bluuebunny/crossref_metadata_2025 huggingface dataset:
Methylenetetrahydrofolate Reductase C677T Genotype and Venous Thromboembolic Disease
Authors: Couturaud F. , Oger E. , Abalain J.H. , Chenu E. , Guias B. , Floch H.H. , Mercier B. , Mottier D. , Leroyer C.
Published: April 2003

Background: Many studies have suggested an increased risk of venous thromboembolism (VTE) in patients with mild hyperhomocysteinemia. The C677T mutation in the MTHFR gene has recently been described as a cause of mild hyperhomocysteinemia.Objectives: To investigate the potential of the C677T mutation in the MTHFR gene in its homozygous state as a risk factor for VTE. Methods: Case-control study design. The presence of the mutation was determined in all consecutive patients referred from July 1994 to September 1997 and in whom the diagnosis was duly confirmed. Analysis was carried out in a subgroup of VTE patients free from both acquired and genetic risk factors (factor-V mutation and/or prothrombin gene mutation). A control group consisted of 105 volunteer blood donors. Results: In the 366 patients with a confirmed VTE, 253 presented acquired risk factors and 58 were carriers of the factor-V Leiden mutation and/or G20210A mutation of the prothrombin gene. In the remaining 55 patients, VTE was considered as ’unexplained’, and the frequency of the C677T mutation MTHFR was 21.8% in its homozygous state and 34.5% in its heterozygous state. In the control group, 9.5% were found homozygous and 34.3% heterozygous. The odds ratio for having VTE in the presence of the mutation in its homozygous state was 2.9 (95% CI 1.0–8.6). Conclusion: This study suggests that the homozygous C677T mutation in the MTHFR gene might be a risk factor of VTE in patients with spontaneous events and without other common genetic risk factors.
Effects of N-Acetylcysteine and Ambroxol on the Production of IL-12 and IL-10 in Human Alveolar Macrophages
Authors: Aihara Masayuki , Dobashi Kunio , Akiyama Masato , Naruse Ichiro , Nakazawa Tsugio , Mori Masatomo
Published: April 2003

Background: N-acetylcysteine (NAC) and ambroxol (AMB) have recently been proposed as possible therapeutic agents in the treatment of pulmonary disorders. IL-12 plays an important role in host resistance to infection and the development of Th-1 cells. In contrast, IL-10 is involved in anti-inflammatory and immunoregulatory mechanisms. Objective: We investigated the effects of NAC and AMB on secretions of IL-12 and IL-10 from human alveolar macrophages. Methods: Alveolar macrophages were obtained from 7 healthy nonsmokers by bronchoalveolar lavage. The cells were first incubated with either NAC or AMB for 2 h and then cultured in lipopolysaccharide (LPS) solution for 24 h. IL-12 and IL-10 secretions were measured by ELISA. Result: Both NAC and AMB enhanced LPS-induced secretion of IL-12. NAC also enhanced LPS-induced IL-10 secretion, while AMB did not. The ratio IL-12/IL-10 secretion was increased by AMB, but NAC did not affect it. Conclusions: The results suggest that NAC enhances inflammatory and immune responses and prevents excessive responses reciprocally, through keeping local balance of IL-12 and IL-10 production in alveolar macrophages at inflammatory sites of bacterial pneumonia. AMB appears to strengthen inflammatory responses and cell-mediated immunity, facilitating the development of Th-1 cells, through shifting the local balance to IL-12 dominance.
Delivery of Fenoterol via Respimat®, a Novel ‘Soft Mist’ Inhaler
Authors: van Noord Jan A. , Smeets Joseph J. , Creemers Jacques P.H.M. , Greefhorst Louis P.M. , Dewberry Helen , Cornelissen Piet J.G.
Published: April 2003

Background: The phase-out of chlorofluorocarbons (CFCs) for metered dose inhalers (MDIs) has prompted the development of alternative propellants and the design of propellant-free devices for inhalation therapy. Objective: This study was carried out to determine the dose of fenoterol inhaled from Respimat® (RMT), a new propellant-free soft mist inhaler, which is equivalent in terms of efficacy and safety to 1 puff of either 100 or 200 µg fenoterol inhaled from a conventional CFC-MDI (Berotec®). Methods: Sixty-two asthmatic patients (35 male, 27 female) with a mean baseline FEV1 of 1.7 liters, corresponding to 55% of the predicted normal value, were randomized at two study centers to 4 of a total of 8 possible treatments: placebo; 12.5, 25, 50, 100, or 200 µg fenoterol via RMT, and 100 or 200 µg fenoterol delivered via the MDI. Results: Fifty-nine patients completed the study as planned. Results of the therapeutic equivalence test for the primary endpoint, average FEV1 (AUC0–6)/6 and for the secondary endpoint, peak FEV1, showed that the 12.5- and 25-µg fenoterol doses administered via RMT were equivalent to the 100 µg fenoterol dose from the MDI. The 50-, 100- and 200-µg fenoterol doses delivered by RMT did not meet the criterion for therapeutic equivalence with the 100-µg dose from the MDI, and if tested for a difference would have been significantly different in favor of RMT. All 5 RMT fenoterol doses were therapeutically equivalent to the MDI 200-µg fenoterol dose. Headache, reported by 4 patients on test days and 2 patients between test days in those randomized to RMT, was the most common adverse event, but the active treatments were generally well tolerated with no dose-dependent increases in incidence or severity of adverse events observed. Conclusions: The results from the study suggest that safe and efficacious bronchodilation can be obtained from single-dose fenoterol administered via RMT. Use of lower absolute doses to obtain a clinically significant improvement in pulmonary function may be possible because of the increased lung deposition achievable with the novel soft mist inhaler.
Adult Croup: A Rare but More Severe Condition
Authors: Woo Patrick C.Y. , Young Karl , Tsang Kenneth W.T. , Ooi Clara G.C. , Peiris Malik , Yuen Kwok-yung
Published: April 2003

We report the first adult patient with virologically confirmed croup caused by parainfluenza virus type 3 and review 10 cases of adult croup described in the English-language literature. Circumstantial evidence of viral infection was present in only 1 other case, in which there was a rise in antibody titer against influenza B virus. Ten patients (91%) required intensive care support. None of the 11 patients died. A comparison was also made between the 11 adults with croup and 43 children hospitalized with severe croup described in a representative paper published in 1984. Adult croup represents an apparently more severe disease entity than pediatric croup.
Are COPD Patients with Nocturnal REM Sleep-Related Desaturations More Prone to Developing Chronic Respiratory Failure Requiring Long-Term Oxygen Therapy?
Authors: Sergi Margherita , Rizzi Maurizio , Andreoli Arnaldo , Pecis Marica , Bruschi Claudio , Fanfulla Francesco
Published: April 2003

Background: Nocturnal oxygen desaturations (NOD), especially during REM sleep, have been described in patients with COPD. However, the role of NOD in the evolution of COPD to chronic respiratory failure has not been well studied. Objective: The aim of our study was to evaluate whether NOD is a risk factor for the development of chronic respiratory failure in COPD patients. Methods: We studied 34 consecutive COPD patients with a stable daytime PaO2 >60 mm Hg over a period of 42 months. We classified patients as desaturators (NOD) when episodic desaturations were found mainly during REM sleep, independently of baseline SaO2 values. Results: At enrolment 19 patients (55.8%) had NOD. Over the follow-up period, 10 patients (29.4%) were included in a long-term oxygen therapy (LTOT) programme (9 were desaturators). The LTOT was initiated a median time of 22 ± 6.8 months after enrolment. Patients who were subsequently prescribed LTOT had lower values of FEV1 at enrolment, with a higher degree of NOD and PaCO2. Stable respiratory failure developed earlier in patients with NOD: the two enrolment curves for LTOT differed significantly (log-rank test 2.56, p = 0.005). PaCO2, NOD and FEV1 were statistically significantly associated, both in univariate and multivariate Cox proportional hazards analyses, with an increased risk of entering a LTOT programme. Conclusions: We conclude that NOD may represent an independent risk factor for the development of chronic respiratory failure in COPD patients with daytime PaO2 >60 mm Hg. A larger study is needed to confirm the role of NOD in the natural history of COPD and subsequently to identify the most appropriate therapeutic approach.
Late-Onset Congenital Cystic Adenomatoid Malformation of the Lung
Authors: Luján Manel , Bosque Montserrat , Mirapeix Rosa M. , Marco M. Teresa , Asensio Oscar , Domingo Christian
Published: April 2003

Background: Congenital cystic adenomatoid malformation of the lung (CCAM) is an embryonic developmental anomaly of an unknown etiology usually diagnosed antenatally by imaging techniques. A minority of cases may not be identified by prenatal imaging techniques and may go unnoticed for the first 6 months of their extrauterine life. Due to its rarity, physicians are unlikely to suspect the condition. Objectives: To highlight the embryology, clinical symptomatology, diagnostic procedures, therapeutic approach and clinical follow-up of a series of 12 patients with late-onset CCAM. Methods: An observational study which offers the description of the clinical presentation, diagnostic methods, treatment and follow-up of 12 patients with late-onset CCAM. Setting: A 600-bed teaching hospital in a reference area of 350,000 inhabitants. Patients: 12 patients from 1983 to 1999. Results: Twelve diagnosed cases of late-onset CCAM. Mean age at diagnosis: 6.7 years (range: 6 months to 23 years). Clinical presentation: 9 out of 12 (75%) with repeated lung infections, 2 out of 12 (16%) chance finding, and 1 case (8%) with pneumothorax. On pathological examination, 7 were found to be CCAM type I and 4 CCAM type II according to Stocker’s classification; 1 patient is currently awaiting surgery. The diagnostic method of choice nowadays is a computed tomography (CT) scan performed in the 7 more recent cases; in the former 5 cases an isotopic lung scan was done (and in 2 of them a bronchography was also performed). Treatment: 11 patients were operated: 8 lobectomies, 2 segmentectomies and 1 localized resection. Mean follow-up: 8 years (range: 6 months to 16 years). Complications: One reintervention due to a reappearance of the lesion in the patient who underwent localized resection of the CCAM. No cases of malignancy were found. Conclusions: Late-onset CCAM is an infrequent illness which requires a high level of clinical suspicion. It usually presents in the form of repeated infections. The most frequent pathological forms are type I and II (Stocker). The diagnostic method of choice is the CT scan. The recommended treatment is radical surgery of the lesion once diagnosis has been established. Malignancy and relapses are very infrequent when radical surgery is not postponed.
EEMCO Guidance to the in vivo Assessment of Tensile Functional Properties of the Skin
Authors: Rodrigues Luis
Published: April 2003

Tensile functions of the skin and subcutaneous tissues contribute to the appearance of the aged and photodamaged skin and to the effects of various other pathophysiological processes. The assessment of tensile functions of skin can be performed by distinct approaches mainly characterized by the orientation and magnitude of the imposed stress and strain over time. Testing methods are basically grouped into five major classes which include tensile, torsional, indentation, impact and elevation modes. Computed tensile variables are reproducible when the experimental procedure occurs under fully controlled conditions. Consistent and relevant information is yielded when the limitations and pitfalls typical for each test method are taken into consideration.
Distribution of Hydrolytic Activity Catalyzes the Biotransformation of Prednisolone 21-Acetate in Human Skin
Authors: Hikima Tomohiro , Maibach Howard I.
Published: April 2003

We investigated the distribution of hydrolytic enzymes which metabolize prednisolone 21-acetate (PNA) to prednisolone (PN) in human skin. Km (Michaelis-Menten constant) and Vmax (maximum rate) of hydrolytic enzyme in human skin was 25.1 µM and 0.46 nmol/min/mg protein, respectively. Specific activities of hydrolysis in dermis and epidermis were similar and, in consideration to their thickness, hydrolytic activity in epidermis was 12.1 times higher than in dermis. Moreover, the highest amount of metabolite (PN) was found at 80–120 µm from the skin surface by skin slicing. Therefore, hydrolytic activity which metabolized PNA was distributed in epidermis, especially in the basement membrane area; epidermis borders dermis in this area and the papillary plexus is reached just beneath the dermal papillae. These results suggest that the distribution of hydrolytic activity in human skin may prevent certain substances from entering the systemic circulation in their unhydrolyzed form.
Metabolism of Prednisolone 21-Acetate in Hairless Mouse Skin
Authors: Hikima Tomohiro , Ohno Yasuo , Maibach Howard I.
Published: April 2003

We investigated the hydrolytic activity of prednisolone 21-acetate (PNA) to prednisolone (PN) in an enzyme solution composed of esterase and skin homogenates from hairless mice. The values of the Michaelis-Menten constant obtained from hairless mouse skin and esterase solution were 14.2 and 10.2 µM, respectively; conversely, the value of the maximum rate from hairless mouse and esterase solution were 0.67 and 1,886 nmol/min/mg protein, respectively. To examine the effect of enzymatic inhibitors on hydrolytic activity, five enzymatic inhibitors, 3,4-dichloroisocoumarine (DCIC), N-tosyl-L-phenylalanine chloromethyl ketone, iodoacetamide, p-hydroxymercuribenzoic acid (HMBA) and sodium dodecylsulfate, were added to the enzyme solution. Sixty-eight percent of hydrolytic activity in skin homogenates were not deactivated by DCIC which completely inhibited the enzymatic activity in esterase solution. We also studied the localization of hydrolytic enzyme with a subcellular faction: 66 and 11% of specific activity existed in microsome (Ms) and cytosol (Cp) fractions, indicating that the hydrolytic activity of PNA was included mainly in the Ms fraction. Hydrolytic activity in Ms and Cp fractions was different from sensitivity to enzymatic inhibitor; DCIC inhibited activity in the Ms fraction and, on the other hand, HMBA inhibited it in the Cp fraction. Therefore, Ms and Cp fractions in skin homogenates include a different esterase isoform and the metabolism of PNA to PN in hairless mouse skin is mediated by these isoforms.
Value of Quantitative Photoplethysmography for Functional Vascular Diagnostics
Authors: Schultz-Ehrenburg Ulrich , Blazek Vladimir
Published: April 2003

The paper presents recent advances in photoplethysmography (PPG) and the role played by PPG in the noninvasive diagnostics of venous and arterial disease. The technical principles of the new self-calibrating photoplethysmographs are explained. These units allow a quantitative evaluation of all measurement data (e.g. time values, amplitudes, flow rates, blood volume kinetics) and hence a precise analysis of both venous and arterial hemodynamics. In combination with appropriate tests (muscle pump test, vein occlusion test, noninvasive venous pressure test, arterial pulse and pressure test), they are suitable for diagnosing and assessing the severity of vascular disease and monitoring its course and the efficacy of therapy. Now that PPG has gained worldwide acceptance as a routine diagnostic technique for venous disease, its spectrum should be expanded to the arterial side as well.
The Role of Follicular Penetration
Authors: Schaefer H. , Lademann J.
Published: April 2003

Textbooks describe percutaneous absorption through normal skin as diffusion through the stratum corneum barrier, i.e., in a simplified view, as a physiochemical interaction of a penetrating compound with the horizontal multilayer lipid structures and the underlying corneocytes within the horny layer. Hair follicles and sweat glands are vertical structures and are considered of little importance since ‘they represent a small and insignificant percentage of the skin surface’. To this integral view, a differentiated hypothesis is proposed: the more perfect the barrier function of the horny layer, the greater the relative role of the imperfections within the skin as a defence organ. Three kinds of imperfections should be taken into account: (1) the follicular apparatus of hair follicles; (2) the sweat glands, and (3) microlesions in the interfollicular horny layer. Each of these can theoretically represent a vertical pathway for percutaneous absorption, i.e. a ‘shunt’.
Modulation of the Barrier Function of the Skin
Authors: Hadgraft J.
Published: April 2003

Transport of xenobiotics across the stratum corneum, the rate-controlling membrane of skin, is slow and the mechanism appears complex. However, the basic transfer is controlled by fundamental physicochemical concepts, the predominant of which are partition (K), diffusion (D) and solubility (Cs). In order to change the rate of penetration it is therefore clear that it is these parameters that should be targeted. In most instances enhancement strategies are adopted to improve D, K or Cs, however there are instances in which permeation reduction may be beneficial. Examples include the topical application of sunscreens or insect repellents. This publication demonstrates the way in which modulation effects can be assessed and the difficulties involved in determining which of the physicochemical parameter(s) are being affected. If the formulation influences more than one, synergism can often be seen. Advances in computer modelling have provided an insight into the mechanisms of action of some of the chemical enhancers at a molecular level. Enhanced skin absorption has been reported for the delivery of macromolecules such as insulin (associated with transfersomes) or DNA (as a DOTAP complex). The barrier property of the skin must be modulated for this to be achieved. However the precise mechanisms of action have not been elucidated.
The Effectiveness and Factors Related to Treatment Results of Gamma Knife Radiosurgery for Meningiomas
Authors: Pan D.H.C. , Guo W.Y. , Chang Y.C. , Chung W.Y. , Shiau C.Y. , Wang L.W. , Wu S.M.
Published: April 2003

A retrospective analysis was conducted on 80 patients with intracranial mengiomas treated with Gamma Knife radiosurgery between 1993 and 1996. The purpose was to analyze the efficacy of the treatment and to assess appropriate treatment parameters. The results were assessed by regular MR examinations, and tumor volume was measured at 6-month intervals. Mean follow-up duration was 21 months (range 6–45 months). 63 meningiomas were at the skull base and 17 were distal from the skull base. Tumor volumes <5 ml (n=38), 5–10 ml (n=21), 10–15 ml (n=14), 15–20 ml (n=7). The patients were divided into 3 groups according to the radiation dose. The groups were high-dose (peripheral dose 17–20 Gy, n=19), medium-dose (15–16 Gy, n=33) and low-dose (12–14 Gy, n=28) groups. A statistical method (Generalized Estimation Equation) was applied to compare treatment results in these groups with different doses and tumor volumes. The volume measurement at the latest follow-up showed 74% (59/80) meningiomas decreased in volume, 17% (14/80) had no tumor enlargement and 9% (7/80) had increased in volume. The increased volume was found more frequently in the patients with a short (6–12 months) follow-up period. In this series, the tumors had 32% reduction in average tumor volume at 3 years after radiosurgery. At the range of 12–20 Gy peripheral dose (PD), radiosurgery was effective to reduce tumor volume 0.7% per month (p<0.05). However, higher doses had no significant difference on tumor volume reduction (p>0.05). On the other hand, high-dose (PD>17 Gy) treatment was associated with a higher risk of temporary tumor swelling and the development of adverse radiation effects (AREs). The AREs detected on MR images occurred in (25/80) 31% patients. Only 6/25 AREs were symptomatic and 2 had neurological sequelae. Peripheral doses, tumor volumes and their locations had significant impacts on the ARE (p<0.05). In conclusion, a peripheral dose of 15–16 Gy may be adequate for meningiomas with small volumes (<5 ml). In larger tumors (>10 ml) a lower PD is preferred (12–14 Gy). To avoid initial tumor swelling and ARE, high-dose irradiation (PD>17 Gy) is not recommended for meningiomas larger than 5 ml.
Cavernous Sinus Meningiomas – What Is the Strategy: Upfront or Adjuvant Gamma Knife Surgery?
Authors: Pendl G. , Schröttner O. , Eustacchio S. , Ganz J.C. , Feichtinger K.
Published: April 2003

43 patients with meningiomas of the cavernous sinus form the basis of this study. Two patients were treated with microsurgery alone, 17 patients were treated by Gamma Knife radiosurgery (GKRS) as a primary treatment modality, and 24 patients underwent a combined treatment of microsurgery followed by GKRS. Therefore, in 17 patients the diagnosis rested on clinical and radiological criteria alone. Cranial nerve disorders (CND) related to open surgical treatment were infrequent in this material (3 of 13 patients) due to deliberate strategies of partial or subtotal resection aimed at sparing cranial nerves from surgical maneuvers. In contrast, 6 of 11 patients, admitted for GKRS from other institutions suffered from considerable CND after open surgery and showed only partial improvement after GKRS. In all GKRS cases, no radiation-related complications were seen after a follow-up of 18–62 months (mean 39 months). Moreover, in all cases tumor control was obtained with a stable tumor volume in 63%, reduction of volume in 34.5% and a disappearance of tumor in 2.5%. GKRS is not only an additional treatment for meningiomas involving the cavernous sinus, but may be offered to the patient as an alternative primary treatment.
Long-Term Complications following Gamma Knife Radiosurgery of Vestibular Schwannomas
Authors: Norén G.
Published: April 2003

Since its inception in 1969, Gamma Knife radiosurgery (GKR) for vestibular schwannomas has been documented as an efficient and safe procedure based on more than 8,000 treatments worldwide. The author’s personal experience comprises 669 treatments for patients with vestibular schwannoma between 1969–1997. This experience demonstrates long-term growth control, usually with shrinkage, in 95% of unilateral tumors. In the mid-1970s, early facial weakness occurred in 38% and facial numbness in 33%. This has gradually decreased to less than 2% in the 1990s. Preservation of hearing (unchanged or almost unchanged) is currently achieved in 65 to 70%. Tinnitus is rarely changed by the treatment. The risks of intracranial bleeding, infection and CSF leak are avoided because of the noninvasive nature of the treatment. Hydrocephalus directly induced by the tumor occurred in 9.2% of patients. On the other hand, a treatment%related peritumoral reaction sufficient to block the CSF circulation and require shunt insertion was seen in only 1.4%. Based on experiences worldwide, the incidence of secondary neoplasia seems to be 0.1%. The effectiveness of GKR together with its low complication rate makes it a suitable treatment for anyone, regardless of age and general health. With few exceptions, schwannomas with an intracranial size of up to approximately 3 cm are suitable for GKR.
Preservation of Hearing in Acoustic Neuromas Treated by Gamma Knife Surgery
Authors: Thomassin J.M. , Epron J.P. , Régis J. , Delsanti C. , Sarabian A. , Peragut J.C. , Pellet W.
Published: April 2003

138 acoustic schwannomas were treated by Gamma Knife surgery from July 1992 to May 1994. Cases with neurofibromatosis were excluded because of differences in the patterns of growth and development of tumors in these cases. Hearing was evaluated by tonal and vocal audiometry and classified using the Gardner and Robertson score. 104 patients were observed at 3 years after treatment. Hearing studies, the relation of tumor volume to hearing, central and marginal dose, number of shots and preoperative brain-stem-evoked responses (BER) were all recorded. 70% of patients with normal hearing maintained a useful hearing, and 50% of patients with useful hearing maintained serviceable hearing. No correlation was found between hearing preservation and tumor volume, central and marginal dose and number of shots. Gamma Knife surgery seems to be superior to microsurgery with regard to preservation of useful hearing.
Stereotactic Radiosurgery Toxicity in the Treatment of Intracanalicular Acoustic Neuromas: The Seattle Northwest Gamma Knife Experience
Authors: Vermeulen S. , Young R. , Posewitz A. , Grimm P. , Blasko J. , Kohler E. , Raisis J.
Published: April 2003

Patients with acoustic neuromas have several treatment options. The appropriate individual treatment decision and expected control rates and risks for the individual techniques have been outlined in several texts [1–4, 6–8]. This article describes radiosurgery toxicity in those patients with acoustic neuromas who have intracanalicular disease. 52 patients with 54 acoustic neuromas were treated between September 1993 and April 1997. 14 tumors were intracanalicular lesions, with a mean diameter <1 cm and volume <1 cm3. Dose to the periphery of the intracanalicular lesion extension ranged from 12–18 Gy (mean 16 Gy). The margin isodose was 40–60% (mean 47%). 32 isocenters were used to treat the 14 intracanalicular tumors (mean 2.3 isocenters per patient). At a mean follow-up of 18 months (range 1–39 months), 12/12 or 100% of the intracanalicular lesions demonstrated regression or no change in size on subsequent imaging. The following acute side effects were observed posttreatment in intracanalicular tumors: diminished hearing 14%, facial neuropathy 43%, trigeminal neuropathy 21%, balance disorder 14%, dizziness 7%, and headache 7%. Facial and trigeminal neuropathy, balance disorder, dizziness, vertigo and headaches were more common in patients with intracanalicular tumors than those with an extracanalicular extension. Although it has been suggested that small acoustic neuromas (i.e. <1 cm3) tolerate doses of 18 Gy with acceptable toxicity, when the lesion is located in the auditory canal a lesser dose may be warranted to minimize potential side effects. For now, our center has established a protocol that limits radiosurgical stereotactic intracanalicular peripheral doses to 12 Gy until further toxicity studies have been collected and reviewed.
Treatment of Carcinoma of the Hard Palate with Gamma Knife Radiosurgery
Authors: Zhao H.Y. , Zhao W.H. , Lin H.
Published: April 2003

The Gamma Knife radiosurgical treatment of two patients suffering from carcinomas of the hard palate is reported. A 67-year-old woman was treated with partial resection of an adenocarcinoma of the hard palate two years previously. Computerized tomographic imaging showed the tumor had grown (T4N1M₀). The second patient, a 58-year-old woman, had a cauliflower-like tumor of the hard palate (T2N₀M₀). Pathological diagnosis obtained by needle biopsy was squamous cell carcinoma. These two patients underwent radiosurgical treatment with the Gamma Knife. A surface dose of 20 Gy was administered at the 35% isodose curve. These two patients were followed up for 18 and 15 months, respectively. Encouraging results were obtained. Further research is needed in order to validate this new treatment of carcinomas of the hard palate.
Gamma Knife Radiosurgery for Hemangioblastomas
Authors: Pan L. , Wang E.M. , Wang B.J. , Zhou L.F. , Zhang N. , Cai P.W. , Da J.Z.
Published: April 2003

Thirteen patients (11 males, 2 females) with cerebral hemangioblastomas (HABs) were treated with Gamma Knife radiosurgery (GKR). Four patients had multiple lesions in the brain. The remainder had a single lesion. The total number of lesions was 20. Eight cases had recurrent or residual HABs after surgery. In one case diagnosis was confirmed following surgical resection 22 months after GKR. One case was diagnosed by computed tomography (CT), magnetic resonance imaging (MRI) and digital subtraction angiography (DSA). Three patients had von Hippel Lindau (VHL) disease. The mean tumor diameter was 20 mm (range 7.5 to .55 mm). The mean margin dose was 18 Gy (range 12 to 24 Gy). In 5 cases, there was an improvement of symptoms and reduction in tumor volume. In 4 cases the tumor volume and clinical status remained unchanged. In 3 patients, there was clinical deterioration. The cause of this was an increase in tumor cyst volume in 2 cases. Subsequent surgery resulted in clinical improvement. In a third patient with multiple lesions, deterioration was the result of adverse radiation effects in the medulla oblongata. Three patients were subjected to post GKR-surgery with subsequent histopathology. In one, this was due to cyst expansion. In one, it was at the patient’s insistence in the presence of a stable clinical and radiological picture. In a third patient with a temporal lobe tumor, it was because of late-developing epileptic seizures. The histopathological findings in these patients showed varying degrees of small vessel thickening and occlusion together with loss of tumor cells. The observations varied in degree according to the time between GKR and the secondary operation. These findings indicate the effectiveness of the treatment. The reduction in vascularity suggests that GKR could make subsequent surgery less hazardous. The observations of this study suggest that while GKR is not adequately reliable for the control of HAB cysts, it can be an effective treatment for solid tumors, especially those in eloquent regions.
Gamma Knife Radiosurgery as the First Surgery for Trigeminal Neuralgia
Authors: Kondziolka D. , Lunsford L.D. , Flickinger J.C.
Published: April 2003

To evaluate the role of Gamma Knife radiosurgery as the first surgical therapy in the management of medically refractory trigeminal neuralgia, we reviewed outcomes on our first 23 patients who had radiosurgery as primary surgical therapy. These patients represented 19% of our overall series. Mean patient age was 66 years, and mean follow-up after radiosurgery was 12 months (range 5–33 months). For most patients, radiosurgery was performed because the patient had medical contraindications to open surgery. 14 patients had 70-Gy radiosurgery, and 9 patients, 80 Gy. Radiosurgery was performed using a single 4 mm isocenter. Postoperative imaging 6 to 9 months following radiosurgery confirmed regions of enhancement at the radiosurgical target. Nine patients received 70 Gy, and 8 patients had 80 Gy. 17 patients (74%) had an excellent result (total pain relief). Five patients (22%) achieved a good result (50–90% improvement). One patient had a poor result (4%) after 70-Gy radiosurgery and subsequently underwent microvascular decompression. No patient developed facial numbness or any other complication after Gamma Knife radiosurgery. Gamma Knife radiosurgery using 70 or 80 Gy targeted to the proximal trigeminal nerve proved to be a safe and effective primary surgical therapy for medically refractory trigeminal neuralgia. The overall response rate (96%) was similar to that obtained with other surgical therapies performed as a first procedure.
Treatment of Cerebral Radionecrosis by Hyperbaric Oxygen Therapy
Authors: Leber K.A. , Eder H.G. , Kovac H. , Anegg U. , Pendl G.
Published: April 2003

Clinically observed adverse radiation effects (ARE) are rather uncommon, but modern imaging reveals that they are more common after radiosurgery than previously believed. Little is known about the pathogenesis, and current treatment is mostly empirical. The benefit of hyperbaric oxygen therapy (HBO) on radiation-induced bone and soft tissue necrosis is known in lesions in the maxillofacial area, the mouth and in the head and neck. HBO raises the tissue pO2 and initiates a cellular and vascular repair mechanism. This forms the basis for the hypothesis that it might also help alleviate the results of cerebral radionecrosis. This study is a preliminary attempt to test this hypothesis. Two patients with arteriovenous malformations (AVMs) were chosen for the study. They had been treated with Gamma Knife radiosurgery (GKRS) and had developed imaging signs consistent with ARE. They were treated by breathing 100% oxygen at 2.5 atmospheres absolute (250 kPa) in sessions of 60 minutes per day. This treatment was repeated 40 times in cycles of ten sessions. Both responded well to HBO, one lesion disappeared and the other was reduced significantly in size. No adjuvant steroids were given. These results give evidence that HBO has a potential value in treating ARE but further experience will be needed to confirm its definite benefit.
Effects of Anterodorsal Pallidal Stimulation on Gait Freezing (Kinesia paradoxa) in Parkinson’s Disease
Authors: Katayama Yoichi , Kasai Masahiko , Oshima Hideki , Fukaya Chikashi , Yamamoto Takamitsu
Published: April 2003

The results of a double-blind evaluation of the effects of internal globus pallidus (GPi) stimulation in 7 patients with advanced Parkinson’s disease are summarized. The evaluation was performed 6–8 months after surgery while the patients were on medication with an optimal dose and schedule. The stimulation was turned off for at least 12 h. It was turned on in the morning (or maintained turned off), and the best and worst scores during their daytime activity were recorded as the on-period and off-period scores, respectively. A significant reduction in the total score on part III of the Unified Parkinson’s Disease Rating Scale was induced by GPi stimulation at the off-period (–57%) as well as the on-period (–36%). Clinically important improvement was also achieved in severe gait freezing (kinesia paradoxa) in 2 patients when stimulation was applied to the anterodorsal portion of the GPi. Such an effect was observed during unilateral stimulation of the right side alone.
Generalized Seizures Induced by an Epileptic Focus in the Mesencephalic Reticular Formation: Impact on the Understanding of the Generalizing Mechanism
Authors: Hashizume Kiyotaka , Tanaka Tatsuya , Fujita Tsutomu , Tanaka Shigeya
Published: April 2003

The mode of seizure propagation was studied using a generalized seizure model induced by microinjection of kainic acid (KA) into a unilateral mesencephalic reticular formation (MRF) in cats and rats. Stereotactic surgery was performed under pentobarbital anesthesia; an injection cannula was placed into a unilateral MRF, and bipolar electrodes were implanted into the MRF and the thalamus. Microinjection of KA induced generalized seizures. Focal electrical seizures were elicited in the injected site of the MRF starting 30 min after the injection. The initial clinical change during each seizure was behavioral arrest. These seizures immediately developed to generalized seizures, which were characterized by generalized tonic convulsions with short-term clonic convulsions. On EEG, each generalized seizure started at the same time in all the sites of the brain recorded. Autoradiographic study using a rat model demonstrated high glucose utilization in the MRF, bilateral thalamus, forebrain and bilateral cerebral cortices. The results demonstrated an active participation of MRF in the mechanism of generalized seizures.
Localisation of the Subthalamic Nucleus Using Radionics Image FusionTM and StereoplanTM Combined with Field Potential Recording
Authors: Liu X. , Rowe J. , Nandi D. , Hayward G. , Parkin S. , Stein J. , Aziz T.
Published: April 2003

Subthalamic nucleus stimulation is an effective therapy for alleviating parkinsonian tremor, rigidity and bradykinesia. Although microelectrode recording is said to be essential for accurate targeting, this often prolongs the operation and the multiple recording tracts required may increase the incidence of complications, particularly haemorrhage. We describe a technique for implantation of deep brain electrodes in the subthalamic nucleus using MRI/CT fusion for anatomical localisation followed by bipolar recording of focal field potentials via the implanted stimulating electrode for neurophysiological confirmation of the stimulation site. The technique is effective, safe and requires much less time, and can be used as an alternative method to microelectrode recording.
Risk Management in a Community Gamma Knife Unit
Authors: Johnstone Peter A.S. , Hodgens David W. , Ott Kenneth , Goetsch Steven J.
Published: April 2003

Objective: The records of the San Diego Gamma Knife Center were retrospectively reviewed for unprogrammed events as part of a risk management assessment. Materials and Methods: Review was made of the physicist notes of the first 1,000 patients successfully treated at the center. This encompassed 1,020 stereotactic frame placement procedures, accompanied by Gamma Knife radiosurgery in 98.0% of intended cases. A total of 7,145 Gamma Knife shots were delivered to 1,509 lesions. Results: Of the 43 unprogrammed events documented, 8 were patient related and 14 were related to lesion growth or location; these were considered unavoidable. Further, one event was related to dose administration, 5 to diagnosis, 15 to technique; these were considered potentially avoidable. This yielded an avoidable error rate of 2.1% per patient, 1.4% per lesion treated, and 0.29% per shot. It was clear that more avoidable errors occurred early in the center’s operation, consistent with a learning curve. Review of individual physician’s cases revealed none appeared more likely to have an avoidable event. Conclusions: Consistently high quality may be achieved at a community-based Gamma Knife center if sufficient multidisciplinary involvement is achieved.
Management of Renal Cell Carcinoma with Inferior Vena cava Tumor Thrombus
Authors: Matsui Yoshiyuki , Fujikawa Keita , Oka Hiroya , Fukuzawa Shigeki , Takeuchi Hideo
Published: April 2003

Objective: The prognostic implication of radical nephrectomy with inferior vena cava tumor thrombectomy for renal cell carcinoma is still controversial. We investigated the type of renal cell carcinoma with vena cava tumor thrombus for which surgical resection was beneficial. Materials and Methods: We retrospectively reviewed the records of 16 patients with renal cell carcinoma and inferior vena cava tumor thrombus. Of these, 10 received surgical treatment and 6 did not. We evaluated the association between the pretreatment serum C-reactive protein (CRP) level and the efficacy of surgery. Results: Among the 8 patients with an elevated pretreatment serum CRP level (CRP ≧1.0 ng/ml), there was no significant difference of the median disease-specific survival between those who did (20.2 months) and did not undergo surgery (8.2 months; p = 0.1946). On the other hand, among the 8 patients who had a pretreatment serum CRP level within normal limits (CRP < 1.0 ng/ml), the median disease-specific survival of those who did not undergo surgery (80.6 months) was significantly better than that of those who did (50.2 months; p = 0.0136). Conclusion: This study suggested that conservative treatment can be recommended for patients with renal cell carcinoma and inferior vena cava tumor thrombus when the pretreatment serum CRP level is normal because tumor progression is usually slow and surgical treatment may actually worsen the prognosis.
The Role of Imprinted Genes in Fetal Growth
Authors: Miozzo Monica , Simoni Giuseppe
Published: April 2003

Genomic imprinting is the phenomenon by which one of the two alleles of a subset of genes is preferentially expressed according to its parental origin. This pattern of inheritance is different from the more frequent mode of Mendelian inheritance, which is not influenced by the parental origin of the allele. The idea that imprinted genes can affect fetal growth is becoming increasingly intriguing as it has been shown that most imprinted genes are expressed in the placenta and some play a role in regulating the interactions between its fetal and maternal interfaces. This article considers genomic imprinting by reviewing recent findings of alterations in fetal growth related to different types of genetic changes affecting the expression of imprinted genes. Among the genetic anomalies, the uniparental disomy (UPD) defines the inheritance of both homologous chromosomes from only one parent. UPDs of a number of chromosomes have been described in association with effects on the phenotype. We reviewed cases of UPD reported till now with particular reference to those associated to growth alterations.
Protective Effect of Dietary Supplementation with L-Arginine and L-Carnitine on Hypoxia/Reoxygenation-Induced Necrotizing Enterocolitis in Young Mice
Authors: Akisu Mete , Ozmen Dilek , Baka Meral , Habif Sara , Yalaz Mehmet , Arslanoglu Sertac , Kultursay Nilgun , Bayindir Oya
Published: April 2003

Oxygen-derived free radicals are important components of gastrointestinal injury in necrotizing enterocolitis (NEC). In the present investigation, we examined the protective actions of L-arginine, a nitric oxide synthase substrate, and L-carnitine against hypoxia-reoxygenation (H/R) induced NEC in young mice. Young mice were divided into four groups: group 1 mice were subjected to H/R only; group 2 H/R mice were supplemented with L-arginine in the drinking water (2 g/l) for 7 days; group 3 H/R mice were given L-carnitine solution in water (50 mg/kg p.o.) for 7 days, and group 4 mice served as controls.Hypoxia was induced by placing the mice in a 100% CO2 chamber for 5 min. After hypoxia, the mice were reoxygenated for 10 min with 100% oxygen. We examined the intestinal lesions by light microscopy and measured the intestinal generation of thiobarbituric acid reactive substances (TBARS) and the activities of superoxide dismutase and catalase in the H/R-induced model of NEC. In both L-arginine and L-carnitine groups, the NEC-induced intestinal tissue damage was greatly attenuated, with necrosis limited partially to the mucosa. The tissue TBARS level was significantly higher in group 1 than in any of the other groups (p < 0.001). However, those treated with L-arginine and L-carnitine had TBARS levels similar to those in the control animals. An increased tissue concentration of nitrate, a stable metabolite of nitric oxide, was found in the L-arginine-supplemented group as compared with the control group (p < 0.05). Both superoxide dismutase and catalase activities in the intestine were similar in H/R groups when compared with the intestine of control animals. The present study suggests that oxygen-derived free radicals are involved in the pathogenesis of H/R-induced NEC. This study also shows that dietary supplementation with L-arginine and L-carnitine ameliorates the histological evidence of H/R-induced intestinal injury and significantly decreases lipid peroxidation in H/R-induced bowel injury. Based on these findings, the beneficial effects of L-arginine and L-carnitine in this model may be mediated via mechanisms preventing free radical damage.
Continuous Positive Airway Pressure and Surfactant; Combined Data from Animal Experiments and Clinical Trials
Authors: Thomson Merran A.
Published: April 2003

Bronchopulmonary dysplasia (BPD) remains a cause of considerable morbidity for the preterm infant. Ventilation is a primary risk factor. This review discusses the rationale for combining surfactant and nasal continuous positive airway pressure (nCPAP) using evidence from both clinical and animal studies. The early application of nCPAP with or without surfactant is safe and reduces the need for mechanical ventilation. Combining nCPAP with surfactant results in dramatically improved lung structure in a primate model of BPD, but still does not allow for normal alveolarization. BPD is a complex condition resulting from the interaction of many factors. Experimental evaluation of nCPAP in appropriate animal models will allow new strategies for prevention and treatment of BPD to be developed.
Cloning of the novel gene TM6SF1 reveals conservation of clusters of paralogous genes between human chromosomes 15q24→q26 and 19p13.3→p12
Authors: Carim-Todd L. , Escarceller M. , Estivill X. , Sumoy L.
Published: April 2003

As the result of the EUROIMAGE Consortium sequencing project, we have isolated and characterized a novel gene on chromosome 15, TM6SF1. It encodes a 370 amino acid product with enhanced expression in spleen, testis and peripheral blood leukocytes. We have identified another gene, paralogous to TM6SF1 on chromosome 19p12, TM6SF2, with an overall similarity of 68% and 52% identity at the protein level. This conservation has led us to uncover a series of eleven genes in 19p13.3→p12 with close homology to genes in 15q24→ q26. The percentage of sequence similarity between each paralogous pair of genes at the protein level ranges between 43 and 89%. A partial conservation of synteny with mouse chromosomes 7, 8 and 9 is also observed. The corresponding orthologous genes in mouse of human TM6SF1 and TM6SF2 show a high degree of amino acid sequence conservation.
Cloning, expression analysis and chromosome mapping of human casein kinase 1 γ1 (CSNK1G1): Identification of two types of cDNA encoding the kinase protein associated with heterologous carboxy-terminal sequences
Authors: Kusuda J. , Hirai M. , Tanuma R. , Hashimoto K.
Published: April 2003

Casein kinase 1 γ1(CK1 γ1) is known to be involved in the growth and morphogenesis of eukaryotic cells. We have isolated two types of cDNA for human casein kinase 1 γ1 (hCK1 γ1). One of them (hCK1 γ1S) was found to encode a polypeptide consisting of 393 amino acids, which is highly homologous with already reported rat CK1 γ1 (rCK1 γ1). The other type of cDNA (hCK1 γ1L) encodes a polypeptide consisting of 422 amino acids, which is quite identical in the kinase domain, but different in the C-terminal sequence from hCK1 γ1S. Namely, hCK1 γ1L has a characteristic sequence of 50 amino acids at the C-terminal end and this motif was shown to be shared by the casein kinase γ2 and γ3 from rat and human, suggesting that it is a signature sequence of the γ-isoforms. In this sense, newly isolated hCK1 γ1L might be the original form of CK1 γ1 subspecies rather than rCK1 γ1 and hCK1 γ1S. RT-PCR analysis revealed that hCK1 γ1S mRNA is predominantly present in the testis, whereas the abundance of hCK1 γ1L mRNA was nearly the same in the twelve tissues examined. These results suggest that novel hCK1 γ1L may have a unique functional role different from that of hCK1 γ1S and rCK1 γ1. The human hCK1 γ1 gene (CSNK1G1) was mapped to chromosome 15q22.1→q22.31 by fluorescence in situ hybridization.
A high frequency of XO offspring from XPafY* male mice: evidence that the Paf mutation involves an inversion spanning the X PAR boundary
Authors: Burgoyne P.S. , Evans E.P.
Published: April 2003

It has previously been reported that 19% of the daughters of males carrying the X-linked mutation patchy fur (Paf) are XO with a maternally derived X chromosome. We now report that hemizygous Paf males that also carry the variant Y chromosome Y*, show a much increased XO production (∼40% of daughters). We hypothesize that the Paf mutation is associated with an inversion spanning the pseudoautosomal region (PAR) boundary, and that this leads to preferential crossing over between the resulting inverted region of PAR and an equivalent inverted PAR region within the compound Y* PAR. This would lead to the production of dicentric X and acentric Y products and consequent sex chromosome loss. This interpretation is supported by analysis of the sex chromosome complements at the second meiotic metaphase, which revealed a high incidence of dicentrics. Another curious feature of the Paf mutation is that mice that are homozygous Paf have more hair than mice that are hemizygous Paf. This can be explained if the Paf mutation is a hypomorphic mutation that escapes X inactivation because, unlike the wild type allele, it is now located within the PAR.
Comparative genomic aspects of rat, mouse and human MHC class I gene regions
Authors: Günther E. , Walter L.
Published: April 2003

In this review a particular aspect of the genomic structure of the major histocompatibility complex (MHC), the organization of MHC class I regions, will be discussed for the rat in comparison to mouse and human.