Improved Survival with Anti-VEGF Therapy in the Treatment of Unresectable Appendiceal Epithelial Neoplasms.

BACKGROUND: Currently, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy are accepted treatments for surgically resectable appendiceal epithelial neoplasms. However, for nonsurgical candidates, systemic treatment may be considered. The purpose of this analysis was to determine the benefit of biologic therapy (anti-vascular endothelial growth factor and anti-epidermal growth factor receptor) in addition to systemic chemotherapy in this select patient population. METHODS: The MD Anderson Cancer Center tumor registry was retrospectively reviewed for systemic treatment-naive appendiceal epithelial neoplasm patients registered between January 2000 to July 2007 for prior cytoreductive surgery and hyperthermic intraperitoneal chemotherapy status, histologic grade, signet ring pathology, systemic chemotherapy, biologic therapy, tumor markers (carcinoembryonic antigen, carbohydrate antigen [CA] 125, and/or CA19-9), progression-free survival (PFS), overall survival (OS), and disease control rate. Kaplan-Meier method, log-rank, and Cox proportional hazard regression models were used for statistical analysis. RESULTS: A total of 353 patients were identified; 130 patients met the inclusion criteria. Fifty-nine patients received biologic therapy. The use of the anti-vascular endothelial growth factor (VEGF) agent bevacizumab improved both OS (42 months vs. 76 months, hazard ratio 0.49 [95 % confidence interval 0.25-0.94] P = 0.03) and PFS (4 months vs. 9 months, hazard ratio 0.69 [95 % confidence interval 0.47-0.995], P = 0.047) for all histologic subtypes. Moderately differentiated tumors had an improved PFS relative to well-differentiated tumors, 9 months versus 3 months (P = 0.05). CONCLUSIONS: Bevacizumab in combination with chemotherapy appears to play a role in surgically unresectable appendiceal epithelial neoplasm patients, with an improvement in PFS and OS. Anti-VEGF agents should be strongly considered in the management of patients with higher-grade appendiceal epithelial neoplasms who are suboptimal candidates for surgical resection.

Biological activity of complement in vivo. Role of C5 in the accumulation of polymorphonuclear leukocytes in inflammatory exudates.

The importance of C5 in the generation of complement (C)-dependent chemotactic activity in vitro is well recognized. However, the actual role C5 may play in the accumulation of polymorphonuclear leukocytes (PMN) at inflammatory sites in vivo has not been established. Injection of glycogen or endotoxin into the peritoneal cavities of guinea pigs resulted, shortly thereafter, in the local accumulation of PMN. Preceding the influx of leukocytes, the peritoneal fluid became chemotactic for rabbit PMN in vitro. The majority of this activity could be attributed to a cleavage product of C5 (C5a). Similarly, injection of endotoxin into the peritoneal cavity of C5-normal mice resulted in the generation of a chemotactic factor for mouse PMN which was followed by the accumulation of PMN in the peritoneal fluid. In contrast, injection of endotoxin into the peritoneal cavity of C5-deficient mice resulted in the generation of virtually no detectable chemotactic activity and a markedly depressed accumulation of PMN during the first 24 hr after injection. The data suggest that C5 plays an important role in the early phases of PMN accumulation in response to inflammatory stimuli. The rapid accumulation of PMN in response to an inflammatory stimulus such as bacterial endotoxin would be expected to be a major factor in host defense against proliferation and dissemination of infectious agents.

Alternating frequency to increase the response to stimulation from medium voltage electrical stimulation and the effect on objective meat quality.

The use of alternating frequencies during stimulation can increase stimulation response of a medium voltage electrical stimulation unit (MVS) by increasing the rate of pH decline. Various combinations of frequency modulation were tested in experiment 1 to determine the treatment resulting in the greatest stimulation response; the lowest initial pH, fastest rate of pH decline, highest temperature at pH 6 and the highest number of carcasses with a pH of 6 by 25(o)C and the treatment achieving the highest number of carcasses in the pH temp window (temperature at pH 6 between 18-25(o)C). The objective meat quality of these treatments compared to an unstimulated treatment was tested in experiment 2. Modulating the frequency (Hz) across the 6 segmented electrodes of the MVS by 10, 15, 25, 10, 15, 25Hz (Treatment 6, using a pulse width: 2.5ms, current: 1A) resulted in the greatest stimulation response. This treatment may be suitable for abattoirs that hot bone sheepmeat and require fast pH declines to ensure minimal cold shortening of meat. However, this treatment did not result in the tenderer meat despite the higher stimulation response. This treatment may have induced a greater number of contractions overall and therefore a greater pH decline response but resulted in less myofibrillar disruption compared to the other treatments due to a concomitant decreased force of contraction thus reducing potential tenderisation. Maintaining a constant frequency of 15Hz (Treatment 1; pulse width: 2.5ms, current: 1A) resulted in a higher number of carcasses in the pH temp window required (temperature at pH 6 between 18-25(o)C) in part A (P<0.05) and in addition to the higher tenderness levels this treatment may be more appropriate to satisfy the overall demands of abattoirs using these systems. This paper has also demonstrated electrical stimulation results in tenderer meat compared to unstimulated meat even after 30d of ageing (2.53±0.4 compared to 2.85±0.1 for the loin (M. longissimus thoracis et lumborum) (P<0.01) possibly due to a protective benefit of stimulation on meat tenderness. Overall, no detrimental effects of modulating frequency were observed on drip loss or retail colour display despite a greater rate of colour change observed with the modulated frequency treatment and the longer aged product.

Impact of prenatal and postnatal maternal environment on nephron endowment, renal function and blood pressure in the Lewis polycystic kidney rat.

Maternal insufficiency during fetal development can have long-lasting effects on the offspring, most notably on nephron endowment. In polycystic kidney disease (PKD), variability in severity of disease is observed and maternal environment may be a modifying factor. In this study, we first established that in a rodent model of PKD, the Lewis polycystic kidney (LPK) rat's nephron numbers are 25% lower compared with wildtype animals. We then investigated the effects of prenatal and postnatal maternal environment on phenotype and nephron number. LPK pups born from and raised by homozygous LPK dams (control) were compared with LPK pups cross-fostered onto heterozygous LPK dams to improve postnatal environment; with LPK pups born from and raised by heterozygous LPK dams to improve both prenatal and postnatal environment and with LPK pups born from and raised by Wistar Kyoto-LPK heterozygous dams to improve both prenatal and postnatal environment on a different genetic background. Improvement in both prenatal and postnatal environment improved postnatal growth, renal function and reduced blood pressure, most notably in animals with different genetic background. Animals with improved postnatal environment only showed improved growth and blood pressure, but to a lesser extent. All intervention groups showed increased nephron number compared with control LPK. In summary, prenatal and postnatal environment had significant effect in delaying progression and reducing severity of PKD, including nephron endowment.

The nuclear oncoprotein TLX1/HOX11 associates with pericentromeric satellite 2 DNA in leukemic T-cells.

TLX1/HOX11, a DNA-binding homeodomain protein, was originally identified by virtue of its aberrant expression in T-cell leukemia and subsequently found to be crucial for normal spleen development. The precise mechanism of TLX1 function remains poorly understood, although it is known that it can act as both a transcriptional activator and repressor and can downregulate the Aldh1a1 gene in embryonic mouse spleen. Using a whole-genome PCR approach, we show here that TLX1 protein directly interacts with pericentromeric human satellite 2 DNA sequences. Such DNA is known to localize to heterochromatin, which among other roles has been implicated in gene silencing. The interaction was confirmed in vitro and in vivo by gel retardation and chromatin immunoprecipitation assays involving satellite 2 DNA, which contained sequences resembling TLX1 binding sites. Using immunofluorescence microscopy, TLX1 demonstrated a punctate pattern of staining in the nuclei of leukemic T-cells (ALL-SIL). Double labelling indicated that TLX1 colocalized with the centromeric protein CENP-B, demonstrating that the TLX1 foci corresponded to clusters of centromeric DNA. The novel interaction of TLX1 with constitutive heterochromatin adds an additional level of complexity to the intracellular functions of this transcriptional regulator and may have relevance to its roles in transcriptional repression and T-cell immortalization.

Uraemia: an unrecognized driver of central neurohumoral dysfunction in chronic kidney disease?

Chronic kidney disease (CKD) carries a large cardiovascular burden in part due to hypertension and neurohumoral dysfunction - manifesting as sympathetic overactivity, baroreflex dysfunction and chronically elevated circulating vasopressin. Alterations within the central nervous system (CNS) are necessary for the expression of neurohumoral dysfunction in CKD; however, the underlying mechanisms are poorly defined. Uraemic toxins are a diverse group of compounds that accumulate as a direct result of renal disease and drive dysfunction in multiple organs, including the brain. Intensive haemodialysis improves both sympathetic overactivity and cardiac baroreflex sensitivity in renal failure patients, indicating that uraemic toxins participate in the maintenance of autonomic dysfunction in CKD. In rodents exposed to uraemia, immediate early gene expression analysis suggests upregulated activity of not only pre-sympathetic but also vasopressin-secretory nuclei. We outline several potential mechanisms by which uraemia might drive neurohumoral dysfunction in CKD. These include superoxide-dependent effects on neural activity, depletion of nitric oxide and induction of low-grade systemic inflammation. Recent evidence has highlighted superoxide production as an intermediate for the depolarizing effect of some uraemic toxins on neuronal cells. We provide preliminary data indicating augmented superoxide production within the hypothalamic paraventricular nucleus in the Lewis polycystic kidney rat, which might be important for mediating the neurohumoral dysfunction exhibited in this CKD model. We speculate that the uraemic state might serve to sensitize the central actions of other sympathoexcitatory factors, including renal afferent nerve inputs to the CNS and angiotensin II, by way of recruiting convergent superoxide-dependent and pro-inflammatory pathways.

Progressive vascular remodelling, endothelial dysfunction and stiffness in mesenteric resistance arteries in a rodent model of chronic kidney disease.

Chronic kidney disease (CKD) and hypertension are co-morbid conditions both associated with altered resistance artery structure, biomechanics and function. We examined these characteristics in mesenteric artery together with renal function and systolic blood pressure (SBP) changes in the Lewis polycystic kidney (LPK) rat model of CKD. Animals were studied at early (6-weeks), intermediate (12-weeks), and late (18-weeks) time-points (n=21), relative to age-matched Lewis controls (n=29). At 12 and 18-weeks, LPK arteries exhibited eutrophic and hypertrophic inward remodelling characterised by thickened medial smooth muscle, decreased lumen diameter, and unchanged or increased media cross-sectional area, respectively. At these later time points, endothelium-dependent vasorelaxation was also compromised, associated with impaired endothelium-dependent hyperpolarisation and reduced nitric oxide synthase activity. Stiffness, elastic-modulus/stress slopes and collagen/elastin ratios were increased in 6 and 18-week-old-LPK, in contrast to greater arterial compliance at 12weeks. Multiple linear regression analysis highlighted SBP as the main predictor of wall-lumen ratio (r=0.536, P<0.001 n=46 pairs). Concentration-response curves revealed increased sensitivity to phenylephrine but not potassium chloride in 18-week-LPK. Our results indicate that impairment in LPK resistance vasculature is evident at 6weeks, and worsens with hypertension and progression of renal disease.

Phosphorylated extracellular signal-regulated kinase 1/2 immunoreactivity identifies a novel subpopulation of sympathetic preganglionic neurons.

Distinct chemical codes are thought to reflect functional specificity in sympathetic preganglionic neurons (SPN). Although a number of chemical candidates have been identified including neurotransmitter-related, calcium-binding and other proteins, signal transduction proteins have been largely neglected. Not only might these chemicals allow discrimination of functionally unique chemical signatures, but they may also identify activated neurons. Immunoreactivity (ir) to phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2) was differentially located within the thoracic spinal cord depending upon which of three forms of killing was used: the only exception to this was the intermediolateral cell column (IML) which was consistently, densely labeled. The presence or absence of p-ERK1/2 in SPN (n=17,541) within the IML of the thoraco-lumbar spinal cord was determined in seven rats. SPN were identified on the basis of their location, size and that they contained choline acetyltransferase ir. On average, 58% of SPN contained p-ERK1/2, however, more SPN in both the upper (72%; C8-T4) and lower (78%; T11-L3) thoraco-lumbar spinal cord contained p-ERK1/2-ir than the middle thoracic region (47%; T4-T10). p-ERK1/2-ir was also examined in SPN (n=1895) innervating the adrenal medulla (identified by retrograde tracing using cholera toxin B subunit) combined with localization of neuronal nitric oxide synthase (nNOS) in three rats. On average, 64% of adrenal SPN contain p-ERK1/2-ir, and it was confirmed that all adrenal SPN contain nNOS-ir. It appears that p-ERK1/2-ir SPN, described in this study, have tonically activated receptors that are coupled to intracellular signal transduction pathways that lead to the phosphorylation of ERK1/2.

Trait perfectionism strengthens the negative effects of moral stressors occurring in veterinary practice.

OBJECTIVE: Moral challenges are a unique class of workplace stressor where behaviours violate one's personal moral beliefs regarding how things should be done or one's perceived obligations. Morally challenging stressors exist in many workplaces and at times can transform into marked emotional distress, referred to as moral distress. In this study we investigated the degree to which morally significant stressors are related to psychological distress and resilience in a sample of Australian veterinarians. Further, we explored the role of trait perfectionism in strengthening the relationship between exposure to morally significant stressors and psychological distress. Trait perfectionism is the tendency to have very high and rigid standards for the self and/or others and is often implicated in the experience of psychological distress. METHODS: A cross-sectional online survey sampled 540 Australian-registered veterinarians (64.2% female), ranging in age from 23 to 74 years. RESULTS: Although morally significant stressors were related to increases in milder expressions of distress, they did not appear to be associated with more severe decrements in psychological wellbeing. Rather, it was the combination of these triggering stressor events and trait perfectionism that appeared to create the vulnerability to moral stressors. CONCLUSION: The findings suggest that trait perfectionism is an individual difference that enhances vulnerability to the risk of greater distress in response to morally challenging events in veterinary practice. The implications of these findings and directions for further research are discussed.

Differential expression of catecholamine synthetic enzymes in the caudal ventral pons.

The analysis of colocalization of multiple catecholamine biosynthetic enzymes within the ventrolateral part of the medulla oblongata of the rat revealed distinct subpopulations of neurons within the C1 region (Phillips et al., J Comp Neurol 2001, 432:20-34). In extending this study to include the caudal pons, it was shown for the first time that the A5 cell group could be distinguished by the presence of immunoreactivity to tyrosine hydroxylase (TH), aromatic l-amino acid decarboxylase (AADC), and dopamine beta hydroxylase (DBH). A novel cell group was also identified. The cells within this new group were immunoreactive to DBH but not TH, AADC, or phenylethanolamine N-methyltransferase (PNMT) and will be referred to as the TH-, DBH+ cell group. The TH-, DBH+ neurons were not immunoreactive for either the dopamine or noradrenaline transporters, suggesting that these neurons do not take up these transmitters. A5 neurons were immunoreactive for the noradrenaline transporter but not the dopamine transporter (as previously shown). Retrograde tracing with cholera toxin B revealed that the TH-, DBH+ neurons do not project to the thoracic spinal cord or to the rostral ventrolateral medulla, but A5 neurons do. A calbindin immunoreactive cell group is located in a region overlapping TH-, DBH+ cell group. However, only a few neurons were immunoreactive for both markers. The physiological role of the TH-, DBH+ cell group remains to be determined.

Differential expression of catecholamine biosynthetic enzymes in the rat ventrolateral medulla.

Adrenergic (C1) neurons located in the rostral ventrolateral medulla are considered a key component in the control of arterial blood pressure. Classically, C1 cells have been identified by their immunoreactivity for the catecholamine biosynthetic enzymes tyrosine hydroxylase (TH) and/or phenylethanolamine N-methyltransferase (PNMT). However, no studies have simultaneously demonstrated the expression of aromatic L-amino acid decarboxylase (AADC) and dopamine beta-hydroxylase (DBH) in these neurons. We examined the expression and colocalization of all four enzymes in the rat ventrolateral medulla using immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR) analysis. Retrograde tracer injected into thoracic spinal segments T2-T4 was used to identify bulbospinal neurons. Using fluorescence and confocal microscopy, most cells of the C1 group were shown to be double or triple labeled with TH, DBH, and PNMT, whereas only 65-78% were immunoreactive for AADC. Cells that lacked detectable immunoreactivity for AADC were located in the rostral C1 region, and approximately 50% were spinally projecting. Some cells in this area lacked DBH immunoreactivity (6.5-8.3%) but were positive for TH and/or PNMT. Small numbers of cells were immunoreactive for only one of the four enzymes. Numerous fibres that were immunoreactive for DBH but not for TH or PNMT were noted in the rostral C1 region. Single-cell RT-PCR analysis conducted on spinally projecting C1 neurons indicated that only 76.5% of cells that contained mRNA for TH, DBH, and PNMT contained detectable message for AADC. These experiments suggest that a proportion of C1 cells may not express all of the enzymes necessary for adrenaline synthesis.

Alpha-adrenergic, neurokinin and muscarinic receptors in rat mesenteric artery; an mRNA study during postnatal development.

Developmental studies show that the innervation of autonomic targets is accompanied by increases in the density of receptors, maturation of receptor-signalling pathways and changes in receptor subtype. The innervation of the rat mesenteric artery occurs over the first 3 postnatal weeks. In this study, we investigated whether alterations in receptor gene expression may underlie physiological changes recorded during development and maturity in this vessel. Total RNA, from mesenteric arteries of rats at birth and postnatal days 7, 14, 28, 240 and 360, was reverse transcribed and amplified using primers specific for the alpha 1 (A, B, D)- and alpha 2 (A, B, C)-adrenergic, neurokinin (NK1-NK3) and muscarinic (m1-m5) receptors. Results showed that all receptor genes expressed at 28 days, except the alpha 1D-adrenergic receptor, were already expressed at birth. Some receptor subtypes showed no change in their relative expression, always being either strongly (alpha 1A, alpha 2B, NK3) or weakly (alpha 2A, alpha 2C, NK1) expressed. Relative to the expression of these receptors, others showed a developmental increase in expression up to 14 days postnatal (alpha 1B, alpha 1D, m2, m3, m5) but no further change with maturity. These latter changes coincide with the development of sympathetic and sensory nerve plexuses in the mesenteric artery, but do not correlate with the physiological changes seen during development and ageing.

Receptors involved in nerve-mediated vasoconstriction in small arteries of the rat hepatic mesentery.

1. We have investigated the neurotransmitters and receptor subtypes involved in nerve-mediated vasoconstriction in small arteries of the rat hepatic mesentery. 2. A dense sympathetic innervation was demonstrated using catecholamine histochemistry and antibodies against the synaptic vesicle protein synaptophysin. 3. Reverse transcription-polymerase chain reaction (RT-PCR) demonstrated very strong expression of the alpha1A-adrenergic, neuropeptide Y (NPY) Y1, P2X1- and P2X4-purinergic receptors, moderate expression of the alpha2B-adrenergic receptor and the purinergic P2X5- and P2X7-receptors and weak expression of the alpha1B-, alpha1D-, alpha2A- and alpha2C-adrenergic receptors and the P2X2- and P2X3-purinergic receptors. NPY2 and P2X6 receptor expression was absent. 4. Electrical field stimulation (10 Hz, 10 s) produced contractions which were abolished by tetrodotoxin (10(-6) M) and/or guanethidine (GE, 5 x 10(-6) M) and a combination of benextramine (10(-5) M) and alpha,beta-methylene ATP, (alpha,beta-mATP, 3 x 10(-6) M) or PPADS (10(-5) M). Selective alpah1-adrenergic receptor antagonists showed the potency order of prazosin > WB-4101 > 5-methyl-urapidil > BMY 7378. Yohimbine (10(-8) M, 10(-7) M), alpha,beta-mATP (3 x 10(-6) M) and PPADS (10(-5) M) each enhanced the response to nerve stimulation. 5. Some experiments demonstrated a slow neurogenic contraction which was abolished by GE or the selective NPY1 receptor antagonist 1229U91 (6 x 10(-7) M). 6. We conclude that nerve-mediated vasoconstriction results from the activation of postsynaptic alpha,beta-adrenergic and P2X-purinergic receptors and under some conditions, NPY1 receptors. Neurotransmitter release is modulated by presynaptic alpha2-adrenergic receptors and possibly also P2X-purinoceptors. The major postsynaptic subtypes involved were well predicted by mRNA expression as measured by RT-PCR, suggesting that this technique may be a useful adjunct to studies aimed at identifying functional receptor subtypes.

Differential expression of the noradrenaline transporter in adrenergic chromaffin cells, ganglion cells and nerve fibres of the rat adrenal medulla.

Expression of the noradrenaline transporter (NAT) was identified in various cell and fibre populations of the rat adrenal medulla, examined with immunohistochemistry and confocal microscopy. Immunoreactivity for the catecholamine biosynthetic enzymes tyrosine hydroxylase (TH), aromatic-L-amino-acid decarboxylase (AADC) and dopamine beta-hydroxylase (DBH) was present in all chromaffin cells, while phenylethanolamine N-methyltransferase (PNMT) was used to determine adrenergic chromaffin cell groups. Labelling with NAT antibody was predominantly cytoplasmic and colocalised with PNMT immunoreactivity. Noradrenergic chromaffin cells were not NAT immunoreactive. Additionally, NAT antibody labelling demonstrated clusters of ganglion cells (presumably Type I) and nerve fibres. Expression of TH, AADC, DBH, PNMT and NAT mRNA was examined using reverse transcription-polymerase chain reaction (RT-PCR) from adrenal medulla punches and single chromaffin cells, and results were consistent with those obtained with immunocytochemistry. Chromaffin cells and fibres labelled with antibodies against growth associated protein-43 (GAP-43) were not NAT immunoreactive, while ganglion cells were doubled labelled with the two antibodies. The presence of NAT in adrenergic chromaffin cells, and its absence from noradrenergic cells, suggests that the adrenergic cell type is primarily responsible for uptake of catecholamines in the adrenal medulla.

Massive bone marrow necrosis and postnecrotic myelofibrosis in a patient with primary thrombocythaemia.

A case of non-fatal massive bone marrow necrosis (MBMN) is reported in a patient with primary thrombocythaemia five years after diagnosis. No precipitating cause was identified. The patient developed postnecrotic myelofibrosis six months later. As far as is known, this is the first report of MBMN in a case of primary thrombocythaemia.

Renal failure caused by leukaemic infiltration in chronic lymphocytic leukaemia.

A case of B-CLL which was complicated by chronic renal failure due to leukaemic infiltration of the kidney is reported. Treatment with chlorambucil, prednisolone, and renal bed irradiation resulted in a substantial improvement in renal function which persisted until the the patient's death from marrow failure some eight years later. The temporal association between treatments and response suggested that renal bed radiotherapy had contributed to the improvement in renal function. This case is one of only two reported cases in which chronic renal failure due to CLL has been treated with radiotherapy. It is unique in that the renal response was shown histologically. Leukaemic infiltration of the kidney is common in CLL but, characteristically, is not associated with renal impairment. An improvement in renal function has been described in two patients with acute renal failure after chemotherapy.

Seasonal variation in preeclampsia based on timing of conception.

OBJECTIVE: Studies have suggested that the incidence of preeclampsia may be partially dependent on the month or season of delivery. We sought to evaluate whether preeclampsia occurs seasonally in our population and whether the timing of conception or delivery is more strongly associated with risk. METHODS: Between January 1995 and August 2003, we identified 142 primiparous women with singleton pregnancies who met the American College of Obstetricians and Gynecologists' definition for preeclampsia and compared them with 7,762 primiparous control deliveries. We analyzed rates of preeclampsia by individual month and 3-month seasonal blocks based on conception and delivery. Data were analyzed with the chi2 test, and logistic regression and odds ratios were calculated where appropriate. RESULTS: Preeclampsia occurred in 1.8% of singleton primiparous gestations (142/7,904). Cases were younger than controls (26.5 +/- 5.6 versus 28.0 +/- 0 6.0 years, P < .003), of similar race (97% white versus 96% white, P = .69), and equally likely to have a female child (45% versus 48%, P = .41). We found no significant association of month (logistic regression P = .20) of delivery with the risk of preeclampsia. There was a significant association of month (P = .003) of conception with risk of preeclampsia. Conception during the summer months had the highest risk (incidence 2.3%; odds ratio 1.7; 95% confidence limits 1.06, 2.75) compared with spring (incidence 1.4%). Fall (1.7%) and winter (1.6%) conceptions were associated with intermediate rates of preeclampsia. CONCLUSION: We identified a seasonal variation in preeclampsia that appears to be more strongly related to timing of conception than to the timing of delivery. The highest incidence of preeclampsia was associated with conception in the summer months. LEVEL OF EVIDENCE: II-2.

VIM-D salvage chemotherapy in Hodgkin's disease.

A total of 15 patients with relapsed or resistant Hodgkin's disease were treated with a combination of etoposide (VP16), ifosfamide, mitozantrone and dexamethasone (VIM-D). The regime was well tolerated, the only major toxicity being myelosuppression. Complete remissions (CRs) were obtained in 4 patients and were maintained for 2, 4, 10 and 14 months. 10 subjects subsequently received an autologous bone marrow transplant with high-dose chemotherapy (ABMT). Previous exposure to VIM-D did not appear to predict for or prejudice the response to subsequent ABMT.

Neuroreceptor mRNA expression in the rat mesenteric artery develops independently of innervation.

Studies in autonomic targets have shown that nerves may be required for the development and maintenance of postsynaptic receptor populations. We have examined this relationship in the rat mesenteric artery, assessing mRNA expression levels for a range of neuroreceptors after neonatal sympathectomy, using 6-hydroxydopamine or antisera directed against nerve growth factor, and sensory denervation, using capsaicin. Total RNA was extracted from 28 day old rats and reverse transcription-polymerase chain reaction was performed, using primers specific for the alpha1(A,B,D)- and alpha2(A,B,C)-adrenergic, neurokinin (NKI-NK3), muscarinic (M1-M5) and P2X purinergic (P2x1-7) receptor families. Results showed no decreases in mRNA expression of any of the specific receptor subtypes after either sympathetic or sensory denervation. Small increases in mRNA expression were detected following sensory denervation for some of the receptor subtypes. We conclude that neither sympathetic nor sensory nerves are mandatory for the expression of mRNA of a range of neuroreceptors in the mesenteric vascular bed of the rat.

A randomized study of MOD versus VAD in the treatment of relapsed and resistant multiple myeloma.

67 patients with relapsed or resistant multiple myeloma were randomized to receive either VAD (vincristine, doxorubicin, dexamethasone) or MOD (mitozantrone, vincristine, dexamethasone). 12/30 (40%) patients receiving VAD and 15/37 (41%) patients receiving MOD achieved plateaux. The median duration of plateaux was significantly longer on VAD (15 months) than on MOD (8 months). No significant difference in overall survival was seen between the two treatment arms. The only toxicity which was severe in more than 5% of treatment cycles on either treatment arm was myelosuppression. No toxicity was significantly more severe on MOD than VAD. However, hair loss was significantly more severe on VAD than MOD. The frequencies of thrombocytopenia, haematuria and cutaneous toxicity were significantly greater on VAD than on MOD. Raised serum direct bilirubin levels were seen significantly more often on MOD than VAD. MOD and VAD have similar efficacy in relapsed/resistant multiple myeloma. MOD is the less toxic of the two regimens.