Spinocerebellar ataxia type 14: study of a family with an exon 5 mutation in the PRKCG gene.

We report our observations in an Australian family with spinocerebellar ataxia type 14 (SCA 14). We describe a novel mutation in exon 5 of the PRKCG gene, altering a highly conserved cysteine to a phenylalanine at codon 150, and record the detailed clinical observations in six affected family members.

Expression of genes encoding Th1 cell-activating cytokines and lymphoid homing chemokines by chlamydia-pulsed dendritic cells correlates with protective immunizing efficacy.

We studied the expression of cytokines, chemokines, and chemokine receptors by the RNase protection assay in chlamydia-pulsed dendritic cells to better understand their potent anti-chlamydial immunizing properties. We found that chlamydia-pulsed dendritic cells express a complex profile of inflammatory and immunomodulatory molecules. These include CCR-7, interleukin-12, and interferon-induced protein 10, molecules that might influence the homing of pulsed dendritic cells to the site of chlamydial infection and the induction of a local protective CD4(+) Th1 cellular immunity.

Analysis of local recurrence and optimizing excision margins for cutaneous melanoma.

BACKGROUND: Current guidelines for the treatment of melanoma favour conservatism; however there is still uncertainty regarding best practice for lesions of intermediate thickness. Local recurrence, a measure of treatment adequacy, can be used to determine optimum excision margins and give prognostic information for survival. METHODS: An analysis of the Auckland Melanoma Unit database was performed. Patients with local recurrence were identified and stratified by lesion thickness. Optimum excision margins were derived by regression analysis and evaluated against the database population. Survival and prognostic factors were studied. RESULTS: Eighty-four of 1155 patients (7 per cent) developed local recurrence. Median follow-up was 51 months. Margins predicted to give a local recurrence of zero were: 1 cm for lesions < or = 1 mm thick; 1.5 cm for lesions 1-2 mm thick; and 2 cm for lesions > 2 mm thick. Applied to 1155 patients, there were significant differences in both local recurrence and mortality rates between optimally and suboptimally excised lesions, except for those > 4 mm thick. Thirty-three patients (39 per cent) with local recurrence died. Thickness, local recurrence and ulceration were of prognostic significance. CONCLUSION: Development of local recurrence in melanomas < or = 4 mm thick is due to inadequate treatment. It signifies progressive disease and a poor prognosis. Care must be taken to ensure that all such lesions are optimally excised.

Frequency of spinocerebellar ataxia types 1, 2, 3, 6, and 7 in Australian patients with spinocerebellar ataxia.

The frequencies of various genetically defined spinocerebellar ataxias (SCAs) vary in different populations presumably due to founder effects. No data have been published on the Australian population. Although predominantly of Anglo-Celtic extraction, Australia has also received considerable influx from southeastern Europe and more recently eastern and southeastern Asia. We examined the frequency of mutations for SCA types 1, 2, 3, 6, and 7 in southeastern Australia. Of 88 pedigrees with multiple-affected members, SCA type 1 (SCA1) accounted for 16%, SCA2 for 6%, SCA3 for 12%, SCA6 for 17%, SCA7 for 2%, and 47% (41 pedigrees) were negative for each of SCA1, 2, 3, and 6. Twenty of the 41 negative pedigrees were also negative for dentatorubralpallidoluysian atrophy, and indeed dentatorubralpallidoluysian atrophy has not been reported in Australia. In addition, no pedigree information was available on a further four patients with SCA1, three patients with SCA2, three patients with SCA3, and three patients with SCA6. One SCA1 and two SCA2 patients had no other known affected family members. In total, of 63 pedigrees or individuals with positive tests, 30% were those with SCA1, 15% with SCA2, 22% with SCA3, 30% with SCA6, and 3% with SCA7. Judging by pedigree names, four of the nine SCA2 positive individuals/pedigrees were of Italian extraction, and four of the 14 SCA3 positive individuals/pedigrees were of Chinese descent, whereas only 1 of the 20 SCA1 positive individuals/pedigrees were non-Anglo-Celtic. These results are in accordance with the known ethnic composition of the Australian population and with gene frequencies in these constituent ethnic groups reported by others. The frequency of large-normal alleles for SCA1 and SCA3 in the population reflects the prevalence of these two diseases, supporting the hypothesis that disease alleles arise by expansion of large-normal alleles.

Incidence of malignant melanoma in Auckland, New Zealand: highest rates in the world.

The calculation of incidence rates of melanoma in New Zealand has been hampered in the past by incomplete registration of cases. The aim of this study was to document the incidence of melanoma in the Auckland Caucasian population and to define the pathologic characteristics of these lesions. Data were collected for the Auckland region from the New Zealand Cancer Registry and the Auckland Melanoma Unit database for 1995 and combined with census statistics to give the crude and age-standardized rates for invasive melanoma. The results were analyzed by gender, morphology, body site, and thickness. The crude annual incidence for invasive cutaneous malignant melanoma was 77.7/100,000. The age-standardized annual rate was 56.2/100,000 with no statistically significant differences in the rates for males and females. The cumulative risk of developing melanoma over a lifetime, from age 0 to 74, was 5.7% overall. The age-specific rates steadily increase with advancing age. The lesions were generally thin; 64% were less than 0.76 mm, and only 7% were thicker than 3.00 mm. In conclusion, the Caucasian population in the Auckland region has the highest incidence of melanoma in the world.

Spinocerebellar ataxia type 2: clinical features of a pedigree displaying prominent frontal-executive dysfunction.

BACKGROUND: Spinocerebellar ataxia type 2 (SCA2) is a recently delineated cause of autosomal dominant cerebellar ataxia type I. The basic clinical neurologic features of SCA2 have been described in the literature, but neuropsychological features have not, despite statements that some patients became demented. OBJECTIVE: To describe the clinical and neuropsychological features of patients from a pedigree with SCA2. PATIENTS AND METHODS: We studied 8 affected members of an Australian pedigree of northern Italian origin with autosomal dominant cerebellar ataxia type I caused by SCA2. Patients underwent clinical neurologic examination and abbreviated neuropsychological testing, while some also underwent magnetic resonance imaging. The results were compared with pooled results from previously published studies of patients with SCA2. RESULTS: The pedigree displayed anticipation, with earlier onset in later generations, and there was an inverse correlation between repeat number and age at onset. The principal difference from other clinical reports of SCA2 was our finding of unequivocal frontal-executive dysfunction in 5 of 6 individuals who could be tested quantitatively, despite Mini-Mental State Examination scores in the nondemented range. This feature did not appear to correlate with either repeat size or duration of illness. CONCLUSIONS: In light of a recent report of frontal-executive dysfunction in spinocerebellar ataxia type III, we postulate that this pattern may be common to the autosomal dominant cerebellar ataxias and frequently may be overlooked because of the insensitivity of routine screening tests such as the Mini-Mental State Examination.

Parathyroid cancer: biology and management.

A review of all reports in the literature of parathyroid carcinoma (PTC) was undertaken to define an optimal management strategy for this rare condition. PTC is uncommon and its etiology of PTC is largely unknown although patients with familial hyperparathyroidism, multiple endocrine neoplasia type 1 and irradiation to the head and neck are at increased risk for developing the disease. PTC occurs with equal frequency in both sexes and is usually diagnosed in the fifth decade. En bloc resection of the carcinoma and the adjacent structures in the neck is the surgical treatment and is associated with an 8% local recurrence rate and a long term overall survival rate of 89% (mean follow up 69 months). In contrast simple parathyroidectomy results in a 51% local recurrence rate and 53% long-term survival rate (mean follow up 62 months). Adverse prognostic factors for survival were initial management with simple parathyroidectomy alone, the presence of nodal or distant metastatic disease at presentation and non-functioning PTC.

A study on betel quid chewing behavior among Kaohsiung residents aged 15 years and above.

A telephone survey was used to study betel quid chewing behavior of Kaohsiung residents aged 15 and above in early 1991. Among the 1,162 subjects, 154 (13.3%) reported that they chewed betel quids and most of them (145/154) were men. Among the chewers, 33 (21.4%) indicated that they chewed it daily; all were men. Age distribution of the chewing behavior suggested that more young people chewed it at the time of the survey than had been the case in the past. The demographic distributions of betel quid chewing behavior were similar to the characteristics of tobacco smoking in Taiwan. The degree of concurrence of these two behaviors was very high. Nearly 90% of the subjects believed that betel quid chewing would cause more harm than good, or it would cause only harm, to their health. Discriminant analyses indicated that smoking behavior and attitude toward the health effect of chewing betel quids were the two most significant and meaningful variables in prediction of the chewing behavior. Strategies for prevention are recommended.

Anabolic and cardiovascular effects of recombinant human growth hormone in surgical patients with sepsis.

The clinical and metabolic effects of 7 days of recombinant human growth hormone (rhGH) and total parenteral nutrition (TPN) in surgical patients with sepsis were determined in a randomized controlled trial. In patients with a mean(s.e.m.) pretreatment rate of net protein catabolism (NPC) of 1.5 g per kg per day or less rhGH treatment decreased NPC from 0.93(0.14) to -0.20(0.24) g per kg per day (n = 5; P < 0.0005) and rendered these patients anabolic. TPN alone decreased NPC from 1.12(0.11) to 0.61(0.11) g per kg per day (n = 5; P < 0.001). In patients with an initial NPC of more than 1.5 g per kg per day rhGH treatment decreased NPC from 2.72(0.12) to 1.08(0.24) g per kg per day (n = 5; P < 0.001) while TPN alone decreased it from 2.41(0.32) to 1.28(0.28) g per kg per day (n = 5; P < 0.005). Use of rhGH was not associated with any adverse effects or improvement in clinical course but did decrease the mean systolic and diastolic pressures during the study period. Thus rhGH is a useful anabolic agent and may have a role in the haemodynamic management of the catabolic patient with sepsis.

Total energy expenditure during total parenteral nutrition: ambulatory patients at home versus patients with sepsis in surgical intensive care.

BACKGROUND: To avoid the complications associated with overfeeding or underfeeding, the energy requirements of patients receiving total parenteral nutrition (TPN) must be accurately prescribed. However, until recently it has not been possible to directly measure the rates of total energy expenditure (TEE) in surgical patients receiving TPN. METHODS: Values for total body water and TEE in four patients with sepsis (mean Acute Physiology and Chronic Health Evaluation [APACHE] score, 10) receiving TPN in surgical intensive care unit and in four patients with chronic intestinal failure receiving long-term TPN at home (HPN) have been determined by using the doubly labeled water technique. The values for TEE have been compared with those of resting energy expenditure obtained with indirect calorimetry (REE CAL) and calculated by using the Harris-Benedict equation (REE HB). RESULTS: In both the patients with sepsis and the patients receiving HPN the proportion of body weight made up of water was normal for patient age and gender. In patients with sepsis the REE HB significantly (p < 0.05) underestimated the REE CAL (15.39 +/- 3.80 kcal/kg/day-1 versus 31.3 +/- 1.23 kcal/kg/day-1) and was significantly less than the TEE derived by using doubly labeled water (44.62 +/- 1.09 kcal/kg/day-1; p < 0.001). In the ambulatory patients receiving HPN no difference was noted between the REE HB and the REE CAL (18.02 +/- 0.41 kcal/kg/day-1 versus 21.37 +/- 0.94 kcal/kg/day-1). The average TEE for these patients was 30.25 +/- 3.42 kcal/kg/day-1, and this was significantly greater (p < 0.006) than both REE CAL and REE HB: CONCLUSIONS: This investigation has shown that in patients with sepsis TEE constitutes 1.4 times the REE CAL or approximately 40 kcal/kg/day, whereas in HPN patients TEE can be estimated by supplying 1.4 times the REE or approximately 30 kcal/kg/day-1.

Maternal uniparental disomy of chromosome 13 in a phenotypically normal child.

A case of maternal uniparental disomy of chromosome 13 is described. The subject is a phenotypically normal male who inherited a t(13;13)(p11.2;p11.2) from his mother who is a carrier of this translocation. The mother was ascertained through a history of recurrent abortion and is phenotypically normal. The translocation in both subjects was studied by cytogenetic and DNA analysis and appears to be a true dicentric isochromosome. These findings show that maternal uniparental disomy of chromosome 13 has had no pathological consequences and suggests that there is no imprinting of genes on maternally derived chromosome 13.

Radiosensitivity of new and established human melanoma cell lines: comparison of [3H]thymidine incorporation and soft agar clonogenic assays.

Seven new low-passage melanoma lines were developed in this laboratory from clinical melanoma specimens and characterised for chromosome complement, DNA ploidy and S-phase content. The radiosensitivity of these lines was compared with that of eight established melanoma cell lines, FME, MM-96, SK-MEL-5, SK-MEL-28, SK-MEL-2, MALME-3M, M19-MEL and LOX-IMVI, using a 96-well microculture assay technique. Dose-response curves were determined using a 5-day incubation period and 6-h terminal [3H]thymidine-labelling period. Radiation (60Co source) was carried out under a lead wedge to provide a radiation dose range of 0-10 Gy, or by irradiating part of the plate (radiation dose 0 or 2 Gy). Data for a range of cell densities in a single 96-well plate were combined into a single regression equation incorporating linear quadratic terms for radiation dose and cell density. SF2 values were defined as the amount of thymidine incorporated following a radiation dose of 2 Gy, expressed as a fraction of that of unirradiated cells, and varied from 0.36 to 0.93. The reproducibility in repeat assays, as defined by the standard error of determinations at different passage numbers, was +/- 0.04. The newly developed lines exhibited a similar range of radiosensitivity to that of the established lines, and melanin content did not correlate with resistance. For nine of the lines, radiation parameters were also determined using a modified Courtenay clonogenic soft agar assay technique, and the results compared with the thymidine incorporation results, and a significant linear correlation was found between SF2 and SF2' (r = 0.89). The linear (alpha) and quadratic (beta) terms of the best-fit linear quadratic dose-response curves, were significantly correlated between the two assays. It is concluded for this series of human melanoma lines that proliferation assays in 96-well plates provide radiosensitivity parameters comparable to those using clonogenic assays.

Growth hormone therapy initiated before starvation ameliorates the catabolic state and enhances the protein-sparing effect of total parenteral nutrition.

The effect of 7 days of subcutaneously administered bovine growth hormone (bGH) (0.2 mg kg-1 day-1; n = 4) or an equivalent volume of 0.15 mol l-1 saline (n = 3) on protein metabolism was assessed in lambs. The catabolic response to 48 h of starvation and subsequent hypocaloric total parenteral nutrition (TPN) was measured using primed constant intravenous infusions of [15N]urea and [14C]leucine. Following 48 h of starvation and 7 h of TPN, bGH-treated animals had a significantly decreased rate of net protein catabolism compared with controls (mean(s.e.m.) 2.4(0.2) versus 3.2(0.3) g kg-1 day-1, P < 0.01). The mean(s.e.m.) rate of whole-body protein catabolism was also significantly decreased in bGH-treated animals at 10.9(0.3) g kg-1 day-1 compared with 12.9(0.7) g kg-1 day-1 in saline-treated controls (P < 0.05). In addition, the rates of net and whole-body protein catabolism decreased significantly (P < 0.05) during the period of hypocaloric parenteral feeding to mean(s.e.m.) values of 2.3(0.2) and 8.6(0.6) g kg-1 day-1 respectively in bGH-treated animals. By contrast, in saline-treated controls net and whole-body protein catabolism continued to increase during hypocaloric parenteral feeding. There was a significant decrease (P < 0.05) in the rate of [14C]leucine uptake in tissues of the gastrointestinal tract, heart and diaphragm in bGH-treated animals compared with controls. These results demonstrate that daily administration of growth hormone decreases the catabolic response to a metabolic stress, resulting in the conservation of protein in the heart, diaphragm, gastrointestinal tract and musculoskeletal system by a primary anticatabolic action. In addition, growth hormone therapy initiated before induction of the catabolic state enhances the protein-sparing effects of TPN. Further study is justified to determine whether growth hormone therapy initiated before elective or urgent surgery in the nutritionally depleted patient may have a role in reducing the severity of the postoperative catabolic state, particularly in the patient in whom a complicated course is anticipated.

Metabolic basis for management of the septic surgical patient.

The physiologic events accompanying postoperative septic complications in surgical patients represent a coordinated response to bacterial invasion, which is aimed at maintaining the function of key organ systems. When sepsis is prolonged or overwhelming, physiologic dysfunction and multiorgan failure develop. This review outlines the pathophysiologic response to sepsis and correlates it with recent therapeutic advances in the metabolic management of the postoperative septic patient.

Anticancer drug sensitivity profiles of new and established melanoma cell lines.

Metastatic melanoma is notable for its resistance to chemotherapy, and methods for determining resistance in cultures would be advantageous. We investigated the chemosensitivities of seven newly derived low passage lines and eight established melanoma lines. A 96-well microculture system utilising [3H]-thymidine incorporation was used to determine IC50 values (50% inhibitory concentrations) for lomustine, mitomycin C, 4-hydroperoxycyclophosphamide, cisplatinum, 5-fluorouracil, vincristine, doxorubicin, etoposide, amsacrine and the amsacrine analogue CI-921. Cytokinetic parameters were determined using 5-bromodeoxyuridine and flow cytometry. The presence of "transport" and "atypical" multidrug resistance was investigated with an IC50 ratio method, using pairs of drugs with differing sensitivity to these multidrug resistance mechanisms. A wide range of chemosensitivity for each of the antitumor agents was observed, and a spectrum of activity was observed in each of the assays for multidrug resistance. Unexpectedly, a number of cell lines displayed coordinate sensitivity or resistance to cytotoxic agents with unrelated mechanisms of action. Resistance mechanisms apart from "transport" and "atypical" multidrug resistance may be required to account for the observed 40-fold range in overall chemosensitivity of the melanoma lines.