Cerebellar rTMS for motor control in progressive supranuclear palsy.

BACKGROUND: Stimulatory cerebellar TMS is a promising tool to improve motor control in neurodegenerative disorders. OBJECTIVE/HYPOTHESIS: Our goal was to use 10Hz cerebellar rTMS to augment cerebellar-brain inhibition (CBI) for improved postural stability and speech in patients with progressive supranuclear palsy (PSP). METHODS: We performed CBI assessments with neuronavigation before and after high frequency cerebellar rTMS or sham TMS in two patients with PSP, using a double cone coil for the conditioning pulse and a figure-of-eight coil for the test pulse and treatments. We collected posturography data and speech samples before and after treatment. RESULTS: After treatment, CBI increased by 50% in subject 1 and by 32% in subject 2, and postural stability and speech improved. The protocol was well tolerated, but the sham was not consistently believable. CONCLUSION: Cerebellar rTMS may improve postural stability and speech in PSP, but cooled coils with vibrotactile sham capability are needed for larger future studies.

Role of protein synthesis in the development of a transcriptionally permissive state in one-cell stage mouse embryos.

The time of onset of gene transcription in the mouse embryo is temporally regulated. A prominent feature of this regulation is a change during the one-cell stage from a transcriptionally nonpermissive state to a transcriptionally permissive state. During the early one-cell stage, the cytoplasm is either inadequate or suppressive for nuclear gene transcription, but by the late one-cell stage, the cytoplasm acquires the ability to support gene transcription either in endogenous nuclei or exogenous nuclei introduced microsurgically. We have investigated the role of protein synthesis in this cytoplasmic transition. Nuclei from two-cell stage embryos treated with alpha-amanitin were used to evaluate the transcriptional permissiveness of late one-cell stage cytoplasm, as indicated by the production of transcripts from four genes that are specifically transcribed at elevated rates during the two-cell stage. Two of these genes were transcribed following nuclear transfer to late one-cell stage cytoplasm, and two were not transcribed. Treatment of the recipient cytoplasm with cycloheximide to inhibit protein synthesis from the early to the late one-cell stage inhibited the transcription of the two genes that were transcribed in the untreated, late one-cell stage recipients. These results indicate that acquisition of the transcriptionally permissive state during the one-cell stage is facilitated by protein synthesis, and that the transcriptional permissiveness in the late one-cell stage cytoplasm is limited to certain genes.

Is there a relationship between hypertension and lower-extremity contracture release in cerebral palsy?

Recent reports have suggested a relationship between release of lower-extremity contractures and the development of hypertension in cerebral palsy and poliomyelitis patients. A retrospective study was performed on 119 cerebral palsy patients who had undergone lower-extremity contracture releases. Temporary elevation of systolic blood pressure in the perioperative and intraoperative periods occurred in 46 patients (39%), and temporary elevation of diastolic blood pressure occurred in 14 patients (12%). Type of cerebral palsy, patient age, patient sex, type of anesthesia, and type of procedure were not significantly correlated with the temporary blood pressure elevations. No patient developed sustained elevation of systolic and diastolic blood pressure. We conclude that lower-extremity contracture release in pediatric patients is not associated with an increased incidence of postoperative hypertension.

Effect of volume variations on osteogenic capabilities of autogenous cancellous bone graft in dogs.

OBJECTIVE: To evaluate the osteogenic effect of differing volumes of autogenous cancellous bone graft (ACBG) placed into partial cortical defects of the ulna. ANIMALS: 15 healthy, mature Beagles. PROCEDURE: Weekly radiographic views of defects were obtained over 8 weeks and were analyzed for bone density by use of radiographic optical densitometry. Histologic sections were obtained 8 weeks after surgery and were planimetrically evaluated for area of total, lamellar, and woven bone. RESULTS: Defects receiving 0.3 and 0.75 g of ACBG had rapid initial bone production, and dogs receiving 0.3 g of ACBG had faster bone ingrowth than did those receiving 0.1 g of ACBG or controls. Defects receiving 0.75 g of ACBG had a rate of bony ingrowth equal to 0.3 g of ACBG. There was no difference in the histomorphometric area fractions of total, lamellar, or woven bone between defects treated with 0.1 or 0.75 g of ACBG, and between grafted or control defects, 8 weeks after surgery. CONCLUSIONS: Overfilling a cortical defect with ACBG does not enhance early osteogenesis within the defect, and underfilling will delay the onset of osteogenesis within the defect. CLINICAL RELEVANCE: A volume of ACBG sufficient only to fill a cortical defect is required to obtain a clinical osteogenic effect from the graft.

Cardiorespiratory interactions in patients with an artificial heart.

A retrospective analysis of the influence of respiration was carried out in three patients with artificial hearts. During spontaneous ventilation, large swings in intrathoracic pressure can produce a pattern reminiscent of pulsus paradoxus in the systemic arterial pressure. A decrease in intrathoracic pressure decreased biventricular filling and enhanced biventricular emptying. An increase in intrathoracic pressure increased biventricular filling, but acting as an increased afterload, impeded biventricular emptying. The influence of respiration on the artificial heart can be considered the result of the artificial ventricles' functioning effectively as extrathoracic pumps, such that changes in intrathoracic pressure produce gradients for biventricular filling and ejection relative to atmospheric pressure (which serves as the reference pressure for the artificial ventricles). Respiratory-induced variation in ventricular performance is clearly present with the artificial heart, but the mechanisms producing these changes appear to be markedly different from normal conditions, in which the ventricles are functionally within the thorax and have a compliant common septum allowing ventricular interaction.

Immunologic complications of long-term implantation of a total artificial heart.

Bacterial infections are a significant complication of long-term total artificial heart implantation. We evaluated the functional capabilities of host defense mechanisms in two patients sustained long-term by a total artificial heart. Although serum complement and polymorphonuclear leukocyte function remained intact, both patients became B and T lymphopenic and there was an initial decrease in the ratio of helper/inducer to suppressor/cytotoxic cells. Histologic examination of their lymphoidal tissue at autopsy further revealed reduced numbers of germinal centers and atrophy of the T lymphocyte-dependent areas. In addition, the reticuloendothelial system was engorged with degenerate erythrocytes. We hypothesize that blockade of the reticuloendothelial system was induced by multiple blood transfusions necessitated by device-associated hemolysis and coagulopathy. This blockade may have led to a progressive loss of content of the antigen-specific lymphoidal elements and, perhaps, to a reduced ability to ingest microbe-antibody complexes.

The role of nuclear medicine in three permanent total artificial heart recipients.

A total of 13 nuclear medicine studies were performed on three permanent total artificial heart (TAH) recipients at Humana Hospital-Audubon. Preoperative radionuclide studies were performed to evaluate left ventricular function for all three patients. Contrast studies were contraindicated because of impaired renal function. Two of the patients had renograms to assess renal function. The two patients who had strokes received 111In Oxine-labeled platelet scans to determine the presence of thrombi in the atria or TAH. No thrombi were evidenced. At autopsy, several septic thrombi were found, none of which contained a detectable amount of platelets.

Nine year experience with the clinical use of total artificial hearts as cardiac support devices.

One hundred sixteen total artificial hearts (TAH) were implanted in 113 patients by 29 centers between April 4, 1969 and March 1, 1988. Five were permanent and 111 were temporary implants (3 patients received second implants). Eight different types of TAHs have been used. The ages ranged from 15 to 62 (mean age: permanent 57, temporary 42). Sixty-seven percent (72/108) of patients receiving the TAH for temporary support were transplanted; 6 patients were waiting for a transplant. Forty-seven percent (34/72) were alive after transplantation. Of the 92 patients receiving the Jarvik TAH (the most frequently used device) as a temporary device, 67% (62/92) were transplanted (6 currently supported) and 55% were alive after transplantation; 85% were back to work, with a normal life-style. The thromboembolic rate for patients who received the device as a temporary support was 10%, with 3 patients having residual sequellae. No deaths resulted from mechanical failure. Experience to date suggests that the use of the TAH as a temporary device can be beneficial if patients are carefully selected.

The physician, the media, and the 'spectacular' case.

KIE: Drawing on his experiences as a pioneer in performing artificial heart transplants for illustration, DeVries considers the dilemmas that the physician-researcher working on a "spectacular" medical case confronts in dealing with the news media. He discusses five major concerns: the patient's privacy; the effects of the media on the treatment of the patient; the integrity of the experiment; hospital disruptions; and the negative reactions of peers who perceive physician-researchers as self-aggrandizing. DeVries concludes that physician cooperation with the press is necessary and desirable, but that it should be based on the following principles: (1) concern for the patient and family is paramount, taking precedence over the public's right to know; (2) any information released must be accurate; and (3) advance preparation regarding the logistics of reporting the news quickly and accurately is essential.^ieng

The permanent artificial heart. Four case reports.

This article describes the clinical course of four patients in whom the Jarvik-7-100 total artificial heart was implanted as a permanent device. Details of their preoperative assessment and comprehensive summaries of their postoperative course are presented. The neurological, hematological, renal, and infectious complications they experienced and the interventions initiated to achieve resolution of these problems are described. Finally, revisions in the treatment protocols as a consequence of the experience and knowledge gained are examined.

Infectious complications in four long-term recipients of the Jarvik-7 artificial heart.

This article describes the infectious complications that occurred among four of the longest-term recipients of the Jarvik-7 artificial heart. Infection arising from the drive lines, with spread to the mediastinal periprosthetic space, was the major limiting factor in long-term use of the device in these patients. Periprosthetic infections were due to coagulase-negative staphylococci, Staphylococcus aureus, Pseudomonas aeruginosa, and other Pseudomonas species. Other infectious complications incurred by some of the patients included pneumonia, empyema, urinary tract infection, and intravascular line sepsis with Candida. Intensive antimicrobial therapy for prolonged periods seemed to suppress but not to eradicate infection and was accompanied by the appearance of multiresistant bacterial strains. Complications of antimicrobial therapy included diarrhea secondary to overgrowth with Clostridium difficile in two patients. Use of the current device for more than 30 days should be considered extraordinary and should be reserved for patients for whom no other form of life support is available.

Biomaterial-centered sepsis and the total artificial heart. Microbial adhesion vs tissue integration.

The principal barrier to the extended use of the total artificial heart is infection that is centered on the biomaterial constituting the prosthetic device and exacerbated by the surrounding damaged tissue. Ultrastructural studies of total artificial hearts removed from two patients indicate a failure of true tissue integration and diffuse, adhesive bacterial colonization of biomaterial surfaces. Biomaterials are, in part, susceptible to infection because, at the present state of the art, they are usually not well integrated with host tissue or, if hemodynamic, not optimally biocompatible or antiadhesive.

Postmortem microbiological findings of two total artificial heart recipients.

This report describes the postmortem microbiological findings and related gross pathology from two patients who had the longest survival after implantation of the Jarvik-7-100 total artificial heart. We documented extensive polymicrobial colonization at the site of the device and adjacent structures; however, the internal drive lines were remarkably free of bacterial colonization despite evidence of infection at the skin junction and in close proximity to the artificial heart. The polyurethane polymer (Biomer) on the external surface of the device was discolored and pitted in appearance and the Velcro material that attaches the two ventricles together was eroded. A nonspecific mass of tissue that was adherent to the device and to portions of the drive lines contained inflammatory cells, fibrinous debris, and colonies of microorganisms.

Alterations in select immunologic parameters following total artificial heart implantation.

We examined select immunologic parameters in three recipients of a total artificial heart and correlated changes with the clinical course. Two patients remain alive and were studied for 320 and 240 days, respectively; the third died 10 days after implantation. All patients demonstrated transient complement activation immediately postoperatively, as indicated by an increase in plasma levels of C3a des Arg. In the two long-term survivors, C3a des Arg levels again increased, concomitant with intravascular hemolysis associated with high blood shear rates imposed by the drive system of the heart. All three patients had a marked lymphopenia immediately postoperatively, and the two long-term survivors demonstrated marked fluctuations in total lymphocyte count. There was a progressive decline in the number of peripheral blood helper/inducer T cells in the two long-term survivors. A large number of activated (HLA-DR positive) suppressor/cytotoxic T cells were also noted in these two patients. A progressive decrease in B cells was also observed; however, total IgG and IgM levels were not decreased. No changes in neutrophil phagocytic or respiratory burst capacities were identified. The cause of these changes in lymphocyte populations is not clear; however, they may have impact on the use of this device as a bridge to transplantation and may lead to decreased immunocompetence during long-term use.

Multigated radionuclide study of the total artificial heart.

A permanent total artificial heart, the Jarvik-7, was implanted into a 61-year-old male with a severe cardiomyopathy. Gated radionuclide studies were performed in the patient both prior to surgery and following implantation. Preoperative gated radionuclide cardiac studies revealed marked left ventricular enlargement, severe hypokinesis and a left ventricular ejection fraction of 10%. The right ventricle was moderately enlarged with a 27% ejection fraction. Following implantation of the Jarvik-7 artificial heart, gated cardiac studies were performed with a computer gated by a signal from the heart controller. The left ventricular ejection fraction was 69% and the right ventricular ejection fraction was 62%. This compared to a theoretical ejection fraction of 74% for each ventricle based on chamber anatomy. There was excellent ventricular emptying. Phase analysis showed uniform diaphragm motion. The use of gated cardiac studies in humans may prove helpful in evaluating mechanical problems with the artificial heart, such as malfunction of the diaphragm, before they become clinically apparent.

Thromboembolic and infectious complications of total artificial heart implantation.

Thromboembolic and infectious events were found to be major complications of long-term total artificial heart implantation in two patients. Similar complications have been reported in other patients, as well as in animal studies. The thromboembolic events and the infectious complications appear to be interrelated. On the one hand, thrombi located on the valves and at the vascular anastomoses of the artificial heart were found to be infected at autopsy; such infections are known to exacerbate formation of thromboemboli. On the other hand, the generation of microthrombi may have contributed to the RES blockade seen in our patients. We hypothesize that this RES blockade led to a progressive decrease in lymphoid system function and impaired the patients' capacity to clear microorganisms from the circulation. These phenomena arose, in part, from the design of the artificial heart and were exacerbated by associated therapy, such as blood transfusions. Our data suggest several measures that might be taken in order to reduce the severity of both the thrombogenic and infectious complications. Improved anticoagulation regimens, which increase the ability of the physician to maintain the proper balance between thrombotic and hemorrhagic potential, are needed. This may require not only improved methods of monitoring anticoagulation and predicting changes in the effectiveness of various agents as other events supervene, but also new anticoagulant and antithrombotic drugs, for example, low molecular weight heparins and prostacyclin derivatives. It is also clear that the design of the artificial heart should be modified in order to improve fluid dynamics so that they will approximate as closely as possible those of the natural heart. This includes redesigning the mounting of the valves to eliminate crevices and discontinuities that allow stagnant flow and predispose to thrombus formation as well as imposing a dP/dt that minimizes shear-related hemolysis, thereby minimizing the need for blood transfusions. Prevention of infections presents a more difficult problem. Transcutaneous lines (regardless of their use) are an obvious route for infection, and attention should be given to minimizing the number and length of use of monitoring lines. However, until a totally implantable drive system is available, the drive lines will remain a potential avenue for the introduction of infections. The risk may be minimized by rigorous attention to care of the exit sites and by improved designs that will provide a better mechanical barrier by, for example, enhancing epithelial ingrowth into the materials of the drive line.(ABSTRACT TRUNCATED AT 250 WORDS)