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A healthy, 15-year-old male received a thiopental, nitrous oxide, oxygen, enflurane anesthetic for appendectomy. Cardiac arrest, following succinylcholine administration, was associated with marked hyperkalemia (potassium levels 8.7 to 11.6 meq), hemolysis (hematocrit fall from 41.7 to 26.6%, plasma hemoglobin 27 mg/dL), and creatine phosphokinase (CPK) elevation (8900 units). Vigorous resuscitative therapy including dantrolene was unsuccessful. The diagnosis of malignant hyperthermia was made by the marked CPK elevation on blood samples drawn during resuscitation and analyzed by the Medical Examiner's Office.

Based on a clinical, pathologic, and genetic study of 14 families, at least three types of familial motor neuron disease can be distinguished, all apparently of autosomal dominant transmission. The first is characterized by rapid, progressive loss of motor function with predominantly lower motor neuron manifestations and a course lasting less than 5 years. Pathologic changes are limited to the anterior horn cells and pyramidal tracts. The second type is clinically identical to the first, but at autopsy additional changes are found in the posterior columns, Clarke's column, and spinocerebellar tracts. The third type is characterized by a much longer survival usually beyond 10 and after more than 20 years in affected family members but is otherwise similar to the second type.

In recent years the extent of the heterogeneity within lethal neonatal short limbed dwarfism has become apparent, with the delineation of numerous distinct syndromes such as thanatophoric dwarfism, achondrogenesis and the short rib polydactyly syndromes. Utilizing a combined clinical, radiologic, histologic and biochemical approach, we have observed further heterogeneity within this group of disorders. For example, we feel we can distinguish at least 3 distinct disorders in what has been called “thanatophoric” dwarfism, by histological and biochemical criteria. One group of patients is recognized by the Kleeblattschadel skull deformity. They differ both radiologically and in the histologic appearance of their growth plates from patients not manifesting this deformity. In this latter group, 2 additional disorders can be distinguished by specific growth plate histopathology and biochemical abnormalities observed on whole chain electrophoresis of collagen isolated from resting cartilage. Similarly, 2 distinct varieties of achondrogenesis can be clearly separated by radiologic and histopathologic criteria. The short rib polydactyly syndromes were originally divided into the Majewski and Saldino-Noonan types on the basis of radiologic criteria. He feel that the latter type can be further subdivided into 2 distinct entities. These studies demonstrate that the true heterogeneity of this group of disorders is only beginning to be appreciated, and that further heterogeneity will likely be found by this multidisciplinary approach.

Endochondral growth plate cartilage from a patient with the typical clinical and radiographic features of acromesomelic dysplasia was studied histochemically and immunohistochemically. The investigation revealed many previously undescribed abnormalities. The cartilage was hypercellular in general. There were numerous small areas of matrix degeneration scattered through the resting zone and a few large islands of hypertrophic cartilage in the growth plate region. Staining indicated excessive amounts of chondroitin sulfate and an absence of collagen fibers in both of these areas. In the remaining cartilage, collagen fibers tended to aggregate around the cells. The resting chondrocytes were irregular in size and distribution, and many exhibited protein containing cytoplasmic inclusions. The growth plate per se was poorly organized; hypertrophic chondrocytes were randomly oriented. The provisional calcification of cartilage matrix was absent, but the mineralization of subchondral bone appeared normal except along the outer margin where bone formation extended into the perichondrial space. These abnormalities appear to be distinct for acromesomelic dysplasia. Moreover, they provide several clues regarding the pathogenesis of the disorder.

Mechanical ventilation with positive end expiratory pressure (PEEP) has been reported to produce prompt improvement in oxygenation when used to treat acute respiratory failure. Reports of the effect of PEEP on cardiac output have been conflicting. We studied 14 patients and found that, although mean values of arterial oxygen tension (Pao 2 ) increased as PEEP increased, on eight occasions in the acute studies and three in the elective studies, it fell as PEEP was increased. On five occasions the fall in Pao 2 was associated with an increased shunt. Arterial pressure did not, on the average, change at any level of PEEP, but in 13 of 30 measurements it fell by more than 20% and necessitated curtailment of the study at blood pressure levels of less than 50 torr. Since these effects of PEEP cannot be predicted, careful patient monitoring is essential when ventilation with PEEP is utilized.

Achondrogenesis II is an inherited disorder of endochondral bone growth characterized clinically by severe (lethal) dwarfism and pathologically by the production of reduced amounts of cartilage matrix. To further define its pathogenesis, we studied growth plate tissue from 4 patients by a combination of microscopic and biochemical methods. Immunostaining of undecalificied Spurr embedded sections with a battery of collagen antibodies revealed that the major collagen of the resting cartilage matrix was type I rather than the expected type II (cartilage) collagen which was much reduced in amount. Analysis of resting cartilage collagens by SDS-PAGE and size exclusion HPLC mapping of cyanogen bromide peptides confirmed that collagen I was the major collagen and failed to detect collagen II. The results suggest at least two possibilities. First, there may be a defect in the structural gene for collagen II which interferes with the synthesis and/or secretion of the protein in an analagous fashion to that which occurs for collagen I in the osteogenesis imperfecta syndromes. Alternatively, the secretion of collagen I may reflect prematurity and/or abnormal regulation of the normal “switch” from collagen II to collagen I synthesis that occurs during later stages of growth plate chondrocyte differentiation. In any event the observations indicate that growth plate collagen production is disturbed in the disorder.

The economic life of polyethylene insulated primary URD cable is defined as the number of years of service such that continued operation of the cable results in greater cost than its replacnt. Formulation of the economic life shows that it is a function of the failure rate of the cable, discount rate, service restoration cost, replacement cost and the value of unserved energy. under simplifying assumptions, the economic life of a given installation is calculated readily.

Disclosed is a shock absorbing wheel hub for attachment to the axle of a vehicle. The hub has a central flange portion and an annular rim. The rim has a pair of spaced mounting surfaces formed on the periphery thereof for attaching a pair of pneumatic tires with inclined road-engaging treads. A flange is formed on the rim between the mounting surfaces and extends radially outward between the tires. A cylindrical contact surface is formed on the exterior of the flange and carries a tread thereon. The central flange is provided with bores for attachment to the lug bolts of a vehicle axle. Circumferentially spaced resilient spokes extend radially from the central flange and are connected to the hub. A pair of inflation check valves are attached to the rim to communicate respectively with the interior of each pneumatic tire. A flow passage is provided in the rim interconnecting the pneumatic tires for allowing air flow therebetween. An interchangeable flow restricter is mounted in the rim for controlling the flow of air between the two tires. In another embodiment, the spokes have semispherical bearing surfaces formed thereon resiliently held in receptacles formed in the rim. In yet another embodiment, the road-engaging surfaces of the tires are curved from side to side.

The A391E mutation in the transmembrane domain of FGFR3 leads to aberrant development of the cranium. It has been hypothesized that the mutant glutamic acid in the membrane enhances FGFR3 ligand-independent activation by over-stabilizing the FGFR3 dimer due to hydrogen bonding. We previously tested this hypothesis in lipid bilayers and showed that the mutation stabilizes the isolated FGFR3 TM domain dimer by −1.3 kcal/mole. Here we further test the hypothesis, by investigating the effect of the A391E mutation on the activation of full-length FGFR3 in HEK293T cells in the absence of ligand. We find that the mutation enhances the ligand-independent activation propensity of FGFR3 by −1.7 kcal/mole. This value is similar to the stabilization of the isolated A391E mutant TM domain dimer in lipid bilayers, and is consistent with the observed strength of hydrogen bonds in membranes, thus supporting the above hypothesis.

Shaker family voltage-gated K+ channel subunits can typically form functional homotetrameric channels or heterotetrameric channels with closely related subunits. Assembly is governed by cytoplasmic T1 domain contacts that are compatible within, but not across, gene subfamilies (Shaker, Shab, Shal and Shaw). Shaker family regulatory subunits differ in that they can only function in heteromeric channels because of T1 self-incompatibility. Mammalian regulatory subunits (Kv6, Kv8, Kv9) are members of the Shab family and modify the functional properties of Kv2.1 and Kv2.2. Kv2.1 and Kv9.3 form functional channels in a 3:1 stoichiometry. Using a combination of TIRF microscopy and electrophysiology, we show here that Kv2.1subunits also exclusively form 3:1 heteromers with Kv6.4. These findings raise the question of how stoichiometry is determined: it is unclear how T1 domain compatibility rules alone could distinguish between formation of 3:1 and 2:2 heteromers. We hypothesized that the activation gate region of the inner pore may be important in refining the stoichiometry of regulatory subunit-containing heteromers because it forms a large contact interface between subunits. Additionally, the sequence of this region in the regulatory subunits has drifted from the highly conserved Shab family consensus. Reverting the gate sequence in Kv6.4 to the Shab family consensus allowed the formation of functional 2:2 heteromers between Kv6.4 and Kv2.1 that could be detected by electrophysiology and TIRF microscopy. Drift of the gate sequence consensus can be observed in all verified regulatory subunits, including these mammalian Shab channels and evolutionarily separate regulatory subunit expansions in the Shaker, Shal and Shaw subfamilies in cnidarians. We suggest that the evolution of T1 self-incompatibility is a key event in the evolution of the regulatory subunit phenotype, but that drift of the activation gate interface plays an important role in fixing heteromeric channel stoichiometry.