Partial molar volume, surface area, and hydration changes for equilibrium unfolding and formation of aggregation transition state: high-pressure and cosolute studies on recombinant human IFN-gamma.

The equilibrium dissociation of recombinant human IFN-gamma was monitored as a function of pressure and sucrose concentration. The partial molar volume change for dissociation was -209 +/- 13 ml/mol of dimer. The specific molar surface area change for dissociation was 12.7 +/- 1.6 nm2/molecule of dimer. The first-order aggregation rate of recombinant human IFN-gamma in 0.45 M guanidine hydrochloride was studied as a function of sucrose concentration and pressure. Aggregation proceeded through a transition-state species, N*. Sucrose reduced aggregation rate by shifting the equilibrium between native state (N) and N* toward the more compact N. Pressure increased aggregation rate through increased solvation of the protein, which exposes more surface area, thus shifting the equilibrium away from N toward N*. The changes in partial molar volume and specific molar surface area between the N* and N were -41 +/- 9 ml/mol of dimer and 3.5 +/- 0.2 nm2/molecule, respectively. Thus, the structural change required for the formation of the transition state for aggregation is small relative to the difference between N and the dissociated state. Changes in waters of hydration were estimated from both specific molar surface area and partial molar volume data. From partial molar volume data, estimates were 25 and 128 mol H2O/mol dimer for formation of the aggregation transition state and for dissociation, respectively. From surface area data, estimates were 27 and 98 mol H2O/mol dimer. Osmotic stress theory yielded values approximately 4-fold larger for both transitions.

A dynamic game-theoretic model of parental care.

We present a model in which members of a mated pair decide whether to care for their offspring or desert them. There is a breeding season of finite length during which it is possible to produce and raise several batches of offspring. On deserting its offspring, an individual can search for a new mate. The probability of finding a mate depends on the number of individuals of each sex that are searching, which in turn depends upon the previous care and desertion decisions of all population members. We find the evolutionarily stable pattern of care over the breeding season. The feedback between behaviour and mating opportunity can result in a pattern of stable oscillations between different forms of care over the breeding season. Oscillations can also arise because the best thing for an individual to do at a particular time in the season depends on future behaviour of all population members. In the baseline model, a pair splits up after a breeding attempt, even if they both care for the offspring. In a version of the model in which a pair stays together if they both care, the feedback between behaviour and mating opportunity can lead to more than one evolutionarily stable form of care.

Stability of subtilisin and lysozyme under high hydrostatic pressure.

The stabilities of subtilisin and lysozyme under hydrostatic pressures up to 200 MPa were investigated for up to 7 days at 25 degrees C. Methods were chosen to assess changes in tertiary and secondary protein structure as well as aggregation state. Tertiary structure was monitored in situ with second derivative UV spectroscopy and after pressure treatment by dynamic light scattering and second derivative UV spectroscopy. Secondary structure and potential secondary structural changes were characterized by second derivative FTIR spectroscopy. Changes in aggregation state were assessed using dynamic light scattering. Additionally, protein concentration balances were carried out to detect any loss of protein as a function of pressure. For the conditions tested, neither protein shows measurable changes in tertiary or secondary structure or signs of aggregation. Lysozyme concentration balances show no dependence on pressure. Subtilisin concentration balances at high protein concentration (4 mg/mL and higher) do not show pressure dependence. However, the concentration balances carried out at 0.4 mg/mL show a clear sign of pressure dependence. These results may be explained by protein interaction with the vial surface and appear to be rate limited by the equilibrium between active and inactive protein on the surface. Pressure increases protein loss, and the estimated partial molar volume change between the two states is estimated to be -20 +/- 10 mL/mol.

A general technique for computing evolutionarily stable strategies based on errors in decision-making.

Realistic models of contests between animals will often involve a series of state-dependent decisions by the contestants. Computation of evolutionarily stable strategies for such state-dependent dynamic games are usually based on damped iterations of the best response map. Typically this map is discontinuous so that iterations may not converge and even if they do converge it may not be clear if the limiting strategy is a Nash equilibrium. We present a general computational technique based on errors in decision making that removes these computational difficulties. We show that the computational technique works for a simple example (the Hawk-Dove game) where an analytic solution is known, and prove general results about the technique for more complex games. It is also argued that there is biological justification for inclusion of the types of errors we have introduced.

Treatment of advanced localised prostatic cancer by orchiectomy, radiotherapy, or combined treatment. A Medical Research Council Study. Urological Cancer Working Party--Subgroup on Prostatic Cancer.

A total of 277 patients with apparently localised prostatic cancer (T2-T4 NXMO) were allocated at random to receive radiotherapy alone (88), orchiectomy alone (90) and combined therapy (99) between 1980 and 1985. The main outcome measures were survival, time to appearance of metastases and treatment of local disease progression by further transurethral resection. Orchiectomy, whether alone or with radiotherapy, produced a significant delay in detection of metastases when compared with radiotherapy alone. There were no statistically significant differences between the 3 treatment groups in local disease control or in overall survival.

Basaloid carcinoma of the prostate gland: histogenesis and review of the literature.

The clinicopathological features of a basaloid carcinoma of the prostate gland are described in a 28-year-old man, and the management and prognosis discussed. Basaloid tumours of the prostate are very rare and only a few cases have been described in detail. Those cases which have been reported as adenoid cystic carcinoma, adenoid cystic-like carcinoma and adenoid basal cell tumour are reviewed.

Prospective study of quantitative aspects of audit in a large general histopathology laboratory.

A non-computerised method of accurate prospective analysis of the quantitative aspects of the work of a general histopathology laboratory was devised. The method entails monitoring the progress of all biopsy and cytology specimens through the laboratory during selected monthly periods of study. The data collected include details of specimen type, block/section/stain details for each specimen, and information about the timed progress through technical, medical, and secretarial stages of specimen/report handling. The results give a detailed breakdown of the biopsy and cytology workload of this department. They give information about the rate of passage of specimens through the system and identify reasons for delay in the reporting of some cases. The method is easy to operate and will allow for the analysis of specific effects--for example, staff changes--on the efficiency of the department. The data will also provide some of the information required for the costing of histopathology laboratory services, and the type of information obtained will probably become a necessary requirement for laboratory accreditation.

Intravesical Evans Bacille Calmette-Guérin in the treatment of carcinoma in situ.

We report our experience in the treatment of carcinoma in situ of the urinary bladder using Evans strain Bacille Calmette-Guérin (BCG). The mean period of follow-up was 30 months; 18 patients received intravesical therapy and 16 of these were evaluable. They received 8 weekly instillations of 60 mg Evans strain BCG in 50 ml of saline. No intradermal BCG was given. The response rate was 93.75% at 3 months; this declined to 57% at 2 years. The complications of therapy were frequent but mild. Seven patients failed to complete the course. These results were comparable to those obtained with other strains of Bacille Calmette-Guérin.

Randomised trial comparing prednimustine with combination chemotherapy in advanced ovarian carcinoma.

A total of 76 patients with advanced epithelial ovarian carcinoma were randomised to receive 6 months of treatment with either a combination of hexamethylmelamine, 5-fluorouracil, cisplatin and prednimustine or prednimustine alone following initial surgery. Pathologically confirmed response rates were 35% for combination chemotherapy and 28% for prednimustine, and the overall survival was identical for the two groups. Seven patients achieved a pathologically defined complete response, one of whom relapsed at 8 months; the others remain disease-free 18-36 months (median, 23 months) after presentation. The extent of initial surgery significantly affected the survival of patients receiving prednimustine but not of those receiving combination chemotherapy. Prednimustine can produce durable responses in advanced ovarian cancer using a schedule that results in negligible toxicity.

Recurrent dislocation of the patella. Histochemical and electromyographic evidence of primary muscle pathology.

The role of muscle function in the aetiology of recurrent dislocation of the patella has been examined. Eleven of the 12 patients we studied had joint hypermobility. Muscle biopsies from eight of nine patients treated by surgery had a predominance of abnormal Type 2C fibres, and three of six patients whose quadriceps muscles were studied by electromyography also had abnormal results. Our preliminary findings suggest that there may be a primary muscular defect in many cases of recurrent dislocation of the patella.

Pain Control via the Dorso-Lumbar Sympathetic Outflow.

No acceptable scientific explanation has yet been found to account for the success of such remote treatments as acupuncture and connective tissue massage which do not conform to the recognized distribution of segmental reference. This paper is the result of clinical observations over the past seven years, revealing previously unsuspected effects from applying various treatments to the area of the sympathetic dorso-lumbar outflow for a wide variety of painful conditions. An hypothesis is offered which may account for those remote effects hitherto poorly understood.

Primary hyperparathyroidism diagnosed at autopsy. A study of eight cases.

This paper describes the clinical and pathological findings of eight cases of primary hyperparathyroidism first diagnosed at autopsy. The eight cases were obtained from the autopsy files of the Western General Hospital, Edinburgh over a decade (1971-80). The duration of the final hospital admission was very short in the majority of cases but analysis of the clinical history, in which gastro-intestinal and neuro-psychiatric disturbances figured prominently, showed that symptoms of the disease may have been present for very much longer--perhaps years in some instances. Details of the main autopsy findings and cause of death are also presented.

Extragonadal presentations of germ cell tumours.

This study reviews our experience over the past 25 years with unusual presentations of germ cell tumours and emphasises the need to consider the diagnosis of germ cell malignancy in any male patient who presents under the age of 60 years with a retroperitoneal or mediastinal tumour reported to be an "undifferentiated carcinoma" of apparently unknown origin.

Osteosarcoma of the esophagus.

The case of a 70-year-old man who underwent esophagectomy for a large polypoid sarcoma is described. Detailed examination of the surgical specimen established a diagnosis of osteosarcoma. Although osteosarcomas of the esophagus have been described in dogs, such tumors in humans do not appear to have been previously reported.

The ultra-structure of a melanotic schwannoma of the skin.

The case is described of a 53-year-old female with a pigmented tumour of the skin of the foot. The light and electron-microscopic findings established that the tumour was a melanotic Schwannoma. The ultra-structural features indicated that the Schwann cells, which contained melanosomes in varying stages of maturation, were producing melanin. A second type of cell within the tumour with features of a mesenchymal cell also contained melanosomes. The interrelationships of nerve sheath tumours, their relationship to pigment cells of neural crest origin and to other pigmented tumours of uncertain histogenesis, is discussed in the light of the findings described in the paper.