Clues from hypercalcaemia

British Journal of Cancer (2002) 86, 1021–1022. DOI: 10.1038/sj/bjc/6600220 www.bjcancer.com© 2002 Cancer Research UKThe conundrum of hypercalcaemia in malignancy occurring in the absence of extensive bony metastases was finally solved in the late 1980s with the identification and cloning of PTHrP (parathyroid hormone-related protein) and the history of this discovery is summarised by Martin and Suva (1988). Original work in cell lines and a renal tumour was followed by the identification of PRHrP in a wide variety of malignances (Honda et al, 1988). PTHrP raises serum calcium and stimulates osteoclast activity, leading to bone destruction. This seemed to suggest a simple sequence of events, but malignancy, bony metastasis and hypercalcaemia are linked by mechanisms more subtle than any single linear chain of cause and effect. PTHrP shares eight of its first 13 amino acids with PTH (Mangin et al, 1988). This structural homology leads to shared receptor binding. There are biochemical differences in the effects of these two hormones. PTHrP is a more potent inhibitor of caliuria and promoter of phosphaturia than PTH. Circulating PTHrP is undetectable in health but present in around 80% of patients with humoral hypercalcaemia. Tissue expression of PTHrP is far more extensive than PTH, and this is reflected in a range of functions beyond calcium homeostasis (Strewler, 2000). The presence of PTHrP in the uterus and the stomach, coupled with its ability to relax smooth muscle, has led to the assertion that, in these tissues at least, it is PTHrP which is the true physiological effector molecule (Martin, 1996). The role of PTHrP in placental calcium transport seems, similarly, to imply far greater functional importance than that of PTH. It is the role of PTHrP in cartilage development, however, which may reveal its significance to the progression of malignant disease. When chondrocytes form new bone they first proliferate then produce the basic extracellular matrix which will be later invaded by cellular components of bone. The chondrocytes then apoptose. The absence of PTHrP, in PTHrP knock-out mice, leads to failure of proliferation and early apoptosis (Amizuka et al, 1996). This protection of chondrocytes from apoptosis in the physiological setting is mirrored in cancer, where transfection of PTHrP into cell lines confers resistance to apoptotic stimuli (Dougherty et al, 1999).PTHrP stimulates osteoclastic bone resorption. Studies in breast cancer have shown that PTHrP is expressed in most breast primaries and bony metastases, but to a lesser extent in visceral metastases (Powell et al, 1991). The question then arises whether PTHrP is not merely a marker for bony metastases but also prognostic factor for progression. Animal experiments using a PTHrP-expressing cell line and blocking monoclonal antibody have demonstrated the importance of PTHrP in progression to metastatic bone disease (Guise et al, 1996), while cell culture work indicates that PTHrP can function as a transforming growth factor. There is, then, a high index of suspicion in breast cancer that PTHrP is a key factor in the development of bony metastases.Prostate cancer has a different natural history to breast cancer. Hypercalcaemia is uncommon in prostate cancer and metastases are predominantly osteoblastic. It is important to realise, however, that the osteoblastic response seen in prostate cancer is preceded, at a cellular level, by osteoclast activation. The difference between breast and prostate, therefore, is not that osteoclast activation occurs or does not occur, but rather that in prostatic metastases an intense osteoblastic reaction is also present (Roodman, 2001). Elegant experiments using in vivo inocculation of paired transfected and untransfected cell lines have, furthermore, indicated a greater metastatic potential for the transfected lines (Rabbani et al, 1999) mirroring the results in breast cancer.The paper by Bryden et al. (2002) in this issue of the journal extends observations of PTHrP expression in other tumours to prostate cancer. The authors have demonstrated a high rate of concordance for the expression of both PTHrP and its receptor in paired primary tumours and bony metastases. The ultimate purpose of studies such as these is either to identify new markers of prognostic importance, or to provide a mechanistic explanation of disease progression which may yield new therapeutic targets. The high frequency of expression in primary prostate cancers would seem to indicate that PTHrP is a poor discriminator of metastatic potential. However, the sample sizes are small, and larger studies linking PTHrP expression to outcome are required to demonstrate any prognostic significance of this observation. The role of experimental therapeutics directed against PTHrP may seem nonsensical, since the numerous factors which come into play by the time metastatic bone disease has developed implies that there is no role for PTHrP-directed intervention. If, however, a link between PTHrP and progression to bone disease is established, then targetting the PTHrP at earlier disease stages might eventually lead to a change in the natural history of prostate cancer.     

Na(v)1.5 underlies the 'third TTX-R sodium current' in rat small DRG neurons

In addition to slow-inactivating and persistent TTX-R Na(+) currents produced by Na(v)1.8 and Na(v)1.9 Na(+) channels, respectively, a third TTX-R Na(+) current with fast activation and inactivation can be recorded in 80% of small neurons of dorsal root ganglia (DRG) from E15 rats, but in only 3% of adult small DRG neurons. The half-time for activation, the time constant for inactivation, and the midpoints of activation and inactivation of the third TTX-R Na(+) currents are significantly different from those of Na(v)1.8 and Na(v)1.9 Na(+) currents. The estimated TTX K(i) (2.11+/-0.34 microM) of the third TTX-R Na(+) current is significantly lower than those of Na(v)1.8 and Na(v)1.9 Na(+) currents. The Cd(2+) sensitivity of third TTX-R Na(+) current is closer to cardiac Na(+) currents. A concentration of 1 mM Cd(2+) is required to completely block this current, which is significantly lower than the 5 mM required to block Na(v)1.8 and Na(v)1.9 currents. The third TTX-R Na(+) channel is not co-expressed with Na(v)1.8 and Na(v)1.9 Na(+) channels in DRG neurons of E18 rats, at a time when all three currents show comparable densities. The physiological and pharmacological profiles of the third TTX-R Na(+) current are similar to those of the cardiac Na(+) channel Na(v)1.5 and RT-PCR and restriction enzyme polymorphism analysis, show a parallel pattern of expression of Na(v)1.5 in DRG during development. Taken together, these results demonstrate that Na(v)1.5 is expressed in a developmentally regulated manner in DRG neurons and suggest that Na(v)1.5 Na(+) channel produces the third TTX-R current.     

Analysis of stromal-epithelial interactions in prostate cancer identifies PTPCAAX2 as a potential oncogene.

A PCR-based subtractive hybridisation technique was used to identify genes involved in stromal-epithelial interactions in prostate cancer. Eight genes were identified as being differentially expressed in benign prostatic fibroblast cells after stimulation with tumourigenic LNCaP conditioned media. One of these genes, protein tyrosine phosphatase CAAX2 (PTPCAAX2; also described as PTP4A and OV-1), has recently been shown to be oncogenic in hamster pancreatic epithelial cells. We show that PTPCAAX2 expression is up-regulated 4-fold in benign prostatic fibroblast cells 24 h after stimulation with LNCaP conditioned media and up-regulated 9-fold in prostatic tumour fibroblast cells. PTPCAAX2 overexpression was also detected in both androgen-dependent and androgen-independent prostate cancer cell lines and prostate tumour tissue, as determined by RT-PCR analysis and in situ hybridisation. These observations of PTPCAAX2 overexpression in prostate tumour cells and tissue suggest that PTPCAAX2 may potentially function as an oncogene in prostate cancer.     

Evaluation of attempted prevention of unexpected infant death in very high-risk infants by planned health care

Three hundred and ninety-six babies born in Sheffield between 1982 and 1990 identified as being at "very high risk" of unexpected infant death by means of a scoring system, received an intensive programme of health care including a case discussion between a paediatrician, the GP and the health visitor held in the family doctor's surgery, weekly visits from the health visitor and informal hospital admission. Significantly fewer sudden unexpected infant deaths occurred in this group than were expected by logistic regression anlysis or occurred in the best available control group with comparable scores ( p = 0.024). Problems in evaluation include identification of an adequate control population, ethical difficulties in introducing a controlled study when the programme is already perceived as effective, and the calculation of "expected death rates". The results of this study indicate that very energetic programmes of intervention may prevent some deaths in vulnerable infants.     

Outcome of congenital lung abnormalities detected antenatally

To determine the outcome of congenital lung abnormalities, data were collected retrospectively between January 1991 and December 1996 on any foetus found to have a lung lesion on antenatal ultrasound. A total of 23 foetuses had lung lesions on antenatal ultrasound. In two foetuses the antenatal ultrasound showed bilateral enlarged "bright" echogenic lungs with evidence of hydrops. Both pregnancies were terminated and tracheal atresia was confirmed. In 15 foetuses the antenatal ultrasound appearance was of a unilateral "bright" echogenic lung. There was one case of bronchial atresia and two cases of congenital lobar emphysema, which all had surgery. In nine cases there was a reduction in the size of the lesion on serial antenatal ultrasounds and no lesion was detected after birth. In three cases a small lesion was present after birth on chest radiography. In six foetuses the antenatal ultrasound appearance was of unilateral cystic or mixed cystic and echogenic lung lesions. Two pregnancies were terminated; both had congenital cystic adenomatoid malformation. Four pregnancies were continued and three infants had surgery soon after birth and were confirmed to have had congenital cystic adenomatoid malformation. One infant has been managed conservatively. In conclusion, a definitive diagnosis cannot usually be made antenatally. A large lesion on initial scan does not necessarily predict a poor outcome. The natural history of small asymptomatic postnatal lesions is unknown and a long-term prospective study is needed to determine the outcome of these lesions.     

An Unusual Angiographic Appearance of Aorto-Iliac Disease Presenting as the Leriche Syndrome

An unusual angiographic presentation of Leriche syndrome is described that demonstrates short segment occlusions of iliac arteries with bilaterally symmetrical post-stenotic dilatations.     

Blood donation-related neurologic needle injury: evaluation of 2 years' worth of data from a large blood center

BACKGROUND: There is little information in the medical literature on t he clinical spectrum of blood donation-related neurologic needle injury and on its frequency in a blood donor population. STUDY DESIGN AND METHODS: Sixty-six cases of blood donation-related neurologic needle injury were identified from nursing reports made during a 2-year collection period involving 419,000 whole blood donations. Telephone follow-up was completed on 56 of the 66 cases to better define clinical symptoms, the donor's desire for physician consultation, recovery times, and residual effects. RESULTS: Symptoms in 66 donors included numbness or tingling (n = 54), excessive or radiating pain (n = 43), and loss of arm or hand strength (n = 8). Of the 56 donors with complete follow-up, 17 (30%) consulted a physician one or more times. Recovery times in these 56 donors were <3 days (n = 22), 4 to 29 days (n = 17), 1 to 3 months (n = 13) 3 to 6 months (n = 2), and >6 months (n = 2). Fifty-two of 56 donors achieved a full recovery, and 4 other donors had only a mild, localized, residual numbness. The incidence of blood donation-related neurologic needle injury was 1 of every 6300 donations. CONCLUSION: While donor recovery may in some cases require a great deal of time and/or physician consultation(s), total recovery appears to be the rule. The incidence of blood donation-related neurologic needle injury is relatively low.     

Ferric ion, ferrocyanide, and inorganic phosphate as cytochemical reactants at peripheral nodes of Ranvier.

Ferric ion (Fe3+) and ferrocyanide (Fe(CN)64-) were used under a variety of conditions to stain nodes of Ranvier in mammalian peripheral nerves. Principal findings are: 1. Ferric ion will bind to the extracellular nodal gap substance if nerves are pretreated with a phosphate buffer; or, it will bind to the cytoplasmic surface of the nodal axolemma if pretreatment is with cacodylate or veronal--acetate buffer. 2. Ferrocyanide will bind to the inner surface of the nodal axolemma, where it may react with ferric ion to form a blue stain, or with an osmium compound to form a black stain. 3. Ferric ion and ferrocyanide are bound to nodes as colloidal precipitates, and may migrate away from their sites of formation. 4. Not all nodes in a single piece of tissue, or in a single fibre have identical staining properties. It is concluded that ferric ion, ferrocyanide, and inorganic phosphate are valuable as cytochemical reactants for peripheral nodes of Ranvier, but they must be used in carefully controlled experimental situations in order to avoid spurious results.