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PubMed1994

Retrotrapezoid nucleus glutamate injections: long-term stimulation of phrenic activity.

In chloralose-urethan anesthetized, paralyzed, vagotomized, glomectomized, and servo-ventilated cats we examined the effects of 10 nl of glutamate (10 mM, 100 mM, and 1 M) injected unilaterally over 60 s into the region of the retrotrapezoid nucleus (RTN). Seven 10 mM glutamate injections produced no consistent effects on the amplitude of the integrated phrenic nerve signal, respiratory cycle duration, or blood pressure. Ten 100 mM injections consistently increased integrated phrenic amplitude significantly from a baseline average of 31 +/- 2% (SE) of maximum to a peak response average of 50 +/- 3% of maximum. This effect was long lasting (45.6 +/- 8.6 min). Blood pressure responses were variable. Seven 1 M glutamate injections consistently decreased integrated phrenic amplitude significantly from a baseline average for all injections of 29 +/- 3% of maximum to a peak average of 20 +/- 5% of maximum. Respiratory cycle duration and blood pressure responses were variable. Prior injection into the RTN of 10 nl of 100 mM kynurenic acid attenuated the subsequent response of the integrated phrenic amplitude to injection of 10 nl of glutamate at the same site. Comparison of glutamate (10 nl, 100 mM) injected over 60 s vs. 30 ms showed that the prolonged increase in phrenic activity was related to the longer-duration (60-s) injections and that RTN single units were stimulated for up to 5 min on average after the 60-s injection with one unit showing an increase in firing rate over 40 min. After the 30-ms injection, integrated phrenic amplitude and RTN unit mean firing rate were increased for the first two breaths and at 5 min after the injection. We conclude that glutamate injected into the RTN increases local single-unit firing rate and the amplitude of the integrated phrenic activity. Injections made over 60 s result in prolonged phrenic stimulation and, in some cases, in RTN single-unit firing rate.

Animals↗
PubMed1996

Accuracy of injection site identification among children with insulin dependent diabetes mellitus: a comparison of traditional and new visual aids.

Children with insulin-dependent diabetes mellitus (IDDM) typically self-inject insulin twice daily. Injection sites must be rotated with each insulin administration to avoid lipohypertrophy. Lipohypertrophy results in erratic insulin release and threatens metabolic stability. To aid rotation, children are usually provided with a picture of a human figure with injection sites identified within a grid. Children often have difficulty using the charts or lack the skills necessary to identify injection sites. An alternative three-dimensional visual aid, a pair of "injection bears", simplifies injection site identification. Fifty-eight 6- to 11-year-old children with IDDM identified 10 injection sites using both the injection chart and the injection bears. Accuracy of injection site identification was compared on five subcomponents. Forty-four percent of informants recalled that their doctors recommended using injection charts. Of those recalling the recommendation, 81% never or rarely used charts at home. Thirty-nine percent of the informants reported a history of lipohypertrophy. Matched sample t-tests demonstrated that children committed significantly fewer identification errors on all subcomponents (P < or = .05) when using the injection bears. Chi square analyses indicated a significant preference (P < or = .05) for the injection bears, which may be a useful tool for insulin injection rotation with younger children.

Age Factors↗
PubMed2004

Could the WHO model list of essential medicines do more for the safe and appropriate use of injections?

A national drug policy addressing the safe and appropriate use of injections is an important element to prevent overuse and unsafe use of injections. Because the World Health Organization World Health Organization Model List of Essential Medicines is a keystone of national drug policies, the authors examined the way it addresses injection practices. They reviewed the 11th World Health Organization Model List of Essential Medicines to collect information on (1) injectable medicines, (2) diluents, and (3) the recommendations regarding the procurement of injection devices. Of 306 active ingredients on the list, 135 (44%) are mentioned in injectable form. Of these, 41 (30%) need diluents for reconstitution. The list does not mention the need to procure appropriate diluents, injection devices, and safety boxes in quantities that match the quantities of injectable medicines. In addition, the list provides limited information that can be used to forecast the needs of injection devices to administer the injectable medicines that are included in the list. Future revisions of the World Health Organization Model List of Essential Medicines should attempt to reduce the number of injectable formulations on the basis of evidence. In addition, the list should specify that when injectable medicines are being supplied, diluents, single-use syringes, and safety boxes should be supplied. The volume of syringes needed for administration should be specified for each injectable medication on the list to facilitate the forecasting of the needs of injection devices.

Drug-Related Side Effects and Adverse Reactions↗
PubMed2005

Safer injections following a new national medicine policy in the public sector, Burkina Faso 1995-2000.

BACKGROUND: The common failure of health systems to ensure adequate and sufficient supplies of injection devices may have a negative impact on injection safety. We conducted an assessment in April 2001 to determine to which extent an increase in safe injection practices between 1995 and 2000 was related to the increased access to injection devices because of a new essential medicine policy in Burkina Faso. METHODS: We reviewed outcomes of the new medicine policy implemented in 1995. In April 2001, a retrospective programme review assessed the situation between 1995 and 2000. We visited 52 health care facilities where injections had been observed during a 2000 injection safety assessment and their adjacent operational public pharmaceutical depots. Data collection included structured observations of available injection devices and an estimation of the proportion of prescriptions including at least one injection. We interviewed wholesaler managers at national and regional levels on supply of injection devices to public health facilities. RESULTS: Fifty of 52 (96%) health care facilities were equipped with a pharmaceutical depot selling syringes and needles, 37 (74%) of which had been established between 1995 and 2000. Of 50 pharmaceutical depots, 96% had single-use 5 ml syringes available. At all facilities, patients were buying syringes and needles out of the depot for their injections prescribed at the dispensary. While injection devices were available in greater quantities, the proportion of prescriptions including at least one injection remained stable between 1995 (26.5%) and 2000 (23.8%). CONCLUSION: The implementation of pharmaceutical depots next to public health care facilities increased geographical access to essential medicines and basic supplies, among which syringes and needles, contributing substantially to safer injection practices in the absence of increased use of therapeutic injections.

Burkina Faso↗
PubMed1996

Intraarticular foot and ankle injections to identify source of pain before arthrodesis.

OBJECTIVE: The purpose of our study was to evaluate the usefulness of diagnostic joint injections in patients with foot and ankle pain when the radiologist attempts to identify the source of pain. This study also correlated the results of injection with outcome after arthrodesis. MATERIAL AND METHODS: We retrospectively reviewed the records of 22 patients who had a foot or ankle joint injected to identify a source of pain and who later underwent arthrodesis of the painful joint. All patients had long-term foot and ankle symptoms of variable causes. Twenty-four joints were assessed: 13 subtalar, five talonavicular, four ankle, one calcaneocuboid, and one metatarsocuneiform. All patients had plain radiographs, 11 had CT studies, and five had bone scans. Contrast material was used to assess adequate positioning of the needle inside the joint before injection. All joints were injected under fluoroscopic control. Steroid was added in eight joints. After injection, patients were assessed for relief of symptoms. Patients subsequently underwent arthrodesis on the basis of the results of the injection. RESULTS: In 20 patients (22 joints), long-term follow-up showed that injections allowed us to correctly identify the source of pain and successfully guide arthrodesis. Of these 20 patients, 17 had significant pain relief after injection and fusion, whereas three patients had mild or no response. With one of these patients, we injected other joints and changed surgical plans. One of the two remaining patients had more pain relief after injection than after arthrodesis. The other patient had no relief after injection, but subsequent fusion because of persistent pain was successful. We found imaging studies to be less useful than diagnostic injections when we were attempting to identify the source of pain. CONCLUSION: Intraarticular injection of anesthetic in painful foot and ankle joints helped us confirm the source of pain in 20 of 22 patients, which in turn led to successful arthrodesis and good outcomes for these patients.

Adult↗
PubMed1999

Unsafe injections in the developing world and transmission of bloodborne pathogens: a review.

Unsafe injections are suspected to occur routinely in developing countries. We carried out a literature review to quantify the prevalence of unsafe injections and to assess the disease burden of bloodborne infections attributable to this practice. Quantitative information on injection use and unsafe injections (defined as the reuse of syringe or needle between patients without sterilization) was obtained by reviewing the published literature and unpublished WHO reports. The transmissibility of hepatitis B and C viruses and human immunodeficiency virus (HIV) was estimated using data from studies of needle-stick injuries. Finally, all epidemiological studies that linked unsafe injections and bloodborne infections were evaluated to assess the attributable burden of bloodborne infections. It was estimated that each person in the developing world receives 1.5 injections per year on average. However, institutionalized children, and children and adults who are ill or hospitalized, including those infected with HIV, are often exposed to 10-100 times as many injections. An average of 95% of all injections are therapeutic, the majority of which were judged to be unnecessary. At least 50% of injections were unsafe in 14 of 19 countries (representing five developing world regions) for which data were available. Eighteen studies reported a convincing link between unsafe injections and the transmission of hepatitis B and C, HIV, Ebola and Lassa virus infections and malaria. Five studies attributed 20-80% of all new hepatitis B infections to unsafe injections, while three implicated unsafe injections as a major mode of transmission of hepatitis C. In conclusion, unsafe injections occur routinely in most developing world regions, implying a significant potential for the transmission of any bloodborne pathogen. Unsafe injections currently account for a significant proportion of all new hepatitis B and C infections. This situation needs to be addressed immediately, as a political and policy issue, with responsibilities clearly defined at the global, country and community levels.

Adult↗
PubMed2001

Subretinal injections in rodent eyes: effects on electrophysiology and histology of rat retina.

PURPOSE: To describe a reliable and fast method for subretinal injection in rodents and to assess the effect of the procedure on retinal function and histology. METHODS: Corneas of rodents were punctured with a 28 gauge hypodermic insulin needle avoiding the lens. The injection procedure can be observed with the aid of a dissecting microscope and methylcellulose solution on the eye. A 33 gauge blunt needle was inserted into the eye through the corneal puncture and guided toward the subretinal matrix. Addition of fluorescein to the injection mixture facilitated immediate evaluation of the injection. Rat eyes were either non-injected (controls), received only a corneal puncture or were injected with fluorescent microspheres or PBS-fluorescein mixture. Retinal function and integrity were assessed through electroretinographic (ERG) analysis and postmortem histology. RESULTS: The anterior injection procedure provided a fast and simple method for subretinal injections. In rats a successful subretinal delivery was achieved in more than 90%, with less than 5% of the injected eyes developing cataracts. No significant differences in b-wave ERG amplitudes in rodent eyes over a five-week period were observed between non-injected control eyes and subretinally injected eyes (1 to 10 microl of PBS-fluorescein or 2 microl fluorescent microspheres). Histological analysis revealed that re-attachment of the rat retina occurred in approximately 1 day post-injection and the phagocytotic ability of RPE cells remained intact. CONCLUSIONS: This method was easily learned and required a minimum of equipment and animal preparation. With experience, 10 to 30 eyes could be injected per h. Furthermore, the injection procedure did not compromise the lens, retina or retinal pigment epithelium (RPE).

Animals↗
PubMed2003

[Rapid assessment of safety injection in one county, north rural area in China].

OBJECTIVE: To estimate the frequency of injections and proportion of unsafe injections and to analyses the critical determinants of poor injection practices in general population in China. Also, to study knowledge, attitudes, practice research in providers and general population. METHODS: A random sample consisting residents and health care providers in a rural county was elected and interview about the frequency of received injection, as well as knowledge, attitudes and practices regarding injections were studied. RESULTS: Overall, 1 004 village residents, and 94 providers were interviewed. Among residents, 145 persons (14.4%), with 457 times (0.46 times per person) had received at least one injection during the previous 3 months. The frequency of injection was 1.84 per year. The proportion of received injections on treatment and immunizations was significantly different among > 12 years age group and < or = 12 years age group. Ninety-four point four percent of disposable syringes/needles were used for injections. Knowledge among the population and providers regarding injection safety was limited. CONCLUSION: Injections were moderately frequent in this rural area and the proportions of disposable syringes/needles used for injections was very high. Knowledge of safe injection and reasonable injection as well as consciousness of self-protection in the providers and residents need to be improved.

Adolescent↗
PubMed2006

Study on the injection practices of health facilities in Jingzhou district, Hubei, China.

BACKGROUND: Some studies indicate unsafe injection practices, which are associated with the transmission of blood-borne pathogens, exist extensively, in the developing countries. AIMS: To investigate the status of injection services, knowledge and attitude of health workers with regard to injection practices at all levels of the health facilities in Jingzhou district of China; and to provide useful scientific data in order to formulate a feasible, standard measure on injection safety. SETTINGS: Four district health care facilities, 6 township health centers, 14 village clinics and 14 community health stations. DESIGN: A retrospective cross-sectional study. MATERIALS AND METHODS: By examining the medical records in 2004, observing injection practices and interviewing health workers, the quantitative and qualitative data were collected and analyzed. RESULTS: Out of 1,452 medical records sampled, 1,450 patients had received at least one injection in the period of hospitalization, with an injection rate of about 100% and an average of 10.9 injections per patient. The most frequent injected drug was antibiotic (48%, 7,674/15,857). The prescriptions of 5,655 outpatients were detected, with an injection rate of 52% (2,962). The field observation found that the proportion of unsafe injections was 16% (28/175) and that of unnecessary injections was 57% (99/175). Among 118 professional employees interviewed, those who knew that human immunodeficiency virus, hepatitis C virus and hepatitis B virus might be transmitted by the contaminated syringes and needles accounted for 95% (112), 59% (70) and 89% (105) respectively. CONCLUSIONS: Among the medical facilities of Jingzhou district, the injection rate was very high and the quality of injection practices should be further improved.

China↗
PubMedDate not supplied

Effect of positioning on discomfort from intramuscular injections in the dorsogluteal site.

An intramuscular injection into a relaxed muscle is believed to result in less discomfort than an injection into a contracted muscle. When the femur is internally rotated, the gluteus maximus muscle is relaxed. The hypothesis that a dorsogluteal injection with the femur internally rotated will cause less discomfort than when the femur is externally rotated was tested in 44 surgical patients who received two injections of preoperative medication. Each patient received an injection of a narcotic medication and one of diazepam. All possible combinations of the factors--position (internal and external rotation), order of injection (first or second injection), and medication (narcotic or diazepam)--were determined, and patients were randomly assigned to one of these conditions. Patients rated their perceived discomfort after each injection on a five-point scale. The hypothesis was supported by discomfort ratings from injections of both types of medications, although diazepam injections caused significantly more discomfort than injections of narcotics. Older patients tended to report less discomfort from diazepam injections than younger patients. Sex, order of injection, and nurse administering the injection did not significantly influence discomfort ratings.

Adult↗
PubMed1986

Intratumoral injection of thymidine: enhancement of the antitumor activity and incorporation of 5-fluorouracil into tumor RNA in a murine tumor system.

Intratumoral injection of thymidine (dThd) into mice bearing an Ehrlich ascites solid tumor in combination with an ip injection of 5-fluorouracil (FUra) was performed to investigate the following: (a) whether intratumoral injection of dThd would increase both the incorporation of FUra into tumor RNA and the antitumor activity of FUra as effectively as ip injection of dThd, and (b) whether intratumoral injection of dThd would have a selective advantage for increasing the incorporation of FUra into the tumor RNA, relative to normal tissue RNA. Pulse-labeling with [3H]FUra at different times after dThd injection indicated that the most effective incorporation of FUra into the tumor RNA occurred with both intratumoral and ip injection of dThd, when FUra and dThd were given simultaneously. The amount of FUra-containing RNA [(FU)RNA] was dThd dose-dependent and reached a maximum at a dThd dose of 100 mg/kg, in the case of either intratumoral or ip injection. The maximal level with intratumoral injection of dThd was twofold higher than the level with ip injection and at least fivefold higher than the level achieved with FUra alone. In a time course study, the amount of (FU)RNA formed after intratumoral injection of dThd was comparable to the level obtained with ip injection, which was fourfold to sixfold greater than that seen with FUra alone. Furthermore, in the four normal organs (bone marrow, intestine, kidneys, and lungs) the amount of (FU)RNA formed after intratumoral injection of dThd was markedly lower than the level with ip injection. Assay of FUra degradation products revealed low levels of FUra catabolism in the tumor tissue compared to liver. In addition, therapy experiments showed that the antitumor activity of FUra was increased 17-fold by coadministration of dThd by either route.

Animals↗
PubMedDate not supplied

Effects of iced and room temperature injectate on cardiac output measurements in critically ill patients with low and high cardiac outputs.

OBJECTIVE: To determine the effect of injectate temperature (iced or room temperature) on cardiac output values in critically ill adults with low and high cardiac outputs. DESIGN: Quasi-experimental. SETTINGS: Two multidisciplinary intensive care units in two large, metropolitan, private, nonprofit hospitals in Texas. SUBJECTS: A convenience sample of 21 critically ill men and women who averaged 61 years of age (range 31 to 82 years) and whose most recent cardiac output measured with room temperature injectate was low (< or = 3.5 L/min) or high (> or = 8.0 L/min). INTERVENTION: Iced injectate and room temperature injectate (randomly ordered) were used to measure cardiac output in each subject. OUTCOME MEASURES: Cardiac output value with iced injectate versus cardiac output value with room temperature injectate. RESULTS: We found significant differences between cardiac output measurements with room temperature and those with iced injectate in eleven critically ill patients with low cardiac outputs (< or = 3.5 L/min) and in ten critically ill patients with high cardiac outputs (> or = 8.0 L/min). In the low cardiac output group, cardiac outputs using room temperature injectate averaged 0.37 L/min (range 0.1 to 1.10 L/min) higher than cardiac outputs using iced injectate (p = 0.001). In the high cardiac output group, measurements with room temperature injectate averaged 1.17 L/min L/min (range 0.3 to 3.0 L/min) higher than cardiac outputs with iced injectate (p = 0.005). Percent differences between room temperature and iced injectate values averaged 13% (range 3% to 27%) in patients with low cardiac outputs and 11% (range 3% to 29%) in patients with high cardiac outputs. Seven (77%) of the patients in the low cardiac output group and four (40%) of the patients in the high cardiac group had a 10% or greater difference--which many clinicians describe as a clinically significant difference--between room temperature and iced injectate cardiac output values. CONCLUSION: Although research is clearly needed to substantiate these findings, we suggest that nurses use iced injectate in patients with low and high cardiac outputs (< or = 3.5 L/min or > or = 8.0 L/min) to ensure accurate measurement of cardiac output.

Adult↗
PubMed1998

Zolpidem self-injection with concurrent physical dependence under conditions of long-term continuous availability in baboons.

Intravenous zolpidem self-injection, and the concurrent development of physical dependence under conditions of continuous drug availability, was characterized in three baboons. Previously, under similar conditions, 1.0 mg/kg midazolam maintained low, but stable, daily rates of self-injection (e.g. less than 20 injections/day) over 30 or more days and resulted in the development of physical dependence in baboons. In the current experiments, saline and zolpidem (1.0 mg/kg) were available for self-injection under a fixed-ratio (FR-30) schedule of lever-pull responses with a 5 min time-out after each injection. Saline maintained only low levels of responding (i.e. less than five injections per day). Zolpidem maintained an orderly spaced within-day pattern of injections and daily rates of self-injection were higher than saline (i.e. 10 or more injections per day). Daily rates of zolpidem self-injection were relatively stable in two baboons, and increased over time in the third baboon. Substitution of saline for zolpidem produced a rapid decrease in responding that remained low (i.e. less than five injections per day) in all three baboons. Chronic self-injection of zolpidem produced an increase in responding maintained by food pellet delivery and an increase in body weights. Administration of flumazenil (0.1-1.0 mg/kg, i.v.) after at least 35 days of zolpidem self-injection produced postures and behavioral signs typical of a classic flumazenil-precipitated benzodiazepine withdrawal syndrome. Substitution of saline after chronic zolpidem self-injection produced a time-limited spontaneous withdrawal syndrome. Behavioral signs and postures were similar to those observed during flumazenil-precipitated withdrawal and were most prominent during the first 8 days after zolpidem was discontinued. Therefore, like midazolam, zolpidem maintained self-injection and physical dependence developed under conditions of long-term continuous availability.

Animals↗
PubMed1989

Induction of soft tissue tumours in F344 rats by subcutaneous, intramuscular, intra-articular, and retroperitoneal injection of nickel sulphide (Ni3S2).

The carcinogenicity of nickel sulphide (Ni3S2) injected into subcutaneous (s.c.), intramuscular (i.m.), or retroperitoneal intrafat (i.f.) tissue, or the intra-articular space (i.a.) of male F344 rats was studied. Rats were given a single injection of 0.5 mg of Ni3S2 and were observed for 48 weeks. Malignant soft tissue tumours were induced in 18/19 rats (95 per cent) by s.c. injection, 19/20 rats (95 per cent) by i.m. injection, in 16/19 rats (84 per cent) by i.a. injection, and in 9/20 rats (45 per cent) by i.f. injection of Ni3S2. The i.f. injection of Ni3S2 resulted in a lower tumour incidence and the appearance of tumours 10 weeks later than its injection by other routes. The tumours were examined histologically, ultrastructurally, and immunohistochemically with antibodies against desmin, vimentin, and cytokeratin. The 62 tumours induced by injection of Ni3S2 by different routes were identified as rhabdomyosarcomas (RMS, 35), malignant fibrous histiocytomas (MFH, 18), fibrosarcomas (FS, 5), and unclassified sarcomas (4). All 19 tumours induced by i.m. injection of Ni3S2 were rhabdomyosarcomas; those induced by s.c. or i.f. injection were mainly MFHs. However, a number of RMSs were also found in groups that received i.a., s.c., and i.f. injections; five FSs also developed in these groups. Four sarcomas induced by s.c. and i.a. injections were not classified. No synovial sarcoma developed.

Animals↗
PubMed2003

Intradermal immunization with novel plasmid DNA-coated nanoparticles via a needle-free injection device.

A high population of dendritic cells in the skin makes intradermal (ID) immunization an attractive route. We sought to further enhance immune responses from a previously reported novel nanoparticle-based DNA vaccine delivery system by administering the system intradermally into mouse skin using Biojector 2000, a needle-free jet injection device. Two mouse studies were carried out. Balb/C mice (n=5-6) were immunized on day 0, 7, and 14 by subcutaneous injection or via the Biojector 2000 with pDNA alone (CMV-beta-galactosidase, 5 micro g), pDNA-coated nanoparticles, or beta-galactosidase protein (10 micro g) adjuvanted with 'Alum' (15 micro g). On day 28, mice were sacrificed and specific serum IgG and IgA titer, in vitro cytokine release, and cell proliferation of isolated splenocytes were determined. Similar to previous reports, in both mouse studies, SC immunization with pDNA-coated nanoparticles led to over a log increase in specific serum IgG titer as compared to immunization with pDNA alone. For pDNA alone, jet and SC injection did not result in significant differences in IgG titer. In contrast, for pDNA-coated nanoparticles, jet injection led to as high as a 20-fold enhancement in IgG titer over SC injection. In addition, jet injection of pDNA-coated nanoparticles enhanced the IgG titer by more than 200-fold over jet injection of pDNA alone. Also, jet injection of pDNA-coated nanoparticles resulted in significantly enhanced specific serum IgA titer. For in vitro cytokine release, immunization with pDNA-coated nanoparticles by jet injection enhanced IFN-gamma and IL-4 release over pDNA alone by 6- and 5-fold, respectively. SC injection of pDNA-coated nanoparticles also resulted in enhanced IFN-gamma and IL-4 release over pDNA alone although with less magnitude. Finally, immunization with pDNA-coated nanoparticles, by both jet injection and SC injection, led to improved splenocyte proliferation over pDNA alone. In conclusion, a combination of a novel cationic nanoparticle-based DNA delivery system with ID jet injection led to enhanced antibody production, Th-1/Th-2 balanced cytokine release, and enhanced splenocyte proliferation.

Animals↗
PubMed1965

THE MECHANISM OF TOLERANCE PRODUCED IN RATS TO SHEEP ERYTHROCYTES. II. THE PLAQUE-FORMING CELL AND ANTIBODY RESPONSE TO MULTIPLE INJECTIONS OF ANTIGEN BEGUN AT BIRTH.

An active immune response to sheep erythrocytes was demonstrated in rats made "tolerant" to sheep erythrocytes by twice-weekly antigen injections beginning on the day of birth. Groups of tolerant rats were sacrificed 4 days after they had received 5 to 42 antigen injections; spleens were sampled for plaque-forming (antibody-releasing) cells and sera were titrated for antibody to sheep erythrocytes using a sensitive "plate hemolysin" technique. During the 3rd week of life and after the 5th antigen injection, the tolerant rats had an immune response equivalent to that of rats of similar age which had received a single antigen injection, but spleens contained only about one-tenth as many plaque-forming cells as adults animals receiving similar antigen injections. Continued antigen injections produced a marked decline and stabilization of this relatively small population of antibody-forming cells; however, the number of plaque-forming cells in the tolerant rats remained considerably elevated above the numbers of plaque-forming cells present in the spleens of non-immunized animals. The sera from all but 1 tolerant rat had demonstrable antibody to sheep erythrocytes in low titer. A progressive recovery of the plaque-forming cell response and rise in antibody titers occurred in adult tolerant rats when the interval between the last 2 antigen injections was increased from 3 days to 14 or 28 days. The decline and stabilization of numbers of plaque-forming cells occurring with continued injections after the 3rd week of life paralleled a similar decline and stabilization in rats receiving similar antigen injections as adults. Also, the recovery of the plaque-forming cell and antibody response of tolerant animals paralleled the recovery observed when the interval between injections was increased in rats receiving similar antigen injections as adults. These findings suggested that the same mechanism controlled numbers of antibody-forming cells in tolerant and normally responsive adult animals. Repeated closely spaced antigen injections presumably interfered with either cell division or maturation of antibody-forming cells. As the interval between injections was increased, additional antibody-forming cells matured or were formed through cell division. Relatively constant antigenic stimulation provided a mechanism for controlling or limiting the response of antibody-forming cells. The mechanism controlling or limiting the response of antibody-forming cells would not account for the stabilization of numbers of antibody-forming cells at high levels for normal animals and at low levels for the tolerant animals. Passive immunization of growing rats with homologous anti-sheep erythrocyte serum markedly inhibited the plaque-forming cell response of growing rats. It was proposed that antibody produced by the small population of antibody-forming cells in the tolerant rats provided a feedback or homeostatic mechanism which inhibited transformation of potential antibody-forming cells to antibody-forming cells. Thus, tolerance to sheep erythrocytes was induced and maintained by two mechanisms. One mechanism, dependent on relatively constant antigenic stimulation, limited or controlled the numbers of antibody-forming cells. The other, dependent on the production of small quantities of antibody by a few antibody-forming cells, limited or controlled the transformation of potential antibody-forming cells to antibody-forming cells.

Animals↗
PubMed2003

Uptake by mouse liver and intracellular fate of plasmid DNA after a rapid tail vein injection of a small or a large volume.

BACKGROUND: An efficient gene transfer can be achieved in mouse liver by a rapid tail vein injection of a large volume of plasmid DNA solution (hydrodynamics-based transfection). The mechanism of gene transfer by this procedure is not known. It must be related to the uptake and intracellular fate of DNA. METHODS: We have investigated the problem by following the uptake by mouse liver and the intracellular distribution of DNA after a rapid tail vein injection of a large (2.0 ml) or a small (0.2 ml) volume of (35)S-DNA solution. Total and acid-soluble radioactivity were measured in liver homogenates at increasing times after injection, and their subcellular distributions were established by centrifugation methods and compared with the distributions of marker enzymes of the membrane compartments involved in endocytosis: alkaline phosphodiesterase (plasma membrane) and cathepsin C (lysosomes). RESULTS: (35)S-DNA uptake by the liver is similar when a small or a large volume of injection is used but its degradation is markedly slower after a 2.0 ml injection. When a small volume of injection is given, distribution of radioactivity after differential centrifugation indicates that the plasmid DNA is endocytosed and reaches lysosomes where it is hydrolysed. After a large volume injection, part of (35)S-DNA has the same fate, another part remains acid-precipitable for at least 1 h and is associated with structures sedimenting at low centrifugation speed in the nuclear fraction N. Analysis of that fraction by gradient centrifugation suggests that these structures are plasma membrane fragments that could originate from the apical domain of hepatocytes. The proportion of (35)S-DNA associated with hepatocytes is about doubled after a large volume injection. Fractionation of isolated hepatocytes by centrifugation confirms results obtained on the whole liver. Treatment of the N fraction or isolated hepatocytes with pancreatic DNAse illustrates that (35)S-DNA that remains bound to plasma membrane after a large volume injection is located on the outer face. CONCLUSIONS: The fact that after an hydrodynamic injection (35)S-DNA remains bound to the outside face of the plasma membrane for at least 1 h indicates that it is not, or very slowly, internalised during that period. The relatively small difference in the amount of DNA picked up by hepatocytes depending on the type of injection could not explain the absence of expression after a conventional injection and the strong expression after a hydrodynamic injection. If DNA enters the cells by endocytosis, even after an hydrodynamic injection, its persistence at the outside face of the plasma membrane could favour transfection by allowing hepatocytes to dispose for a relatively long time of a reservoir of intact DNA.

Animals↗
PubMed2001

Internal anal sphincter augmentation for fecal incontinence using injectable silicone biomaterial.

PURPOSE: A disrupted or weak internal anal sphincter can lead to passive fecal incontinence. This muscle is not amenable to direct surgical repair. Previous preliminary attempts to restore functional continuity have included a cutaneous flap to fill an anal canal defect, and injection therapy using polytetrafluoroethylene, collagen, or autologous fat. Urologists have also used injections of collagen or silicone to enhance bladder neck function. This pilot study aimed to assess the efficacy of single or multiple injections of the silicone-based product Bioplastique for the symptoms of passive fecal incontinence caused by an anatomically disrupted or intact but weak internal anal sphincter. PATIENTS AND METHODS: Ten patients (6 females; median age, 64, range, 41-80 years) with passive incontinence secondary to a weak (n = 6) or disrupted (n = 4) internal anal sphincter were injected either circumferentially or at a single site, respectively. Patients were assessed before and six weeks after treatment by clinical assessment, two-week bowel diary card, anorectal physiologic testing, and endoanal ultrasound. Patients failing to show improvement after the first injection were offered a second injection six weeks after the first injection. Clinical assessment was further repeated at six months, and five patients had a further ultrasound examination. RESULTS: At six weeks, six of ten patients showed either marked improvement (n = 3) or complete cessation of leakage (n = 3). A further patient was greatly improved after a second injection. Three patients were not improved. At six months, two of the seven patients had maintained marked improvement, and one patient had maintained minor improvement; all of these three patients had circumferential multiple injections. Maximum resting and squeeze anal pressures did not differ significantly between before vs. six weeks after vs. six months after injection. At six weeks endoanal ultrasound (n = 9) confirmed the presence and correct position of the silicone in all but one patient who had experienced obvious external leakage of the product. At six months the silicone remained in the correct position in the five endosonographically assessed patients. Five of the initial patients experienced pain or minor ulceration at the injection site. CONCLUSIONS: Although clinically effective immediately after injection, the benefit of an injectable biomaterial was maintained in only a minority of patients. This occurred despite the continued presence of material in the correct anatomical site. Patients with diffuse weakness treated by circumferential injection seemed to be the most responsive, but further studies are required to clarify this.

Adult↗