Optic neuropathy as the presenting feature of HIV infection: recovery of vision with highly active antiretroviral therapy.
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Anti-HIV Agents↗
Biomedical subjects
R E Jones
Publications and source records attributed to R E Jones.
Gout: beyond the stereotype.
Not all gout presents with involvement of the big toe, and not all gout patients are middle-aged men. Chronic gout may mimic rheumatoid arthritis; hyperuricemia may develop in postmenopausal women and in organ transplant recipients who are being treated with immunosuppressive agents. Both classic and nonclassic cases may benefit from new therapeutic agents.
Aged↗
Myelin basic protein-specific T lymphocytes induce chronic relapsing experimental autoimmune encephalomyelitis in lymphocyte-deficient (SCID) mice.
Myelin basic protein (BP)-specific T lymphocyte cell lines were selected from the lymph nodes (LN) of BP-immunized, H-2d, CXJ-1 mice prior to the onset of clinical disease. These CD4+ T cells induced severe acute experimental autoimmune encephalomyelitis (EAE) in MHC-compatible (H-2d), lymphocyte-deficient (SCID) mice (C.B-17scid/scid). The incidence of disease was much higher in immunodeficient SCID mice (71%) than in syngeneic immunocompetent CXJ-1 mice (5%). SCID mice with EAE had an acute progressive paralytic disease with inflammation and myelin loss detected in the spinal cord. Eighty-six percent (12/14) of mice followed for more than 2 weeks had 1 or more relapses of EAE. These results demonstrate that clinical remission and relapse of EAE can be induced by the single adoptive transfer of a LN-derived BP-specific T cell line in the absence of host-derived effector and regulatory lymphocytes. Furthermore, the data demonstrate that the pathogenic potential of BP-specific T cells is greater in lymphocyte-deficient SCID mice compared with immunocompetent mice, suggesting that autoreactive T cells are controlled by potent inhibitory mechanisms associated with regulatory lymphocytes. These results are relevant to mechanisms of disease remission and relapse mediated by lymphocytes involved in paralytic inflammatory diseases such as multiple sclerosis (MS).
Animals↗
Drug retention and distribution after intratumoral chemotherapy with fluorouracil/epinephrine injectable gel in human pancreatic cancer xenografts.
PURPOSE: Pancreatic cancer is widespread, associated with high mortality, and rapidly fatal. Most cases are diagnosed too late for surgical treatment, and the disease responds poorly to systemic chemotherapy. Nevertheless, pancreatic cancer cells are sensitive to fluorouracil (5-FU) in a time- and dose-dependent manner, suggesting that improved retention of drug in the tumor may improve patient prognosis. In this study, we evaluated a novel drug delivery system, 5-FU/epinephrine injectable gel (5-FU/epi gel), designed to improve drug retention in tumors. METHODS: We used a BxPC-3 human pancreatic cancer xenograft model in athymic mice to examine drug levels in tumor, liver, and kidney tissue following administration of: (a) 5-FU/epi gel (30 mg 5-FU/ml) intratumorally (i.t.); (b) 5-FU solution i.t.; and (c) 5-FU solution intraperitoneally (i.p.). [(3)H]5-FU was added as a radiolabeled marker to all test formulations. Animals were sacrificed at designated times, and the tumor, liver, and one kidney from each animal were excised and processed for radioactivity analysis. Drug concentration was quantified by both storage-phosphor autoradiography (SPA) and liquid scintillation counting (LSC). RESULTS: Higher and sustained i.t. drug levels were achieved following i.t. administration of 5-FU/epi gel (SPA AUC 18.4 mM. h, LSC AUC 13.0 mM. h) compared with 5-FU solution i.t. (SPA AUC 2.02 mM. h, LSC AUC 1.92 mM. h) or 5-FU solution i.p. (SPA AUC 0.07 mM. h, LSC AUC 0.04 mM. h). Use of the 5-FU/gel system was associated with lower drug levels in liver and kidney, indicating that it produces far less systemic exposure. CONCLUSION: In the human pancreatic cancer xenografts, i.t. administration of 5-FU/epi injectable gel provided significantly higher drug and/or metabolite concentrations for extended periods than was possible with either i.t. or i.p administration of drug solution. This i.t. drug delivery system could potentially be used to treat patients with pancreatic cancer to increase tumor exposure to drug and improve the therapeutic index in comparison to systemic drug administration.
Animals↗
Update on sarcoidosis.
The local inflammatory response in sarcoidosis appears to be a Th1-mediated process. Evidence exists that the systemic immune response, however, shows a Th2 predominance. Mycobacteria species, particularly cell wall-deficient forms, continue to be candidates for an infectious cause of the disease. Evidence for a possible role for human herpesvirus 8 has also been submitted. The relationship between sarcoidosis and infectious pathogens remains open to investigation. Both Sjögren's syndrome and common variable immunodeficiency display clinical and immunopathologic overlap with sarcoidosis. Blau's syndrome, a genetic disorder of autosomal dominant inheritance, may be confused with infantile sarcoidosis. Vasculitis in sarcoidosis may be underappreciated. Virtually any size vessel may be involved, thus adding to the multiplicity of clinical settings in which sarcoidosis can occur.
Sarcoidosis↗
Comparative micromotion of fully and proximally cemented femoral stems.
This investigation studied the differences of in vitro micromotion between two stem designs. The two stem types investigated were a proximally cemented stem with distal press fit and a fully cemented stem. After initial micromotion testing to 2250 N in simulated single leg stance and stair climb, six of each stem type were loaded dynamically for 1 million cycles at 950 N at 1 Hz. Micromotion studies were repeated. The two stem types had similar micromotion. For the single leg stance, fully cemented implant motion averaged (+/- 95% confidence) 18 +/- 8 microns toggle, 41 +/- 5 microns axial, and 59 +/- 22 microns rotation. Proximally cemented implant motion averaged 20 +/- 6 microns toggle, 42 +/- 6 microns axial, and 31 +/- 15 microns rotation. For the simulated stair climb, fully cemented implant motion averaged 24 +/- 10 microns toggle, 45 +/- 8 microns axial, and 92 +/- 32 microns rotation. Proximally cemented implant motion averaged 19 +/- 10 microns toggle, 42 +/- 9 microns axial, and 87 +/- 53 microns rotation. For both loading conditions, there were no significant differences measurable between the two systems. After dynamic testing of the fully cemented implants, there were no significant changes in the micromotion of either the toggle or the rotation, but an average of 18 microns increase of axial motion was measured in the fully cemented stem. For the proximally cemented implants, there were no significant changes after dynamic testing. This differences was not considered clinically significant because roentgen stereophotogrammetric analysis studies have shown that more than 4 mm of migration is required before clinical symptoms manifest. The protocol developed in this study may help provide a screening process to determine the stability of femoral stem designs before these devices are used clinically.
Adult↗
Primary total hip arthroplasty with use of the modular S-ROM prosthesis. Four to seven-year clinical and radiographic results.
BACKGROUND: A multicenter retrospective study was conducted to determine the clinical and radiographic results of primary total hip arthroplasty with insertion of the S-ROM modular femoral stem without cement in a series of patients who had been followed for four to seven years. Four centers participated in the study, with one contributing surgeon at each center. METHODS: Two hundred and eight consecutive patients who had a total hip arthroplasty with implantation of the S-ROM femoral prosthesis at one of the four centers during the study period were identified. Twenty-nine patients were lost to follow-up or had incomplete radiographic data, and twenty patients died from causes unrelated to the index arthroplasty. The remaining 159 patients formed the basis of this study. Sixteen of these patients had a bilateral procedure, resulting in 175 hips with complete clinical and radiographic data. The average age of the patients at the time of the index operation was fifty-nine years (range, twenty-two to ninety-three years). The duration of clinical follow-up averaged 5.3 years (range, four to 7.8 years), and the duration of radiographic follow-up averaged 4.9 years (range, four to 7.3 years). RESULTS: One patient (0.6 percent) had a failed femoral component, which was evidenced by progressive subsidence and lack of bone ingrowth. In addition, two patients (1 percent) had a revision of the acetabular component. The average Harris hip score increased from 35 points (range, 10 to 76 points) preoperatively to 91 points (range, 52 to 100 points) at the most recent follow-up examination. The radiographic evaluation revealed that 172 hips (98 percent) had stable bone ingrowth, two hips (1 percent) had stable fibrous ingrowth, and one hip (0.6 percent) had unstable fibrous ingrowth. Periprosthetic osteolytic lesions were noted in twelve hips (7 percent). The lesions were observed in the femur in eight hips, in the acetabulum in two hips, and in both the femur and the acetabulum in two hips. All femoral osteolytic lesions were localized within the greater trochanter or the proximal-medial portion of the femoral neck. No osteolytic lesions were evident distal to the stem-sleeve junction. CONCLUSIONS: Use of the modular S-ROM femoral prosthesis yielded excellent intermediate-term outcomes with respect to standard radiographic and clinical criteria. The issue regarding the theoretical increase in the rate of osteolysis due to metal debris generated at the modular femoral stem-sleeve junction was specifically addressed. We found that the rate of osteolysis in this series was not notably higher than that in other series reported in the orthopaedic literature. Although many possible factors may influence the rate of osteolysis in total hip arthroplasty, this finding suggests that the potential increase in osteolysis theoretically associated with this modular femoral implant was not observed at intermediate-term follow-up. Although longer follow-up is warranted so that the potential for osteolysis can be evaluated fully, no osteolytic lesions were evident distal to the stem-sleeve interface at the time of intermediate-term follow-up. This finding suggests that there is a circumferential seal at the modular junction of the stem that prevents the distal egress of wear debris.
Adult↗
Tumor necrosis factor inhibitors for rheumatoid arthritis.
Tumor necrosis factor antagonists such as infliximab and etanercept represent a new and powerful approach to managing RA. In studies published to date, TNF antagonists appear to be safe and effective agents for short-term therapeutic use in RA. Defining when in the course of RA to use TNF antagonists and determining the effectiveness of combinations of these biologic agents with DMARDs or other cytokine antagonists are areas of current and future studies. Other cytokine antagonists that may be promising subjects for further study are IL-1 antagonists. Like TNF, IL-1 is a member of the inflammatory cascade, but may play a different role in the development of inflammatory arthritis. In animal models, inhibition of TNF suppressed the inflammatory response while IL-1 antagonism prevented joint destruction (2). These results imply that combination therapy providing inhibition of both IL-1 and TNF might be an effective treatment in humans with RA, but clinical trials in humans have not yet been performed. Studies are underway in people with early RA to determine if the new TNF inhibitors are more effective or safer than currently available therapies, such as methotrexate. Other agents that inhibit TNF activity are also being tested at this time in people with RA.
Anti-Inflammatory Agents, Non-Steroidal↗
Simplified method of identifying severe combined immunodeficient (SCID) mice versus non-SCID mice by flow cytometric analysis of peripheral blood.
Several studies have utilized simple breeding strategies to create new immunodeficient mouse strains from severe combined immunodeficient (SCID) mice and non-SCID mice with secondary traits in order to evaluate the involvement of lymphocytes and immune responses in a variety of processes. We utilized a breeding strategy with C.B-17scid/scid (SCID) (H-2d) mice and SJL (H-2s) mice to generate immunodeficient mice that were histocompatible with the inbred SJL strain (H-2s) in order to evaluate the role of histocompatible recipient lymphocytes in adoptively transferred autoimmune disease mediated by SJL T lymphocytes. [SCID x SJL]F1 mice (heterozygous for H-2 loci and heterozygous for the SCID mutation) were backcrossed with SCID mice and the resulting offspring expressed a variety of phenotypes, including SCID or non-SCID and H-2s/H-2d or H-2d/H-2d. In order to screen offspring for the desired phenotype (SCID, H-2s), a flow cytometric method utilizing forward- and side-scatter parameters of peripheral blood cells was used to distinguish SCID from non-SCID animals. This method simplified the screening process and was as reliable as anti-CD3 fluorescent monoclonal antibody staining for detecting the presence (non-SCID) or absence (SCID) of T lymphocytes in peripheral blood.
Animals↗
Longitudinal analysis of deciduous tooth emergence: II. Parametric survival analysis in Bangladeshi, Guatemalan, Japanese, and Javanese children.
We present a form of parametric survival analysis that incorporates exact, interval-censored, and right-censored times to deciduous tooth emergence. The method is an extension of common cross-sectional procedures such as logit and probit analysis, so that data arising from mixed longitudinal and cross-sectional studies can be properly combined. We extended the method to incorporate and estimate a proportion of agenic teeth. While we concentrate on deciduous tooth emergence, the method is relevant to studies of permanent tooth emergence and other developmental events. Deciduous tooth emergence data were analyzed from four longitudinal studies. The samples are 1,271 rural Guatemalan children examined every three months up to age two and every six months thereafter as part of the INCAP study; 397 rural Bangladeshi children examined monthly to age one and quarterly thereafter as part of the Meheran Growth and Development Study; 468 rural Indonesian children examined monthly as part of the Ngaglik study; and 114 urban Japanese children examined monthly in studies from 1910 and 1920. Although all four studies were longitudinal, many observations from the Guatemala and Bangladesh studies were effectively cross-sectionally observed. Three different parametric forms were used to model the eruption process: a normal distribution, a lognormal distribution, and a lognormal distribution with age shifted to shortly after conception. All three distributions produced reliable estimates of central tendencies, but the shifted lognormal distribution produced the best overall estimates of shape (variance) parameters. Estimates of emergence were compared to other studies that used similar methods. Japanese children showed relatively fast emergence times for all teeth. Bangladeshi and Javanese children showed emergence times that were slower than are found in most previous studies. Estimates of agenesis were not significantly different from zero for most teeth. One or two central incisors showed significant agenesis that ranged from 0.1 to 0.8% in three of the samples; even so, failure to model the agenic proportion did not seriously bias the estimates.
Bangladesh↗
Interactions of gonadal steroids and pesticides (DDT, DDE) on gonaduct growth in larval tiger salamanders, Ambystoma tigrinum.
In view of the current worldwide decline in amphibian populations, exploratory studies are needed to assess the potential for environmental contaminants to act as endocrine disrupters of the amphibian reproductive system. The present study investigated the effects of DDT dichlorodiphenyltrichloroethane (DDT) and dichlorodiphenyldichloroethylene (DDE) on the development of amphibian gonaducts. Larval male and female tiger salamanders (Ambystoma tigrinum), with immature gonads, were immersed in a sublethal solution of p,p'-DDE or technical-grade DDT (80% p,p'-DDT and 20% o,p'-DDT). Additionally, larvae were injected with the steroid hormones estradiol or dihydrotestosterone (DHT). Morphometrics were used to analyze the effects and interactions of steroid and pesticide treatments on larval gonaducts. Estradiol and DHT stimulated cell proliferation and hypertrophy of the müllerian duct epithelium in both sexes. Wolffian duct epithelium, however, was stimulated only by DHT treatment. The pesticide DDT antagonized the estrogenic actions of the steroid treatments, and p,p'-DDE acted as an estrogen on the müllerian ducts of females only. The müllerian ducts of males, and the wolffian ducts of both sexes, were unaffected by DDT or DDE alone. While confirming the previously reported estrogenic actions of estradiol and DHT on urodelean gonaducts, the results contradict the expected estrogenic actions of DDT and antiandrogenic actions of p,p'-DDE. Instead, in A. tigrinum, technical-grade DDT had an antiestrogenic action and p,p'-DDE an estrogenic action.
Animals↗
Joint replacement surgery: preoperative management.
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Arthroplasty, Replacement, Hip↗
Characterization of five different proteins produced by alternatively spliced mRNAs from the human cAMP-specific phosphodiesterase PDE4D gene.
We have isolated and characterized complete cDNAs for two isoforms (HSPDE4D4 and HSPDE4A5) encoded by the human PDE4D gene, one of four genes that encode cAMP-specific rolipram-inhibited 3',5'-cyclic nucleotide phosphodiesterases (type IVPDEs; PDE4 family). The HSPDE4D4 and HSPDE4D5 cDNAs encode proteins of 810 and 746 amino acids respectively. A comparison of the nucleotide sequences of these two cDNAs with those encoding the three other human PDE4D proteins (HSPDE4D1, HSPDE4D2 and HSPDE4D3) demonstrates that each corresponding mRNA transcript has a unique region of sequence at or near its 5'-end, consistent with alternative mRNA splicing. Transient expression of the five cDNAs in monkey COS-7 cells produced proteins of apparent molecular mass under denaturing conditions of 68, 68, 95, 119 and 105 kDa for isoforms HSPDE4D1-5 respectively. Immunoblotting of human cell lines and rat brain demonstrated the presence of species that co-migrated with the proteins produced in COS-7 cells. COS-cell-expressed and native HSPDE4D1 and HSPDE4D2 were found to exist only in the cytosol, whereas HSPDE4D3, HSPDE4D4 and HSPDE4D5 were found in both cytosolic and particulate fractions. The IC50 values for the selective PDE4 inhibitor rolipram for the cytosolic forms of the five enzymes were similar (0.05-0.14 microM), whereas they were 2-7-fold higher for the particulate forms of HSPDE4D3 and HSPDE4D5 (0.32 and 0.59 microM respectively), than for the corresponding cytosolic forms. Our data indicate that the N-terminal regions of the HSPDE4D3, HSPDE4D4 and HSPDE4D5 proteins, which are derived from alternatively spliced regions of their mRNAs, are important in determining their subcellular localization, activity and differential sensitivity to inhibitors.
3',5'-Cyclic-AMP Phosphodiesterases↗
Immunoreactive gonadotropin-releasing hormone (GnRH) is detected only in the form of chicken GnRH-II within the brain of the green anole, Anolis carolinensis.
The presence of multiple forms of gonadotropin-releasing hormone (GnRH) within a single brain is common among vertebrate species. In previous studies of reptiles, two forms of GnRH were isolated from the brain of alligators and the primary structure was determined to be that of chicken (c)GnRH-I and cGnRH-II. GnRH has also been detected by indirect methods in other reptiles including turtles, lizards, and snakes. We used a combination of high-performance liquid chromatography (HPLC) and radioimmunoassay to determine the number and molecular form(s) of GnRH in the brain of a lizard, Anolis carolinensis, that was reported to lack GnRH cells in the forebrain. Immunoreactivity was detected in the same HPLC elution position in which synthetic cGnRH-II elutes, but not in any other position. Detection was based on five antisera that among them detect the 12 known forms of GnRH; these antisera include ones that are specific to cGnRH-I and cGnRH-II. We conclude that the lizard A. carolinensis contains cGnRH-II, but not cGnRH-I or another known form of GnRH. These data, coupled with our earlier immunocytochemical study, suggest that the lizard studied here lacks cGnRH-I, the form that is found in the terminal nerve, olfactory bulb, and forebrain in nonsquamate reptiles and in birds. Our hypothesis is that the presence of both cGnRH-I and cGnRH-II in the brain is ancestral in the reptilian lineage and retained in the orders that include turtles (Chelonia) or alligators (Crocodilia). However, the pattern in the order Squamata varies: in A. carolinensis, only cGnRH-II is present in the brain and cGnRH-I is absent, whereas in the snake Thamnophilis sirtalis, cGnRH-I is retained and cGnRH-II is absent in the brain, as recently reported. This raises the question of how reproduction is controlled in reptiles that lack one form of GnRH.
Animals↗
Unilateral ovariectomy influences hypothalamic monoamine asymmetries in a lizard (Anolis) that exhibits alternation of ovulation.
The lizard Anolis carolinensis alternates ovulation, and the resultant ovarian asymmetry correlates with alternating asymmetry of hypothalamic catecholamines. Unilateral and bilateral ovariectomies of cycling females were performed to determine if ovarian manipulations influence hypothalamic catecholamine asymmetries. During the middle of the ovarian cycle, we removed the larger ovary, i.e., the next one to ovulate an egg (N = 9), the smaller ovary with its corpus luteum (N = 8), or both ovaries (N = 5). A sham-operated control group was included (N = 9). The diameter of the largest ovarian follicle in each ovary was measured at the beginning and end of the experiment. After 12 days, the hemihypothalami from the sides of the initial smaller ovary (SO) and larger ovary (LO) were dissected and frozen for determination of monoamines and their metabolites using HPLC and electrochemical detection. Monoamine and metabolite concentrations at the end of the experiment in the original SO and LO sides of each hypothalamus were compared with an asymmetry ratio, or AR, of (SO side - LO side)/(SO side + LO side). No female ovulated during the experiment. Unilateral ovariectomy caused compensatory growth of the largest follicle in the remaining ovary. Removal of the SO or LO caused the AR of DOPAC to favor the brain side ipsilateral to that of the ovarian removal. Removal of the LO switched the NE AR from the SO to the LO side. Removal of the LO or SO caused the MHPG AR to favor the LO side. Ovariectomy of any kind caused 5-HT, which in the sham-operated animals favored the SO side, to become symmetric, and removal of the LO caused the 5-HIAA AR to favor the LO side. We conclude that the ovaries influence hypothalamic catecholamine asymmetries in Anolis via direct neural (as well as hormonal) pathways and that sensory input from the ovaries to the hypothalamus could be involved in control of ovarian alternation via both neural and hormonal efferent mechanisms.
3,4-Dihydroxyphenylacetic Acid↗
Hypothyroid Graves' disease.
BACKGROUND: Spontaneous conversion from hypothyroidism to hyperthyroidism has generally been considered uncommon. METHODS: Values obtained were serum thyroid-stimulating hormone (TSH), thyroxine, free thyroxine index, radioactive iodine uptake (RAIU), thyroid-stimulating immunoglobulins (TSI), and thyrotropin-binding inhibitory immunoglobulin (TBII). RESULTS: Five patients spontaneously had a minimum of two cycles in thyroid function with extremes of hypothyroxinemia to hyperthyroxinemia. One patient had four documented cyclic shifts in thyroid status. When measurements were obtained in the hyperthyroid phase, all patients had TSI, increased RAIU, and an undetectable TSH. When measurements were done in the hypothyroid phase, all patients had positive TBII but negative TSI. CONCLUSIONS: Spontaneous reversal of thyroid function may be more common than previously thought. Clinical features associated with lability of thyroid function were abrupt change in goiter size, exaggerated response to therapy, or the presence of TSH-receptor antibodies.
Adolescent↗
Parotid sparing study in head and neck cancer patients receiving bilateral radiation therapy: one-year results.
Many patients with head and neck cancers receive radiation therapy as part of their treatment which frequently causes considerable morbidity, including various degrees of permanent salivary gland dysfunction. Three-dimensional treatment planning [3-DTP] and conformational dose delivery constitute a new therapeutic modality that conforms the high-dose radiation volume to the shape of the tumor volume while minimizing the dose to tissue that is not at risk of containing cancer. The treatment volumes for head and neck tumors as well as parotid glands can be well-defined on cross-sectional CT imaging techniques. The purpose of this investigation is to determine if 3-DTP and conformational dose-delivery could minimize radiation dose and salivary gland dysfunction to contralateral parotid glands in patients with head and neck cancers. Eleven patients with head and neck cancers who required bilateral radiation therapy were treated with 3-DTP. Unstimulated and stimulated bilateral parotid saliva was collected prior to radiotherapy, weekly during treatment, and 1, 3, 6, and 12 months after the completion of radiotherapy. Treated parotid glands received an average dose of 5745 cGy, while spared glands received only 1986 cGy (p < 0.0001). Unstimulated and stimulated parotid flow rates decreased dramatically in treated glands after the initiation of radiotherapy, remained at extremely low rates without any improvements, and were significantly lower at 1 year after radiotherapy compared with baseline. Conversely, parotid flow rates in spared glands underwent mild changes during radiotherapy and were approximately 50% of baseline values. The results of this study suggest that with the use of 3-DTP, contralateral parotid gland function can be partially preserved for at least 1 year in patients with head and neck cancers requiring bilateral radiation.
Aged↗
Giant lymph node hyperplasia (Castleman's disease) presenting with chylous pleural effusion.
A case of giant lymph node hyperplasia (Castleman's disease) with an original presentation of a chylous pleural effusion occurred in a female adolescent. CT scans showed mediastinal lymphadenopathy. Lymph node biopsy was consistent with the plasmacytic variant of Castleman's disease.
Adolescent↗