Sjogrens syndrome--the non-apoptotic model of glandular hypofunction.
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Apoptosis↗
Biomedical subjects
L J Dawson
Publications and source records attributed to L J Dawson.
Antimuscarinic antibodies in primary Sjögren's syndrome reversibly inhibit the mechanism of fluid secretion by human submandibular salivary acinar cells.
OBJECTIVE: Sjögren's syndrome (SS) is an autoimmune condition affecting salivary glands, for which a clearly defined pathogenic autoantibody has yet to be identified. Autoantibodies that bind to the muscarinic M3 receptors (M3R), which regulate fluid secretion in salivary glands, have been proposed in this context. However, there are no previous data that directly show antisecretory activity. This study was undertaken to investigate and characterize the antisecretory activity of anti-M3R. METHODS: Microfluorimetric Ca2+ imaging and patch clamp electrophysiologic techniques were used to measure the secretagogue-evoked increase in [Ca2+]i and consequent activation of Ca2+-dependent ion channels in individual mouse and human submandibular acinar cells. Together, these techniques form a sensitive bioassay that was used to determine whether IgG isolated from patients with primary SS and from control subjects has antisecretory activity. RESULTS: IgG (2 mg/ml) from patients with primary SS reduced the carbachol-evoked increase in [Ca2+]i in both mouse and human acinar cells by approximately 50%. IgG from control subjects had no effect on the Ca2+ signal. Furthermore, the inhibitory action of primary SS patient IgG on the Ca2+ signal was acutely reversible. We repeated our observations using rabbit serum containing antibodies raised against the second extracellular loop of M3R and found an identical pattern of acutely reversible inhibition. Anti-M3R-positive serum had no effect on Ca2+-dependent ion channel activation evoked by the direct intracellular infusion of inositol 1,4,5-triphosphate. CONCLUSION: These observations show for the first time that IgG from patients with primary SS contains autoantibodies capable of damaging saliva production and contributing to xerostomia. The unusual but not unprecedented acute reversibility of the effects of anti-M3 autoantibodies is the subject of further research.
Animals↗
Congenital heart block associated with undiagnosed maternal Primary Sjögren's Syndrome -- a case report and discussion.
Congenital heart block (CHB) has been linked with Sjögren's Syndrome. This paper reports a case of previously undiagnosed maternal Primary Sjögren's Syndrome (1 degrees SS) that was only discovered following the birth of the patient's first child with CHB. The possible pathophysiological mechanisms underlying CHB associated with 1 degrees SS are discussed.
Adult↗
Hydroxychloroquine therapy in patients with primary Sjögren's syndrome may improve salivary gland hypofunction by inhibition of glandular cholinesterase.
OBJECTIVE: To determine whether (i) cholinesterase activity is increased in the saliva of patients with primary Sjogren's syndrome (pSS), (ii) increased levels of cholinesterase of lymphocyte origin could interfere with the secretory activity of submandibular acinar cells, and (iii) hydroxychloroquine at therapeutic doses could interfere with cholinesterase activity. METHODS: The Ellman method was used to determine the levels of salivary cholinesterase activity and the K(i) of both chloroquine and hydroxychloroquine for serum cholinesterase. The ability of lymphocyte cholinesterase to inhibit the acetylcholine (ACh)-evoked rise in [Ca(2+)](i) in mouse submandibular acinar cells was determined using fura-2 microfluorimetry. RESULTS: Patients with pSS had significantly higher levels of cholinesterase activity in both their unstimulated (P < 0.05) and stimulated saliva (P < 0.0001) compared with control subjects. Lymphocyte cholinesterase was capable of inhibiting the ACh-evoked rise in [Ca(2+)](i). The in vitro K(i) for hydroxychloroquine inhibition of cholinesterase was 0.38 +/- 1.4 microM. CONCLUSION: These data suggest that increased levels of cholinesterase present in the salivary glands of patients with pSS may contribute to glandular hypofunction and provide evidence that the therapeutic enhancement of salivary secretion in patients with pSS by hydroxychloroquine may be mediated by inhibition of glandular cholinesterase activity, although further in vivo investigation is needed.
Animals↗
Putative anti-muscarinic antibodies cannot be detected in patients with primary Sjogren's syndrome using conventional immunological approaches.
OBJECTIVE: To determine whether autoantibodies directed against muscarinic M3 receptors are present in the serum of patients with primary Sjogren's syndrome (pSS), and if so whether these autoantibodies inhibit secretion by intact salivary acinar cells. METHODS: IgG was purified by affinity chromatography using protein G from sera collected from 15 patients with pSS. Antibody detection was by Western blotting, whole-cell enzyme-linked immunosorbent assay (ELISA) and immunoblotting. The antisecretory activity of the IgG faction was determined using fura-2 microfluorimetry to measure changes in intracellular Ca(2+) activity ([Ca(2+)](i)) in human and mouse salivary gland acinar cells and in Chinese hamster ovary (CHO) cells transfected with human M3 receptors (CHO-M3). RESULTS: We found no specific M3 receptor recognition by the IgG fraction obtained from pSS patients using either Western blotting or ELISA or immunoblot techniques in which epitope conformation were preserved. Chronic exposure to pSS IgG had no effect on agonist-evoked Ca(2+) signals measured in human or mouse submandibular acinar cells or in CHO-M3 cells. However, acute application of IgG from Sjogren's syndrome patients produced a rapidly reversible reduction in the agonist-stimulated elevation in [Ca(2+)](i). CONCLUSION: These data represent the first demonstration of salivary acinar cell inhibition by pSS IgG; however, this inhibition was found to be reversible. Our data also show that pSS IgG binding to M3R cannot be visualized by conventional immunological approaches.
Animals↗
Dental management of the myasthenic patient.
Myasthenia gravis (MG) is an auto-immune disorder of neuromuscular transmission which results in weakness and fatigue of skeletal muscles. The defect in neuromuscular transmission is most commonly seen in the muscles of the eyes, face, neck and shoulders but, in some patients, the respiratory muscles are involved. Patients with this condition may present with problems that necessitate special consideration when managing their dental treatment. Patients who are only mildly affected by MG can be treated in general dental practice for routine care. There are no contra-indications to the use of local anaesthetic agents and the presence of a vasoconstrictor is desirable. More severely affected patients and those who are very anxious about dental treatment should be cared for within the hospital environment. In these patients, respiratory muscles may be affected and, as a result, a myasthenic crisis may arise which requires assisted ventilation and, in some cases, intubation. Those patients who are fearful of the dental environment are likely to be emotionally stressed during such times and this increases the risk of a myasthenic crisis; sedation techniques can be beneficial in this group of patients.
Anesthesia, Dental↗
Acetylcholine-evoked calcium mobilization and ion channel activation in human labial gland acinar cells from patients with primary Sjögren's syndrome.
Recent evidence has indicated that the salivary gland dysfunction associated with Sjögren's syndrome (SjS) is not necessarily due to immune-mediated destruction of acinar tissue. SjS sufferers may possess substantial reserves of acinar tissue but nevertheless be incapable of maintaining salivary flow rates in the normal range. We have investigated the ability of isolated labial gland acinar cells from SjS patients to fluid secrete by measuring agonist-evoked changes in intracellular Ca(2+) ([Ca(2+)](i)) using fura-2 microfluorimetry and activation of K(+) and Cl(-) channels using the patch-clamp whole cell technique. We can confirm that stimulation with a super-maximal dose of acetylcholine (ACh) increased [Ca(2+)]i equally in both control acinar cells and those derived from SjS patients. However, at submaximal concentrations, the dose-response curve for ACh was shifted to the right by approximately one order of magnitude in acinar cells from SjS patients compared to control acinar cells. Patch-clamp measurements consistent with the presence of Ca(2+)-activated K(+) and Cl(-) conductances were obtained from both control acinar cells and those obtained from SjS patients. Dose-dependent activation of the ion channels by acetylcholine was also right-shifted in acinar cells from SjS patients compared to control cells. Our data show that labial gland acinar cells from SjS patients were capable of responding to agonist stimulation by mobilizing [Ca(2+)](i) and activating K(+) and Cl(-) channels consistent with the requirements of fluid secretion. However, the persistent loss of sensitivity to ACh observed in from SjS patients may account for the lack of saliva production observed in these patients in vivo.
Acetylcholine↗
The role of academic discipline and gender in high school teachers' AIDS-related knowledge and attitudes.
Adolescents represent the fastest growing segment of HIV+ individuals in the United States. Therefore, high school teachers should be both knowledgeable of and comfortable with issues related to HIV/AIDS. This study examined high school teachers' AIDS-related knowledge and attitudes. One hundred forty-one high school teachers from nine central Massachusetts high schools participated. Participants completed the "HIV/AIDS Knowledge and Attitudes Scales for Teachers," as well as questions regarding their teaching experience and academic disciplines. Results indicated a direct relationship between teachers' knowledge of HIV/AIDS and positive or supportive attitudes toward HIV/AIDS. Significant differences were found based on academic discipline, with allied health teachers scoring significantly higher on the knowledge scale than teachers in any other discipline. Specific examples are discussed, as is the need for increased teacher training and comprehensive AIDS education.
Acquired Immunodeficiency Syndrome↗
A comparison of salivary gland hypofunction in primary and secondary Sjögren's syndrome.
OBJECTIVE: A commonly held view by clinicians is that the salivary gland hypofunction associated with primary Sjögren's syndrome (SS-1) is more severe than that associated with secondary Sjögren's syndrome (SS-2). This study aimed to determine if this view could be substantiated, when applied to a large sample group. METHOD: Unstimulated and paraffin wax-stimulated whole salivary flow rates were retrospectively compared for age and gender matched, patients diagnosed with SS-1 or SS-2 according to the preliminary European criteria. The patients had attended the Xerostomia Clinic, in the Oral Medicine Department, at the Liverpool University Dental Hospital. RESULTS: Sixty-seven patients with SS-1 (average age 57.1 years) were matched with 67 patients with SS-2 (average age 57.6 years), according to gender and age, within 5 years. The mean unstimulated whole salivary flow rates (+/- s.d.) for patients with SS-1 and SS-2 were 0.11 (+/- 0.15) and 0.12 (+/- 0.18) mL min-1 respectively. The mean paraffin wax stimulated, whole salivary flow rates (+/- s.d.) for patients with SS-1 and SS-22 were 0.45 (+/- 0.02) and 0.47 (+/- 0.49) mL/min-1 respectively. No significant differences, in either stimulated (P = 0.54) or unstimulated (P = 0.60) whole salivary flow rates were found between individuals with SS-1 or SS-2. CONCLUSION: The severity of salivary gland hypofunction does not appear to be related to the clinical variant of Sjögren's syndrome.
Adolescent↗
An investigation of interactions between the immune system and stimulus-secretion coupling in mouse submandibular acinar cells. A possible mechanism to account for reduced salivary flow rates associated with the onset of Sjögren's syndrome.
OBJECTIVES: To determine whether chronic exposure to lymphocyte-derived cytokines could inhibit the fluid secretory mechanism in salivary gland acinar cells and so account for the loss of gland function seen in the early stages of Sjögren's syndrome. METHODS: Mouse submandibular acinar cells maintained in primary culture were exposed to a profile of cytokines produced by concanavalin A-activated splenic lymphocytes in vitro for periods up to 72 h. Agonist-evoked changes in intracellular Ca(2+) were determined microfluorimetrically in both control and cytokine-treated cells. RESULTS: Acinar cells maintained in primary culture in the presence of cytokines for up to 72 h were able to mobilize intracellular calcium in response to stimulus by acetylcholine in an identical fashion to those maintained in primary culture in the absence of cytokines. Acute application of the conditioned medium produced by the activated lymphocytes had an antisecretory effect on acetylcholine-evoked Ca(2+) mobilization, which was found to be mediated by cholinesterase rather than by cytokines. CONCLUSION: Neither chronic nor acute exposure to the profile of cytokines released by concanavalin A-activated splenic lymphocytes interfered in any way with the second messenger cascade and fluid and electrolyte secretion in acinar cells. Our data suggest an alternative hypothesis, in which elevated levels of cholinesterase can metabolize acetylcholine released within the salivary glands and thus prevent fluid secretion.
Acetylcholine↗
Sjögren's syndrome-time for a new approach.
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Animal Testing Alternatives↗
Effects of dietary protein concentration on postweaning growth of Boer crossbred and Spanish goat wethers.
Boer (3/4) x Spanish (1/4) (BC; n = 23) and Spanish (SP; n = 22) goat wethers, 4 to 4.5 mo of age and 17.6 and 19.4 kg initial BW, respectively (SE = 0.57), were used to determine effects on growth of protein concentration in 70% concentrate diets provided for ad libitum intake for 30 wk in confinement. Offered diets contained 10.2, 14.2, 18.3, and 23.6% CP (DM basis), and CP concentration in consumed DM was 9.3, 13.8, 17.1, and 22.1% (P1, P2, P3, and P4, respectively); supplemental protein was from soybean meal for P1 and P2 and from soybean meal plus a blend of blood, fish, and feather meals for P3 and P4. Dry matter intake was similar between breeds and among diets (732, 712, 698, and 740 g/d for P1, P2, P3, and P4, respectively; SE = 27.0). Average daily gain was greater for P2 (P = 0.07) and P4 (P < 0.05) than for P1 (76, 90, 85, and 100 g/d for P1, P2, P3, and P4, respectively; SE = 5.3) and for BC than for SP (97 vs 78 g/d, SE = 3.7; P = 0.05). Similarly, ADG:DMI was lowest (P < 0.05) among diets for P1 (0.106, 0.126, 0.121, and 0.132 for P1, P2, P3, and P4, respectively; SE = 0.0053) and greater (P < 0.05) for BC than for SP (0.135 vs 0.108; SE = 0.0037). In conclusion, with 70% concentrate diets, the protein requirement for both BC and SP seemed to have been met by consumption of diets with at least 14% CP, with no apparent benefit from addition of ruminally undegraded protein.
Animal Feed↗
Famciclovir and valacyclovir.
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2-Aminopurine↗
Use of a nonradioactive DNA probe for detection of Anaplasma marginale infection in field cattle: comparison with complement fixation serology and microscopic examination.
A sensitive Anaplasma marginale-specific 409-base pair DNA probe was developed in a previous study for detection of A. marginale infection in experimentally infected cattle with a test that employed slot-blot and in situ hybridization. To test the suitability of the probe to detect A. marginale in the blood of naturally infected carrier cattle, slot-blot hybridization was used to determine the infection rate of A. marginale in cattle from 3 geographic areas in Oklahoma. For comparison, blood samples from the same cattle were also examined by light microscopy and were tested by the complement fixation test. For the DNA hybridization assay, the probe was labeled with digoxigenin 11-dUTP by polymerase chain reaction (PCR). DNA was extracted from blood using the QIAamp blood kit and then applied to a nylon membrane and hybridized with the probe. The study herds consisted of 31 beef cows in Harper County, OK, and 42 and 70 dairy cows from Payne and Pittsburg counties, OK, respectively. In the 3 herds, 80.6%, 92.8%, and 57.1% of the cows were positive for A. marginale as assessed with the DNA hybridization assay. In contrast, only 25.8% and 2.86% were complement fixation positive in 2 herds, and no complement fixation positives were found in 1 herd. Uncountable parasitemia that was too low to accurately determine (< 0.01%) from 29.0%, 4.8%, and 11.4% of the samples, respectively, was demonstrated by microscopic examination. All samples positive by complement fixation and microscopic examination had positive probe reactions in the DNA hybridization assay. Therefore, the PCR-mediated nonradioactive DNA probe described here may be useful in epidemiologic investigations and in identification of carrier cattle. This assay could be adapted for use in diagnostic laboratories because it is sensitive, specific, nontoxic, quickly executed, and inexpensive.
Anaplasma↗
Salivary factors in vomiting bulimics with and without pathological tooth wear.
The increased occurrence of dental erosion from self-induced vomiting in bulimia nervosa is not linearly associated with the frequency or the duration of vomiting. Possible changes in the buffering and lubricating role of saliva in bulimia nervosa and their relationship to erosion have not been previously investigated. Chewing-gum-stimulated salivary flow rate, pH, bicarbonate concentration and viscosity were compared between two groups of vomiting bulimics and with 10 healthy controls. One bulimic group (n = 9) had pathological tooth wear present according to the criteria of the Tooth Wear Index and the other bulimic group (n = 10) did not. The influence of salivary pellicle on enamel acid dissolution by perchloric acid was also assessed by an enamel biopsy method. Bicarbonate was measured in a Natelson microgasometer. Both the bulimic groups had mean initial 3-min flow rates and overall 9-min flow rates significantly lower (p < 0.01) than the healthy subjects. The mean pH values were not significantly different between the two bulimic groups or the control group. However, the mean bicarbonate concentration in both bulimic groups was significantly less (p < 0.01) than in the control group. The mean salivary viscosity of 7.4 centipoise (cP), measured by a DV1 Brookfield viscometer, was significantly greater (p < 0.05) in the pathological tooth-wear-present group than in the tooth-wear-absent group (4.5 cP) and the control group (4.1 cP). Slightly more calcium was released from the pellicle-free surface in both groups but this was not statistically significant, whilst the dissolved calcium in enamel biopsies was significantly lower (p < 0.05) in the tooth-wear-present group.
Adult↗
Levels of insulin-like growth factor (IGF) binding proteins, luteinizing hormone and IGF-I receptors, and steroids in dominant follicles during the first follicular wave in cattle exhibiting regular estrous cycles.
Objectives of this study were to determine if concentrations of steroids, insulin-like growth factor -I (IGF-I), and IGF binding proteins (IGFBP) in follicular fluid and numbers of LH and IGF-I receptors change during growth of the dominant follicle. Ovarian follicular development was monitored daily via ultrasound in lactating Holstein cows. Animals underwent bilateral ovariectomy when the dominant follicle was first identified (days 4-6; estrus = day 0; early; n = 5) or when it stopped growing (days 8-12; late; n = 8). All follicles were classified as dominant (DF), large (LG; > = 6 mm in diameter, excluding DF) or small (SM; < 6 mm), follicular fluid was aspirated, and theca and granulosa cells were collected. Levels of IGFBP-2, assessed via ligand blotting, were greater (P < 0.05) in LG and SM follicles compared with DF in early cows. Levels of IGFBP-3 in follicular fluid were unaffected by follicle class. Numbers of specific 125I-hCG/LH binding sites in thecal cells were greater (P < 0.01) in DF compared with LG and SM follicles of both early and late cows. Numbers of specific 125I-hCG/LH binding sites in granulosa cells were similar for follicle sizes in early cows, but, in late cows, were greater (P < 0.01) in DF compared with SM follicles and were severalfold greater (P < 0.01) in late DF compared with early DF. Numbers of receptors for IGF-I in thecal cells were 2-fold greater (P < 0.05) in DP and LG compared with SM in late cows. Numbers of IGF-I receptors in granulosa cells were unaffected by size or growth of follicles, but were severalfold greater than in theca cells. Concentrations of estradiol were severalfold greater (P < 0.01) in DF compared with LG and SM in both early and late cows. Concentrations of androstenedione in early cows were greater (P < 0.05) in DF and SM compared with LG follicles. Concentrations of progesterone and IGF-I did not differ (P > 0.10) among follicle classes, but both were greater (P < 0.10) in late LG compared with early LG follicles. Concentrations of IGF-II in follicular fluid did not differ (P > 0.10) between early and late cows but were greater (P < 0.10) in SM than DF or LG follicles. We conclude that low amounts of IGFBP-2 and increased thecal binding sites for hCG/LH appear to be related to establishment of the dominant follicle during the first follicular wave in cattle exhibiting regular estrous cycles during late lactation.
Androstenedione↗
Influence of fiber form in a complete mixed ration on incidence of left displaced abomasum in postpartum dairy cows.
During the fall of 1982, increased incidence of left displaced abomasum (LDA) was seen in a group of cows fed a complete pelleted ration (3/16 inch) at the university's dairy center during the early postpartum period. Of these, 17.4% developed LDA when fed this experimental ration, whereas only 1.6% of the remaining cows in the herd developed LDA. The latter cows (as a control) were fed loose alfalfa hay, sorghum silage, and an 18% crude protein mix. Most of the fiber in the experimental diet or pelleted diet was alfalfa hay (30% as-fed basis) that was ground through a quarter-inch screen for incorporation into the pellet. Another 10% of the dietary fiber was contributed by cottonseed hulls. Thus, increased incidence of LDA may be associated with short length of the dietary fiber in the pelleted form.
Abomasum↗
Preputial injuries in beef bulls: 172 cases (1980-1985).
One hundred seventy-two bulls with preputial injuries were treated from 1980 through 1985. Most of the injuries developed during the breeding season (April through August), with a peak during June. The number (111) of bulls represented by 3 beef breeds (Brangus, Brahman, Beefmaster) was greater than the number (61) of the other 9 breeds included in the survey. Preputial prolapse (PP) and posthitis without obvious laceration was diagnosed in 82 of 172 bulls. Preputial laceration, abscessation, stricture with phimosis, and PP with penile hematoma were diagnosed in 46, 22, 15, and 9 bulls, respectively. These abnormalities were treated medically and/or surgically. Questionnaires (n = 145) were mailed, and 83 (57.4%) replies were received. Owners (80/83) of affected bulls responded to questions regarding the future use of their bulls for breeding. Of the bulls with PP and posthitis (n = 34), laceration (n = 17), abscessation (n = 15), stricture with phimosis (n = 8) and PP with penile hematoma (n = 6) and treated medically and/or surgically, 30, 11, 7, 7, and 4 bulls, respectively, (74% overall) were returned to breeding use successfully.
Animals↗