced) POMC mRNA in skin cells were determined by qRT-PCR using specific probes. The full-length POMC mRNA in HDF is neither constitutively expressed, nor could be induced by corticotropin releasing hormone (CRH) or cytokines interferon γ (IFN-γ) and transforming growth factor-ß1 (TGF-ß1). However, the truncated/alternatively spliced POMC mRNA variants are constitutively expressed in HDF and could be moderately increased with CRH and the cytokines. Primary keratinocytes, in addition to truncated/alternatively spliced POMC mRNA variants, also constitutively express full-length POMC mRNA, both being downregulated during in vitro culturing. Unlike primary keratinocytes, HaCaT cells, express only truncated/alternatively spliced POMC mRNA variants. The level of POMC mRNA expression in HaCaT cells was associated with differentiation stage, being higher in more differentiated cells. Thus, in this study we have shown for the first time that HDF do not express the full-length POMC mRNA, either constitutively or upon activation, opposing to primary keratinocytes which constitutively express the full-length POMC mRNA as a minor variant. Although expressing only truncated/alternatively spliced POMC mRNA variant, HDF express POMC peptide, showing that those transcriptional variants are translatable. Truncated/alternatively spliced POMC mRNA variants, expressed both in HDF and keratinocytes are subjected to regulation, implicating their functionality. Furthermore, the IFN-γ-induced up-regulation at transcriptional level was associated with increased level of POMC peptide detected in HDF lysates. Thus, data of this study have shown that HDF express only truncated/alternatively spliced POMC mRNA variants, which are probably biologically relevant as they could be translated to POMC peptide, both constitutively and upon activation.

Micropapillary urothelial carcinoma of the ureter.

Micropapillary urothelial carcinoma (MPUC) is a rare aggressive variant of urothelial carcinoma, associated with advanced tumor stage, high tendency to invade lymphovascular spaces, and metastasize to lymph nodes and other organs. Therefore, it has a poor prognosis. One of the most prominent histological features is the presence of small, round empty spaces surrounding infiltrating tumor nests. If detected, even a small focus of micropapillary pattern may be therapeutically significant; the higher proportion of micropapillary component, the worse the prognosis. Radical nephroureterectomy is the treatment of choice even in the setting of superficially invasive disease. Although, MPUC has been well studied in urinary bladder, only a few cases of MPUC in upper urinary tract have been described. We are describing a case of a 79-year old woman with micropapillary urothelial carcinoma involving ureter and review the literature of this rare entity.

Aggressiveness of inflammation in histological prostatitis--correlation with total and free prostate specific antigen levels in men with biochemical criteria for prostate biopsy.

BACKGROUND AND AIMS: Although prostatitis can contribute to the lack of prostate specific antigen (tPSA) specificity, there is disagreement concerning the effect of histological inflammation on free PSA (fPSA). We investigated the correlation between aggressiveness of histological inflammation and tPSA, fPSA and f/tPSA in patients without detectable prostate cancer (PC). METHODS: The study included 106 patients with tPSA <10 ng/mL, without clinical prostatitis and with biopsy negative for PC. The inflammation in prostate biopsies was scored for aggressiveness using the four-point scale reported by Irani. The patients were divided into two groups of less aggressive and more aggressive inflammation and compared by use of regression analysis. RESULTS: The median tPSA, fPSA and f/tPSA levels were 6.39 ng/mL, 1.1 ng/mL and 16% in the less aggressive inflammation group and 7.3 ng/mL, 0.79 ng/mL and 10.7% in the more aggressive inflammation group, respectively. There was no significant between-group difference in tPSA levels (P=0.16), however, statistically significant between-group differences were recorded in fPSA and f/tPSA levels (P<0.001 both). Spearman's analysis yielded a significant negative correlation of inflammation aggressiveness with fPSA (r=-0.34; P<0.001) and f/tPSA (r=-0.45; P<0.001). Free PSA and f/tPSA were lower in the group with more aggressive inflammation. CONCLUSIONS: Histological inflammation has a high prevalence in cancer-free prostate biopsy specimens and exerts similar effects on fPSA and f/tPSA levels as PC. Our study suggests histological prostatitis to be an important cause of decreased fPSA and f/tPSA values; therefore, when it is identified, antibiotic or anti-inflammatory therapy should be introduced to reduce the percentage of men with a continuing indication for prostate biopsy.

Chronic prostatitis/chronic pelvic pain syndrome in males may be an autoimmune disease, potentially responsive to corticosteroid therapy.

UNLABELLED: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) represents the most common form of prostatitis. No known etiology factor in most cases can be found. It is possible that at least in some cases autoimmune response could be causative factor. Common treatment options include antibiotics, alpha blockers, myorelaxants, phytotherapeuticals, non steroidal anti-inflammatory drugs, hormonal treatment and surgery but corticosteroids have not been investigated. HYPOTHESIS: Chronic pelvic pain syndrome is in some cases autoimmune disease and this could have repercussions on treatment using low dose corticosteroids. RATIONALE: Currently corticosteroids are not a standard treatment option in CP/CPPS. Theoretical, experimental and scarce clinical evidence suggest that treatment with low dose corticosteroids could be beneficial in some patients with chronic prostatitis. If our hypothesis could be supported with well designed, randomized clinical trials this could change the approach of the medical treatment of CP/CPPS.

The impact of Syme amputation in surgical treatment of patients with diabetic foot syndrome and Charcot-neuro-osteoarthropathy.

INTRODUCTION: Charcot-neuro-osteoarthropathy with its severe destruction of bones remains a challenge for physicians and surgeons. The aim of the study was to characterise a patient population treated in a specialised foot care centre who underwent surgical treatment for their diabetic foot syndrome. Special attention was paid to patients who suffered from Charcot-neuro-osteoarthropathy and the impact of Syme amputation if amputation of the foot was inevitable. MATERIALS AND METHODS: A total of 121 patients with diabetic foot syndrome and ulcerations underwent an interdisciplinary strategy for diagnostic and therapeutic procedures including MRI and surgical interventions. If peripheral arterial vessel disease was present, revascularisation by distal bypass grafting was done before the orthopaedic intervention. Some 24% showed the typical neuro-osteoarthropathy with severe bone destruction. In 8 cases amputation of the foot was performed using the Syme technique. RESULTS: In our population the short-term results (follow-up 12 months, 20% lost to follow-up) are good, only 4% of the patients required further surgery on the same foot. In all patients with Charcot feet, plain radiographs showed the typical radiographic signs of the disease, and MRI was most helpful to detect abscess formations. The typical clinical problems of patients with Charcot disease are pointed out, and conservative and surgical treatment options are discussed. All patients with Syme amputation did well, wound healing and weight-bearing of the limb were accomplished. CONCLUSION: The crucial diagnostic tool for decision-making in diabetic foot syndrome was MRI, which normally shows osteomyelitis with high sensitivity and specificity. In patients with Charcot-neuro-osteoarthropathy, the bone marrow oedema of the involved parts of the skeleton might misleadingly suggest the diagnosis of osteomyelitis. If amputation is inevitable in severe abscess formation combined with instability and perforation of the dislocated and destroyed bones in Charcot-neuro-osteoarthropathy, these patients might benefit from a foot amputation according to the technique Syme described. For this procedure the blood supply of the posterior tibial artery is essential. All these patients were able to walk without support. The material presented helps to generate hypotheses for further prospective studies.

[Limb salvage in diabetic foot syndrome with pedal bypass using the in-situ technique]. / Extremitätenerhalt durch pedalen In-situ-Bypass beim diabetischen Fusssyndrom.

INTRODUCTION: Treatment of the ischemic diabetic foot syndrome still represents a medical and economic challenge. Contrary to the aims of the Saint Vincent declaration a dramatic reduction of major amputations in Germany was not noted, although in the diabetic patients the predominant type of tibial artery occlusion allows construction of pedal bypasses for limb salvage. METHOD: In patients with ischemic diabetic foot syndrome following angiographic evaluation of the ischemic limb, the indication for surgical revascularisation of patent pedal arteries was established. The in-situ technique was preferred in the presence of a suitable ipsilateral greater saphenous vein whenever possible. Revascularisation was followed by treatment of foot ulcerations or, if necessary, minor amputations. Patients were followed by clinical examination and duplex scan investigation of the bypass in regular intervals. RESULTS: From 01/89 to 12/01 in 79 patients (59 men and 20 women) with non healing ulcerations or established gangrene from a total of 175 pedal bypasses 84 pedal bypass operations in 84 limbs were performed using the in-situ technique. All patients were diabetic and in addition 13.9% were dependent on hemodialysis for end stage renal disease. 59.5% of the bypasses originated from the popliteal artery (distal origin bypass). The dorsalis pedis artery was chosen for the distal anastomosis in 83% and the posterior tibial artery in 17%. Two patients (2.4%) died postoperatively from cardiac events. Early bypass occlusion occurred in 8.4% resulting in a major amputation rate of 6%. After 60 months primary, primary assisted and secondary patency was 67.7%, 71.5% and 75.3% respectively with a limb salvage rate of 78%. CONCLUSION: Pedal bypass using the in-situ technique provides excellent long term limb salvage rates in a disease with a generally unjustified bad prognosis with respect to limb salvage.

[Short distal origin vein graft in diabetic foot syndrome]. / Der kurze popliteodistale Venenbypass beim diabetischen Fusssyndrom DFS.

PURPOSE: World wide increase of diabetes compound with diabetic foot syndrome becomes a challenge in vascular surgery to avoid limb loss. In diabetics a special pattern of atherosclerosis is prevalent with disease limited to the infrageniculate arteries but sparing inflow vessels and distal tibial and pedal arteries. This provides short bypass grafting from popliteal to tibial and pedal arteries, a concept first described by F. Veith in 1981. METHODS: Diabetics with severe atherosclerotic disease and limb-threatening ischemia got general evaluation and vascular imaging. Falling in this special category the patients underwent short vein bypass grafting originating at the first or third popliteal segment extending to the tibial or pedal arteries. Follow up of patency and limb salvage was nearly complete. RESULTS: From 1988 to 2001 124 diabetics received 140 vein bypass grafts for limb salvage, 95.7% already preoperatively with foot necrosis. Operative mortality rate was 1.4%, major morbidity rate was 9.3%, early graft failure rate 8.5% and early amputation rate was 3.8%. 2 year primary patency, primary assisted patency, secondary patency rates and limb salvage were 73.3%, 75.7%, 76.4% and 87.2%. 5 years results were 63.6%, 69.2%, 70.0% and 81.9% respectively. DISCUSSION: This series revealed exceptionally good results in patients with diabetes mellitus after short vein bypass grafting in concert with earlier studies since 1981. Compared to long femorodistal grafts there was no difference in longterm patency. Bypass grafting in diabetic foot syndrome is still regarded to have a poor prognosis. Just the contrary is the case. This study in concert with former studies revealed distal origin bypass grafting a durable and effective procedure to fight limb loss in diabetic foot syndrome. CONCLUSION: Distal origin vein bypass grafting is an excellent method just for patients with diabetes. Looking at limb salvage rates over 80 % in 5 years, this procedure should be offered more often suitable patients with diabetic foot syndrome.

[Interdisciplinary treatment of diabetic foot syndrome]. / Die interdisziplinäre Therapie des diabetischen Fusssyndroms.

The amputation rate in patients with diabetic foot syndrome (DFS) in Germany is still as high as 28,000 per year. Ischemia and osteomyelitis often complicate the DFS. Impaired wound healing frequently requires further surgery with a higher amputation level. The results of treating patients with DFS in our specialized foot care center were evaluated in order to assess our interdisciplinary strategy. Advanced diabetic foot wounds in patients with ischemia and osteomyelitis first require diagnostics concerning polyneuropathy, osteomyelitis, and blood supply. If peripheral arterial vessel disease is present, surgical revascularization by distal bypass grafting is the first and crucially important element of the interdisciplinary approach. Minor amputation or elective resection of the infected bone improves wound healing. Post-interventional care for wounds with secondary healing and prevention of new ulcers are provided in a foot care clinic specialized in diabetes. The clinical and radiological results of 77 patients who underwent this treatment algorithm including bypass surgery and bone resection within 1 year were collected using a standardized questionnaire. Those results were subjected to a historical comparison. Only three patients needed further intervention because of persisting ulcers and osteomyelitis. The frequency of major amputations in all patients with DFS and ischemia combined with osteomyelitis was low (10.3%). This interdisciplinary concept of treatment guarantees a high healing rate in patients even with osteomyelitis and ischemia and allows the reduction of the rate of major amputations. The data obtained allow a fact-based design for future studies.

Distribution of the vacuolar H+ atpase along the rat and human male reproductive tract.

Luminal acidification in parts of the male reproductive tract generates an appropriate pH environment in which spermatozoa mature and are stored. The cellular mechanisms of proton (H+) secretion in the epididymis and the proximal vas deferens involve the activity of an apical vacuolar H+ ATPase in specialized cell types, as well as an apical Na+/H+ exchanger in some tubule segments. In this study we used Western blotting and immunocytochemistry to localize the H+ ATPase in various segments of the male reproductive tract in rat and man as a first step toward a more complete understanding of luminal acidification processes in this complex system of tissues. Immunoblotting of isolated total cell membranes indicated a variable amount of H+ ATPase in various segments of the rat reproductive tract. In addition to its known expression in distinct cell types in the epididymis and vas deferens, the H+ ATPase was also localized at the apical pole and in the cytoplasm of epithelial cells in the efferent duct (nonciliated cells), the ampulla of the vas deferens and the ventral prostate (scattered individual cells), the dorsal and lateral prostate, the ampullary gland, the coagulating gland, and all epithelial cells of the prostatic and penile urethra. Both apical and basolateral localization of the protein were found in epithelial cells of the prostatic ducts in the lateral prostate and in periurethral tissue. Only cytoplasmic, mostly perinuclear localization of the H+ ATPase was found in all epithelial cells of the seminal vesicles and in most cells of the ventral prostate and coagulating gland. No staining was detected in the seminiferous tubules, rete testis, and bulbourethral gland. In human tissue, H+ ATPase-rich cells were detected in the epididymis, prostate, and prostatic urethra. We conclude that the vacuolar H+ ATPase is highly expressed in epithelial cells of most segments of the male reproductive tract in rat and man, where it may be involved in H+ secretion and/or intracellular processing of the material endocytosed from the luminal fluid or destined to be secreted by exocytosis.

Individual variation in response to lead exposure: a dilemma for the occupational health physician.

Subclinical lead poisoning with no clinical symptoms is a dilemma for the occupational health physician. He is supposed to assess when and how to treat workers at risk mainly by the results of biological monitoring. The aim of this study was to demonstrate different responses of biological indices in 50 lead-exposed workers who have been working in the same plant of lead pigment production factory. Twenty-one had normal, that is, permissible blood lead concentrations (PbB), erythrocyte protoporphyrin (EP), and aminolevulinic acid activity (ALAD) measured during regular periodic examinations (group 1). No differences between two measurements were found, although they were continuously working with lead. In 18 of the 50 workers (group 2), PbB and EP concentrations increased, whereas ALAD activity decreased: those parameters improved after a 3- to 6-month cessation of lead exposure. Seven of the 50 workers also had altered values of biological indices, but their condition improved spontaneously without cessation of lead exposure (group 3), while in the remaining four workers, elevated concentrations of biological indices did not change during the observation period. The reasons for such discrepancies and indications for chelation therapy are discussed.

[Assessment of intestinal permeability using 51 CrEDTA: clinical usefulness in the detection of small bowel epithelial structural abnormalities]. / Estudo da permeabilidade intestinal pelo teste do 51CrEDTA: utilidade clínica na detecção de alterações estruturais do epitélio do intestino delgado.

Intestinal permeability tests have been increasingly used in the clinical management of small bowel diseases. Nevertheless, the application of such tests in Brazil is still limited. In this study we report the results of the application of 51Cr-EDTA for assessment of intestinal permeability in 13 healthy volunteers, 10 control patients with miscellaneous disorders, but without evidence of small bowel involvement, 11 patients with well characterized diseases affecting the small bowel, and five patients with inflammatory conditions affecting exclusively the colon. Urinary radioactivity levels in the 24 h following the ingestion of 51Cr-EDTA, expressed as the percentage of the ingested dosis, ranged from 1.99 to 5.93% (median: 3.14%) in healthy volunteers and was not significantly different from the results obtained in control patients (range: 1.48-3.98%; median 3.32%). Based on data from these two control groups, an upper limit of the normal range was set at 5.17% (95% confidence interval). Among patients with diseases of the small bowel, results ranged from 1.58 to 14.85% (median: 8.07%) and were significantly different from those observed in the control groups. Only two out of the 11 patients in this group had abnormal results. In the group of patients with diseases of the colon, results ranged from 3.48 to 5.13% (medium: 4.54%) and were not significantly different from the results obtained in control subjects. All patients in this group had results within the normal range. Data from control subjects and patients with diseases of the small bowel were used for the calculations of sensitivity (81%), specificity (96%), as well as false-positive (4.3%) and false-negative (18.1%) rates. Taken as a whole, the results of the present study indicate that the 51Cr EDTA test of intestinal permeability is accurate and may be useful in the clinical management of small bowel diseases in Brazilian patients.

Balkan endemic nephropathy: still a mysterious disease.

Balkan endemic nephropathy (BEN) is an acquired, environmental, polytopical disease of the entire urinary tract, with long latency. Tubulointerstitial chronic nephritis, urotheliomas of all localities, and renal cell carcinoma occur with a significantly higher frequency in the affected population. These represent only clinical manifestations of one unique nosological entity. BEN occurs in focuses. Within them, it agglomerates in households, without any evidence of hereditary background. Patients with various clinical manifestations of the disease can be simultaneously found within one single household. BEN appears equally among members of different ethnic groups. Its aetiology is not clear enough. There is no evidence of a causal relationship with silicon compounds, heavy metals and viruses. Much attention has been recently focused on research of the aetiological role of mycotoxins, mainly ochratoxin A. Toxic and carcinogenic agents of natural origin are commonly accepted as the major cause of BEN.

Environmental effects on chromosomes in oncology and radiology department personnel.

Long-term, low levels of antineoplastic drugs and ionizing radiation in the work environment may have genotoxic effects on chromosomes in personnel. The effects of ionizing radiation is acknowledged in occupational medicine and therefore various measures have been undertaken to prevent such effects. However, there are no protective measures for workers exposed to antineoplastic drugs. In this study metaphase chromosome preparations were analyzed in 126 nurses and radiology technicians. They were divided into three equal groups. The first group consisted of shift nurses in an oncology department handling antineoplastic drugs. The second group consisted of radiology technicians in a radiology department and the third group acted as controls. Structural chromosomal aberrations were increased among those nurses exposed to antineoplastic drugs in comparison with technicians (P less than 0.05) and controls (P less than 0.01), respectively.

Continent sigmoid bladder after cystectomy: 20 years' experience.

Twenty years' experience in the substitution of an isolated sigmoid segment after radical cystectomy for bladder carcinoma is described. The indication for surgery was isolated, non-transitional cell bladder cancer. The isolated sigmoid segment is placed longitudinally in the isoperistaltic direction. The study is made up of 73 cases. This operation does not make the procedure more radical since it does not increase survival for this illness. However, in relation to other bladder substitution methods, it guarantees a better quality of life after the operation.

Effects of local chemotherapy and immunotherapy on the recurrence and progression of superficial bladder cancer.

409 cases of superficial bladder carcinoma (pTa, pTi, Tis) are reported. They are divided into three groups: 171 patients treated by TUR alone, 124 treated by TUR and local thio-TEPA, and 114 patients treated by TUR and BCG vaccine locally. It was found that the frequency of recurrence fell by 56.7, 41.9 and 26.3%, while the progression of the illness declined correspondingly by 19.8, 16.9 and 11.4%. In other words, in terms of recurrence and progression, the poorest results were found for the group treated by TUR only, and the best results were found with the TUR and BCG group.

The Aarskog syndrome.

The Aarskog syndrome is characterized by short stature, peculiar facies, shawl scrotum, cryptorchism, broad, short hands and hyperextensibility of the proximal interphalangeal joints. A boy with typical features of the Aarskog syndrome is presented. The proband's mother, sister and grandmother were short and strongly resembled him. Palmar dermatoglyphics showed the presence of whorls in the interdigital areas of the affected mother and son and the absence of this pattern on the palms of the sister.

Surgical approach to penile and penoscrotal hypospadias.

A two-step procedure for repairing penile and penoscrotal hypospadias using the scrotum tube in situ for urethral reconstruction is described. This method is applicable in both scrotal and perineal hypospadias, but in this case the meatus must first be transposed to the penoscrotal junction. There were five complications--three fistulae and two stenosis of the new urethra--out of 27 operated patients.