Future directions for the concept of salutogenesis: a position article.

Aaron Antonovsky advanced the concept of salutogenesis almost four decades ago (Antonovsky, Health, Stress and Coping. Jossey-Bass, San Francisco, CA, 1979; Unravelling the Mystery of Health. Jossey-Bass, San Francisco, CA, 1987). Salutogenesis posits that life experiences shape the sense of coherence (SOC) that helps to mobilize resources to cope with stressors and manage tension successfully (determining one's movement on the health Ease/Dis-ease continuum). Antonovsky considered the three-dimensional SOC (i.e. comprehensibility, manageability, meaningfulness) as the key answer to his question about the origin of health. The field of health promotion has adopted the concept of salutogenesis as reflected in the international Handbook of Salutogenesis (Mittelmark et al., The Handbook of Salutogenesis. Springer, New York, 2016). However, health promotion mostly builds on the more vague, general salutogenic orientation that implies the need to foster resources and capacities to promote health and wellbeing. To strengthen the knowledge base of salutogenesis, the Global Working Group on Salutogenesis (GWG-Sal) of the International Union of Health Promotion and Education produced the Handbook of Salutogenesis. During the creation of the handbook and the regular meetings of the GWG-Sal, the working group identified four key conceptual issues to be advanced: (i) the overall salutogenic model of health; (ii) the SOC concept; (iii) the design of salutogenic interventions and change processes in complex systems; (iv) the application of salutogenesis beyond health sector. For each of these areas, we first highlight Antonovsky's original contribution and then present suggestions for future development. These ideas will help guide GWG-Sal's work to strengthen salutogenesis as a theory base for health promotion.

Volumetric dynamic oxygen-enhanced MRI (OE-MRI): comparison with CT Brody score and lung function in cystic fibrosis patients.

OBJECTIVES: To demonstrate, in patients with cystic fibrosis (CF), the correlation between three-dimensional dynamic oxygen-enhanced magnetic resonance imaging (OE-MRI) measurements and computed tomography Brody score (CF-CT) and lung function testing (LFT). METHODS: Twenty-one patients (median age, 25 years; female, n = 8) with a range of CF lung disease and five healthy volunteers (median age, 31 years; female, n = 2) underwent OE-MRI performed on a 1.5-T MRI scanner. Coronal volumes were acquired while patients alternately breathed room air and 100% oxygen. Pre-oxygen T1 was measured. Dynamic series of T1-weighted volumes were then obtained while breathing oxygen. T1-parameter maps were generated and the following OE-MRI parameters were measured: oxygen uptake (ΔPO2max), wash-in time and wash-out time. High-resolution CT and LFT were performed. The relationship between CF-CT, LFT and OE-MRI parameters were evaluated using Pearson correlation for the whole lung and regionally. RESULTS: Mean CF-CT was 24.1±17.1. Mean ΔPO2max and mean wash-in as well as skewness of wash-out showed significant correlation with CF-CT (ΔPO2max: r = -0.741, p < 0.001; mean wash-in: r = 0.501, p = 0.017; skewness of wash-out: r = 0.597, p = 0.001). There was significant correlation for the whole lung and regionally between LFT parameters and OE-MR (ΔPO2max: r = 0.718, p < 0.001; wash-in: r = -0.576, p = 0.003; wash-out skewness: r = -0.552, p = 0.004). CONCLUSIONS: Functional lung imaging using OE-MRI has the capability to assess the severity of CF lung disease and shows a significant correlation with LFT and CF-CT. KEY POINTS: • Oxygen-enhanced MRI might play a future role in evaluation and follow-up of cystic fibrosis. • Heterogeneity of parameter maps reflects localised functional impairment in cystic fibrosis. • Avoidance of cumulative radiation burden in CF is feasible using OE-MRI.

Correction to: Volumetric dynamic oxygen-enhanced MRI (OE-MRI): comparison with CT Brody score and lung function in cystic fibrosis patients.

The original version of this article, published on 13 April 2018, unfortunately contained a mistake.

Differential modification of genetic susceptibility to childhood eczema by two probiotics.

BACKGROUND: In a double-blind, randomized, placebo-controlled birth cohort, we have recently shown a beneficial effect of Lactobacillus rhamnosus HN001 (HN001) for the prevention of eczema in children through to 6 years of age but no effect of Bifidobacterium animalis subsp lactis HN019 (HN019). OBJECTIVE: Among this cohort of children, we aim to investigate whether these probiotics could modify the expression of genetic predisposition to eczema conferred by genetic variation in susceptibility genes. METHODS: Thirty-three eczema susceptibility SNPs (in eleven genes) were genotyped in 331 children of European ancestry. RESULTS: Children who carried a genetic variant that put them at a high risk of developing eczema were less likely to develop eczema if they had been randomized to the HN001 intervention group compared to those in the placebo group. HN019 was also able to protect against the effects of some SNPs. As well as modifying genetic susceptibility to childhood eczema, HN001 was also found to modify genetic susceptibility to eczema severity and atopy risk. CONCLUSION AND CLINICAL RELEVANCE: This is the first study to show an effect of a probiotic on reducing eczema risk amongst those with particular eczema-associated genotypes. Our findings suggest that Lactobacillus rhamnosus HN001 may be particularly effective in preventing eczema in children with specific high-risk genotypes.

Permanent stoma rates: a misleading marker of quality in rectal cancer surgery.

AIM: The latest National Bowel Cancer Audit Programme (NBOCAP) audit identified our colorectal unit as an outlier with regard to the high permanent stoma rate. The aim of this study was to perform an audit of the rationale for stoma formation in patients undergoing rectal cancer resection in our unit. METHOD: A review was conducted of all rectal cancer operations between April 2011 and March 2013. Preoperative staging investigations and operation reports were reviewed to identify the reasons for nonrestorative surgery. Postoperative histology reports were used to identify circumferential resection margin (CRM) involvement and tumour height. RESULTS: One-hundred and twenty-five patients underwent surgery for rectal cancer, of whom 102 underwent elective resection with curative intent. The permanent stoma rate was 63.2% when emergency and palliative procedures were included and 54.9% when only elective curative cases were considered. Tertiary referrals made up 31.4% of elective cases. The main reasons for nonrestorative surgery included multivisceral resection (n = 24) for locally advanced cancer and operations for lesions close to the anal sphincter (n = 21). The median length of stay was 8 days, the 90-day mortality was 2.9% and the rate of CRM involvement was 2.0%. CONCLUSION: Our unit provides multivisceral surgery for locally advanced rectal cancer and receives a substantial number of tertiary referrals. Many of the rectal cancers referred are locally advanced or threaten the anal sphincter. This study demonstrates that the complexity of a unit's case-mix can have a profound effect on the permanent stoma rate. Stoma rates taken at face value do not therefore provide an accurate representation of surgical quality. What does this paper add to the literature? The study reviews the practice of a colorectal surgical unit with an interest in multivisceral surgery with regard to the permanent stoma rate. The reasons for nonrestorative surgery are analysed, and the problems associated with the use of stoma rates as a marker of quality in colorectal surgery are highlighted.

PTPN2 but not PTPN22 is associated with Crohn's disease in a New Zealand population.

Recent genome-wide association studies have provided evidence for the involvement of the genes PTPN2 and PTPN22 in the pathogenesis of Crohn's disease (CD). We investigated whether genetic variants in these genes were associated with CD in a New Zealand population. Single-nucleotide polymorphisms (SNPs) rs2542151 (PTPN2) and rs2476601 (PTPN22) were genotyped in 315 CD cases and 481 controls. In this sample, we were able to confirm an association between CD and PTPN2 (genotypic P = 0.019 and allelic P = 0.011), and phenotypic analysis showed an association of this SNP with late age at first diagnosis, inflammatory and penetrating CD behaviour, requirement of bowel resection and being a smoker at diagnosis. There was no evidence for an association with PTPN22.

Local recurrence after abdomino-perineal resection.

OBJECTIVE: Local recurrence of rectal cancer is a major cause of morbidity and mortality following curative resection. The published rates vary after abdomino-perineal resection (APR) from 5% to 47%. The aim of this study was to evaluate local recurrence following curative APR for low rectal cancer in our unit. METHOD: The medical notes of patients treated between 1st January 1996 and 31st December 2000 were retrieved. Local recurrence was defined as the presence of tumour within the pelvis confirmed by clinical findings, pathological specimen or radiological reports. A curative resection was defined as excision of tumour in the absence of macroscopic metastatic disease and whose resection margins were greater than 1 mm circumferentially and 10 mm distally. Outcomes and survival were compared using Fisher's exact test and Kaplan-Meier method. RESULTS: Two hundred consecutive cases with a diagnosis of rectal cancer were identified of which 139 underwent a curative resection (69.5%). Of these 40 patients (28%) underwent APR with curative intent. Two patients (5%) developed local recurrence at 18 and 24 months respectively. The overall local recurrence rate for all curative rectal cancer surgery, in the same period was 2.6%. Eleven patients have died in the follow-up period of which nine were cancer-related deaths. CONCLUSION: The local recurrence rates achieved with APR were not significantly different from those achieved with restorative operations. Tumours at the ano-rectal junction should not be dissected off the pelvic floor, but radically excised en bloc with the surrounding levator ani, as a cylinder, as originally described by Miles.

Association analysis of dynamin-binding protein (DNMBP) on chromosome 10q with late onset Alzheimer's disease in a large caucasian UK sample.

A recent scan of single nucleotide polymorphisms (SNPs) in the region 40-107 Mb on chromosome 10q in a large Japanese case-control cohort identified six SNPs in or near the dynamin-binding protein gene (DNMBP) that were associated with late onset Alzheimer's disease (LOAD) in individuals lacking the APOE epsilon4 allele [Kuwano et al. (2006); Hum Mol Genet 15:2170-2182]. We genotyped these six SNPs in 1,212 unrelated Caucasian patients of UK origin with LOAD and 1,389 ethnically, gender and age matched control subjects. We did not observe a statistically significant association with the risk of LOAD for any of the six SNPs in the sample as a whole. When stratifying the sample by APOE one SNP (intergenic SNP rs11190302) was associated with LOAD in individuals lacking the epsilon4 allele (genotypic P = 0.027, allelic P = 0.066). However this association was in the opposite direction to that detected in the Japanese population. It remains to be determined whether DNMBP is associated with LOAD.

Base mismatches and mutagenesis: how important is tautomerism?

Tautomerism of nucleotides is an attractive model to explain transitional mutations; the structure of the mismatched base pairs in their enol or imino forms do not distort the DNA double helix. However recent structural data suggest that the mismatched nucleotides are in their normal keto and amino forms. 'Wobble' and other base pairings (for transversions) have C1'-C1' distances close to those found in the classical Watson-Crick base pairs. Kinetic studies show substrates are in their major tautomeric forms in their transition states. This suggests tautomerism may not be important for substitution mutations.

Association analysis of 528 intra-genic SNPs in a region of chromosome 10 linked to late onset Alzheimer's disease.

Late-onset Alzheimer's disease (LOAD) is a genetically complex neurodegenerative disorder. Currently, only the epsilon4 allele of the Apolipoprotein E gene has been identified unequivocally as a genetic susceptibility factor for LOAD. Others remain to be found. In 2002 we observed genome-wide significant evidence of linkage to a region on chromosome 10q11.23-q21.3 [Myers et al. (2002) Am J Med Genet 114:235-244]. Our objective in this study was to test every gene within the maximum LOD-1 linkage region, for association with LOAD. We obtained results for 528 SNPs from 67 genes, with an average density of 1 SNP every 10 kb within the genes. We demonstrated nominally significant association with LOAD for 4 SNPs: rs1881747 near DKK1 (P = 0.011, OR = 1.24), rs2279420 in ANK3 (P = 0.022, OR = 0.79), rs2306402 in CTNNA3 (P = 0.024, OR = 1.18), and rs5030882 in CXXC6 (P = 0.046, OR = 1.29) in 1,160 cases and 1,389 controls. These results would not survive correction for multiple testing but warrant attempts at confirmation in independent samples.

Dopamine transporter (DAT1/SLC6A3) polymorphism and the association between being born small for gestational age and symptoms of ADHD.

Being small for gestational age (SGA) has been established as a risk factor for Attention Deficit Hyperactivity Disorder (ADHD). Likewise, several molecular genetic studies have found a link between DAT1 and ADHD. This study investigated whether SGA moderates the effect of dopamine transporter gene variants on the risk of ADHD. A total of 546 children of European descent were genotyped at age 11 for seven DAT1 SNPs (rs6347, rs11564774, rs40184, rs1042098, rs2702, rs8179029 and rs3863145). The Strengths and Difficulties Questionnaire was used to measure symptoms of ADHD at ages 3.5, 7 and 11. We found significant gene-environment interactions between birth weight and DAT1 SNPs (rs6347, rs40184, rs1042098, rs3863145) on ADHD symptoms at 3.5 years only. Results suggest that genotypic variation of DAT1 may confer a relative protective effect against ADHD in SGA individuals. This study supports the idea that being born SGA moderates the effect of the DAT1 gene on ADHD symptoms in the preschool years and may help to explain some of the heterogeneity in ADHD outcomes.

New photosensitizers for photodynamic therapy: combined effect of metallopurpurin derivatives and light on transplantable bladder tumors.

A series of metallopurpurins was tested for their photodynamic activity against transplantable N-[4-(5-nitro-2-furyl)-2-thiazoyl]formamide-induced urothelial tumors growing in male Fischer CDF (F344/CrlBR) rats. Histological examination of tumors in animals treated with the metallopurpurins and red light (greater than 590 nm, 360 J/cm2) revealed tumor necrosis 24 h after completion of therapy. Control tumors showed no histological change. In 30-day tumor regrowth studies, 70% of animals treated with the metallopurpurin derivative SnET2 were free of tumors while 50% of the animals treated with the free-base purpurin ET2 were free of tumor. Metallopurpurins have intense absorptions in the red region of the visible spectrum, a region with good tissue penetration. The metallopurpurins are easily prepared from the corresponding purpurins with a high degree of purity. This study demonstrates the potential of these photosensitizers for photodynamic cancer therapy.

Morphological study of the combined effect of purpurin derivatives and light on transplantable rat bladder tumors.

Purpurin derivatives, a group of synthetic photosensitizers, were tested for their photodynamic activity against transplantable N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide-induced urothelial tumors growing in male Fischer 344 rats. Histological examination of tumors in animals treated with the purpurin derivatives and red light (greater than 590 nm, 360 joules/cm2) revealed tumor cell necrosis 24 h after completion of therapy. Control tumors showed no histological change. Purpurins have a major absorption peak in the red region (greater than 650 nm) of the visible spectrum, a region with good tissue penetration, and purpurins can be synthesized with a high degree of purity. This study demonstrates the potential of purpurin derivatives as photosensitizers for photodynamic cancer therapy.

Conformational isomerization of the Holliday junction associated with a cruciform during branch migration in supercoiled plasmid DNA.

The variable positions of a branch-migrating cruciform junction in supercoiled plasmid DNA were mapped following cleavage of the DNA with bacteriophage T7 endonuclease I. T7 endonuclease I specifically cleaved, and thereby resolved, the Holliday junction existing at the base of the cruciform in the circular bacterial plasmid pSA1B.56A. Cruciform extrusion of cloned sequences in pSA1B.56A (containing a 322 base-pair inverted repeat insert composed of poxvirus telomeric sequences) topologically relaxed the plasmid substrate in vitro. Thus, numerous crossover positions were identified within the region of cloned sequences, reflecting the range of superhelical densities in the native plasmid preparation. Endonuclease I-sensitive crossover positions, mapped to both strands of the viral insert following the T7 endonuclease I digestion of either plasmid preparations or individual topoisomers, were regularly separated by approximately ten nucleotides. The appearance of sensitive crossovers every ten nucleotides corresponds to a change in linking difference (delta Lk) of +/- 2 in the circular core domain of the plasmid during branch point migration. In contrast, individual topoisomers of a plasmid preparation differ in linking number in increments of +/- 1. Thus, the observed linearization of each individual topoisomer following enzyme treatment, as a result of resolution of the crossovers associated with each topoisomer, showed that branch point migration to sensitive crossover positions must have occurred facilely. T7 endonuclease I randomly resolved across either axis of the cruciform, though some discrimination (related to the sequence specificity of the enzyme) was observed. The ten-nucleotide spacing between sensitive crossover positions is accounted for by an isomerization of the cruciform junction on branch point migration. An hypothesis is that this isomerization was imposed upon the cruciform junction by the change in helix twist (delta Tw) in the two branches that compose the topologically closed, circular domain of the plasmid. T7 endonuclease I may discriminate between the various isomeric forms and cleave a sensitive conformation that appears with every turn of branch migration which leads to the extrusion, or absorption, of two turns of helix from the circular core.

Cruciform extrusion in plasmids bearing the replicative intermediate configuration of a poxvirus telomere.

The transition from lineform DNA to cruciform DNA (cruciformation) within the cloned telomere sequences of the Leporipoxvirus Shope fibroma virus (SFV) has been studied. The viral telomere sequences have been cloned in recombination-deficient Escherichia coli as a 322 base-pair, imperfect palindromic insert in pUC13. The inverted repeat configuration is equivalent to the arrangement of the telomere structures observed within viral DNA replicative intermediates. A major cruciform structure in the purified recombinant plasmid has been identified and mapped using, as probes, the enzymes AflII, nuclease S1 and bacteriophage T7 endonuclease I. It was extruded from the central axis of the cloned viral inverted repeat and, by unrestricted branch migration, attained a size commensurate with the superhelical density of the plasmid molecule at native superhelical densities. This major cruciform extrusion event was the only detectable duplex DNA perturbation, induced by negative superhelical torsion, in the insert viral sequences. No significant steady-state pool of extruded cruciform was identified in E. coli. However, the identification of a major deletion variant generated even in the recombination-deficient E. coli strain DB1256 (recA recBC sbcB) suggested that the cruciform may be extruded transiently in vivo. The lineform to cruciform transition has been further characterized in vitro using two-dimensional agarose gel electrophoresis. The transition was marked by a high energy of formation (delta Gf = 44 kcal/mol), and an apparently low activation energy that enabled facile transitions at physiological temperatures provided there was sufficient torsional energy. By comparing cruciformation in a series of related bidirectional central axis deletions of the telomeric insert, it has been concluded that the presence of extrahelical bases in the terminal hairpin structures contributes substantially to the high delta Gf value. Also, viral sequences flanking the extruded cruciform were shown to influence the measured delta Gf value. Several general features of poxvirus telomere structure that would be expected to influence the facility of cruciform extrusion are discussed along with the implications of the observed cruciform transition event on the replicative process of poxviruses in vivo.

Base alterations in yeast induced by alkylating agents with differing Swain-Scott substrate constants.

The base alterations induced by four alkylating agents, methyl methanesulfonate (MMS), ethyl methanesulfonate (EMS), N-nitroso-N-methylurea (MNU), and N-nitroso-N-ethylurea (ENU), have been determined at the URA3 locus in the yeast Saccharomyces cerevisiae. The mutagen treatment was carried out on yeast cells in the logarithmic phase of growth. The mutants were selected by their resistance to 7.3 mM-5-fluoroorotic acid at pH 3.8. DNA sequence analysis was carried out by the dideoxy chain termination method. The alkylating agents were selected for their widely differing Swain-Scott substrate constants (s values), which are as follows: MMS, s = 0.83; EMS, s = 0.67; MNU, s = 0.42; ENU, s = 0.26. A higher s value is correlated with a higher ratio of 7-alkylguanine to O6-alkylguanine in native DNA in vitro. 125 forward mutations from URA3----ura3 were sequenced with marked differences in the mutational spectra being observed as the s value changed. Five hotspots were recorded for the four alkylating agents. They were all G.C----A.T transition mutations. There was one common hotspot for all of them; there were two additional ones for the two ethylating agents (ENU and EMS) and two different ones for MNU. Four of the five hotspots have the 5'-GG-3' sequence with the 3'-guanine mutated. It was seen that MMS, which has the highest Swain-Scott substrate constant, yielded the widest array of mutational types. As the substrate constants decreased, the types of mutations became more and more restricted to the G.C----A.T transitions and the A.T----T.A transversions. The transitions are consistent with the concept that mutations arise from O6-alkylation of guanine and alkylation of thymine. The transversions are consistent with the notion of N1-alkylation of adenosine or adenylic acid.

Binding of etiopurpurin and tin-coordinated etiopurpurin to human plasma proteins. Delivery in cremophore EL and dimethyl sulfoxide (paper II).

Purpurins are potent hydrophobic photosensitizers in vivo. Cremopfore EL is an important vehicle for the administration of hydrophobic drugs. Mode-delivery-effects on the binding of etiopurpurin (ET2) to human plasma (LDL, HDL, and high density proteins, HDP) is studied for delivery in CRMaq and in DMSO by ultracentrifugation. A similar study of SnET2 is available (Kongshaug et al., 1993) and has been extended. In the absence of plasma, only nonfluorescent ET2 entities (aggregates) were present, a portion of which moved unaffected by gravity (small aggregates), the remainder according to their densities (high density aggregates). Aggregated ET2 showed, at high salt density, similar positions and halfwidths in the gradient, and similar adsorption properties as the aggregates in plasma-containing samples. In CRMaq (1 mg CRM/ml) the adsorptive loss of the dye affected only marginally the binding of fluorescent monomeric ET2. In this mode (i) 20% of ET2 was bound as monomers, about 70% of which to CRM-modified LDL, most of the remainder to CRM-modified HDL; (ii) such HDL also marginally bound small aggregates; (iii) only monomeric ET2 was bound to CRM-modified LDL. In delivery in DMSO, aggregated ET2 (98% of ET2 in the gradient) converted, post centrifugally, into minor amounts of HDL-bound monomeric ET2; LDL-bound ET2 included monomers (about 50%) and small aggregates, mainly dimers. The percentage binding of SnET2 to HDP was independent of the concentrations of CRMaq and HDL. Plasma-bound small aggregates (such as dimers) and plasma-unbound high density aggregates (mean densities of 1.13-1.19 g/ml) were substantially present in the plasma-containing samples. There were mode-delivery-effects upon the yields and properties of aggregated ET2, and upon the yields of plasma-bound monomeric ET2. Monomeric ET2 showed a remarkably high percentage binding to LDL and was similarly distributed among the lipoproteins as is total cholesterol. There was little or no real mode-delivery-effect upon the distribution of monomeric ET2 among the plasma proteins. The affinity of CRM-modified LDL for SnET2 was similar to that of HDL plus HDP in native plasma.

Binding of etiopurpurin to human plasma proteins. Delivery in cremophor EL and dimethyl sulphoxide. III.

Binding of the photosensitizer etiopurpurin (ET2) to human plasma was assessed, using conditions that would yield a high percentage of ET2 in the form of LDL-bound monomers which may favor photosensitizer tumor localization. Two delivery systems, Cremophor EL (CRM) and dimethyl sulphoxide (DMSO), were used. The binding of ET2 to CRM-modified lipoproteins was compared to the binding of the dye to the native proteins using delivery in DMSO. Plasma-bound monomers and unbound high density aggregates were shown to coexist. The density and rate of formation of the dye aggregates were correlated. The aggregates formed by delivery in DMSO could be partially converted into plasma-bound monomeric ET2. There was no mode-delivery-effect upon the distribution of monomeric ET2 among the plasma proteins. 70% of monomeric ET2 was bound to LDL and most of the remainder to HDL. In delivery in DMSO the yield of LDL-bound dye monomers (up to 30% of added ET2) increased with decreasing concentration of ET2 in the delivery solution and with increasing time of incubation (< or = 48 hr). Long incubation also induced changes in the densities of LDL and HDL. The yields of LDL-bound monomers (up to 40%) increased with increasing concentration of CRM-bound ET2. High yields of LDL-bound monomers were obtained using both modes of delivery. Although the aggregates associated with the two modes of delivery had different properties. The change in lipoprotein composition might be involved in the conversion of aggregates into plasma-bound monomers.

Development of a whole blood assay to measure T cell responses to leprosy: a new tool for immuno-epidemiological field studies of leprosy immunity.

A whole blood assay is described to measure T cell mediated immune responses to leprosy and provide an alternative to the conventional lymphocyte transformation test. Optimal conditions were defined for the whole blood assay, and interferon-gamma measurement was found to be a more sensitive way of measuring responses than tritiated thymidine incorporation. The assay was shown to be useful for investigating responses to a range of leprosy antigens. A whole blood assay has the advantages of being quick, simple and requiring only a small volume of blood, making it more appropriate as an immuno-epidemiological field test in leprosy endemic areas.

New sensitizers for photodynamic therapy: controlled synthesis of purpurins and their effect on normal tissue.

Purpurins are a class of porphyrin derivative that have been shown to have good in vivo cytotoxicity to N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) induced rat bladder tumors (AY-27) implanted into Fisher 344 rats. The synthesis of purpurins from etioporphyrin I and coproporphyrin I proceeds in high yield and with a high degree of regioselectivity. Product formation can be rationalized in terms of relief of steric strain about the periphery of the purpurin macrocycle. The effect of therapeutic light doses using the rat footpad model suggests that, at therapeutic sensitizer doses, normal tissue damage is within acceptable limits, particularly for metalated purpurins.