Biomedical subjects

J Marcelino

Publications and source records attributed to J Marcelino.

10 recordsLinked to original sources

PubMed2001

LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development.

In humans, low peak bone mass is a significant risk factor for osteoporosis. We report that LRP5, encoding the low-density lipoprotein receptor-related protein 5, affects bone mass accrual during growth. Mutations in LRP5 cause the autosomal recessive disorder osteoporosis-pseudoglioma syndrome (OPPG). We find that OPPG carriers have reduced bone mass when compared to age- and gender-matched controls. We demonstrate LRP5 expression by osteoblasts in situ and show that LRP5 can transduce Wnt signaling in vitro via the canonical pathway. We further show that a mutant-secreted form of LRP5 can reduce bone thickness in mouse calvarial explant cultures. These data indicate that Wnt-mediated signaling via LRP5 affects bone accrual during growth and is important for the establishment of peak bone mass.

Adaptor Proteins, Signal Transducing↗

PubMed2001

Human disease-causing NOG missense mutations: effects on noggin secretion, dimer formation, and bone morphogenetic protein binding.

Secreted noggin protein regulates bone morphogenetic protein activity during development. In mice, a complete loss of noggin protein leads to multiple malformations including joint fusion, whereas mice heterozygous for Nog loss-of-function mutations are normal. In humans, heterozygous NOG missense mutations have been found in patients with two autosomal dominant disorders of joint development, multiple synostosis syndrome (SYNS1) and a milder disorder proximal symphalangism (SYM1). This study investigated the effect of one SYNS1 and two SYM1 disease-causing missense mutations on the structure and function of noggin. The SYNS1 mutation abolished, and the SYM1 mutations reduced, the secretion of functional noggin dimers in transiently transfected COS-7 cells. Coexpression of mutant noggin with wild-type noggin, to resemble the heterozygous state, did not interfere with wild-type noggin secretion. These data indicate that the human disease-causing mutations are hypomorphic alleles that reduce secretion of functional dimeric noggin. Therefore, we conclude that noggin has both species-specific and joint-specific dosage-dependent roles during joint formation. Surprisingly, in contrast to the COS-7 cell studies, the SYNS1 mutant was able to form dimers in Xenopus laevis oocytes. This finding indicates that there also exist species-specific differences in the ability to process mutant noggin polypeptides.

Animals↗

PubMed2001

An assessment of the clinical efficacy of intranasal desmopressin spray in the treatment of renal colic.

OBJECTIVES: To assess the efficacy of desmopressin nasal spray compared with diclofenac given intramuscularly in patients with acute renal colic caused by urolithiasis. PATIENTS AND METHODS: The study included 61 patients randomized into three different groups; group A received desmopressin (40 microg, nasal spray), group B diclofenac (75 mg) intramuscularly and group C, both desmopressin and diclofenac. Pain was assessed using a visual analogue scale (a 10-cm horizontal scale ranging from 'no pain' to 'unbearable pain') at baseline, 10, 20 and 30 min after administering the treatments. RESULTS: On admission, the pain level was the same in all three groups. At 10 min the pain decreased in all groups to a level that was not significantly different. At 20 min groups B and C had similar mean pain levels (3.7), whereas in group A it was 5.0. At 30 min, groups B and C scored 2-3, and group A 5.6. All three treatments were equally effective at 10 and 20 min but at 30 min there was a stabilization/slight increase in pain level in group A. CONCLUSIONS: Desmopressin has several advantages, e.g. ease of administration, simplicity of delivery and apparent lack of side-effects, which makes it suitable for ambulatory use. Desmopressin acts rapidly and seems to be effective in both single and combined therapy with diclofenac; it decreases the need for a second treatment and increases the analgesic effect of diclofenac. Some patients responded well to desmopressin, with rapid and complete pain relief. These results indicate that desmopressin may be used to treat renal colic either alone or combined, increasing the analgesic effect of other drugs. More studies are needed to validate and confirm the results; it would also be useful to determine factors that may identify the subgroup of patients who respond quickly and with almost complete pain relief.

Administration, Intranasal↗

PubMed1999

CACP, encoding a secreted proteoglycan, is mutated in camptodactyly-arthropathy-coxa vara-pericarditis syndrome.

Altered growth and function of synoviocytes, the intimal cells which line joint cavities and tendon sheaths, occur in a number of skeletal diseases. Hyperplasia of synoviocytes is found in both rheumatoid arthritis and osteoarthritis, despite differences in the underlying aetiologies of the two disorders. We have studied the autosomal recessive disorder camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP; MIM 208250) to identify biological pathways that lead to synoviocyte hyperplasia, the principal pathological feature of this syndrome. Using a positional-candidate approach, we identified mutations in a gene (CACP) encoding a secreted proteoglycan as the cause of CACP. The CACP protein, which has previously been identified as both 'megakaryocyte stimulating factor precursor' and 'superficial zone protein', contains domains that have homology to somatomedin B, heparin-binding proteins, mucins and haemopexins. In addition to expression in joint synovium and cartilage, CACP is expressed in non-skeletal tissues including liver and pericardium. The similarity of CACP sequence to that of other protein families and the expression of CACP in non-skeletal tissues suggest it may have diverse biological activities.

Amino Acid Sequence↗

PubMed1999

Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis.

The secreted polypeptide noggin (encoded by the Nog gene) binds and inactivates members of the transforming growth factor beta superfamily of signalling proteins (TGFbeta-FMs), such as BMP4 (ref. 1). By diffusing through extracellular matrices more efficiently than TGFbeta-FMs, noggin may have a principal role in creating morphogenic gradients. During mouse embryogenesis, Nog is expressed at multiple sites, including developing bones. Nog-/- mice die at birth from multiple defects that include bony fusion of the appendicular skeleton. We have identified five dominant human NOG mutations in unrelated families segregating proximal symphalangism (SYM1; OMIM 185800) and a de novo mutation in a patient with unaffected parents. We also found a dominant NOG mutation in a family segregating multiple synostoses syndrome (SYNS1; OMIM 186500); both SYM1 and SYNS1 have multiple joint fusion as their principal feature. All seven NOG mutations alter evolutionarily conserved amino acid residues. The findings reported here confirm that NOG is essential for joint formation and suggest that NOG requirements during skeletogenesis differ between species and between specific skeletal elements within species.

Abnormalities, Multiple↗

PubMed1995

Differential testicular responses to short daylength in deer mice are reflected by regional and morphological differences in the GnRH neuronal system.

Male deer mice (Peromyscus maniculatus) respond to short photoperiod with a range of spermatogenic responses. About one-third of all short day exposed mice exhibit a complete cessation of spermatogenesis (reproductive responsive), while about an equal number remain reproductively competent (reproductive nonresponsive). These differential spermatogenic responses are mirrored by endocrine measures; reproductive responsive males exhibit reduced circulating levels of testosterone and luteinizing hormone, while reproductive nonresponsive males exhibit long day levels of both hormones. A variety of evidence indicates that despite individual differences in reproductive responses, all short day exposed mice detect and respond to the change in photoperiod at the level of the hypothalamus, irrespective of gonadal response. We investigated whether deer mice exhibiting disparate gonadal responses to short days differed in aspects of the GnRH neuronal system, as revealed by immunocytochemistry. Reproductively mature males were maintained on either long (16L:8D) or short (8L:16D) photoperiod for 8 weeks. Thereafter, regional and morphological differences in GnRH-containing neurons were compared among long day (n = 8) and short day reproductive responsive (n = 8) and nonresponsive (n = 8) deer mice. Results demonstrate both an effect of photoperiod and reproductive state on the number, location and morphology of immunoreactive-GnRH neurons. Short days caused immunoreactive GnRH cell number to increase in both short day phenotypes relative to long day mice. Significant differences among treatment groups in the numbers of cells per region were confined to the lateral hypothalamus and lateral preoptic area. Both short day phenotypes exhibited an increase in cell number in the lateral preoptic area, compared to long day mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗

PubMed1995

Attachment of articular cartilage chondrocytes to the tissue form of type VI collagen.

Type VI collagen is composed of a short triple helix rich in RGD sequences with globular domains at each extremity of the helix. Disulfide-bonded tetramers of the monomeric molecule associate non-covalently to form networks of microfibrils in connective tissues, including cartilage. The disulfide-bonded tetramer can be extracted with 6 M guanidine HCl and purified without pepsin digestion and is referred to here as the tissue form of type VI collagen. Type VI collagen in mature articular cartilage appears to be concentrated pericellularly. We undertook a systematic investigation using solid phase assays to establish the nature of the attachment of bovine articular cartilage chondrocytes to the intact, tissue form of bovine type VI collagen. The tissue form of type VI collagen was extracted from bovine meniscus cartilage with 6 M guanidine HCl and purified by polyethylene glycol precipitation. When equal molar quantities were coated on microwells, the tissue form of type VI collagen attached more cells than the pepsin-digested form of the molecule that lacked the globular domains. The attachment to the intact, tissue form was dose-dependent and saturable and was not inhibited by heparin or type II collagen. A linear GRGDSP peptide failed to inhibit attachment of the chondrocytes to the intact, tissue or pepsin-digested forms of type VI collagen, but totally inhibited the interaction when the intact molecule was reduced and alkylated. In contrast, a cyclic C*GRGDSPC* peptide inhibited attachment to the tissue form of type VI collagen, but not to fibronectin. The attachment had a metal ion dependence that could be satisfied by MnCl2, slightly less by MgCl2, but not at all by CaCl2. A direct interaction between the tissue form of type VI collagen and a chondrocyte cell surface receptor or receptors is a structural feature of the pericellular matrix in cartilage.

Amino Acid Sequence↗

PubMed1995

Assessment of a circuit of exercises through heart rate response.

OBJECTIVE: A circuit of seven exercises was designed for a cardiac population. This study evaluated whether the patients achieved their training heart rate during the circuit, recommended to be 70-85% of the maximum heart rate achieved during an exercise test. DESIGN: Patients were randomly allocated to a starting exercise to balance any order effect from performing the exercises in a given sequence. Each of the seven exercises was performed for 30 s, so one circuit lasted 3.5 min. The circuit was repeated five times. PATIENTS: Twenty patients who had had myocardial infarctions within 6 weeks of the study participated. OUTCOME: Heart rate was measured to assess the stress placed on the cardiorespiratory system during the circuit. Measurements were taken at 10 and 20 s following the termination of each exercise and over two repetitions of the circuit (a total of 14 exercise periods). RESULTS AND CONCLUSION: Comparisons of the readings taken at 10 and 20 s indicated, contrary to previously published findings, that no significant heart rate deceleration occurred within this period. Every exercise maintained the mean heart rate within the specified band of 70-85% of the maximum heart rate achieved during the exercise test. The study has shown that the selected exercises were suitable for use during a cardiac rehabilitation programme.

Aged↗

PubMed1991

Interaction of intact type VI collagen with hyaluronan.

The capacity of non-pepsinyzed type VI collagen to bind to hyaluronan was investigated. Type VI collagen was extracted from bovine meniscal cartilage with 6 M GuHCl and purified by extraction of PEG precipitates and dissociative Sephacryl S-500 HR chromatography. Type VI collagen, detected with a monoclonal antibody, bound in 0.5 M NaCl to hyaluronan-coated micro-wells, the degree of binding being higher at 37 degrees C than 23 degrees C and 4 degrees C. Incubation of type VI collagen in competitive inhibition assays with testicular hyaluronidase digests of hyaluronan in liquid phase, reduced binding of the protein to hyaluronan-coated microwells to background levels. Thus, non-pepsinyzed type VI collagen binds to hyaluronan in vitro.

Animals↗

PubMedDate not supplied

Brain acetylcholinesterase activity and optomotor behavior in bluegills, Lepomis macrochirus exposed to different concentrations of diazinon.

Organophosphorus pesticides inhibit acetylcholinesterase (AChE) activity to varying degrees in different species of fish. Estimation of AChE activity is a useful tool for establishing the degree of pollution caused by these pesticides. Behavioral changes are very good and sensitive indicators of any chemical pollution. Changes in the optomotor behavior are easily quantifiable. Therefore estimation of AChE activity and changes in the optomotor response are taken as criteria to study the effects of different concentrations (15, 30, 45, 60 and 75 micrograms/l) of diazinon, an organophosphorus compound, in bluegill Sunfish, Lepomis macrochirus. The fish were exposed for a period of 24 hours. In this study, AChE activity showed a significant decline above an exposure concentration of 45 micrograms/l exposure concentration. In the case of optomotor behavior, a decline in the scores of the "following" responses of the fish was noticed from an exposure concentration of 30 micrograms/l. It seems that a behavioral bioassay is more sensitive than other types of testing.

Acetylcholinesterase↗