Genomic enhancers in cardiac development and disease.

The Human Genome Project marked a major milestone in the scientific community as it unravelled the ~3 billion bases that are central to crucial aspects of human life. Despite this achievement, it only scratched the surface of understanding how each nucleotide matters, both individually and as part of a larger unit. Beyond the coding genome, which comprises only ~2% of the whole genome, scientists have realized that large portions of the genome, not known to code for any protein, were crucial for regulating the coding genes. These large portions of the genome comprise the 'non-coding genome'. The history of gene regulation mediated by proteins that bind to the regulatory non-coding genome dates back many decades to the 1960s. However, the original definition of 'enhancers' was first used in the early 1980s. In this Review, we summarize benchmark studies that have mapped the role of cardiac enhancers in disease and development. We highlight instances in which enhancer-localized genetic variants explain the missing link to cardiac pathogenesis. Finally, we inspire readers to consider the next phase of exploring enhancer-based gene therapy for cardiovascular disease.

P2RX7: A bipolar and unipolar disorder candidate susceptibility gene?

The chromosomal region 12q24 has been previously implicated by linkage studies of both bipolar disorder and unipolar mood disorder and we have reported two pedigrees segregating both bipolar disorder and Darier's disease that show linkage across this region. The gene P2RX7 is located in this chromosomal region and has been recently reported as a susceptibility gene for bipolar disorder and unipolar depression. The non-synonymous SNP rs2230912 (resulting in amino-acid polymorphism Q460R) showed the strongest association and has been postulated to be pathogenically relevant. We have investigated this gene in a large UK case-control sample (bipolar I disorder N = 687, unipolar recurrent major depression N = 1,036, controls N = 1,204). Neither rs2230912 nor any of 8 other SNPs genotyped across P2RX7 was found to be associated with mood disorder in general, nor specifically with bipolar or unipolar disorder. Further, sequencing of our two chromosome 12-linked bipolar-Darier families showed no evidence of rare variants at P2RX7 that could explain the linkage. Our data do not provide support for rs2230912 or the other polymorphisms studied within the P2RX7 locus, being involved in susceptibility to mood disorders.

Varus migration of PCA stems.

Forty-seven patients with cementless, porous-coated anatomic hip replacements were evaluated after a minimum 2-year follow up with specific attention to varus migration of the stem. A cadaver study was done to define a relationship between projected size of the lesser trochanter seen radiographically, rotation of the femur, and stem position. Seven (15%) of the stems migrated into varus with the distal tip moving laterally. Thigh pain occurred in patients with varus migration and those with no change in stem position. A lower percent canal fill was seen on the lateral radiograph (P < .001) and larger average width of radiodense lines in zone 1 superolateral, and zone 6, midstem medial (P < .005) in the patients with varus migration. Poor distal stability associated with a lower percent canal fill at the stem tip seen on the lateral radiograph may result in varus migration.

Burst fractures of the fifth lumbar vertebra.

Eleven patients with burst fractures of the fifth lumbar vertebra were reviewed. The results of nonoperative treatment were compared with that of immediate surgery and stabilization with pedicle screw fixation. Five patients were treated nonoperatively and six patients underwent pedicle screw instrumentation and spinal fusion. Five patients had neurologic injury associated with their L5 burst fracture. Nonoperative treatment yielded excellent results in young patients with minimal canal compromise. Neurologic deficits responded more predictably to surgical decompression than to conservative treatment and internal fixation with pedicle screws restores spinal stability and allows early mobilization.

[Sternocostoclavicular hyperostosis--case reports and differential diagnosis]. / Sternocostoclaviculäre Hyperostose--Kasuistik und Differentialdiagnose.

Sternocostoclavicular hyperostosis (SCCH) is a disorder related to collagenoses. SCCH is typically characterised by the triad of swelling of the sternoclavicular and/or sternocostal joints of the first or second rib, palmar and plantar pustulosis (PPP), only limited elevation of inflammation indicating laboratory parameters. Till today the etiology is unclear and no causal therapy is known. Symptomatic treatment consists of administration of NSAID and cortisone, irradiation and even limited resection of the clavicle and rib.

Pulmonary function during and after total hip replacement. Findings in patients who have insertion of a femoral component with and without cement.

Eleven patients who had a femoral component inserted with cement and twenty-three who had a femoral component inserted without cement were studied prospectively for changes in the pulmonary shunt associated with total hip replacement. The levels of oxygen in the arterial blood and the platelet counts were measured preoperatively and each morning for three days after the arthroplasty. Levels of oxygen in the arterial blood were determined intraoperatively, once before and once after the femoral component was inserted. Intraoperative shunt values increased 28 per cent when a femoral component was inserted with cement (p < 0.05), but they did not change when cement was not used. The average postoperative shunt values were higher than the average preoperative shunt values for both groups of patients, but only the values on the second postoperative day after a procedure with cement were significantly higher (p < 0.05). The ability of the patient to tolerate an increase in pulmonary shunt should be assessed when the femoral component is to be cemented during total hip replacement.

Nonunion of the humeral shaft.

Retrospective review of records of 26 patients with nonunion of the humeral shaft revealed several factors frequently associated with the development of nonunion. The fractures were transverse and short oblique and treated per primam with hanging casts or open reduction. Surgical fixation was unstable. The types of nonunion were atrophic in 19 patients, hypertrophic in five patients, and synovial pseudarthrosis in two patients. Twenty-four of 26 nonunions (92%) treated with bone grafts and rigid internal fixation healed in an average of 5.6 months. Overall, 47 surgical procedures, including prior procedures, were performed on these 26 nonunions. The average number of operations per patient was 1.8. Successful platings produced immobilization, consisting of an average of 6.8 points of cortical fixation above the nonunion and 7.1 cortices below. Rigid fixation was not obtained in the unsuccessful procedures. Unsuccessful platings were noted to have unstable fixation, with an average of 2.7 points of cortical fixation above the nonunion and 3.0 cortices below. Bone grafting was performed in only 55% of the unsuccessful platings. Optimal treatment of nonunions of the humeral shaft consists of resecting atrophic nonunions, shortening the bones, drilling sclerotic areas, and apposing bleeding diaphyseal surfaces; open reduction with internal fixation with a broad compression plate, including at least six points of cortical fixation above and below the nonunion; compression of the nonunion by means of interfragmentary lag screws, prestressing of the plate, dynamic compression by the plate, or direct compression by the external compression device; and autogeneic cancellous iliac bone grafts.

Percutaneous trephine bone biopsy of the thoracic spine.

The authors performed six consecutive percutaneous trephine biopsies of the thoracic spine under local anesthesia, using computed tomography to localize lesions and guide needle placement. The details of the technique are illustrated. Complications were not found. The authors conclude that closed large needle biopsy of the thoracic spine can be performed safely with the aid of computed tomography.

Prolactin directly stimulates the liver in vivo to secrete a factor (synlactin) which acts synergistically with the hormone.

Recent studies in our laboratory indicated that the liver of rats, mice, and pigeons secretes a PRL-synergizing activity (synlactin) in vitro. Accordingly, we investigated whether PRL and/or GH could stimulate the secretion of synlactin by the pigeon liver or kidney. Young birds received twice daily injections of PBS, ovine (o) PRL, or oGH for 5 days. On the sixth day, their livers and kidneys were removed, and slices of these organs were incubated in medium 199 for 4 h. The medium samples were filtered and diluted, then tested for PRL-like activity and synlactin activity in the local pigeon crop-sac bioassay. The latter test involved adding a dose of 1.0 microgram oPRL to the medium samples. None of the liver or kidney medium samples had PRL-like activity when tested alone. Only the liver incubation medium from the PRL-injected pigeons contained significant amounts of synlactin activity. Our next experiment was designed to determine whether PRL stimulation of hepatic secretion of synlactin involved a direct action of the hormone on the liver in vivo. A catheter attached to a coil of tubing and an osmotic minipump was inserted into an intestinal vein of pigeons, and the pump and coil were left in the abdomen. By this means, solvent, or GH or PRL in solvent, was pulse infused (four pulses of 2 h each per day) into the intestinal venous drainage. Thus, the hormones were delivered directly to the liver via the hepatic portal vein. During the last 3 of the 7 days of infusion, the pigeons received two daily injections of PBS or oPRL over the contralateral lobes of the crop-sac. Intrahepatic infusion of PRL, but not GH, caused a marked augmentation of the response of the crop to local injections of PRL. Pulse infusion of the same dose of oPRL into the external jugular vein of pigeons did not have this effect; hence, it appears to be mediated by the liver. These results indicate that one of the actions of PRL on the liver is to stimulate the secretion of a factor (synlactin) which acts synergistically with the hormone to promote growth of its target organs.

Pseudoarthrosis of a fracture of the acromion.

Fractures of the acromion are rare. Conservative therapy in the majority of cases results in return to full function of the shoulder. Occasionally, however, a painful pseudoarthrosis will develop and surgical care is required. The American literature reports several cases of acromial fracture but has not specifically addressed the treatment of pseudoarthrosis with open reduction and internal fixation. We report such a case and review the American and European literature.

The role of the dorsomedial-ventromedial area of the hypothalamus in the control of prolactin secretion induced by cervical stimulation.

Cervical stimulation (CS) initiates daily nocturnal (N) and diurnal (D) surges of PRL, which persist for at least 10 days, in intact and ovariectomized (OVX) rats. To affect pituitary PRL release, CS probably acts through several areas of the hypothalamus. PRL regulation by one hypothalamic area, the dorsomedial-ventromedial nuclei (DMN-VMN), was investigated in the present study. Electrical stimulation of the DMN-VMN of rats with intact ovaries produces both N and D PRL surges of the same magnitude, timing, and persistence as those initiated by CS. However, in long term OVX rats, stimulation of the DMN-VMN results in N surges which last only until day 6 and D surges present only through day 2. OVX rats receiving sc Silastic implants containing progesterone on the day after DMN-VMN stimulation had larger N surges, which persisted only as long as those secreted by long term OVX untreated rats. The D surge was unaffected. Rats OVX immediately after DMN-VMN stimulation secreted N surges through day 10, but D surges only through day 6. CS of long term OVX rats bearing lesions or sham lesions within the DMN-VMN results in N surges persisting through day 10. However, D surges could not be initiated by CS in rats bearing DMN-VMN lesions. These results suggest that the DMN-VMN is one area which responds to CS by initiating N and D surges of PRL. Excitation of this area is a requirement for the initiation of D, but not N, surges of PRL. However, continuation of the N surge probably involves the excitation of other areas within the central nervous system.