bluuebunny/crossref_metadata_2025 huggingface dataset:
Stereotactic Radiosurgery for Primary Trigeminal Neuralgia Using the Leksell Gamma Unit
Authors: Zheng Li-Gao , Xu De-Sheng , Kang Chun-Sheng , Zhang Zhi-Yuan , Li Yan-He , Zhang Yi-Pei , Liu Dong , Jia Qiang
Published: April 2003

Objective: Previous papers have reported Gamma Knife radiosurgery to be a safe, effective method for primary trigeminal neuralgia. Since November 1996, we have treated primary trigeminal neuralgia using the Leksell Gamma Knife at the Tianjin Medical University. The present study reports clinical results of Gamma Knife radiosurgery in the treatment of trigeminal neuralgia in 80 cases. Methods: The mean patient age was 67 years (range 32–92), the mean duration of facial pain was 7.6 years (range 1.5–29). The male:female ratio was 31:49. The right side of the face was involved in 45 patients (56.25%) and the left side in 30 cases (37.5%), with bilateral involvement in 5 cases (6.25%). Under local anesthesia, all patients underwent stereotactic MRI to identify the trigeminal nerve. A single isocenter, using a 4-mm collimator, was positioned at the sensory root of the trigeminal nerve entry zone of the pons, 4–6 mm from the brainstem surface, so that no more than the 20% isodose was administered to the brainstem. The maximum dose was between 70 and 90 Gy, with a mean of 75.6 Gy. For bilateral trigeminal neuralgia, two separate matrices were employed, and bilateral Gamma Knife radiosurgery was performed on the same day. Results: Follow-up ranged from 12 to 43 months (mean 23.7 months). Neurological evaluation indicated excellent response in 42 cases (52.5%), good response in 25 cases (31.25%), effective response in 8 cases (10%), so the total pain control rate was 93.75%. The latency from Gamma Knife surgery to pain relief ranged from 1 to 120 days (mean 22 days). Among the 75 patients 7 with pain control experienced pain recurrence 5–26 months after being completely free from pain. A second Gamma Knife radiosurgery was performed in 7 recurrent cases and 5 patients with treatment failure. A maximal dose ranging from 70 to 80 Gy was given (mean 74.2 Gy). After a mean follow-up of 18 months (8–33 months), 9 patients achieved excellent results, and 2 had good results. The latency interval to pain relief ranged from 1 to 120 days (mean 15 days). Nine patients developed new facial numbness, while no other complication appeared in the remainder of the patients. Conclusions: Gamma Knife radiosurgery is a safe and effective method in the treatment of trigeminal neuralgia once diagnosis is established.
Delayed Onset of the Supplementary Motor Area Syndrome after Surgical Resection of the Mesial Frontal Lobe: A Time Course Study Using Intraoperative Mapping in an Awake Patient
Authors: Duffau Hugues , Lopes Manuel , Denvil Dominique , Capelle Laurent
Published: April 2003

Although the occurrence of the supplementary motor area (SMA) syndrome has been extensively reported following mesial lobe surgery, to our knowledge the time course of disease onset was never accurately documented. We describe a patient without deficit, despite harboring a glioma invading the left SMA. This patient was operated under local anesthesia, to perform intraoperative online sensorimotor and language mapping using electrical stimulations throughout the resection. No deficit was noted at the end of the tumor and SMA removal. The patient was maintained awake to perform an immediate control MRI. Aphasia and right hemiplegia occurred 30 min after the SMA resection. Total recovery was observed within 2 months. This work shows that the SMA syndrome may not occur immediately after SMA resection. We suggest that the transient compensation of the SMA function is likely due to residual activity of an oscillatory loop and/or short-term plasticity (rapid unmasking of parallel networks), with final recovery occurring due to long-term plasticity (neosynaptogenesis).
Eosinophilic Cystitis Presenting as Urinary Retention
Authors: van den Ouden D. , van Kaam N. , Eland D.
Published: April 2003

Objective: To evaluate the incidence, etiology, diagnosis, therapy and results in patients with eosinophilic cystitis (EC), with special attention to patients with urinary retention as presenting symptom. Patients and Methods: Between 1988 and 1999, 3 patients with EC were diagnosed. One patient presented with urinary retention, without other symptoms. All patients were evaluated for symptoms, urine culture, hematology including cell differentiation, blood chemistry, cystoscopy and intravenous urography. The international literature was reviewed for incidence, etiological factors, diagnostic procedures, therapies and outcome of EC presenting with urinary retention. Results: Two male patients presented with pain, frequency of micturition and nocturia. One female patient presented with urinary retention. One patient had an urinary tract infection. One patient showed eosinophilia of the peripheral blood. Intravenous urography revealed hydroureteronephrosis in 2 patients (1 unilateral and 1 bilateral). Cystoscopy showed tumor-like lesions in 2 patients. Therapy consisted of oral or intravesical corticosteroids or transurethral resection of the lesions. All patients were cured. A review of the literature revealed that 14 patients with EC (10%) presented with urinary retention; the majority (79%) being children and women. All patients returned to normal miction following therapy. Conclusions: The clinical presentation of EC is varied. When the lesion is located at or near the bladder neck, it may present as urinary retention. In children and women with urinary retention, EC must be considered in the differential diagnosis. Corticosteroids are the mainstay of efficient therapy.
Huge Renal Arteriovenous Malformation Mimicking a Simple Para-Pelvic Cyst
Authors: Mishal Joseph , Leibovici Octavian , Bregman Lora , London Daniel , Yoffe Boris , Sherer Yaniv
Published: April 2003

The presenting symptoms of renal arteriovenous malformation are usually gross hematuria and hypertension. Herein we present an unusual case of a huge renal arteriovenous malformation without these signs, but with an ultrasound picture mimicking a simple para-pelvic cyst. Other imaging tests, including duplex ultrasound, computerized tomography and aortography, demonstrated the vascular lesion. We suggest that duplex ultrasound should accompany routine renal ultrasound in order not to miss such cases, especially when the physical examination suggests an intra-abdominal vascular lesion or bleeding.
A Case of Bladder Pheochromocytoma
Authors: Seki Narihito , Mukai Shoichiro , Gamachi Ayako , Migita Toshiro , Maeda Kohshiro , Ogata Nobuo
Published: April 2003

The clinical picture of bladder pheochromocytoma is usually typical; however, the diagnosis is occasionally delayed because of the rarity of this neoplasm. We report a case of unsuspected bladder pheochromocytoma in which the patient had a hypertensive episode during transurethral resection. A 67-year-old male presented with the chief complaint of painless macrohematuria. Cystoscopy revealed a submucosal tumor on the right lateral wall of the bladder. The tumor was operated on transurethrally, followed by partial cystectomy. The pathological diagnosis was pheochromocytoma, primarily occurring in the bladder. Treatment of this lesion requires a high degree of clinical suspicion based on the patient’s symptom complex in order to enable adequate preparation prior to surgical manipulation.
Unilateral Testicular Torsion: Evaluation of bcl-2, p-53 and PCNA Expression in Contralateral Testes
Authors: Sarıca Kemal , Bakır Kemal , Erbagci Ahmet , Yagcı Faruk , Uysal Okan , Uçak Ramazan
Published: April 2003

Objectives and Methods: The present study aims to evaluate the histologic as well as apoptotic changes indicated by PCNA, p-53 and bcl-2 expression in the contralateral testes after a period of unilateral testicular torsion of 4 h. Results: Regarding the histologic changes, while some significant alterations such as complete or incomplete spermatocytic arrest as well as sertoli cell only formation have to some extent been noted after the detorsion procedure, reasonably better preserved histology could be demonstrated following the orchiectomy procedure both in the early and late follow-up. Thus, the orchiectomy procedure was found to be limiting enough on the severity of the histologic changes in the contralateral testes after a certain period of time following the torsion procedure. On the other hand, however, in relation to the apoptotic events indicated by the three markers, while PCNA activity was found to be significantly different depending on the procedure performed (detorsion or orchiectomy), p-53 and bcl-2 positivity did not exhibit any difference in this aspect. Increased PCNA activity (especially after the detorsion procedure) together with marked positivity of p-53 both in the early and late follow-up indicated the increased cell turnover in the contralateral testes, which in turn may be accepted as a sign of increased apoptosis in these testes. In addition to these findings, bcl-2 expression has been found to be consistently negative in all specimens evaluated both in the early and late follow-up. Conclusion: Taking into account the strong inhibitory effect of bcl-2 during apoptotic events, these findings again support the likelihood of increased apoptosis in the contralateral testes.
Differential Expression of Cytokines and Cytokine Receptors in Renal Cell Carcinoma
Authors: Steiner T. , Junker U. , Salamon A. , Nuske K. , Schubert J.
Published: April 2003

Modulation of immunomechanisms by tumor cells can be caused by secretion of cytokines. In vitro data are usually gained in culture systems. It is debatable whether these systems are representative of the conditions inside the respective tumor tissues. Immunohistochemical studies of tumor tissue cryostats were compared with those in matched primary renal cell carcinoma tumor cell cultures. Results were correlated with histopathological characteristics and the in vitro cytotoxic effect of autologous tumor infiltrating lymphocytes (TILs). Expression of all studied cytokines and cytokine receptors could be shown in cryostats and cell cultures, but the detection pattern varied individually. The immunohistochemical results in cryostats were in good accordance with those in cell cultures. Expression of TGFβ1 both in cryostats and cell cultures significantly correlated with the lack of cytotoxic activity of autologous TILs. Representative data can be obtained in tumor culture systems of primary renal cell carcinoma. TGFβ1 secretion could play an important role in the interactions between tumor and cytotoxic cells.
Glycosaminoglycans: Urinary Excretion in Children with Myelomeningocele
Authors: Salvaggio E. , Antuzzi D. , Ferrara P. , Scanu M. , Pulitanò S. , Venuti L. , Tarquini E. , De Michele T. , Ricci R.
Published: April 2003

Background: The main consequences of neurogenic bladder dysfunction are renal damage related to high intravesical pressure, vesicoureteral reflux (VUR) and urinary tract infections (UTIs). Neurologic impairment, UTIs and VUR are known to be linked with a potential for renal scarring. Of paramount importance as predisposing conditions for UTIs in neurogenic bladder are poor bladder drainage and detrusor-sphincter dyssynergy which cause further abnormalities on the internal bladder surface and, consequently, a bladder wall rich in glycosaminoglycans (GAGs). Materials and Methods: The aim of this study is to investigate the correlation between GAG excretion and bladder wall degeneration in 43 patients affected by spina bifida (SB) and 40 healthy age-matched control children. Results: The amounts of GAGs excreted vary greatly in SB patients aged from 0 to 5 years, and values are comparable to those observed in normal controls. They are significantly higher in children over 5 years of age. Conclusion: The increased excretion of GAGs in older SB patients is an important parameter in the evaluation of the physiopathological condition of the bladder wall and hence may be considered a possible marker for monitoring the beginning of bladder damage.
Penile Metastasis Arising from Transitional Cell Carcinoma of the Urinary Bladder
Authors: Khan M.A. , Tao W. , Mathews P. , Potluri B.S.
Published: April 2003

Metastatic spread of transitional cell carcinoma of the bladder to the penis is very rare. We present 1 such case in a 63-year-old man that was treated by total penectomy and adjuvant systemic chemotherapy.
Bilateral Transection of the Vas deferens: An Unusual Trauma from a Cross Stab Injury of the Scrotum
Authors: Dorairajan L.N. , Kumar S. , Madhekar N.
Published: April 2003

An unusual case of division of both vas deferens in a patient with a cross stab injury to the root of scrotum is described. The management of this case in the emergency setting is discussed. The case illustrates the need to explore every case of penetrating trauma to the scrotum, even in the absence of active bleeding, to avoid missing such injuries. These injuries, although not life-threatening, can have a profound impact on the patient’s future fertility and this may only manifest several years after the injury.
Transitional Zone and Anterior Peripheral Zone of the Prostate
Authors: Mai Kien T. , Moazin Maher , Morash Christopher , Collins John P.
Published: April 2003

Introduction: Prognostically significant prostatic adenocarcinomas (PAC) may pose diagnostic problems if they were localized in the anterior peripheral zone (APZ) or transitional zone (TZ). Materials and Methods: 108 cases of PAC were reviewed along with serum PSA and TRUS biopsies. The PACs were divided into 22 TZ, 17 APZ and 69 posterior peripheral zone (PPZ) PACs according to the location of the main tumor mass in the TZ and anterior or posterior half of the peripheral zone in the radical prostatectomy (RP) specimens. Results: In comparison with PPZ PAC, TZ PAC had a higher cancer volume in RP specimens (4 ± 2.1 vs. 2.5 ± 1.7 cm3, p < 0.01), a higher serum PSA (16.5 ± 9.8 vs. 8.4 ± 4.5 µg/l, p < 0.001), a biopsy with a small cancer volume (3.8 ± 2.1 vs. 11.8 ± 9.4 mm, p < 0.005), and a lower Gleason’s score (4.8 ± 2.1 vs. 6.5 ± 1.7). APZ PAC was characterized by the cancer volume in RP and biopsy and PSA intermediate between those of TZ and PPZ PAC. Among 24 PACs with a total cancer core length of <3 mm, 19 cases were from the TZ and APZ groups and also had a higher cancer volume and PSA than those from the PPZ group (2.9 ± 1.8 vs. 1.5 ± 1.3 and 13.7 ± 8.3 vs. 9.6 ± 4 µg/l, respectively). Furthermore, there was a better correlation coefficient (r2) of tumor volume in the biopsy and RP for PPZ than for all zones PAC (r2 = 0.75 vs. 0.29). TZ and APZ carcinomas were associated with extension or satellite nodules of PAC in the PPZ that may be diagnosed with biopsies. These PACs were associated with positive anterior resection margin due to extracapsular extension of the carcinoma or intracapsular dissection in 6 and 5 cases respectively. Conclusions: TZ and APZ PACs accounted for the poor correlation between the tumor volume in the biopsy and the RP, and were associated with positive anterior resection margins. One core biopsy with a total cancer core length of <3 mm and PSA >10 µg/l are suspicious for TZ and APZ PCA in patients with undetectable tumors with DRE or TRUS. Clinically insignificant PACs tend to be associated with cancer core <3 mm and PSA <10 µg/l.
Prostatic Malacoplakia Associated with Prostatic Abscess: Diagnosis and Treatment
Authors: Arena F. , Fortunati C. , di Stefano C. , Peracchia G. , Cortellini P.
Published: April 2003

Prostatic malacoplakia associated with prostatic abscess is an extremely rare disease. We present a case of prostatic malacoplakia presenting as a prostatic and seminal vesicle abscess in a patient with diabetes. The diagnosis and management are discussed, and the literature is reviewed.
Divergent human and mouse orthologs of a novel gene (WBSCR15/Wbscr15) reside within the genomic interval commonly deleted in Williams syndrome
Authors: Doyle J.L. , DeSilva U. , Miller W. , Green E.D.
Published: April 2003

Williams syndrome (WS) is a contiguous gene deletion disorder resulting in complex and intriguing clinical features. Detailed molecular characterization studies of the genomic segment on human chromosome 7q11.23 commonly deleted in WS have uncovered numerous genes, each of which is being actively studied for its possible role in the etiology of the syndrome. Our efforts have focused on the comparative mapping and sequencing of the WS region in human and mouse. In previous studies, we uncovered important differences in the long-range organization of these human and mouse genomic regions; in particular, the notable absence of large duplicated blocks of DNA in mouse that are present in human. Aided by available genomic sequence data, we have used a combination of gene-prediction programs and cDNA isolation to identify the human and mouse orthologs of a novel gene (WBSCR15 and Wbscr15, respectively) residing within the genomic segment commonly deleted in WS. Unlike the flanking genes, which are closely related in human and mouse, WBSCR15 and Wbscr15 are strikingly different with respect to their cDNA and corresponding protein sequences as well as tissue-expression pattern. Neither theWBSCR15- nor Wbscr15-encoded amino acid sequence shows a statistically significant similarity to any characterized protein. These findings reveal another interesting evolutionary difference between the human and mouse WS regions and provide an additional candidate gene to evaluate with respect to its possible role in the pathogenesis of WS.
Isolation and initial characterization of the mouse Dnmt3l gene
Authors: Aapola U. , Lyle R. , Krohn K. , Antonarakis S.E. , Peterson P.
Published: April 2003

We have isolated and sequenced the mouse zinc finger gene, Dnmt3l (DNA cytosine-5-methyltransferase 3-like), on mouse chromosome 10, showing similarity to members of the DNMT3/Dnmt3 family. The Dnmt3l protein contains an ADD zinc finger, which Dnmt3l shares with other Dnmt3 family members and Atrx. RT-PCR analysis showed Dnmt3l expression in testis, thymus, ovary, and heart, as well as in 7-day, 15-day, and 17-day mouse embryos.
Expansion of repetitive DNA into cytogenetically visible elements
Authors: Serakıncı N. , Pedersen B. , Koch J.
Published: April 2003

Two cases of amplified repetitive elements accidentally identified in cancer samples are reported. In both cases, repeated DNA that is normally not visible by traditional chromosome banding had increased in amount to become cytogenetically visible. In one case, an addition to the short arm of chromosome 1 was originally diagnosed. However, upon molecular analysis the diagnosis could be corrected to an amplification of the D1Z2 repeat. In the second case, a strongly DAPI-positive band was visible at the top of the short arm of chromosome 22, and the original diagnosis was add(22). Staining for telomeric repeats revealed their presence inside the DAPI-positive element, thus confirming that the element in question was truly added to the end of the chromosome. Curiously, no telomeric repeats could be detected distal to the DAPI-positive element. The identity of the DAPI-positive element could not be established, as it was not stained by any of the specific probes applied, nor in a scanning hybridization with labeled Cot-1 DNA. It thus seems to represent an expansion from some lowly repetitive AT-rich DNA translocated to the tip of chromosome 22.
The origin of four squirrel monkey cell lines established by karyotype analysis
Authors: Scammell J.G. , Wright J.L. , Tuck-Muller C.M.
Published: April 2003

The squirrel monkey is a neotropical primate genus which is widely used in biomedical research but includes individual species and subspecies that respond differently to experimental perturbations. GTG-banding patterns of chromosomes 15 and 16, which are distinct among different squirrel monkey species and subspecies, were used to determine the origin of three lung fibroblast cell lines from squirrel monkeys of unknown genetic background (DPSO 114/74, SqMkLu/68, and 7603830) and to confirm the origin of a lymphoblast cell line (GSML) recently established from Guyanese squirrel monkey. DPSO 114/74 cells are from Peruvian squirrel monkey, SqMkLu/68 cells are Bolivian squirrel monkey, and 7603830 cells are from a Peruvian/Bolivian hybrid. Chromosome analysis of GSML cells confirmed that they are from Guyanese squirrel monkey.
Self-Regulation of Normative and Non-Normative Developmental Challenges1
Authors: Wrosch Carsten , Freund Alexandra M.
Published: April 2003

The article develops the argument that successful management of normatively less expected life events and transitions requires from the individual a greater degree of self-regulatory skills than the management of normative events. It is argued that, based on recent historical change, individuals have to master both normative and non-normative developmental demands. With regard to the mastery of non-normative developmental demands, the individual may have to play a more important and active role to compensate for a lack of social structuring and normative orientation. Based on a discussion of literature from the areas of life-span psychology, life-course sociology, and self-regulation, evidence for the importance of the individual in adaptive regulation of non-normative developmental challenges is presented.
Failure of Platelet Parameters and Biomarkers to Correlate Platelet Function to Severity and Etiology of Heart Failure in Patients Enrolled in the EPCOT Trial
Authors: Serebruany Victor L. , McKenzie Marcus E. , Meister Andrew F. , Fuzaylov Sergey Y. , Gurbel Paul A. , Atar Dan , Gattis Wendy A. , O’Connor Christopher M.
Published: April 2003

Data from small studies have suggested the presence of platelet abnormalities in patients with congestive heart failure (CHF). We sought to characterize the diagnostic utility of different platelet parameters and platelet-endothelial biomarkers in a random outpatient CHF population investigated in the EPCOT (‘Whole Blood Impedance Aggregometry for the Assessment of Platelet Function in Patients with Congestive Heart Failure’) Trial. Blood samples were obtained for measurement of platelet contractile force (PCF), whole blood aggregation, shear-induced closure time, expression of glycoprotein (GP) IIb/IIIa, and P-selectin in 100 consecutive patients with CHF. Substantial interindividual variability of platelet characteristics exists in patients with CHF. There were no statistically significant differences when patients were grouped according to incidence of vascular events, emergency revascularization needs, survival, or etiology of heart failure. Aspirin use did not affect instrument readings either. PCF correlates very poorly with whole blood aggregometry (r2 = 0.023), closure time (r2 = 0.028), platelet GP IIb/IIIa (r2 = 0.0028), and P-selectin (r2 = 0.002) expression. Furthermore, there was no correlation with brain natriuretic peptide concentrations, a marker of severity and prognosis in heart failure reflecting the neurohumoral status. Patients with heart failure enrolled in the EPCOT Trial exhibited a marginal, sometimes oppositely directed change in platelet function, challenging the diagnostic utility of these platelet parameters and biomarkers to serve as useful tools for the identification of platelet abnormalities, for predicting clinical outcomes, or for monitoring antiplatelet strategies in this population. The usefulness of these measurements for assessing platelets in the different clinical settings remains to be explored. Taken together, opposite to our expectations, major clinical characteristics of heart failure did not correlate well with the platelet characteristics investigated in this study.
Effects of Aspirin and Clopidogrel versus Oral Anticoagulation on Platelet Function and on Coagulation in Patients with Nonvalvular Atrial Fibrillation (CLAFIB)
Authors: Müller Iris , Massberg Steffen , Zierhut Wolfgang , Binz Christiane , Schuster Alexander , Rüdiger-von Hoch Silja , Braun Siegmund , Gawaz Meinrad
Published: April 2003

The aim of the study was to evaluate the effect of two antithrombotic therapies on platelet function and on coagulation in patients with nonvalvular atrial fibrillation (NVAF). Twenty patients with NVAF were treated with aspirin (300 mg/day) and clopidogrel (75 mg/day) for 2 weeks immediately followed by oral anticoagulation (target international normalized ratio 2.0–3.0). Parameters of platelet function and coagulation were evaluated before antithrombotic therapy, at the end of aspirin plus clopidogrel and during subsequent anticoagulation treatment. Aspirin plus clopidogrel significantly inhibited platelet aggregation, fibrinogen receptor activation and release of P-selectin and prolonged in vitro bleeding time (p < 0.01). Coagulation parameters (platelet-dependent thrombin generation, antithrombin III, thrombin-antithrombin III complex, prothrombin fragment 1 + 2) were not significantly affected. During the subsequent oral anticoagulation phase platelet function was not substantially reduced; however, coagulation parameters were significantly inhibited (p < 0.001). The results indicate that combined antiplatelet therapy is superior to aspirin monotherapy in inhibiting platelet function but does not seem to substantially modulate coagulation cascade in patients with NVAF.
The Evidence behind Inhibitor Treatment with Porcine Factor VIII
Authors: Lee Christine A.
Published: April 2003

Factor VIII auto- and alloantibodies neutralise porcine factor VIII to a lesser extent than factor VIII of human origin. The reduced reactivity of the porcine molecule, predominantly due to sequence variation in the A2 and C2 domains, has been the rationale for using porcine factor VIII to secure haemostasis for patients with factor VIII inhibitors. Porcine factor VIII has been shown to provide effective haemostatic control particularly for patients with intermediate inhibitor titres with limited porcine cross-reactivity. Small studies have indicated porcine factor VIII can be associated with desensitisation of some factor VIII inhibitor patients. Porcine factor VIII has been shown to produce mild platelet agglutination, an effect that may enhance its efficacy. Adverse reactions are dose-related and do not preclude safe and effective long-term home use for the subgroup of inhibitor patients with modest or absent anamnestic response. Efforts to secure source plasma free of viral markers, particularly porcine parvovirus, have limited the supply of this therapeutic product.
The Use of Recombinant Factor VIIa in Controlling Surgical Bleeding in Non-Haemophiliac Patients
Authors: Aldouri Maadh
Published: April 2003

Recombinant factor VIIa (rFVIIa, NovoSeven®) is effective and appears safe in the management of bleeding episodes and provision of surgical cover in haemophilia patients with inhibitors. Additionally, rFVIIa has been considered as a universal haemostatic agent, prompting its use in the management of severe uncontrolled surgical bleeding in patients without pre-existing coagulopathies. Recombinant FVIIa has been used in 5 patients (aged 2.5 to 73.0 years; median 48 years) with uncontrolled bleeding during or after open-heart surgery. Satisfactory haemostasis was achieved with a single dose or rFVIIa 30 µg/kg, that resulted in reduction of blood loss from a mean of 4,170 ml (650–8,000 ml) to 262.5 ml (220–334 ml). No significant adverse events were reported. Recombinant FVIIa was also successfully used in controlling post-surgical bleeding in two patients with Crohn’s disease, one patient with bleeding duodenal ulcer and another with false thoracic aneurysm. It was also effective in controlling bleeding post-splenectomy in a patient with chronic myeloid leukaemia, and following anterior exenteration in a patient with cervical carcinoma. A randomised study comparing the efficacy of a single perioperative dose of rFVIIa with placebo in patients undergoing transabdominal prostatectomy was conducted by Levi and colleagues [6]. An interim analysis showed a significant reduction in mean blood loss from 2,450 ± 350 ml to 1,400 ± 190 ml between placebo and rFVIIa groups respectively (p = 0.007). Among trauma patients, Kenet et al. reported success in treating uncontrolled bleeding from a gun-shot wound to the inferior vena cava, using two doses of rFVIIa 60 µg/kg [7]. This treatment has subsequently been used in 6 surgical patients with uncontrolled bleeding and in 7 cases of traumatic bleeding, with remarkable results. In conclusion, rFVIIa appears to be effective and safe in the management of uncontrolled surgical and traumatic haemorrhage in patients not known to have inherited coagulopathy.
Progesterone Induces Dephosphorylation and Inactivation of Tyrosine Hydroxylase in Rat Hypothalamic Dopaminergic Neurons
Authors: Arbogast Lydia A. , Voogt James L.
Published: April 2003

After in vivo treatment, progesterone initially decreases tyrosine hydroxylase (TH) activity in the TIDA neurons, but subsequently increases TH activity with prolonged treatment. In order to explore the cellular mechanism for progesterone’s effect, this study examined the acute inhibitory action of progesterone on TH activity in rat fetal hypothalamic dopaminergic neurons in vitro. Progesterone caused a rapid decrease in TH activity within 1 h, which was sustained for at least 6 h. However, the dopaminergic cells became refractory to progesterone with continuous treatment for 12 h to 10 days. Progesterone (10–100 nM) treatment suppressed TH activity in a concentration-dependent manner. The inhibitory effect of progesterone was dependent on prior exposure to estradiol. Whereas progesterone decreased TH activity, A ring-reduced metabolites of progesterone did not alter TH activity, suggesting that the response was specific to progesterone. Progesterone decreased radiolabeled phosphate incorporation into TH protein. Okadaic acid, a phosphoprotein phosphatase inhibitor, prevented the progesterone-induced suppression of TH activity and phosphate incorporation into TH, implicating dephosphorylation of TH as the cellular mechanism. In contrast, neither TH mRNA levels nor TH protein content was altered after 1 or 12 h of progesterone treatment. Progesterone decreased TH activity after pretreatment of the hypothalamic cells for 2 or 24 h with actinomycin D, an RNA synthesis inhibitor, suggesting that increased transcription does not mediate the effect. These data indicate that the acute progesterone-induced decline in TH activity is caused by dephosphorylation of TH.
Vaginocervical Stimulation Releases Oxytocin within the Spinal Cord in Rats
Authors: Sansone Giorgio R. , Gerdes Carolyn A. , Steinman Judith L. , Winslow James T. , Ottenweller John E. , Komisaruk Barry R. , Insel Thomas R.
Published: April 2003

Vaginocervical stimulation (VS) significantly elevated the concentration of oxytocin (OT) in spinal cord superfusates of 8 intact urethane-anesthetized rats measured 10–15 min after VS (median [interquartile range]: 1.7 [1.00–3.37] pg/ml) compared to that measured 10–15 min before VS (1.1 [1.01–1.40] pg/ml). When VS was administered once (n = 8), it produced a 55% increase over baseline values; when administered a second time 45 min later (n = 6), it produced only a 22% increase over pre-VS values. The effects of estrogen on the VS-induced release of OT were then investigated using ovariectomized rats that were treated either with estradiol benzoate (EB; 10 µg/100 g bw) (n = 6) or with an oil vehicle (n = 6) subcutaneously for 3 days. The EB treatment significantly elevated the basal levels of OT released into spinal cord superfusates above vehicle control levels. Within 5–10 min after the onset of VS, OT concentrations in the superfusates were significantly higher in EB-treated than in vehicle-treated rats. The vehicle-treated rats did not show a significant elevation in OT concentration following VS. To rule out the possibility that the posterior pituitary gland was the source of this OT, the effect of hypophysectomy (HYPOX) was assessed on the VS-induced release of OT into spinal cord superfusates and plasma. The concentration of OT in spinal cord superfusates of both the HYPOX (n = 5) and intact rats (n = 6) increased significantly from 5.8 [4.4–6.5] pg/ml pre-VS to 7.9 [6.7–10.3] pg/ml immediately after VS, and from 4.4 [3.8–5] pg/ml pre-VS to 5.1 [4.6–5.7] pg/ml immediately after VS, respectively. There was no significant difference in baseline levels of OT in cerebrospinal fluid between the two groups. By contrast, plasma OT levels, while significantly elevated in response to VS from 3.42 [2.9–5.34] pg/ml baseline to 7.25 [5.33–15.77] pg/ml in the intact group, failed to respond significantly to VS in the HYPOX group (n = 5). The present findings provide evidence of a direct estrogen-dependent release of OT within the spinal cord in response to VS, presumably via descending oxytocinergic neurons.
The Impact of Malnutrition on Kidney Function
Authors: Benabe Julio E. , Martinez-Maldonado Manuel
Published: April 2003

Malnutrition is the most common cause of mortality in the world. It affects underdeveloped as well as industrialized societies, in the latter demonstrating a prevalence in hospitalized patients of between 30 and 50%. Although the prevalence has decreased in recent studies, the problem is still significant among a selected group of patients. The clinical manifestations of malnutrition may be evident on physical examination but alterations in renal function may not show up at the initial exam. Clinical and experimental models of protein-calorie malnutrition have confirmed significant alterations in renal hemodynamics, renal concentration capacity, and renal acid excretion. Children and adults with malnutrition have been shown to have a decreased glomerular filtration rate and renal plasma flow (RPF), as well as a lowered capacity to concentrate the urine and excrete an acid load. Moreover, clinical and experimental models of protein-calorie malnutrition have unravelled the roles of the renin-angiotensin system, renal prostaglandins, and urea production in the renal function changes associated with malnutrition. We have reviewed the most pertinent and recent studies from our and other laboratories which have improved our understanding of renal functional alterations in malnutrition.
TGF-β Receptors and Signalling Mechanisms
Authors: Wrana Jeffrey L.
Published: April 2003

Transforming growth factor-β (TGF-β) is the founding member of a large superfamily of related growth and differentiation factors that include bone morphogenetic proteins and activins. TGF-β signals through two related transmembrane ser/thr kinase receptors, the type I and type II receptors. Signalling is initiated when the ligand binds to the type II receptor which is followed by recruitment of the type I receptor into a heteromeric complex. Within the complex the type II receptor transphosphorylates and activates the type I receptor kinase which targets downstream signalling components of the pathway. Proteins related to the Drosophila gene Mothers against dpp (MAD) are critical downstream substrates of the type I kinase. The vertebrate members of the MAD-related family, termed Smad 2 and Smad3, interact specifically with the TGF-β type I receptor and are phosphorylated on the last two serines of a conserved C-terminal SSXS motif. This phosphorylation induces association between these receptor-regulated Smads and Smad4 followed by translocation of the heteromeric complex to the nucleus. In the nucleus, heteromeric complexes of Smads can interact with DNA and with specific DNA binding transcription factors to elicit gene responses to TGF-β. Thus TGF-β signalling involves a direct pathway from the cell surface receptors to the nucleus. Recently, a novel mechanism to negatively regulate TGF-β signalling was described that involves another class of MADR proteins. These anti-MADR proteins potently inhibit TGF-β signalling by functioning as direct antagonists of the TGF-β receptor type I kinase domain.
Link between Angiotensin II and TGF-β in the Kidney
Authors: Wolf Gunter
Published: April 2003

Glomerulosclerosis and tubulointerstitial fibrosis are common morphological correlates of many end-stage kidneys. There is ample evidence that transforming growth factor-β (TGF-β) plays a major role in these alterations by directly stimulating synthesis of many extracellular matrix components and reducing collagenase production, finally leading to renal scarring. Although many factors may induce TGF-β expression in the kidney, one very interesting aspect is the link between angiotensin II (ANG II) and TGF-β. Originating from observations in vascular smooth muscle cells, there are now several additional studies showing that ANG II stimulates TGF-β expression in the kidney. Although cell culture studies have convincingly demonstrated that the vasoactive peptide directly stimulates transcription as well as bioactivation of TGF-β, the in vivo evidence is more indirect. Nevertheless, there are several pathophysiological situations including unilateral ureteral obstruction, chronic cyclosporin A nephrotoxicity, various models of hypertension, and probably diabetic nephropathy in which ANG II-mediated TGF-β induction has been demonstrated to play an important role in the progression of the disease. The fascinating aspect of this relationship between ANG II and TGF-β is the fact that hemodynamic changes as well as structural changes are linked together generating a unifying model of progression of chronic renal failure with ANG II as the key player. Angiotensin-converting enzyme (ACE) inhibitor and the more recently introduced AT1-receptor blocker may be potential drugs to interfere with this ANG II-mediated TGF-β expression. Therefore, these drugs should not only be considered as antihypertensive medications, but should rather be viewed as renoprotective substances influencing renal remodeling by preventing local TGF-β expression.
TGF-β and Regulation ofInterstitial Nephritis
Authors: Frishberg Yaacov , Kelly Carolyn J.
Published: April 2003

TGF-β1 has been implicated as a profibrotic growth factor in the bulk of published experimental work regarding the actions of this cytokine in kidney disease. Such investigations have spanned a methodologic spectrum from in vivo analyses to cell culture work with purified growth factors and analyses of gene expression. Important correlative work using clinical specimens has established the presence of augmented TGF-β expression in renal diseases characterized by excessive sclerosis or fibrosis. While in the aggregate this information supports a compelling argument in favor of TGF-β having a predominant effect to accelerate progressive renal failure, the cytokine clearly also demonstrates effects which would tend to abrogate renal injury. We provide a summary of published and new experimental data outlining immunosuppressive and ‘renal-protective’ actions of TGF-β1.
Potential Role of TGF-β in Diabetic Nephropathy
Authors: Hoffman Brenda B. , Sharma Kumar , Ziyadeh Fuad N.
Published: April 2003

Renal injury in diabetes mellitus is a major cause of morbidity and mortality. Several manifestations of diabetic nephropathy may be a consequence of altered production and/or response to cytokines or growth factors. Transforming growth factor-β (TGF-β) is one such factor because it promotes renal cell hypertrophy and regulates the production of extracellular matrix molecules. In addition, high ambient glucose increases TGF-β1 mRNA and protein level in cultured proximal tubular cells and glomerular epithelial and mesangial cells. Neutralizing anti-TGF-β antibodies or antisense TGF-β1 oligodeoxynucleotides prevents the hypertrophic effects of high glucose and the stimulation of matrix synthesis in renal cells. Several reports have described overexpression of TGF-β in the glomeruli and tubulointerstitium of experimental and human diabetes mellitus. We recently provided evidence that the kidney in diabetic patients displays net renal production of immunoreactive TGF-β1, whereas there is net renal extraction in nondiabetic subjects. We also demonstrated that short-term treatment of streptozotocin-diabetic mice with neutralizing monoclonal antibody directed against TGF-β significantly reduces kidney weight and glomerular hypertrophy, and attenuates the increase in extracellular matrix mRNA levels. The factors that mediate increased renal TGF-β activity involve hyperglycemia per se and the intermediary action of other potent mediators such as angiotensin II, thromboxane, endothelins, and platelet-derived growth factor.
High-Glucose Media Enhance the Responsiveness of Tubular Cells to Growth Promoters: Effect on Lysosomal Cathepsins and Protein Degradation
Authors: Schenk Oliver , Ling Hong , Šebeková Katarina , Vamvakas Spiros , Heidland August
Published: April 2003

Nephromegaly is a prominent feature of diabetic nephropathy and predominantly reflects increased renal tubule mass, mostly due to hypertrophy. To elucidate pathogenetic factors involved, we studied the effects of high glucose (HG) alone, and in combination with hormones/growth promoters: angiotensin II (10–7 M); parathyroid hormone (10–7 M); insulin-like growth factor-1 (10–7 M), or transforming growth factor-β1 (TGF-β1, 10 ng/ml) in a renal cell line (LLC-PK1) with many characteristics of the proximal tubule. Activities of lysosomal cathepsins (B, L+B and H) and the protein turnover were investigated. Exposure to HG (25 mM) for up to 48 h increased cellular protein content, due to enhanced protein synthesis, while protein degradation rate and cathepsin activities tended to lower values. Hyperosmotic mechanisms of glucose action were excluded, since these effects were not induced by mannitol. In normoglycemic conditions only TGF-β1 decreased cathepsin activities and protein degradation rate significantly. However, in HG media all applied hormones/growth factors significantly lowered the protein degradation rate, as well as lysosomal cathepsin activities. The enhanced responsiveness could contribute to the impaired protein turnover, with consequent hypertrophy of the tubulointerstitium in diabetic nephropathy.
Inhibition of Protein Synthesis by Acid in L6 Skeletal Muscle Cells: Analogies with the Acute Starvation Response
Authors: Bevington Alan , Poulter Chris , Brown Jeremy , Walls John
Published: April 2003

Impaired protein synthesis (PS) occurs in skeletal muscle during acute starvation. Even though it is well established that uraemic metabolic acidosis (MA) stimulates protein degradation (PD) and is a major contributor to skeletal muscle wasting in chronic renal failure, the accompanying effects of MA on PS are much less clear. Previous work has shown that, in cultured L6 skeletal muscle cells, PD and leucine oxidation are stimulated by acid. The aim of the present study was to determine whether acid (like acute starvation) can also inhibit PS. PS (14C-phenylalanine incorporation) was measured in L6 cells in MEM + 2% serum at acid pH (7.1) or control pH (7.5). After 24 h, acid inhibited PS (7.7 ± 0.2 vs. 8.9 ± 0.1 nmol Phe/4 h/35-mm culture well in controls, p = 0.01) and this was maintained at 72 h. In vitro this could arise because acid only inhibits the rapid PS occurring in dividing cells. However, when division was abolished with 10–5 mol/l cytosine arabinoside, PS inhibition by acid still occurred (6.9 ± 0.1 vs. 8.3 ± 0.2 at control pH, p < 0.05). Acid also had no effect on the specific radioactivity of cellular phenylalanine, suggesting that the impaired PS was not a consequence of inadequate labelling of this pool. Elevated PD and impaired PS together led to loss of 7% of the total protein in only 28 h (–21 ± 3 µg/well, p = 0.004). This combination of impaired PS with increased PD and increased leucine oxidation in response to acid resembles the response of skeletal muscle to acute starvation. These superficial similarities between the starvation state and MA suggest that fundamental metabolic signals may occur which are common to both states.
Normal Vitamin D Receptor Concentration and Responsiveness to 1,25-Dihydroxyvitamin D3 in Skin Fibroblasts from Patients with Absorptive Hypercalciuria
Authors: Zerwekh Joseph E. , Reed Bernice Y. , Heller Howard J. , González Gilberto B. , Haussler Mark R. , Pak Charles Y.C.
Published: April 2003

To evaluate whether there is an increase in vitamin D receptor (VDR) concentration which could raise intestinal calcium absorption in absorptive hypercalciuric (AH) patients and promote hypercalciuria, we measured VDR concentration and VDR mRNA levels in skin fibroblasts from 16 patients with AH and 17 age-matched normal subjects before and following a 16-hour incubation in the presence of 10–8 M 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. There were no significant differences in VDR concentration between normal subjects and AH patients in the basal state (30 ± 11 vs. 30 ± 15 ng/mg protein, respectively) or following 1,25(OH)2D3-mediated upregulation (43 ± 18 vs. 42 ± 16 ng/mg protein) as measured by immunoblot methodology. Analysis of VDR mRNA/β-actin mRNA ratios demonstrated no significant differences between normal subjects and AH patients prior to (2.1 ± 1.7 vs. 1.8 ± 2.4) or following (2.7 ± 2.8 vs. 1.9 ± 1.8) 1,25(OH)2D3 exposure. As a measure of VDR bioactivity, we quantitated 1,25(OH)2D3-mediated induction of 25-hydroxyvitamin D3-24-hydroxylase. Again, no significant differences were observed between normal subjects and all patients (2.1 ± 1.6 vs. 1.9 ± 1.6 pmol/mg/30 min, respectively). These findings indicate that there is neither an increase in VDR concentration in skin fibroblasts, a recognized vitamin D responsive cell, nor increased sensitivity to upregulation of VDR numbers by 1,25(OH)2D3 in patients with AH. This suggests an alternative cause of intestinal hyperabsorption of calcium in AH other than alteration of the VDR number.
Effect of Diuretics on Sodium and Chloride Permeability in the Rat Papillary Collecting Duct
Authors: Ray Cheryl , Carney Shane , Gillies Allistair
Published: April 2003

While in vivo data suggests that diuretics such as furosemide and hydrochlorothiazide alter inner medulla collecting duct (IMCD) cell electrolyte transport, this has not been confirmed by in vivo studies nor have the mechanisms been evaluated. This study evaluated the direct effect of these diuretics as well as amiloride on sodium and chloride unidirectional permeability in the isolated perfused rat IMCD. In the absence of diuretics, the permeability of sodium was lower than that of chloride (0.63 ± 0.05 compared with 0.83 ± 0.08 µm/s), although both were relatively impermeable when compared to water. Furosemide (10–4) and hydrochlorothiazide (10–3) both increased the diffusional permeability of chloride by approximately 30% (0.80 ± 0.06 to 1.04 ± 0.09 µm/s, p < 0.01, and 0.74 ± 0.09 to 0.98 ± 0.10 µm/s, p < 0.02, respectively). However, sodium permeability was unaltered. Inhibition of Na+, K+-ATPase by ouabain or cooling (4°C) inhibited basal sodium but not chloride permeability while a maximal antidiuretic AVP concentration did not alter sodium or chloride permeability. However, increasing the lumen and bath sodium chloride concentration from 150 to 300 and 600 mM significantly increased both sodium and particularly chloride conductance. In contrast, amiloride (10–4) significantly reduced both sodium and chloride permeability. These studies support a direct effect of furosemide and hydrochlorothiazide on the IMCD and suggest that their in vivo effect is primarily mediated by facilitating the passive movement of chloride into the lumen via a favourable electrochemical gradient. These results also demonstrate that amiloride inhibits both sodium and chloride unidirectional permeability by mechanisms separate to that of the sulphonamide-related diuretics.