Multicentric EORTC retrospective study shows efficacy of brentuximab vedotin in patients who have mycosis fungoides and Sézary syndrome with variable CD30 positivity.

BACKGROUND: Brentuximab vedotin (BV) was approved as a therapy for mycosis fungoides (MF) based on the ALCANZA trial. Little real-world data, however, are available. OBJECTIVES: To evaluate the efficacy and safety of BV in patients with MF/Sézary Syndrome (SS) with variable CD30 positivity in a real-world cohort and to explore potential predictors of response. METHODS: Data from 72 patients with MF/SS across nine EORTC (European Organization for Research and Treatment of Cancer) centres were included. The primary endpoint was to evaluate the proportion of patients with: overall response (ORR), ORR lasting over 4 months (ORR4), time to response (TTR), response duration (RD), progression-free survival (PFS) and time to next treatment (TTNT). Secondary aims included a safety evaluation and the association of clinicopathological features with ORR, RD and TTNT. RESULTS: All 72 patients had received at least one systemic treatment. ORR was achieved in 45 of 67; ORR4 in 28 of 67 with a median TTR of 8 weeks [interquartile range (IQR) 5·5-14] and with a median RD of 9 months (IQR 3·4-14). Median PFS was 7 months (IQR 2-12) and median TTNT was 30 days (6-157·5). Patient response, RD, PFS and TTNT were not associated with any clinicopathological characteristics. In the MF group, patients with stage IIB/III vs. IV achieved longer PFS and had a higher percentage of ORR4. There was a statistically significant association between large-cell transformation and skin ORR (P = 0·03). ORR4 was more frequently achieved in patients without lymph node involvement (P = 0·04). CONCLUSIONS: BV is an effective option for patients with MF/SS, including those with variable CD30 positivity, large-cell transformation, SS, longer disease duration and who have been treated previously with several therapies.

Prognostic indicators for mycosis fungoides in a Greek population.

BACKGROUND: Mycosis fungoides (MF) is an indolent cutaneous lymphoma with excellent prognosis at early stages and much poorer outcome during disease progression. Old age, male sex and folliculotropism have been proposed as relevant prognostic factors; however, their exact effect remains debatable. OBJECTIVES: To evaluate MF prognostic indicators and survival rates in a Greek population. METHODS: Prognostic variables affecting survival rates were studied in 473 patients with MF diagnosed and treated by two academic referral centres in Greece. Kaplan-Meier estimates were used to determine survival rates and progression. The Cox proportional hazards regression model was used to assess prognostic factors. RESULTS: The mean age of diagnosis was 61·7 years (SD 16·33). Five-year disease-specific survival was 96% in patients with stage IA disease and 52% in patients with stage IIB disease. Univariate analysis certified that large-cell transformation, clonal rearrangements of the TCR gene, severe pruritus and presence of plaques were the most important prognostic factors. Folliculotropism altered disease progression only in patients with early-stage disease. The application of the Cutaneous Lymphoma International Prognostic Index (CLIPI) on our late-stage group failed to provide reliable evidence. The current Cutaneous Lymphoma International Consortium (CLIC) prognostic index can efficiently distinguish a low-risk from a high-risk group of patients. Tumour-Node-Metastasis-Blood (TNMB) staging was the most important prognostic factor for survival rates in multivariate analysis. CONCLUSIONS: In our study we validated the current prognostic indicators for MF in a Greek population and identified new potential prognostic factors for survival outcome. Our findings contribute to the ongoing investigation of prognostic indicators of MF, further validation of which is highly needed through prospective studies and among different populations.

Behavioural response of wheat bulb fly (Delia coarctata, Diptera: Anthomyiidae) larvae to the primary plant metabolite carbon dioxide.

Wheat bulb fly (WBF) larvae use chemotaxis to orientate towards host-plant root exudates. This study aimed to investigate the role of the primary plant metabolite carbon dioxide (CO2) in host-plant location by WBF. Arena based behavioural experiments were used to identify whether CO2 induced chemotaxis (directional movement in response to a chemical stimulus) or kinesis (non-directional movement in response to a stimulus) from WBF larvae. No chemotactic response was observed when larvae were presented to a point source of CO2. However, elevated levels of CO2 induced kinesis, with both track length and tortuosity (number of twists and turns in the movement path) increasing at elevated CO2 levels of 1000-2000 ppm, demonstrating increased searching behaviour. Soil emission of CO2 was quantified to compare soil levels with those identified as eliciting behavioural effects on the larvae. Samples removed from soil gave a mean CO2 concentration of 557 (±46) ppm, which is lower than the lowest concentration of CO2 found to induce a behavioural response and higher than the lowest CO2 concentration tested, which was found not to alter behaviour. It is proposed that increased CO2 concentrations in the soil act as a behavioural trigger, inducing intensive searching of an area by WBF larvae. This increases the likelihood of finding more host-specific identifiers, such as secondary metabolites when near a potential host-plant.

Thromboembolic events in patients with paroxysmal nocturnal hemoglobinuria (PNH): Real world data of a Greek nationwide multicenter retrospective study.

Thrombosis is the most common and a life-threatening complication in patients with Paroxysmal Nocturnal Hemoglobinuria. One-third of patients with PNH experience at least one thromboembolic event during the course of the disease, with thrombosis being the most common cause of death in these patients. The mechanism of thrombosis in PNH is complex and continues to be of great research interest. Since the introduction of C5 complement inhibitors in the treatment of PNH, the incidence of thromboembolic events has decreased substantially. We retrospectively analyzed data concerning the thrombotic episodes of 41 patients with PNH from 14 different national hematology centers in Greece. Sixteen patients (39%) experienced at least one episode of thrombosis, including, seven (43.8%) at diagnosis, seven (43.8%) during the course of the disease and two (12.5%) patients prior to PNH diagnosis. Nearly half of these individuals (n=7, 43.8%) had multiple episodes of thrombosis during the course of their disease. The most common sites of thrombosis were intra-abdominal veins. Three out of 26 patients developed thrombosis while on eculizumab. In none of the 16 patients, the thrombotic event was fatal. Our findings, despite the small number of patients, confirmed that thrombosis continues to be a significant complication of PNH affecting more than one third of the patients.

Knowledge and attitudes to sun exposure among adolescents in Korinthos, Greece.

INTRODUCTION: Extended sun exposure may lead to serious health problems, and evidence of this is in the increase in skin cancer and malignant melanoma worldwide. Extended sun exposure during childhood or adolescence increases the probability of skin cancer in adulthood. The aim of the study was to identify and examine the knowledge, attitude, behaviour and beliefs of Greek adolescents (high school students) related to sun exposure and its adverse effects on health. The majority of participants (89.7%) were of Greek nationality. METHODS: The study took place in 5 schools in the prefecture of Korinthos, and 816 of the total 925 students aged 15-18 years participated. The questionnaire was pilot tested and assessed for validity and reliability, both of which were adequate (Cronbach's alpha = 0.70 and r(s) = 0.78); SPSS 13.0 software was used for analysis. RESULTS: Only 37.9% of participants knew that melanoma was a type of skin cancer; 50% said they did not know what melanoma was. Regarding behavior, 35.5% reported that during the last summer they went to the beach on 20 to 50 occasions, and only 50% reported that they wore a sunhat or stayed in the shade. The frequency of sunscreen use was alarmingly low, with the majority of the adolescents unfamiliar with its proper use, and 50% not using a sunscreen with sufficient sun protection factor. Television was an important source of information about protection from sun exposure, while the family was the most important provider of advice. CONCLUSIONS: Participants' knowledge of sun exposure was insufficient and they reported risky behaviours in the summer months. Despite health promotion and community education programs focusing on sun smart strategies, these young people still associated suntans with beauty. Health promotion and education programs need to challenge such beliefs. However, as a sole approach to health promotion, teaching protective measures and appropriate ways for youth to protect themselves against the harmful effects of sunbathing may be insufficient to reduce the epidemic of skin cancer.

Analysis of apoptosis regulatory genes expression in the bone marrow (BM) of adult de novo myelodysplastic syndromes (MDS).

The aim of the present study was to examine caspases, granzyme B and bcl-2 family mRNA expression and the degree of apoptosis in the bone marrow (BM) of 46 Myelodysplastic Syndromes (MDS) and to correlate our findings with clinical parameters. The degree of apoptosis was determined by Annexin V, whereas expression of genes was determined using a multiprobe RNase Protection System. A positive correlation was found between caspases 8, 5, 3, 2, 1 and the level of apoptosis. bfl1 and mcl1 levels were significantly higher in patients with BM blasts >5%. Cases with ratio of bid expression >1 compared to normal pool were associated with IPSS values < or =1.

Keratinocyte growth factor is effective in the prevention of intestinal mucositis in patients with hematological malignancies treated with high-dose chemotherapy and autologous hematopoietic SCT: a video-capsule endoscopy study.

Oral and/or intestinal mucositis is a severe complication of hematopoietic SCT. Keratinocyte growth factor (KGF) has proven activity in the prevention of oral mucositis. We examined the efficacy of KGF in the prevention of intestinal mucositis. From January 2006 until December 2007, 35 consecutive patients underwent autologous SCT (auto-SCT) in our institution. A total of 15 consecutive patients who underwent auto-SCT from March 2007 to December 2007 received KGF for the prevention of mucositis and were included in the study group A, whereas 20 consecutive patients treated from January 2006 to March 2007, were included in the historical control group B. Oral and intestinal mucositis were significantly less severe in group A (P=0.002 and P<0.001, respectively). These results were confirmed with the use of video-capsule endoscopy. Patients in group A had a significantly lower incidence of neutropenic fever (P=0.026). Severe intestinal mucositis was significantly associated with a higher incidence of documented infections too (P=0.019). KGF is effective in the prevention of intestinal mucositis in patients undergoing auto-SCT. Patients with severe intestinal mucositis run a higher risk to develop infections.

Poly (ADP-ribose) polymerase 1 mRNA levels strongly correlate with the prognosis of myelodysplastic syndromes.

Poly (ADP-ribose) polymerase 1 (PARP-1) has a central role in the repair of DNA breaks and is a promising treatment target in malignancy. We measured PARP1 mRNA levels by a SYBR-green-based PCR in the bone marrow of 74 patients with myelodysplastic syndrome (MDS) and correlated them to their demographic, hematologic and prognostic characteristics. The median PARP1 mRNA levels were correlated to the type of MDS (2008/2016 WHO classification, P=0.005) and to the IPSS score (P=0.002). A correlation was also found with the IPSS-R score (P=0.011) and the cytogenetic risk (P=0.008). In all cases, higher PARP1 levels were correlated with a higher risk category. Moreover, we found a significant survival disadvantage for patients with high PARP1 levels (median survival of 37.4 months versus 'not reached' for low PARP1 levels, P=0.0001, and a 5-year survival rate of 29.8 versus 88.9%, respectively). PARP1 mRNA levels were found to be the stronger predictor of survival in multivariate analysis. These correlations have never been reported in the past and may render PARP1 a prognostic factor to be incorporated in the current prognostic systems for MDS, also laying the basis for clinical trials evaluating PARP1 inhibitors in higher-risk MDS.

Role of image-guided core-needle biopsy in the management of patients with lymphoma.

PURPOSE: The results of 106 radiologically guided core needle biopsies in 96 patients were analyzed retrospectively to evaluate the accuracy, safety, and role of this technique in the management of patients with lymphoma and to determine factors predictive of success. PATIENTS AND METHODS: Biopsies were performed in 51 patients with low-grade non-Hodgkin's lymphoma (NHL), 24 with high-grade NHL, 16 with previously diagnosed Hodgkin's disease (HD), and 15 with no previous history of lymphoma. Disease was infradiaphragmatic in 92 patients and supradiaphragmatic in 14. Computed tomography (CT) guidance was used in 98 biopsies and ultrasonography (US) in eight. RESULTS: The biopsy was diagnostic and yielded information on the basis of which treatment was started in 88 of 106 patients. The procedure was well tolerated and there were no major complications. Small size of the sample or inappropriate tissue sampled were the main causes of failure. The technique was equally successful in the diagnosis of HD and both high-grade and low-grade NHL as in nonlymphoproliferative disorders. The procedure was equally successful at diagnosis as at suspected recurrence or progression. In 33 of 80 cases in which the biopsy was performed at the time of recurrence or progression, the histology had changed; in 31 of 33, this influenced treatment. The technique was efficient at diagnosing transformation of follicular NHL in 16 of 18 patients, which allowed early adjustment of treatment at recurrence. CONCLUSION: At St Bartholomew's Hospital (SBH), image-guided core-needle biopsy has proven to be a quick, safe, and efficient alternative to excisional biopsy in the evaluation of lymphoproliferative disorders at presentation, recurrence, or progression. It should become the procedure of choice for histologic sampling in the absence of peripheral lymphadenopathy.

High-dose therapy with autologous bone marrow support as consolidation of remission in follicular lymphoma: long-term clinical and molecular follow-up.

PURPOSE: To evaluate the long-term results of high-dose therapy (HDT) in follicular lymphoma, with specific emphasis on the prognostic significance of polymerase chain reaction (PCR)-detectable Bcl-2/IgH rearrangements. PATIENTS AND METHODS: Between June 1985 and October 1995, 99 patients with follicular lymphoma received HDT as consolidation of second or subsequent remission. Bone marrow was treated in vitro with anti-B-cell antibodies and complement. RESULTS: Sixty-five patients remained alive, 49 treatment-failure free, with a median follow-up of 5.5 years (range, 1.5 to 12.5 years). Four "early" and 10 "late" deaths occurred from treatment-related causes; seven of the latter were due to secondary myelodysplasia (s-MDS) or secondary acute myeloblastic leukemia. Overall, 12 (12%) of the 99 patients developed s-MDS or acute myeloblastic leukemia. Kaplan-Meier estimates of freedom from recurrence (FFR) and survival rates at 5 years were 63% (95% confidence interval [CI], 52% to 72%) and 69% (95% CI, 58% to 78%), respectively. For all 99 patients, in multivariate analysis, absence of the Bcl-2/IgH rearrangement at the time of diagnosis (hazards ratio [HR], 0.39; P =.04) and three or fewer treatment episodes before HDT (HR, 0.03; P =.001) were significant prognostic factors for improved survival. For patients bearing Bcl-2/IgH rearrangements, in univariate and multivariate analyses, absence of a PCR-detectable Bcl-2/IgH rearrangement during follow-up was associated with a significantly lower risk of recurrence (adjusted HR, 0.13; P <.001) and death (HR, 0.25; P =.02), whereas the PCR status of the reinfused bone marrow did not correlate with outcome. CONCLUSION: Prolonged FFR can be achieved in patients with follicular lymphoma after HDT, but as yet there is no survival advantage compared with conventional treatment. These results confirm that elimination of cells bearing the Bcl-2/IgH rearrangement is highly desirable and should be attempted. The incidence of s-MDS is of increasing concern in this setting.

A novel p27 gene mutation in a case of unclassified myeloproliferative disorder.

P27 encodes a member of Cip/Kip family of cyclin dependent kinase inhibitors, the inactivation of which has been implicated in the pathogenesis of various hematological neoplasias. We report on a novel point mutation of this gene identified in a case of unclassified myeloproliferative syndrome consisting of a T --> C transversion at 821bp of p27 exon 1, resulting in a Ile --> Thr substitution at codon 119. The analysis of larger number of cases as well as the effect of this mutation on protein's function will help to clarify its significance in the pathogenesis of myeloproliferative syndromes.

Treatment of anemia in low risk myelodysplastic syndromes with granulocyte-macrophage colony-stimulating factor plus recombinant human erythropoietin.

The aim of this prospective study was to determine whether treatment with a combination of GM-CSF and erythropoietin (rhEpo) can improve the anemia associated with low risk myelodysplastic syndrome (MDS), namely refractory anemia (RA), RA with ring sideroblasts (RAS), and RA with excess of blasts (RAEB) with bone marrow blasts less than 10%. Eligibility criteria included an Hb level of less than 10.5 g/dl for newly diagnosed patients, or symptomatic anemia. GM-CSF was given at a dose of 3 microg/kg s.c. on days 1-2, rhEpo at a dose of 60 U/kg s.c. on days 3-5. No treatment was given on days 6-7. Patients were followed-up with full blood count on a weekly basis. The treatment was repeated for a total of 6 weeks. At that time, if a rise in Hb above 1.5 g/dl had not been achieved, the dose of rhEpo increased to 120 U/kg. Post-treatment evaluation was performed at the completion of 12 weeks. Erythroid response was defined as good (GR), if an increase in untransfused Hb values above 2 g/dl or a 100% decrease in red blood cell transfusion requirements, over the treatment period was observed, while an increase in untransfused Hb values 1-2 g/dl or a >50% decrease in transfusion requirements, were considered as partial response. Responders continued to receive the same treatment until disease progression. Nineteen patients (13 male and six female) with a median age of 69 years were enrolled in the study. The FAB subtypes were: RA one case, RAS eight cases and RAEB 10 cases. Ten of 19 patients (52.6%) responded to the treatment: 7/19 (36.8%) achieved a GR and 3/19 (15.8%) a PR. Six of eight (75%) patients with RAS, one case with RA and 3/10 (30%) of cases with RAEB responded to treatment. Pretreatment serum epo levels were generally low (less than 200 Mu/ml) in responding patients. At the completion of the initial 12 weeks, 8/12 responding patients (5 RAS, 2 RAEB and 1 RA) continued to receive the same treatment. All responding patients with RAS continued to show an erythroid response in a time period from 3 to 24 months, whilst one patient with RA and two with RAEB did not have a continuing response at 2, 4 and 12 months, respectively. The above data suggest that the combination of rhEpo and GM-CSF should be recommended in all cases with RARS. However, the clear indication of this combination for other patients with MDS remains to be determined.

Monoclonal gammopathies in B-cell non-Hodgkin's lymphomas.

The association of monoclonal gammopathy (MG) with B-cell non-Hodgkin's lymphomas (NHL) is a well known phenomenon. The aim of the present work was to study the incidence, type of monoclonal component and prognostic significance of MG in a population of 255 cases with B-cell NHL. Among 255 evaluable patients with B-cell NHL, 145 were males and 110 females with a median age of 58 years (range 18-85). There were 166 patients with the various subtypes of aggressive (intermediate/high grade) NHL and 89 with the various subtypes of low risk. MG was detected in 44 patients (17.2%) with a median age of 61 years (range 23-79). There were 22 cases (8.6%) with IgG type (IgG/(k) 15, IgG/(lambda) 7), 4 cases (1.6%) with (IgA/(k) 3, IgA/(lambda) 1) and 18 cases (7.0%) with IgM (IgM/(k) 12 IgM/(lambda) 6). MG was found in 15.6% of the patients with aggressive NHL, while in low risk NHL the incidence was 20.2% (N.S.). The type of MG according to histological classification was as follows: Aggressive NHL: IgG 17 cases, IgA 2 cases, IgM 7 cases: low risk NHL: IgG 5 cases, IgA 2 cases, IgM 11 cases. The distribution of MG according to stage of the disease was as follows: stage I (4.5%), stage II (18%), stage III (6.8%) and stage IV (70.4%). The median survival of patients with aggressive NHL with MG was 17 months compared to 40 months of those without (P=0.22). Similarly the median survival of patients with low risk NHL and MG was 51.5 months compared to 38.5 months of those without (P=0.90). In conclusion MG was detected in 17.2% of cases with B-cell NHL. IgG-MG was more frequent in cases with aggressive NHL, while IgM in cases with low risk NHL. MG was mostly associated with advanced stage and had not any prognostic significance on survival.

Detection of somatic mutations of the bcl-2 oncogene in B cell lymphomas with the t(14;18).

The incidence of mutations within the first 582 bp of the open reading frame of the bcl-2 gene, has been investigated in presentation lymph node samples, from 7 cases with follicular non-Hodgkin's lymphoma (NHL), 1 case with centroblactic NHL, the DOHH, cell line derived from the immunoblastic transformation of a follicular NHL and one case with benign follicular hyperplasia. A total number of 43 point mutations within the examined portion of the bcl-2 gene were detected in the cases analysed including the DOHH, cell line. Similar analysis of peripheral blood lymphocytes from 2 normal individuals that lacked the t(14;18), revealed no mutations in one case and a single 101 bp A-->G transition in clone, in the other. Missense mutations were detected in 7/8 NHLs, the DOHH2 cell line and the case of benign follicular hyperplasia. There was a significantly higher frequency of mutations within the region corresponding to the BH1, one of the two known functional domains, of the bcl-2 protein. The same position, 445 bp of the bcl-2 gene, was found to be involved in missense mutations affecting the DOHH2 cell line and 3 cases with follicular NHL.

Use of the polymerase chain reaction and direct sequencing analysis to detect cells with the t(14;18) in autologous bone marrow from patients with follicular lymphoma, before and after in vitro treatment.

Between August 1993 and February 1994, 25 patients with follicular or transformed follicular lymphoma had bone marrow harvested at St Bartholomew's Hospital (SBH) with a view to proceeding to high-dose treatment comprising: cyclophosphamide 60 mg/kg x 2 and total body irradiation, 200 cGy x 6, supported by autologous bone marrow transplantation (ABMT). The marrow mononuclear cell fraction was treated in vitro with four anti-B cell antibodies and baby rabbit complement. The aim of this study was to determine whether in vitro treatment of the marrow could remove morphologically undetectable lymphoma cells. PCR analysis for the t(14;18) was used to determine the presence or absence of lymphoma. At the time of the bone marrow harvest, 21/25 bone marrow samples were positive for the t(14;18), in 15/22 patients, the rearrangement could also be demonstrated in peripheral blood. After in vitro treatment, 18/21 samples (86%) remained 'PCR positive'. Sequence analysis of the t(14;18) PCR products was performed on the latter and on lymph node biopsy material taken at diagnosis from 12 patients. The same t(14;18) sequences were found in the bone marrow harvest samples as in the patients' original biopsies. These results suggest that this form of in vitro treatment does not completely eradicate the t(14;18) bearing clone. New and better methods need to be developed.

Expression of the long and short leptin receptor isoforms in peripheral blood mononuclear cells: implications for leptin's actions.

Leptin, the adipocyte-derived hormone, is secreted into the blood and regulates body weight via its receptors in the hypothalamus. Leptin receptors are also present in many peripheral tissues implicating leptin in the regulation of other body functions, including reproduction, liver and enteric metabolism, hematopoiesis, and immunity. Four splice variants of the leptin receptor have been identified in humans: the long isoform that has full intracellular signaling capacity and 3 shorter isoforms that differ in the length of their cytoplasmic tail. Here, we report the quantification by reverse transcriptase-polymerase chain reaction (RT-PCR) of the relative expression levels of the 2 major leptin receptor splice variants, the long (OB-RL) and the shortest membrane bound variant (OB-RS) in mononuclear cells from peripheral blood of 15 healthy human subjects (9 women and 6 men), with a body mass index (BMI) that ranged from 19.7 to 41.6. Both OB-RL and OB-RS were coexpressed in all mRNAs tested. However, the expression of the short form (OB-RS), was on average 8-fold higher than the expression of the long form (OB-RL) (120.8 +/- 12.9 v 14.6 +/- 3.0 relative intensity units, P < .001). The predominance of the short splice variant over the long one was apparent in all samples and ranged from 4- to 27-fold. There was no significant difference in the expression of either isoform between men and women. However, the relative expression of both OB-RS and OB-RL isoforms was significantly lower in the overweight (BMI > 26), compared with the lean subjects (BMI < 25) (78.8 +/- 9.1 and 6.2 +/- 1.1 v148.8 +/- 14.4 and 18.9 +/- 4.0 relative intensity units, respectively, P < .03) and was inversely correlated with the BMI and plasma leptin levels (P < .01). In conclusion, the expression of OB-RS and OB-RL leptin receptor isoforms appears to be reduced in human peripheral blood mononuclear cells from obese individuals, with OB-RS remaining the predominant leptin receptor isoform. This might have implications for the bioavailability and/or action of circulating leptin not only on these cells, but also on other target tissues.

Involvement of chromosome 13 in myelodysplastic syndromes.

We report 2 of 80 cases of myelodysplastic syndromes (MDS) cytogenetically studied, with involvement of chromosome 13. The first case had a t(6;13), and the second had a t(1;13). Abnormalities of chromosome 13 mainly involving loss of band 13q14 have been described in hematologic malignancies. In both our cases band 13q14 did not participate in the deleted segment.

[Effect of starvation and phenobarbital on the activity of liver uroporphyrinogen synthetase]. / Effet du jeûne et du phénobarbital sur l'activité de l'uroporphyrinogène synthétase hépatique.

Liver uroporphyrinogen synthetase activity was measured in 45 mice, divided in three groups. The mice of the 1st group served as controls, those of the 2nd starved for 24 hours, while those of the 3rd were injected intraperitoneally with phenobarbital. The enzymic activity was found significantly (p less than 0.001) lower in the animals of the 2nd group (17.49 +/- 2.25 nmol/g/h) and higher in those of the 3rd (25.82 +/- 3.73 nmol/g/h) as compared to the controls (20.89 +/- 2.11 nmol/g/h). If these effects also exist in the human it could be suggested that starvation may be doubly harmful for the patients with acute intermittent porphyria by aggravating both their enzymic disorders. On the contrary, in the case of phenobarbital its undesired effect on porphyria may be moderated by a simultaneous induction of the uroporphyrinogen synthetase.

UK emissions of the greenhouse gas nitrous oxide.

Signatories of the Kyoto Protocol are obliged to submit annual accounts of their anthropogenic greenhouse gas emissions, which include nitrous oxide (N(2)O). Emissions from the sectors industry (3.8 Gg), energy (14.4 Gg), agriculture (86.8 Gg), wastewater (4.4 Gg), land use, land-use change and forestry (2.1 Gg) can be calculated by multiplying activity data (i.e. amount of fertilizer applied, animal numbers) with simple emission factors (Tier 1 approach), which are generally applied across wide geographical regions. The agricultural sector is the largest anthropogenic source of N(2)O in many countries and responsible for 75 per cent of UK N(2)O emissions. Microbial N(2)O production in nitrogen-fertilized soils (27.6 Gg), nitrogen-enriched waters (24.2 Gg) and manure storage systems (6.4 Gg) dominate agricultural emission budgets. For the agricultural sector, the Tier 1 emission factor approach is too simplistic to reflect local variations in climate, ecosystems and management, and is unable to take into account some of the mitigation strategies applied. This paper reviews deviations of observed emissions from those calculated using the simple emission factor approach for all anthropogenic sectors, briefly discusses the need to adopt specific emission factors that reflect regional variability in climate, soil type and management, and explains how bottom-up emission inventories can be verified by top-down modelling.