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Biomedical subjects

J M Henry

Publications and source records attributed to J M Henry.

At least 19 recordsLinked to original sources

Purging of myeloma cells using all-trans retinoic acid in a mouse model.

OBJECTIVE: The 5T33 murine model of multiple myeloma was used to investigate the potential of all-trans retinoic acid (ATRA) to purge clonogenic myeloma cells from autologous hemopoietic stem-cell harvests by differentiating immature 5T33 cells into terminal-stage plasma cells with limited repopulation capacity. MATERIALS AND METHODS: 5T33 cells were treated with 10 microM ATRA and the effect on cell clonogenicity was determined by measuring the time to paraprotein detection in C57Bl/KaLwRij mice compared to control animals. Cell differentiation and apoptosis following ATRA treatment were investigated using flow cytometry and caspase-3 assay. Treatment with ATRA resulted in a 33% reduction in the in vitro cloning efficiency of 5T33 cells. Reduced in vitro clonogenicity of 5T33 cells following ATRA treatment was supported by a 16-49% increase in the time taken for C57Bl/KaLwRij mice to develop paraprotein following injection of 5T33 cells pretreated with ATRA for 8 days. Although ATRA was shown not to alter the in vitro growth characteristics of 5T33 cells, significant inhibition of apoptosis was observed. RESULTS: Treatment with ATRA also resulted in an increase in the proportion of 5T33 cells expressing the CD54 adhesion molecule, which is known to be highly expressed on mature myeloma cells. CONCLUSION: The ability of ATRA to decrease the clonogenicity of 5T33 cells in vitro and increase the time to disease development in vivo suggests that this drug may be useful for purging autologous stem cell harvests in the clinical setting.

Animals↗

Experimenting on the past: the enigma of von Economo's encephalitis lethargica.

Encephalitis lethargica (EL) was a complex and mysterious disease that appeared around the same time as the great influenza pandemic of 1918. The contemporaneous relationship of the 2 diseases led to speculation that they were causally related. Contemporary and subsequent observers conjectured that the influenza virus, directly responsible for the deaths of more than 20 million people, might also have been the cause of EL. A review of the extensive literature by observers of the EL epidemic suggests that most contemporary clinicians, epidemiologists, and pathologists rejected the theory that the 1918 influenza virus was directly responsible for EL. Disappearance of the acute form of EL during the 1920s has precluded direct study of this entity. However, modern molecular biology techniques have made it possible to examine archival tissue samples from victims of the 1918 pandemic in order to detect and study the genetic structure of the killer virus. Similarly, tissue samples from EL victims can now be examined for evidence of infection by the 1918 influenza virus.

Causality↗

Influenza RNA not detected in archival brain tissues from acute encephalitis lethargica cases or in postencephalitic Parkinson cases.

Encephalitis lethargica (EL) was a mysterious epidemic. temporally associated with the 1918 Spanish influenza pandemic. Numerous symptoms characterized this disease, including headache, diplopia, fever, fatal coma, delirium, oculogyric crisis, lethargy, catatonia, and psychiatric symptoms. Many patients who initially recovered subsequently developed profound, chronic parkinsonism. The etiologic association of influenza with EL is controversial. Five acute EL autopsies and more than 70 postencephalitic parkinsonian autopsies were available in the Armed Forces Institute of Pathology (AFIP) tissue repository. Two of these 5 acute EL cases had histopathologic changes consistent with that diagnosis. The remaining 3 cases were classified as possible acute EL cases as the autopsy material was insufficient for detailed histopathologic examination. RNA lysates were prepared from 29 CNS autopsy tissue blocks from the 5 acute cases and 9 lysates from blocks containing substantia nigra from 2 postencephalitic cases. RNA recovery was assessed by amplification of beta-2-microglobulin mRNA and 65% of the tissue blocks contained amplifiable RNA. Reverse transcription-polymerase chain reaction (RT-PCR) for influenza matrix and nucleoprotein genes was negative in all cases. Thus, it is unlikely that the 1918 influenza virus was neurotropic and directly responsible for the outbreak of EL.

Adult↗

Cataract with multifocal AMO ARRAY implants.

We have conducted a retrospective study on three hundred cataract surgeries over one year with insertion of the AMO ARRAY multifocal implant dominant for far vision. Under condition of presurgical selection and postsurgery emmetropia, 80% of patients gains multifocality without glasses.

Astigmatism↗

Human herpesvirus 6 and multiple sclerosis: systemic active infections in patients with early disease.

By means of immunohistochemical staining, cells actively infected with human herpesvirus 6 (HHV-6) were found in central nervous system tissues from 8 (73%) of 11 patients with definite multiple sclerosis (MS). Interestingly, 17 (90%) of 19 tissue sections showing active demyelination were positive for HHV-6-infected cells compared with only 3 (13%) of 23 tissue sections free of active disease (P<.0001). Central nervous system tissues from 2 of 28 normal persons and patients with other inflammatory demyelinative diseases were positive for HHV-6-infected cells (P<.0001), and the 2 positive cases were diagnosed as having HHV-6 leukoencephalitis. By use of a rapid culture assay, blood samples from 22 (54%) of 41 patients with definite MS were found to contain active HHV-6 infections, compared with 0 of 61 normal controls (P<.0001). No significant difference was found between HHV-6 viremia-positive and HHV-6 viremia-negative MS patients with respect to type of disease (relapsing/remitting or progressive). In contrast, patients with active HHV-6 viremia were significantly younger and had shorter durations of disease than did HHV-6 viremia-negative patients.

Adult↗

The management of elderly blunt trauma victims in Scotland: evidence of ageism?

Health services are challenged with providing trauma care to an increasingly elderly population. The objectives of this study were to determine the in-hospital mortality for injured elderly patients, and by analysing key features of their management, to ascertain whether these trauma patients were managed less aggressively than their younger counterparts. Main outcome measures included; use of resuscitation room facilities, senior medical staff involvement, admission to intensive care units, transfers to regional neurosurgical centres and mortality. Three thousand seven hundred patients initially managed in a resuscitation room were significantly younger (mean age 43) than those not treated in this area (mean age 54, 95% CI 10.7-12.4). Considering seriously injured patients with a significant head injury (who did not present in coma) those transferred to neurosurgical care were younger (mean age 44) than patients who were not transferred (mean age 49, 95% CI 1. 6-8.6). Logistic regression analysis showed that age did not have a significant independent effect on the seniority of medical response from key specialties. For the severely injured, the odds of being admitted to an intensive care unit when aged 70 in comparison to age 30 were 0.7436 (95% CI 0.5787-0.9559). Overall in-hospital mortality of the 290 elderly patients who had sustained major trauma was 42.1%. Significantly more of the elderly died than would be predicted. Age appears to be an independent factor in the process of trauma care in Scottish hospitals. We consider that outcomes for the injured elderly could be improved by a more dynamic approach to their management.

Adult↗

Possible involvement of the dopamine D3 receptor locus in subtypes of bipolar affective disorder.

The dopamine D3 receptor gene is of potential interest in the physiopathology of affective disorder because of its expression pattern in brain structures controlling various aspects of behaviour, cognition and emotions. Moreover, it encodes for a receptor protein that is a target for psychotropic drugs, which turn out to be efficient in the treatment of this disorder. Two polymorphisms have been described at this locus (the Bal I and the Msp I Restriction Fragment Length Polymorphisms) that are useful in genetic studies. We therefore researched these polymorphisms in 60 patients suffering from bipolar affective disorder who were compared with 60 healthy volunteers. No statistical difference was observed between the whole patient sample versus the controls. However, one subgroup [homozygous for the (2-2) Bal I polymorphism] exhibits a characteristic clinical pattern consisting of: manic monopolar form of bipolar disorder, low age of onset and initiation by an acute delusional episode. A gender distribution difference for the Bal I polymorphism (chi 2 = 6.61, degrees of freedom = 1, P = 0.01) was then noted, the bipolar females being preferentially heterozygous, and the males homozygous. These results could involve the dopamine D3 receptor locus as a minor effect gene in the manic depression condition.

Adult↗

National audit of the management of injured patients in 20 Scottish hospitals.

The Scottish Trauma Audit Group was established in 1991 to observe and improve the management of seriously injured patients in four Scottish teaching hospitals. There are currently 25 hospitals contributing to the national database. This prospective audit monitors the management of approximately 98% of seriously injured patients in Scotland. This report presents an analysis of the management of 23479 patients who were admitted to hospital for at least three days or who died in hospital as a result of their injuries. The audit has specifically addressed the concerns raised by the working party of the Royal College of Surgeons in 1988 and the National Audit Office in 1992. National standards were agreed and implemented by STAG in 1997. STAG has demonstrated that 73.5% of seriously injured patients presented outwith 'normal' working hours when staffing and support services are at their lowest level. Seniority of accident and emergency doctor was associated with improved outcome in injured patients. An increase in the presence of consultants in accident and emergency medicine, anaesthetics and surgery has been demonstrated and a reduction in the mortality of seriously injured patients is evident. There was no evidence of a trimodal distribution of death as a result of injury. There has been a significant increase in the survival of seriously injured patients over the last six years from 65.3% to 75.6%. In terms of survival, the management of injured patients in Scotland is significantly better than that of the rest of the UK.

Hospital Mortality↗

Neurons and Nobel Prizes: a centennial history of neuropathology.

Camillo Golgi and Santiago Ramón Y Cajal were selected as joint Nobel Prize recipients in 1906, "in recognition of their work on the structure of the nervous system." This posthumous Festschrift is written in celebration and commemoration of the 90th anniversary of that event, and the reader is invited to participate in an entertaining journey through the history of neuropathology, as it evolved from the time of Golgi and Cajal. The story, of necessity, is written in broad descriptive terms, highlighting major events and personalities, and strives for continuity of narration and coherence of presentation. The historical framework reflects the personal experience and purview of the author and his mentor, Kenneth M. Earle, who began their careers in neurology and neurosurgery, respectively. Emphasis on the close interface linking clinical neuroscience and neuropathology indicates the antecedents of the latter discipline as well as the overlap characterizing current modes of investigation at the cellular and molecular levels. This article is intended to provide a younger generation of neurologists and neurosurgeons with a review of what has gone before as a foundation for their current studies and future careers.

History, 20th Century↗

Comparison of myeloma cell contamination of bone marrow and peripheral blood stem cell harvests.

lt could be speculated for patients with myeloma and other lymphoproliferative disorders that peripheral blood stem cells may be preferable to bone marrow for autologous transplantation because they may be less contaminated by neoplastic cells. To test this possibility, the immunoglobulin heavy chain gene rearrangement and limiting dilution polymerase chain reaction were used to sensitively quantify myeloma cells in bone marrow and peripheral blood stem cell collections, taken at a similar time, from eight patients with multiple myeloma. Levels of residual disease in the peripheral blood stem cell harvests were variable and did not reflect the tumour burden in the marrow. Peripheral blood stem cells contained 1.7 to 23700-fold fewer myeloma cells compared with the bone marrow and would have resulted in reinfusion of 0.08 to 59480-fold fewer myeloma cells based on total reinfused CFU-GM and 0.24 to 24700-fold fewer myeloma cells based on total reinfused nucleated cells. Assuming that the proportion of clonogenic myeloma cells is equivalent, peripheral blood stem cells may be better than bone marrow as a source of haemopoietic stem cells for transplantation in multiple myeloma. The clinical followup suggested that patients transplanted with peripheral blood stem cells containing a low number of myeloma cells had better disease control than those transplanted with peripheral blood stem cells containing a high number.

Adult↗

Isolation of high-molecular-weight DNA from insects.

A simple and rapid method for the isolation of high-molecular-weight DNA from insects is described. The method does not require CsCl ultracentrifugation or extensive dialysis. High-molecular-weight DNA was obtained within 24 h. Since the entire insect was used for DNA isolation, an initial nuclei-enriched fraction was required. Genomic DNA was extracted from lysed nuclei by organic phase separation (liquid/liquid extraction). This method has been successfully applied to the isolation and purification of DNA from eight different adult insects (Heliothis zea, Musca autumnalis, M. domestica, Blatta orientalis, Tenebrio molitor, Lymantria dispar, Ostrinia nubilalis, and Manduca sexta). The recovered DNA can be cleaved with restriction endonucleases, ligated efficiently using standard cloning vectors, and hybridized to synthetic oligonucleotides.

Animals↗

Increased efficiency of gene transfer with retroviral vectors in neonatal hematopoietic progenitor cells.

The retroviral vector N2, which is derived from the Moloney murine leukemia retrovirus, was used to transfer the bacterial NeoR gene (conferring resistance to the neomycin analogue G418) into hematopoietic progenitor cells from fetal, neonatal, and adult dogs and cats. Infection of canine and feline bone marrow cells with the N2 vector resulted in resistance of granulocyte-macrophage colony-forming units (CFU-GM) to G418. Approximately 2%-4% of fetal liver, fetal bone marrow, and adult bone marrow day-7 CFU-GM were resistant to 1.75 mg/ml G418, a dose toxic to cells not expressing the NeoR gene, after infection with the N2 retrovirus. In sharp contrast to the low rate of infectivity of both fetal and adult marrow samples, the mean +/- SD of G418-resistant CFU-GM was 11.7% +/- 14.1% and 14.0% +/- 18.1% for neonatal dog and cat marrow samples, respectively. The neomycin phosphotransferase enzyme activity was detected in G418-resistant CFU-GM, confirming that G418-resistant CFU-GM expressed the NeoR gene. The increased efficiency of retroviral vector-mediated gene transfer into neonatal hematopoietic progenitor cells was not due to an increased fraction of actively dividing cells, as determined by tritiated thymidine suicide. Understanding the basis for increased gene transfer into neonatal hematopoietic progenitor cells may be helpful in designing effective retroviral vectors/gene transfer protocols for gene therapy.

Animals↗

Synergistic enhancement of the efficacy of the bioreductively activated alkylating agent RSU-1164 in the treatment of prostatic cancer by photodynamic therapy.

Bioreductively activated alkylating agents (BAA) require metabolic reduction to become cytotoxic. Hypoxia induces a massive increase in reductive metabolism activating BAA to their cytotoxic form. One of these BAA agents is cis-2,3-dimethyl 1-(2-nitro-1-imidazolyl)-3-(1-aziridinyl)-2-propanol referred to as RSU-1164. In a hypoxic environment, RSU-1164 is activated to a highly reactive bifunctional alkylating agent capable of crosslinking macromolecules which results in cell death. Photodynamic therapy (PDT) is a treatment modality which consists of the initial accumulation of hematoporphyrin derivative (HPD) within a tumor followed by the activation of the HPD by 630 nm. light to induce a cytotoxic response. The precise mechanism of PDT is not known, however, two actions of the activated HPD have been documented. The first is a direct cytotoxic effect, secondary to singlet oxygen production. The second is through vascular collapse and subsequent hypoxia. The combination of a chemotherapeutic agent like RSU-1164, which is activated by hypoxia, with PDT to produce such hypoxia, therefore, should greatly increase the efficiency and utility of RSU-1164. To test this hypothesis, Copenhagen rats bearing established Dunning R-3327 AT-2 prostate cancers were treated with PDT treatment alone (HPD 20 mg./kg. injected IP and then 24 hr. later, the tumor exposed to 630 nm. light at 400 mW/cm.2 for 30 min. [total dose 720 J/cm.2]), RSU-1164 alone (injected IP at a dose of 200 mg./kg.) or with the combination of this PDT treatment plus RSU-1164 given 30 min. before light exposure. These results demonstrated that this combinational treatment synergistically produces a greater retardation in the growth of the AT-2 tumor than either of the monotherapies of RSU-1164 or PDT alone.

Animals↗

Relationship between tumor size and the curability of metastatic prostatic cancer by surgery alone or in combination with adjuvant chemotherapy.

The MAT-Lu subline of the Dunning R3327 system of rat prostatic adenocarcinomas universally metastasizes to the lungs of untreated recipient hosts. The MAT-Lu cancer was implanted into the hind leg of animals and the primary tumor was allowed to grow to various sizes before the tumor bearing leg was surgically removed. These studies demonstrated that there is a direct relationship between the size of the primary tumor at the time of surgical removal and the number of metastases already established in the lungs. Once the primary MAT-Lu reaches a size of greater than or equal to 0.5 cc, greater than or equal to 50% of all inoculated animals already have established lung metastases and are thus not cured by surgery alone. In an attempt to increase the cure rates, adjuvant chemotherapy (cytoxan given at a dose of 90 mg./kg. body weight) was used in combination with surgery. These studies demonstrated that if chemotherapy was given by itself to animals bearing macroscopically established (greater than or equal to 0.5 cc) MAT-Lu cancers, no animals could be cured. In direct contrast, by combining the same intensity of adjuvant chemotherapy with the removal of the primary MAT-Lu cancer, cures could be produced in high (greater than 90%) frequency, but only if this combinational approach was simultaneously initiated when the primary tumor was less than 2 cc in size. If the primary MAT-Lu cancer was allowed to grow to too large a size before surgery (greater than 2 cc) or if the chemotherapy was delayed following surgery (both processes allowing the metastatic tumor burden to increase before initiating adjuvant chemotherapy), the ability of the adjuvant chemotherapy to cure the host of its metastatic tumor burden is lost. These results demonstrate that the MAT-Lu rat prostatic cancer, like human prostatic cancer, is not effectively treated by chemotherapy alone or by adjuvant chemotherapy combined with surgery if the treatment is given too late in the course of the disease. These studies emphasize the critical requirement of combining surgery and adjuvant chemotherapy as early as possible in the treatment of metastatic prostatic cancer in order to minimize the total metastatic tumor burden and maximize the possibility of cure.

Adenocarcinoma↗

Effect of aging on striatal dopamine receptor subtype recovery following N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline blockade and relation to motor function in Wistar rats.

Recovery of D1- and D2-dopamine receptors in Wistar rat corpora striata were assessed following N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ blockade). Absolute recovery declines during senescence approximately 25 and 40% for the D1- and D2-subtypes, respectively. Net biosynthetic reductions are comparable to the overall age-related decreases in receptor concentrations for this rat strain. EEDQ administration also induces catalepsy behavior and impairs ability of animals to remain on an inclined screen. Recovery of inclined screen performance is also reduced with age, but is not strictly proportional to recovery of receptor concentrations.

Aging↗