John Hayman

The Pathology of Mycobacterium Ulcerans Infection

&NA; The pathology of cutaneous ulcers resulting from Mycobacterium ulcerans infection is reviewed. Initial infection causes ulceration with necrosis of the dermis and a septate panniculitis in subcutaneous fat. There is little cellular reaction despite the presence of large numbers of organisms. Recurrent or persistent infection produces a granulomatous reaction with epithelioid macrophages, variable numbers of giant cells of the Langhans type, and relatively few organisms. This type of reaction is associated with more successful treatment of the disease and appears analogous to the tuberculoid form of leprosy.

Identification of Parathyroid Hormone-related Protein in Canine Apocrine Adenocarcinoma of the Anal Sac

The presence of parathyroid hormone-related protein (PTHrP) in the apocrine adenocarcinoma tumor line (CAC-8) derived from a hypercalcemic dog was demonstrated by western and northern blot analyses. Western blots of CAC-8 tumor extracts revealed a major protein with a molecular weight of approximately 18,000 daltons that cross-reacted with antiserum to human PTHrP. Northern blots demonstrated multiple-sized messenger RNA transcripts in CAC-8 that hybridized to a full-length cDNA probe to human PTHrP. Adenocarcinomas derived from apocrine glands of the anal sac also were stained immunohistochemically for antigens that cross-react with antiserum to human PTHrP. The tumor line (CAC-8) maintained in nude mice stained positively for PTHrP in 13 of 24 tumors. Three of ten apocrine adenocarcinomas from dogs with hypercalcemia stained for PTHrP, whereas zero of ten tumors were positive from normocalcemic dogs. Normal canine epidermal keratinocytes and areas of squamous metaplasia in a perianal gland carcinoma also were positive for PTHrP. These data demonstrated that canine tissues contained a homologue to human PTHrP that likely is important in the pathogenesis of humoral hypercalcemia of malignancy.

Underexpression of the 43 kDa inositol polyphosphate 5-phosphatase is associated with cellular transformation.

The 43 kDa inositol polyphosphate 5‐phosphatase (5‐phosphatase) hydrolyses the second messenger molecules inositol 1,4,5‐trisphosphate [Ins(1,4,5)P3] and inositol 1,3,4,5‐tetrakisphosphate [Ins(1,3,4,5)P4]. We have underexpressed the 43 kDa 5‐phosphatase by stably transfecting normal rat kidney cells with the cDNA encoding the enzyme, cloned in the antisense orientation into the tetracycline‐inducible expression vector pUHD10–3. Antisense‐transfected cells demonstrated a 45% reduction in Ins(1,4,5)P3 5‐phosphatase activity in the total cell homogenate upon withdrawal of tetracycline, and an approximately 80% reduction in the detergent‐soluble membrane fraction of the cell, as compared with antisense‐transfected cells in the presence of tetracycline. Unstimulated antisense‐transfected cells showed a concomitant 2‐fold increase in Ins(1,4,5)P3 and 4‐fold increase in Ins(1,3,4,5)P4 levels. The basal intracellular calcium concentration of antisense‐transfected cells (170 +/− 25 nM) was increased 1.9‐fold, compared with cells transfected with vector alone (90 +/− 25 nM). Cells underexpressing the 43 kDa 5‐phosphatase demonstrated a transformed phenotype. Antisense‐transfected cells grew at a 1.7‐fold faster rate, reached confluence at higher density and demonstrated increased [3H]thymidine incorporation compared with cells transfected with vector alone. Furthermore, antisense‐transfected cells formed colonies in soft agar and tumours in nude mice. These studies support the contention that a decrease in Ins(1,4,5)P3 5‐phosphatase activity is associated with cellular transformation.

Datura Poisoning—the Angel's Trumpet

&NA; A group of seven ate flowers of Datura arborea (“The Angels Trumpet” or “Trumpet Lilies”) and suffered severe hallucinations. One member of the group drowned in shallow water while suffering from these effects. Although poisoning with related species is common, poisoning with this plant is rare, perhaps due to its terrifying rather than pleasurable hallucinogenic effect.

Ovarian mucinous tumour with a focus of anaplastic carcinoma: A case report

&NA; A 50‐yr‐old patient presented with abdominal symptoms due to the presence of cystic ovarian tumours. After hysterectomy and bilateral salpingo‐oophorectomy, the diagnosis of a mucinous tumour with a focus of anaplastic carcinoma in one ovary and a dermoid cyst in the other was made. Further treatment was refused and the patient died 12 mth after operation with disseminated anaplastic carcinoma. The case is the first reported when adjuvant therapy has not been given and illustrates the poor natural history of this disease.

Carcinoma of the Urachus

Summary Two cases of carcinoma of the urachus are reported, 1 involving the dome of the bladder and 1 occurring beneath the peritoneum of the anterior abdominal wall below the umbilicus at the apex of an elongated bladder. Both patients died shortly after diagnosis, a fact which emphasizes the poor prognosis of this group of patients. The poor prognosis and need for more than local resection of the tumour may not be widely appreciated. Tumours arising above the bladder have a different mode of presentation from those arising within the bladder wall. Bladder wall tumours are most frequently mucus‐secreting adenocarcinomas; tumours arising above the bladder may be more variable in their histological type, and include squamous and undifferentiated cancer. A simple classification into vesical and supra‐vesical tumours is proposed, to replace an early classification into 7 groups.

Charles Darwin’s Mitochondria

Charles Darwin’s long-term illness has been the subject of much speculation. His numerous symptoms have led to conclusions that his illness was essentially psychogenic in nature. These diagnoses have never been fully convincing, however, particularly in regard to the proposed underlying psychological background causes of the illness. Similarly, two proposed somatic causes of illness, Chagas disease and arsenic poisoning, lack credibility and appear inconsistent with the lifetime history of the illness. Other physical explanations are simply too incomplete to explain the range of symptoms. Here, a very different sort of explanation will be offered. We now know that mitochondrial mutations producing impaired mitochondrial function may result in a wide range of differing symptoms, including symptoms thought to be primarily psychological. Examination of Darwin’s maternal family history supports the contention that his illness was mitochondrial in nature; his mother and one maternal uncle had strange illnesses and the youngest maternal sibling died of an infirmity with symptoms characteristic of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS syndrome), a condition rooted in mitochondrial dysfunction. Darwin’s own symptoms are described here and are in accord with the hypothesis that he had the mtDNA mutation commonly associated with the MELAS syndrome.

Altered thrombomodulin staining in blistering dermatoses

&NA; The immunocytochemical distribution of thrombomodulin (TM) was examined in sections of skin from patients with blistering dermatoses occurring in the presence and absence of acantholysis. Skin sections were stained using polyclonal and monoclonal anti‐human TM antibodies and were correlated with the staining pattern that resulted when using the monoclonal antibody 32‐2B, which recognises the chief desmosomal adhesion molecule desmoglein I (DG I). Our study demonstrates a loss of TM staining in acantholytic dermatoses, occurring only in the region of actual disruption of the intercellular bridging between keratinocytes in the stratum spinosum. The thrombomodulin antigen expression paralleled the DG I expression. The strong correlation between the DG I and TM immunostaining pattern in both normal skin and acantholytic dermatoses supports the concept that TM has a role in mediating adhesion processes between keratinocytes.

Fatal dissecting aneurysm of the aorta in a diver

&NA; A 20‐yr‐old trained sports diver developed severe chest pain shortly after decompressing from a 40 m repetitive freshwater sinkhole dive, and died 6 h later. An autopsy examination showed a dissecting aneurysm of the aorta with rupture into the left pleural cavity. The relationship between the fatal event and the diving is discussed.

Deep-diving dinosaurs

Dysbaric bone necrosis demonstrated in ichthyosaurs may be the result of prolonged deep diving rather than rapid ascent to escape predators. The bone lesions show structural and anatomical similarity to those that may occur in human divers and in the deep diving sperm whale, Physeter macrocephalus.