Molecular genetic analysis of von Hippel-Lindau disease

Von Hippel-Lindau (VHL) disease is a dominantly inherited multisystem family cancer syndrome predisposing to retinal and central nervous system haemangioblastomas, renal carcinoma, phaeochromocytoma, pancreatic islet cell tumours and endolymphatic sac tumours. In addition, renal, pancreatic and epididymal cysts occur. Morbidity and mortality from VHL disease can be reduced by the identification and surveillance of affected individuals and at-risk relatives so that complications are diagnosed at an early presymptomatic stage. The detailed mapping and subsequent isolation of the VHL tumour suppressor gene has enabled molecular genetic analysis in families and patients with definite or possible VHL disease. Initially, linked DNA markers were used in informative families to modify individual risks and then to make appropriate alterations in surveillance programs. However, currently most DNA analysis involves the characterisation of germline mutations. World-wide, mutations have been identified in almost 500 families (including 132 in our laboratory). These studies have revealed considerable heterogeneity both in the type and in the location of mutations within the VHL gene. In our experience, most recurrent mutations result from de novo mutations at hypermutable sequences, although a founder effect for the Tyr98His ('Black Forest') mutation has been reported in German and American families. Although many mutations are predicted to impair the ability of pVHL to combine with the elongin regulatory subunits, analysis of genotype-phenotype relationships suggests that the VHL protein has multiple and tissue specific functions. Calculation of tumour risks for different classes of VHL mutations has provided important prognostic information especially with respect to the likelihood of phaeochromocytoma. However, there is evidence that retinal involvement does not correlate with allelic heterogeneity, but that the variability in retinal angiomatosis is influenced by modifier gene effects. VHL gene mutation analysis also provides a basis for investigating the genetic basis of familial phaeochromocytoma and renal cell carcinoma, and apparently isolated retinal angiomas. Results to date suggest that a substantial proportion of patients with familial pheochromocytoma have VHL gene mutations but in contrast, most familial clusters of clear cell renal cell carcinoma (RCC) without evidence of VHL do not have germline VHL mutations.     

Instruments for sampling and measuring the volume output of urine from grazing female sheep

The technics of T-tube suction drainage of the retroperitoneal space and of prophylactic antibiotics were evaluated each alone and then in combination in a randomized study of 451 private patients undergoing abdominal or vaginal hysterectomy. As compared with results in a control group, suction drainage alone and prophylactic antibiotics alone were equally effective in reducing the incidence of postoperative pelvic infection and febrile morbidity. When the two technics were used in combination, there was further reduction in the incidence of pelvic infection and febrile morbidity. However, these results were not statistically different from those of either technic alone. Date are presented to indicate that hysterectomy is performed in a bacteriologically contaminated operative field and that a contaminated fluid collection routinely accumulates in the retroperitoneal space. It is therefore suggested that hysterectomy be managed as a potentially infected surgical wound.     

Effects of an ionophore, X-537A, on mouse CNS cultures: a light and electron microscope study

The effects of the ionophore X-537A on organotypic CNS tissue culture were investigated with bright field and electron microscopy. In addition to condensation of mitochondria this agent was found to induce a relatively selective vacuolation of the Golgi apparatus of neurons and glial cells. At the dosages used (50 mug/ml for 2-3 hours and 100 mug/ml for 1 hour) these changes were irreversible. Additional experiments suggested that the cellular effects of X-537A were primarily due to its ability to translocate Na+ across cellular membranes.     

Intensity and frequency discrimination monitored by evoked response audiometry: clinical application

Delta 1 and delta f repetitive stimuli superimposed on continuous 0.5-, 1- and 4-kHz carrier tones were administered to 20 normally hearing persons, 8 adults with sensorineural hearing loss, 10 adults with conductive hearing loss and 22 children subjected to evoked response audiometry (ERA) for assessment of hearing acuity. The intensity modulation depth ranged from + 1 to 10 dB. In the subjects with normal hearing and in the adult patients, three carrier tone levels were used whenever possible: 20, 40, and 60 dB SL. The frequency modulation depth ranged from -1 to -10% of the carrier tone frequency. The same levels for the carrier tone were used: 20, 40, and 60 dB SL. With a carrier tone level of 20 dB SL, a clear-cut vertex response was noted in 80% of the tests carried out in the normal adults with 5-dB delta i stimuli and with delta f stimuli of -3 to -5% in magnitude; the same figures are valid for the patients with sensorineural and conductive hearing loss. The patients with sensorineural hearing loss showed a tendency to give vertex responses with lower delta i stimuli than subjects with normal hearing. However, this difference was not statistically significant. According to our results, the children tested can be roughly divided into two groups, the first including subjects with responses to delta i stimuli of +5 and +10 dB and delta f stimuli of -5% and -10%; the second group including subjects with no clear-cut responses to these stimuli.     

Triple tenodesis of the knee. A soft-tissue operation for the correction of paralytic genu recurvatum

There are two types of genu recurvatum: one with bone deformity, which responds well to osteotomy, and one with posterior soft-tissue laxity with secondary bone changes. To date, no reliable treatment short of arthrodesis has been effective for the second type. An operation for this type of genu recurvatum (post-poliomyelitic) is described: a soft-tissue reconstruction of the lax tissues posterior to the knee joint done in three layers. The operation was done on sixteen knees in fourteen patients, with an average follow-up of four years and three months. The average recurvatum before surgery was 42 degrees and at the time of follow-up it was 6 degrees. Preliminary surgery is often required and precise surgical technique and prolonged bracing after surgery also are needed. All but one patient was made brace-free provided the limb operated on was not flail.