Male genital lichen sclerosus in recipients of bone marrow transplants.

We describe two patients who received haematopoietic stem cell marrow transplantation, and developed male genital lichen sclerosus (MGLSc), one of whom also had squamous carcinoma in situ (Bowen disease). MGLSc has previously been associated with graft-versus-host disease. Various aetiological factors for LSc have been proposed, including a role for chronic occluded epithelial exposure to urine. A number of factors imply that the risk of malignant transformation in this bone marrow transplant group is likely to be higher than the overall figure of 2-9% cited for MGLSc. It is vital, therefore, that clinicians involved in the care of those with haematological malignancies are adequately prepared to examine the genitals of their patients, and to recognize and refer any suspect penile lesions.

Patients with xeroderma pigmentosum complementation groups C, E and V do not have abnormal sunburn reactions.

BACKGROUND: Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder of DNA repair. It is divided into eight complementation groups: XP-A to XP-G (classical XP) and XP variant (XP-V). Severe and prolonged sunburn reactions on minimal sun exposure have been considered a cardinal feature of classical XP. However, it has recently become clear that not all patients have abnormal sunburn reactions. OBJECTIVES: To examine sunburn reactions in a cohort of patients with XP and correlate this to the complementation group. METHODS: Sixty patients with XP attending the U.K. National XP Service from 2010 to 2012 were studied. Their history of burning after minimal sun exposure was assessed using a newly developed sunburn severity score. The age at which the first skin cancer was histologically diagnosed in each patient, and the presence of any neurological abnormality, was also recorded. RESULTS: Sunburn severity scores were abnormally high in patients with XP-A, XP-D, XP-F and XP-G compared with non-XP controls. There was no significant difference in sunburn score of patients with XP-C, XP-E and XP-V compared with controls (P > 0·05). Patients with XP-C, XP-E and XP-V were more likely to have skin cancer diagnosed at an earlier age than those with severe sunburn on minimal sun exposure. In addition, patients with XP with severe sunburn had an increased frequency of neurological abnormalities. CONCLUSIONS: Not all patients with XP have a history of severe and prolonged sunburn on minimal sun exposure. The normal sunburn response of patients with XP-C, XP-E and XP-V may relate to the preservation of transcription-coupled DNA repair in these groups. Those with a history of severe sunburn on minimal sun exposure developed their first skin cancer at an older age compared with patients with XP-C, XP-E and XP-V, but they had an increased frequency of neurological abnormalities. Physicians need to be aware that about half of all patients with XP will present without a history of abnormal sunburn.

A novel mutation in the XPA gene associated with unusually mild clinical features in a patient who developed a spindle cell melanoma.

BACKGROUND: Xeroderma pigmentosum (XP) is an autosomal recessive disorder of, in most cases, defective nucleotide excision repair (NER) of ultraviolet radiation (UV)- and chemical-induced DNA damage. The condition is characterized by an increased sensitivity of the skin to UV radiation, with early development of pigmentary changes and premalignant lesions in sun-exposed areas of the skin, signs of photoageing and a greatly increased incidence from a young age of skin tumours including melanoma. Approximately 20% of patients with XP show neurological abnormalities of varying severity due to primary neuronal degeneration. Genetic analysis by somatic cell hybridization has led to the identification in the NER-defective form of XP of seven complementation groups, designated XP-A to XP-G. These complementation groups correspond to different proteins involved in the NER process. XP-A classically includes some of the most severely affected patients. OBJECTIVES: We describe a 61-year-old Punjabi woman with XP. Remarkably she had only mild cutaneous abnormalities, minimal neurological features and unusual longevity, and developed a malignant spindle cell melanoma. There are few previous reports of spindle cell melanoma associated with XP. To gain insight into the aetiology of these unusual features, we sought to analyse the DNA repair properties of the patient and identify the complementation group and the causative mutation in the defective gene. METHODS: Unscheduled DNA synthesis and the inhibition of RNA synthesis were measured. The complementation group was assigned by fusing the cells of our patient with XP cells of known complementation groups and determining the ability to carry out unscheduled DNA repair. Molecular analysis of the cDNA was carried out by polymerase chain reaction and DNA sequencing. RESULTS: Levels of DNA repair were extremely low and complementation analysis assigned the defect to the XP-A group. Sequencing of the XPA gene revealed a novel homozygous mutation of A-->G at the eighth nucleotide of intron 4 causing aberrant splicing and a nonfunctional truncated XP-A protein. However, a small amount of normally spliced mRNA was detected at <5% the level in normal cells. CONCLUSIONS: The small amount of normally spliced mRNA detected may be sufficient to explain the relatively mild clinical features in our patient.

Two individuals with features of both xeroderma pigmentosum and trichothiodystrophy highlight the complexity of the clinical outcomes of mutations in the XPD gene.

The xeroderma pigmentosum group D (XPD) protein is a subunit of transcription factor TFIIH with DNA helicase activity. TFIIH has two functions, in basal transcription and nucleotide excision repair. Mutations in XPD that affect DNA repair but not transcription result in the skin cancer-prone disorder, xeroderma pigmentosum (XP). If transcription is also affected, the result is the multi-system disorder trichothiodystrophy (TTD), in which there is no skin cancer predisposition, or in rare cases, XP combined with Cockayne syndrome. Up till now there have been no reports of combined clinical features of XP and TTD. We have now identified two patients with some features of both these disorders. One of these, XP189MA, a 3-year-old girl with sun sensitivity, mental and physical developmental delay, has XPD mutations not previously reported, and barely detectable levels of nucleotide excision repair. The other, XP38BR, a 28-year-old woman with sun sensitivity, pigmentation changes and skin cancers typical of XP, has a mutation that has been identified previously, but only in TTD patients with no features of XP. The level of repair of UV damage in XP38BR is substantially higher than that in other patients with the same mutation. With both patients, polarized light microscopy revealed a 'tiger-tail' appearance of the hair, and amino acid analysis of the hair shafts show levels of sulfur-containing proteins intermediate between those of normal and TTD individuals. Our findings highlight the complexities of genotype-phenotype relationships in the XPD gene.

A double blind, randomised, controlled trial of glutamine supplementation in parenteral nutrition.

BACKGROUND AND AIMS: To determine whether the inclusion of 20 g free glutamine as part of the nitrogen source of parenteral feeds reduces length of hospital stay or mortality. METHODS: In a randomised, double blind, controlled trial in 168 patients clinically accepted for parenteral nutrition, standard feeds were compared with feeds in which 3.8 g of the total nitrogen was replaced with the equivalent 20 g glutamine. A minimum of 11 g nitrogen/day was used in all patients. Daily intakes of energy and nitrogen were determined using a validated computer protocol and were similar for the two groups. All feeds included trace elements, vitamins, electrolytes, and minerals. RESULTS: A total of 85 patients received a median of eight (interquartile range 5-13) daily feeds containing glutamine while 83 received a median of eight (5-15) standard feeds. No difference between groups was detected for infective complications. Twenty control patients and 14 who had received glutamine died during their hospital stay (NS). Median length of stay was 32 (23-52) days on glutamine, which was not significantly different from the control value of 35 (25-55) days. Glutamine was associated with a significant (p<0.03) reduction in length of stay in surgical patients (45 days (range 29-81) versus 30 days (range 19-54)). CONCLUSION: The benefit from glutamine supplementation of parenteral feeds as used in this trial has not been proved. Supplementation may have advantages in surgical patients and in haematological malignancy. Further trials are required.

Xeroderma pigmentosum and trichothiodystrophy are associated with different mutations in the XPD (ERCC2) repair/transcription gene.

The xeroderma pigmentosum group D (XPD) protein has a dual function, both in nucleotide excision repair of DNA damage and in basal transcription. Mutations in the XPD gene can result in three distinct clinical phenotypes, XP, trichothiodystrophy (TTD), and XP with Cockayne syndrome. To determine if the clinical phenotypes of XP and TTD can be attributed to the sites of the mutations, we have identified the mutations in a large group of TTD and XP-D patients. Most sites of mutations differed between XP and TTD, but there are three sites at which the same mutation is found in XP and TTD patients. Since the corresponding patients were all compound heterozygotes with different mutations in the two alleles, the alleles were tested separately in a yeast complementation assay. The mutations which are found in both XP and TTD patients behaved as null alleles, suggesting that the disease phenotype was determined by the other allele. If we eliminate the null mutations, the remaining mutagenic pattern is consistent with the site of the mutation determining the phenotype.

Cutaneous crystalline deposits in myeloma.

BACKGROUND: Myeloma is a plasma cell malignancy that usually presents with systemic manifestations or symptoms related to bone involvement. We describe the first case of crystalline protein deposition in the skin as the initial manifestation of myeloma. OBSERVATIONS: Crystals were found mainly in the extracellular space in the dermis of both involved and uninvolved skin in the absence of plasma cell infiltration. Crystals were also found in conjunctival tissue and bone marrow. CONCLUSIONS: We have described a unique case of myeloma that presented as facial and eyelid swelling. There were crystalline deposits in the skin and conjunctivae, but mechanisms of crystal formation and the factors causing local deposition were not established. However, treatment of the underlying disorder leads to resolution of the cutaneous features of crystal deposition.

The use of multiple-pin peptide synthesis in an analysis of the continuous epitopes recognised by various anti-(recombinant bovine growth hormone) sera. Comparison with predicted regions of immunogenicity and location within the three-dimensional structure of the molecule.

A recently developed technology called epitope scanning permits the rapid and accurate delineation of continuous stretches of amino acids in a protein which constitute the sequential epitopes recognised by an antiserum raised to that protein. In the present report, we describe the use of this technique to identify the epitopes in the recombinant bovine growth-hormone (rbGH) molecule recognised by three polyclonal guinea-pig antisera and two polyclonal rabbit antisera. The results obtained show that, for guinea-pig antisera, 3 or 4, very-well-defined major continuous epitopes are present. As would be expected given the intrinsic genetic factors (major histocompatibility restriction, antigen processing and presentation) controlling the immune response in individual animals, subtle differences are evident in the precise location and relative reactivities of these epitopes in different guinea-pig antisera. Nevertheless, there is a large degree of overlap in these epitopes, such that immunodominant regions of the antigen can be clearly delineated. In a structural sense, these epitopes share a common motif in that they are sited in areas of the protein antigen with little secondary structure (loop/coil), although there is some contribution by neighbouring alpha-helices. For the two rabbit antisera, the response tends to be rather more heterogeneous, with recognition of more peptides and less clearly defined epitopes than was the case with the guinea-pig antiserum. Comparison of the four guinea-pig epitopes, identified by our experimental methods with computer predictions for this molecule (Jameson-Wolf antigenic index), indicate that two are strongly predicted, one is weakly predicted and one is not predicted. These observations, together with the displayed intraspecies and interspecies variation clearly indicate the limitations of these predictive methods. In conclusion, we have demonstrated that, despite the expected variation in the exact location of continuous epitopes defined by different anti-rbGH sera, there are large regions of overlap defining immunogenic core regions within the molecule. We believe that studies of this nature, together with further understanding of antigen processing and peptide presentation to immune cells, may have a role to play in the development of candidate peptide vaccines.

Nutritional support in patients with low volume chylous fistula following radical neck dissection.

One of the well known complications of radical neck dissection is a chylous fistula, which results from injury to the thoracic duct as it enters the left subclavian vein. Such fistulae may cause considerable increased morbidity to a patient who is already debilitated by malignancy and by the increased catabolic response to surgery. Further surgery may be appropriate for those with a high fistula output but conservative therapy is normally advocated for the remainder. Nutritional and electrolyte support for these patients is essential and poses potential problems in management. We present three such patients. One was fed parenterally and two enterally and in all cases the fistulae closed spontaneously. We examine the known physiological stimuli to chyle production and conclude that the enteral feedings of these patients with fat or an isomolar enteral feed does not, contrary to current belief, increase chyle flow or delay the healing of these fistulae.

Uptake of 131I-metaiodobenzylguanidine by 6-23 rat medullary thyroid carcinoma.

Uptake of 131iodine-metaiodobenzylguanidine (131I-MIBG) by 6-23 rat medullary thyroid carcinoma (MTC), was studied in vitro and in vivo. In vitro, there was an 8-fold increase in 131I uptake by 6-23 cells when labeled with 131I-MIBG (131I 24 +/- 15 cpm/10(6) cells, 131I-MIBG 196 +/- 9 cpm/10(6) cells). MIBG uptake in vitro was the same at 4 degrees C and 37 degrees C. In contrast, 131I-MIBG uptake by PC-12 rat pheochromocytoma cells were 200 times greater (131I-MIBG 42,412 +/- 6,755 cpm/10(6) cells). 131I-MIBG uptake by rat MTC cells in vitro were of a comparable magnitude to the uptake of 131I-MIBG by rat ileal enterochromaffin cells (RIE-1) and mouse colon cancer cells (MC-26). In vivo, uptake of 131I-MIBG by 6-23 MTC tumor was considerably less than in the normal tissues (muscle, liver, spleen, kidney, adrenal and thyroid). Gamma camera studies of 131I-MIBG uptake by 6-23 MTC tumors growing in Wag-Rij rats were only transiently positive in 1 out of 4 rats studied. We conclude that 131I-MIBG is poorly taken up by rat medullary thyroid carcinoma and is an unpredictable marker for localization of rat MTC.

Renal transplant dysfunction: MR evaluation.

The results of 45 MR examinations were prospectively compared with the clinical course and biopsy results in 38 renal transplant patients to determine the role of MR in evaluating allograft dysfunction. Twenty-six patients underwent allograft biopsy. In eight patients in whom the biopsy was performed more than 48 hr after MR examination and in 19 patients who did not have a biopsy, the subsequent clinical course was sufficiently diagnostic to determine the specific cause of the transplant dysfunction. Corticomedullary differentiation, graded from 0 to 3, was not helpful in separating rejection (n = 20) from acute tubular necrosis (n = 9), drug toxicity (n = 7), pyelonephritis (n = 2), or normal grafts (n = 7) because of overlap between groups (sensitivity =; 60%, specificity = 60%). In the six patients with two or more MR studies, serial changes in corticomedullary differentiation were not consistent and could not be used to diagnose rejection. When any abnormality of allograft sinus fat, size or shape, or corticomedullary differentiation was considered, the sensitivity for the diagnosis of rejection approached 80%; however, specificity was low (48%). We conclude that MR imaging is not sufficiently accurate to replace transplant biopsy and therefore has a limited role in the evaluation of transplant dysfunction.

Hyperthyroidism and the single lobe.

A practical approach to the hyperthyroid patient with a single lobe visualized on thyroid scintigraphy, and its impact on therapy is discussed. An illustrative case is also presented.

Urinary tract infections in childhood: a current imaging approach.

The authors present their approach to the evaluation of urinary tract infection in childhood based on real time sonography, 99m-Tc-DTPA scintigraphy and voiding cystourethography.

Indium-111 chloride bone marrow imaging in chronic renal disease.

Eight patients with anemia and chronic renal disease being maintained by chronic hemodialysis were evaluated with In-111 chloride bone marrow imaging and bone marrow core biopsies. There was no correlation between the erythrocyte cellularity of the marrow and the indium bone marrow scan grade in any patient. Bone marrow imaging can not be used as an indicator of the presence of erythroid marrow in these patients.

Indium-111 chloride for detecting suspected hepatomas in patients with focal defects on technetium-99m sulfur colloid liver imaging.

Twenty-three patients with hepatic cirrhosis and focal defects on Tc-99m sulfur colloid (SC) scintigrams were restudied with In-111 chloride to determine if indium localization in the focal defect is indicative of a hepatoma. Seven of eight patients with proven hepatomas had positive studies; however, six of 15 patients without hepatomas also had studies interpreted as positive. Thus, In-111 chloride is highly sensitive for the detection of hepatomas, and a negative indium study would militate against this diagnosis. The high false-positive rate found may be due to technical factors rather than a lack of specificity of localization; the experience of others seems to support this impression. At present, In-111 chloride scintigraphy for focal hepatic defects appears to be useful in ruling out hepatoma.

Aggressive nature of a "cold" lesion depicted by positive flow and blood pool phases of a bone scan.

One of the explanations of a cold lesion on static bone imaging is the presence of an aggressive, destructive lesion. This is the first reported case of such a lesion with an aggressive nature that was confirmed by abnormal flow and pool images.