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K High

Publications and source records attributed to K High.

At least 19 recordsLinked to original sources
PubMed2006

Cellular and genetic therapies for haemophilia.

Haemophilia continues to be a prime target for a variety of gene and cell-based therapies. Pre-clinical successes in both mouse and dog models of the disease have been documented with a variety of approaches over the past decade, and there have now been six small clinical trials of gene transfer in haemophilia. To date, the only significant adverse events documented in these trials have been related to host immune responses, indicating that immunologic barriers continue to represent the major obstacle to achieving success of gene transfer in humans. Despite these challenges, new strategies are being explored with novel serotypes of viral vectors and with the use of transient periods of immunosuppression to attenuate the immune response to the vector and transgene product following gene delivery. Two new clinical trials, both using AAV vectors, will likely start within the next year, and additional large animal pre-clinical studies using other viral vector-mediated approaches for gene transfer are expected in the near future.

Animals↗
PubMed2005

Gene transfer for hemophilia: can therapeutic efficacy in large animals be safely translated to patients?

Gene transfer is a novel area of therapeutics in which the active agent is a nucleic acid rather than a protein or small molecule. As early as 1997, investigators reported long-term expression of therapeutic levels of factor IX using gene transfer techniques in hemophilia B mice, and similar data were thereafter reported in mice with hemophilia A. Efforts to translate these results to hemophilic dog models at first yielded only marginally therapeutic levels (1%-2% normal circulating levels), but within the past few years have achieved levels in the range of 10%-20% through multiple different gene transfer strategies. Early phase clinical testing has revealed that many aspects of gene transfer in humans were accurately predicted by studies in hemophilic dogs, but that other aspects were not, and were only appreciated as a result of clinical testing. Studies in the next few years will determine whether the problems identified in preclinical and early phase clinical testing can be solved to develop a therapeutic gene transfer approach to hemophilia.

Adenoviridae↗
PubMed2001

Practice guideline for evaluation of fever and infection in long-term care facilities.

The elderly population (i.e., persons aged > or = 65 years) in the United States is rapidly expanding and will nearly double in number over the next 30 years. It is estimated that >40% of persons aged > or = 65 years will require care in a long-term care facility (LTCF), such as a skilled nursing facility (SNF), at some point during their lifetime. For the most part, residents of LTCFs are very old and have age-related immunologic changes, chronic cognitive and/or physical impairments, and diseases that alter host resistance; therefore, they are highly susceptible to infections and their complications. The diagnosis of infections in residents of LTCFs is often difficult because LTCFs differ from acute-care facilities in their goals of care, staffing ratios, types of primary care providers, availability of laboratory tests, and criteria for infections. Consequently, guidelines and standards of practice used for diagnosis of infections in patients in acute-care facilities may not be applicable nor appropriate for residents in LTCFs. Moreover, the clinical manifestations of diseases and infections are often subtle, atypical, or nonexistent in the very old. Fever may be low or absent in LTCF residents with infection. The initial evaluation of an LTCF resident suspected of an infection may not be done by a physician. Although nurses commonly perform initial assessments for infection in residents of LTCFs, further studies are needed to determine the appropriateness and validity of this practice. Provided there are no directives (advance or current by resident or caregiver) limiting diagnostic or therapeutic interventions, all residents of LTCFs with suspected symptomatic infection should have appropriate diagnostic laboratory studies done promptly, and the findings should be discussed with the primary care clinician (see Recommendations). The most common infections among LTCF residents are urinary tract infections, respiratory infections, skin or soft tissue infections, and gastroenteritis. Decisions concerning possible transfer of an LTCF resident to an acute-care facility are best expressed through an advance directive or, when not available, through transfer policies developed by the LTCF. In general, LTCF residents have been transferred to an acute-care facility when any of the following conditions exist: (1) the resident is clinically unstable and the resident or family goals indicate aggressive interventions should be initiated, (2) critical diagnostic tests are not available in the LTCF, (3) necessary therapy or the mode of administration of therapy (frequency or monitoring) are beyond the capacity of the LTCF, (4) comfort measures cannot be assured in the LTCF, and (5) specific infection-control measures are not available in the LTCF.

Aged↗
PubMed2001

Glucuronidation of the nonsteroidal antiestrogen EM-652 (SCH 57068), by human and monkey steroid conjugating UDP-glucuronosyltransferase enzymes.

EM-652 (SCH 57068) is a new orally active antiestrogen that demonstrates pure antagonistic effects in the mammary gland and endometrium. In vivo studies have shown that EM-652 is primarily glucuronidated at the 7-hydroxy position in rats and that the metabolite is present in the plasma of female monkeys and human subjects after EM-800 (SCH 57050) or EM-652.HCl oral administration. Using hepatic microsomes from rat, monkey, and human, the formation of two EM-652 monoglucuronides at positions 4' and 7 was demonstrated by a liquid chromatographic tandem mass spectrometric method. Although no difference in EM-652 conjugation was observed between male and female monkey livers, an interindividual variation of hepatic EM-652 glucuronidation was shown with female human donors. Using microsome preparations from human embryonic kidney 293 cells stably expressing each of the 12 human and 11 monkey UGT enzymes cloned to date, the two EM-652-monoglucuronides were detected after incubation with microsomes containing human UGT1A1, UGT1A3, UGT1A8, UGT1A9, and monkey monUGT1A01, monUGT1A03, and monUGT1A09. Despite human UGT1A1 and monkey monUGT1A09 favored formation of EM-652-7-glucuronide, other active UGT1A enzymes formed both 4'- and 7-glucuronide derivatives in equal amounts. Kinetic analysis of EM-652 glucuronidation by these enzymes showed Michaelis constant (K(m)) values between 36 and 302 microM for EM-652-4'-glucuronide and 19 and 233 microM for EM-652-7-glucuronide. The present results demonstrate the importance of UGT1A isoforms, mainly UGT1A1, for EM-652 metabolism in humans.

Animals↗
PubMed2000

Phase III study of granulocyte-macrophage colony-stimulating factor in advanced HIV disease: effect on infections, CD4 cell counts and HIV suppression. Leukine/HIV Study Group.

OBJECTIVE: To evaluate the effect of adjuvant granulocyte-macrophage colony-stimulating factor (GM-CSF) (sargramostim, yeast-derived recombinant human GM-CSF) on incidence and time to opportunistic infection or death, plasma HIV-RNA, and CD4 cell count in patients with advanced HIV disease. METHODS: This Phase III randomized, double-blind, placebo-controlled trial enrolled subjects with CD4 cell counts < or = 50 x 10(6)/l or < or = 100 x 10(6)/l with a prior AIDS-defining illness on stable antiretroviral therapy. Subjects were stratified by baseline HIV-RNA level (> or = or < 30,000 copies/ml) and randomized to receive subcutaneous injections of GM-CSF 250 microg or placebo three times per week for 24 weeks. Subjects were permitted to continue on blinded drug for up to 20 months. Subjects were evaluated for infections, plasma HIV-RNA, lymphocyte counts, changes in antiretroviral therapy, toxicity, and survival. RESULTS: Three-hundred and nine subjects received at least one dose of study drug, 70% completed 24 weeks of therapy. Groups were well matched at baseline. Significant increases in CD4 cell and neutrophil counts were observed at 1, 3, and 6 months in the GM-CSF group. GM-CSF significantly reduced the incidence of overall infections (78% placebo versus 67% GM-CSF; P = 0.03) and delayed time to first infection (56 days placebo versus 97 days GM-CSF; P = 0.04). No statistical difference in cumulative opportunistic infections was observed between groups; however, among subjects without an opportunistic infection prior to study, the GM-CSF group demonstrated a trend towards fewer subjects with an opportunistic infection on study (26% placebo versus 8% GM-CSF; P = 0.08). Change in HIV-RNA was not significantly different between groups, but significantly fewer GM-CSF subjects with baseline viral load < 30,000 copies/ml had changes in antiretroviral therapy for increased viral load (42% placebo versus 21% GM-CSF; P = 0.01). In patients with HIV-RNA levels below the limit of detection at baseline, more GM-CSF patients maintained an undetectable viral load at 24 weeks (54% placebo versus 83% GM-CSF; P = 0.02). GM-CSF was well tolerated. CONCLUSIONS: GM-CSF significantly increased CD4 cell count and decreased virological breakthrough and overall infection rate in subjects with advanced HIV disease.

AIDS-Related Opportunistic Infections↗
PubMed1997

Recombinant adeno-associated virus for muscle directed gene therapy.

Although gene transfer with adeno-associated virus (AAV) vectors has typically been low, transduction can be enhanced in the presence of adenovirus gene products through the formation of double stranded, non-integrated AAV genomes. We describe the unexpected finding of high level and stable transgene expression in mice following intramuscular injection of purified recombinant AAV (rAAV). The rAAV genome is efficiently incorporated into nuclei of differentiated muscle fibers where it persists as head-to-tail concatamers. Fluorescent in situ hybridization of muscle tissue suggests single integration sites. Neutralizing antibody against AAV capsid proteins does not prevent readministration of vector. Remarkably, no humoral or cellular immune responses are elicited to the neoantigenic transgene product E. coli beta-galactosidase. The favorable biology of rAAV in muscle-directed gene therapy described in this study expands the potential of this vector for the treatment of inherited and acquired diseases.

Animals↗
PubMed1997

Treatment of considerations in patients with compartment syndrome and an inherited bleeding disorder.

In addition to consultation with an experienced hematologist, the following are recommendations regarding compartment syndrome in a patient with an inherited bleeding disorder. Von Willebrand's Disease. Humate-P (rich in von Willebrand factor) is the replacement therapy of choice for surgical procedures in patients with von Willebrand's disease. In general, in the perioperative period, factor VIII levels between 50% and 100% are ideal with a gradual tapering to maintain levels at 50% for approximately 2 weeks. Adjuncts to therapy are DDAVP and EACA. Hemophilia A. During the initial evaluation and with measurement of compartment pressures, factor VIII replacement to levels in the range of 40% to 60% of normal is appropriate replacement therapy. For fasciotomy, however, factor VIII levels greater than 50% to 100% are required. In patients who have developed antibodies to factor VIII, a number of options are available. With low titers of factor VIII inhibitor, higher doses of factor VIII may be successful in overriding the inhibitor. In patients with higher titers of inhibitor, activated factor VII or porcine factor VIII is recommended. Hemophilia B. Highly purified factor IX replacement aimed at keeping factor levels between 50% and 100% in the perioperative period, followed by maintenance at 50% for approximately 2 weeks, is optimal management. Treatment Algorithm: The Figure outlines an algorithm to aid in the diagnosis and treatment of compartment syndrome in the patient with an inherited bleeding disorder. In a suspected case of compartment syndrome due to a soft-tissue hemorrhage or injury, factor replacement as outlined above should be initiated. Unequivocal clinical findings in the normal patient usually would be an indication to proceed to fasciotomy without obtaining compartment pressures. In the patient with an inherited bleeding disorder, however, factor replacement and subsequent normalization of the clotting cascade may help lowe compartment pressures. Therefore, we advocate obtaining initial pressures even with clinical findings of an acute compartment syndrome. At our institution, we advocate using an automated handheld pressure monitor (Stryker, Ontario, Canada) or the needle injection technique as described by Whitesides et al. In interpreting the obtained pressures, we choose to use the guidelines as described by Heppenstall et al. Briefly, Heppenstall et al determined that the pressure threshold at which cellular damage occurred was related more closely to the difference between the mean arterial blood pressure and compartment pressure than with the absolute compartment pressure alone; this measurement is called delta P. If delta P is > 30 mm Hg, then one should continue factor replacements and perform serial clinical and pressure examinations. Pressures should be taken every hour for 2 hours total. If the patient worsens in either respect, then the physician should enter the other limb of the algorithm for delta P < 30 mm Hg. For the patient with a delta P < 30 mm Hg, the amount of time since onset of symptoms must be considered. Since the patient may improve with adequate factor replacement, a delta P < 30 mm Hg mercury does not dictate automatic fasciotomy. An adequate time trial of replacement therapy may be attempted. In patients whose pressures do not begin normalizing, we advocate proceeding to fasciotomy. Patients who begin to normalize pressures during a 2-hour trial can be followed with serial clinical and pressure examinations. Any worsening in either scenario is an indication for fasciotomy; otherwise, observation and factor replacement may be continued. After initial decompression, staples may be placed in both wound edges with an elastic vascular loop woven between the two edges in a "shoelace" pattern. Then while waiting for closure, the loops can be gradually tightened at the bedside. Definitive closure should be attempted around the fifth postoperative day. All closure techniques should be pre

Algorithms↗
PubMed1988

The use of high-dose intravenous gamma-globulin in acquired von Willebrand syndrome.

Acquired von Willebrand syndrome has been reported in patients with a variety of primary diseases, many immunologic in nature. Usually, an autoantibody to von Willebrand factor can be identified. These patients often experience severe hemorrhages requiring large doses of cryoprecipitate or factor VIII concentrates, thus exposing them to viral and allergic complications. The success of intravenous gamma-globulin in the treatment of other autoimmune diseases prompted us to treat two patients with acquired von Willebrand syndrome with high-dose intravenous gamma-globulin. Two days after initiation of therapy, von Willebrand factor and factor VIII rose to normal levels in both patients. Patient 1 underwent dental surgery, and patient 2 underwent a splenectomy without increased bleeding and without additional factor coverage or desmopressin acetate therapy. Thus, intravenous gamma-globulin is efficacious for acquired von Willebrand syndrome and obviates the need for replacement therapy with its attendant complications.

Aged↗