Do obstetric risk factors truly influence the etiopathogenesis of congenital muscular torticollis?

BACKGROUND: Congenital muscular torticollis (CMT) is seen in childhood and presents within months after birth. The etiology remains unknown; however, medical textbooks suggest trauma at birth as a main reason. The aim of this study was to systematically describe obstetric and perinatal outcomes in a population of children with a confirmed congenital muscular torticollis diagnosis. MATERIALS AND METHODS: Children with a validated diagnosis of congenital muscular torticollis born at Aarhus University Hospital from 2000 to 2014 were included in the study. Information on perinatal, intrapartum and neonatal characteristics were obtained from databases and from medical records, and systematically described. RESULTS: In this study, there were no differences in birth characteristics in children with left- and right-sided torticollis, between boys and girls or between the conservatively treated and the children who needed surgery. Most of the children with congenital muscular torticollis in this study were delivered at term without signs of birth complications or trauma. None experienced moderate or severe asphyxia. CONCLUSIONS: The results of the present study suggests that complicated birth or birth trauma may not be the main cause of congenital muscular torticollis and point towards intrauterine and prenatal reasons for its development. LEVEL OF EVIDENCE ACCORDING TO OCEBM LEVELS OF EVIDENCE WORKING GROUP: 3.

Association between polymorphisms of apolipoprotein E, bone mineral density of the lower forearm, quantitative ultrasound of the calcaneus and osteoporotic fractures in postmenopausal women with hip or lower forearm fracture.

A genetic contribution to the development of osteoporosis is well documented. Although the association between the common allelic variation of apolipoprotein E (APOE), fracture risk, bone loss and bone mineral density (BMD) has been examined in several studies, the results of these investigations are contradictory. The aim of this study was to examine the association between polymorphisms of APOE, BMD of the lower forearm, quantitative ultrasound of the calcaneus and osteoporotic fractures in a population of postmenopausal women with hip or lower forearm fractures admitted to a department of orthopaedic surgery and age-matched controls from the population register. The APOE genotypes of 327 women were studied: 73 with lower forearm fractures, 43 with hip fractures and 211 age-matched controls. The participants were not receiving antiosteoporotic treatment. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) was used to detect the APOE genotypes. Quantitative ultrasound was measured at the calcaneus. Bone mineral density (BMD) of the lower forearm was measured with dual-energy X-ray absorptiometry. The distributions of genotype frequencies in this study were: E2/E2: 0.3%; E2/E3: 16.5%; E2/E4: 2.5%; E3/E3: 54.7%; E3/E4: 24.2%; E4/E4: 1.8%. All subpopulations were in Hardy-Weinburg equilibrium. There was no association between bone mass parameters and the APOE allele groups. Logistic regression analysis did not show any association between fractures and APOE allele groups. In conclusion, this study showed no association between bone mass parameters (BMD, speed of sound (SOS), broadband ultrasound attenuation (BUA)), hip or lower forearm fracture and APOE genotypes in a population of postmenopausal women and age-matched controls.

[Osteogenesis imperfecta. The effect of intramedullary nails in long tubular bones]. / Osteogenesis imperfecta. Effekt af marvsøm i lange rørknogler.

INTRODUCTION: The aim of the study was to describe the clinical, radiological, and functional results of intramedullary nailing of deformities in the lower extremities of children with osteogenesis imperfecta after the use of multiple osteotomies and non-telescoping rods (rush pins). MATERIAL AND METHODS: Eight children with osteogenesis imperfecta, who consecutively underwent surgery during 1991-1994, were entered in the study. RESULTS: Sixteen operations were performed on eight children: 12 on the femur and four on the tibia. Like others, we found a high complication rate, 50%. Radiological correction of angular deformities was good. The functional outcome was satisfactory and the patients were satisfied. CONCLUSION: Correction and stabilisation of deformities in the lower extremities in children with osteogenesis imperfecta with the use of non-telescoping rods is an acceptable method of decreasing fractures and allowing most formerly non-ambulatory children to walk. Furthermore, the cosmetics were improved.

Estradiol down regulates expression of vasoactive intestinal polypeptide receptor type-1 in breast cancer cell lines.

Three breast carcinoma cell lines were tested for 17beta-estradiol (E(2)) mediated regulation of vasoactive intestinal polypeptide receptor type-1 (VPAC(1)) expression. In all three, E(2) was found to down-regulate the mRNA level. We studied T47D cells in more details and found a 25 and 70% decrease in the VPAC(1) mRNA level upon 7 and 48 h of E(2) treatment, respectively. The number of vasoactive intestinal polypeptide (VIP) binding sites was reduced 66% upon treatment with E(2) for 72 h. After cycloheximide pretreatment, the E(2) mediated mRNA reduction was attenuated from 50% to 25% after 24 h suggesting the effect to be at least partly independent of protein synthesis. Experiments with the transcriptional inhibitor actinomycin D showed that E(2) did not influence the VPAC(1) mRNA half-life while nuclear run-on experiments indicated that E(2) decreased the VPAC(1) transcription rate. Two antiestrogens: ICI 182780 (ICI) and 4-hydroxy-tamoxifen (4-OHT) mediated a concentration dependent inhibition of E(2)'s effect on the mRNA level. Transient transfection with reporter-gene constructs containing various portions of the VPAC(1) 5'-flanking sequence revealed the most proximal 100 bp to be essential for the basal transcriptional activity. However, E(2) did not influence the expression of the reporter gene using up to 3250 bp of the VPAC(1) 5'-flariking region.

Long-term results of periosteal transplantation in osteochondritis dissecans of the knee.

Between 1986 and 1991, a total of 18 patients (11 men and 7 women) with osteochondritis dissecans of the knee were treated with periosteal transplantation. Median patient age was 19 years (range: 16-45 years). Eight patients were reoperated up to 8 years postoperatively, due to reduced range of motion, synovitis, or formation of an exostosis in the transplanted area. Of 14 patients who were available for follow-up after 8 years (range: 5-10), 2 were completely pain free. Six patients had reduced range of motion, knee instability, or quadriceps muscle atrophy. The number of reoperations and the presence of continued knee pain in most patients does not justify the extensive procedure of periosteal transplantation.

Downregulation of VPAC1R expression in breast cancer cell lines.

The breast carcinoma cell line T47D was tested for 17 beta-estradiol (E2) mediated regulation of vasoactive intestinal polypeptide receptor type-1 (VPAC1) expression. E2 was found to downregulate the mRNA level. The number of VIP binding sites was reduced 66% on treatment with E2 for 72 h. Experiments with cycloheximide suggested that the effect was independent (at least partly so) of protein synthesis. Experiments with the transcriptional inhibitor, actinomycin D, showed that E2 did not influence the VPAC1 mRNA halflife. Both of two antiestrogens, ICI 182,780 and 4-hydroxy-tamoxifen, mediated a concentration dependent inhibition of the effect of E2 on the mRNA level. Transient transfection with reporter-gene constructs containing various portions of the VPAC1 5'-flanking sequence revealed the most proximal 100 bp to be essential for the basal transcriptional activity. However, E2 did not influence the expression of the reporter gene using up to 3,250 bp of the VPAC1 5'-flanking region.

X-ray diffraction on spider silk during controlled extrusion under a synchrotron radiation X-ray beam.

The structure of a single thread of Nephila edulis silk has been studied by in situ X-ray diffraction from a living spider. A systematic increase of orientational order with increasing silking speed up to 40 mm s-1 was observed. Within a few mm from the spinnerets exit, crystalline domains with a beta-poly(L-alanine) structure were observed. The data also suggest an increase in crystalline fraction in the immediate vicinity of the spigot exit.

Identification of a new promoter in the early region of the human papillomavirus type 16 genome.

Transcription of the human papillomavirus type 16 (HPV-16) genome is controlled by several promoters; the P(97) promoter is considered to be the main one. An additional promoter has been identified within the E7 ORF as well as an antisense promoter just upstream of the L2 ORF. The significance of these promoters for early and late gene expression and their activity related to cell differentiation is not known in detail. Identification of two new, previously undescribed transcription start sites at nt 542 just upstream of the E7 ORF and at nt 611 within the E7 ORF is reported. The promoter responsible for the start site at nt 542 (P(542)) was active in SiHa, HeLa and C33A cells. Very low promoter activity was found upstream of the nt 611 start site. The E7 protein has previously been shown to be synthesized from a polycistronic mRNA encoding both the E6 and E7 proteins under the control of the P(97) promoter. The data reported in the present paper suggest that promoter P(542) may control synthesis of the E7 oncoprotein from a monocistronic mRNA.

Possible carcinogenic effect of 6-mercaptopurine on bone marrow stem cells: relation to thiopurine metabolism.

BACKGROUND: 6-Mercaptopurine (6MP) has been regarded as nonleukemogenic, even though the cytotoxicity of 6MP depends on the incorporation of 6-thioguanine nucleotides (6TGN) into DNA. In hematopoietic cells this pathway competes with S-methylation catalyzed by thiopurine methyltransferase (TPMT). However, methylated 6MP metabolites inhibit purine de novo synthesis and thus may enhance incorporation of 6TGN into DNA. Approximately 10% of white individuals have low TPMT activity as a result of polymorphisms in the TPMT gene. The authors attempted to test the hypothesis that the degree of DNA damage during 6MP therapy might reflect variations in 6MP metabolism and pharmacokinetics. METHODS: The authors measured TPMT activity as well as erythrocyte levels of 6TGN (E-6TGN) and methylated 6MP metabolites (E-MeMP) during 6MP therapy in 439 children with acute lymphoblastic leukemia, 5 of whom later developed secondary myelodysplasia or acute myeloid leukemia (sMDS/AML). RESULTS: The patients who developed sMDS/AML had significantly lower TPMT activity compared with the remaining patients (P = 0.03). The 55 patients with TPMT activity <14 U/mL red blood cells (RBC) (antimode of the bimodal distribution) had a 5-year risk of sMDS/AML of 9 +/- 6% versus 1 +/- 1% for the remaining patients (P = 0.002). Cox regression analysis identified TPMT activity and E-MeMP level as the strongest predictors of risk for sMDS/AML (global P value = 0.02). Patients with low TPMT activity and high E-MeMP levels had the highest risk. All 5 patients with sMDS/AML had E-6TGN and/or E-MeMP levels > the 90% percentiles or had TPMT activity < 14 U/mL RBC. CONCLUSIONS: These data demonstrate an increased leukemogenic risk when 6MP is administered with other cytotoxic agents in patients with low TPMT activity, and indicate that not only high 6TGN levels but also high levels of methylated metabolites may lead to DNA damage.

[Adults treated as children for acute lymphocytic leukemia--methotrexate, late effects and quality of life]. / Voksne behandlet for akutt lymfatisk leukemi som barn--metotreksat, seneffekter og livskvalitet.

From 1975 to 1980, 153 Norwegian children were diagnosed with acute lymphocytic leukaemia. In 1995, all 98 survivors were studied and compared to matched family controls. 132 children were treated with the national protocol. Of these, 93 (70.5%) were survivors at the time of the study. The remaining five survivors were treated with different treatment schemes. The national protocol included methotrexate infusions combined with intrathecal methotrexate as prophylactics against neuroleukaemia, instead of the irradiation. Neither doxorubicin nor cyclophosphamide were included. In this study, a questionnaire was used that covered demographic data, quality of life, and medical information the response rates were 96% (94 persons) for survivors and 92% (90 persons) for family controls. Information was also obtained for the remaining four survivors. No significant differences were found between survivors and controls with regard to quality of life and demographics, with one exception, Somatisation on the GHQ-28. Hospital records of all patients were checked for possible late effects. One case of serious sequela (hemiparesis during therapy) was found, probably related to methotrexate therapy. Seven other serious, possible sequelae were recorded, but probably not related to methotrexate. There were no cases of secondary malignant neoplasm.

Port-site recurrence after laparoscopic surgery for endometrial carcinoma.

BACKGROUND: Women with endometrial carcinoma are being treated with laparoscopic surgery, but the risk of port-site recurrences remains undefined. CASE: A 58-year-old woman underwent laparoscopically assisted vaginal hysterectomy, bilateral salpingo-oophorectomy, and laparoscopic lymphadenectomy for endometrial cancer. Final surgical stage was IA, with grade 2 histology. Twenty-one months later, she developed a 5-cm recurrent tumor mass at a lateral laparoscopic port site. The mass was resected, and a restaging laparotomy performed, without evidence of other metastases. Radiation therapy was administered to the involved anterior abdominal wall. Two and one half years later, there is no evidence of recurrence. CONCLUSION: An isolated laparoscopic port-site recurrence might be attributable to the initial laparoscopic management of an otherwise good-prognosis endometrial carcinoma.

Retinoic acid down-regulates the expression of the vasoactive intestinal polypeptide receptor type-1 in human breast carcinoma cell lines.

Four breast carcinoma cell lines (T47D, ZR-75-1, MDA-MB-231, and MCF-7) were tested for regulation of the expression of vasoactive intestinal polypeptide receptor type-1 (VIP-R1). In all four cell lines, retinoic acid (RA) treatment caused a fast and marked decrease in VIP-R1 mRNA level as examined by Northern blots. Cycloheximide pretreatment attenuated the effect from 3- to 2-fold, indicating that existing proteins can mediate the decreasing effect of RA, but to attain the maximal effect new protein synthesis might be needed. Transcriptional inhibition with Actinomyocin D showed that RA did not influence the VIP-R1 mRNA half-life, indicating that the decreasing effect of RA on the mRNA level is due to transcriptional inhibition. In agreement with the observations on mRNA level, we found that the VIP receptor number was reduced 3-fold from 88 to 32 fmol/10(6) cells in T47D cells and from 222 to 73 fmol/10(6) cells in MDA-MB-231 cells upon RA treatment for 72 h. The promoter and 5'-flanking region of the VIP-R1 gene were cloned from a human placental cosmid library, and 2.5 kb were sequenced to search for regulatory elements. Our results, therefore, imply that the regulation of VIP-R1 gene expression by RA could have a role in human mammary tumor biology.

The clinical indications for identical pathogenesis of isolated and non-isolated testicular relapses in acute lymphoblastic leukaemia.

In the present population-based study, we compared the clinical data of testicular relapses with and without concurrent bone marrow relapse and clinical data of the relapses in other locations among boys with acute lymphoblastic leukaemia (ALL), in order to study the possible evidence of early sequestration and local regulation of leukaemic lymphoblast in the testis of humans. The results suggest that the pathogenesis of isolated testicular relapse (T) and testicular relapse with a concurrent bone marrow relapse (T + BM) is likely to be similar. Isolated and non-isolated testicular relapses appeared late after the achievement of remission (T 34 +/- 16 months, T + BM 32 +/- 15 months) in ALL compared to relapses in other locations (CNS 23 +/- 11 months, BM 25 +/- 19 months). The better prognosis after testicular relapses (estimated second event free survival probability, 2-EFS: T 0.63, T + BM 0.32) compared to bone marrow relapse (2-EFS: BM 0.13) further suggests that testicular relapse with a concurrent bone marrow relapse possibly originates from the isolated testicular relapse, and that the isolated testicular relapse is a separate entity and not a manifestation of systemic recurrence. Higher frequencies of isolated and non-isolated testicular relapses (T 9%, T + BM 5%) were observed among boys with onset of ALL in early puberty (10-12 y) compared to those among younger (T 4%, T + BM 2%) and older (T 0%, T + BM 0%) boys. The late occurrence, the possible association with hormonal maturation and the good prognosis after testicular relapses suggest a possible local regulation of the residual leukaemic lymphoblast in human testis.

Characterization of the inhibitory effect of growth hormone on primary preadipocyte differentiation.

GH exerts adipogenic activity in several preadipocyte cell lines, whereas in primary rat preadipocytes, GH has an antiadipogenic activity. To better understand the molecular mechanism involved in adipocyte differentiation, the expression of adipocyte-specific genes was analyzed in differentiating preadipocytes in response to GH. We found that the expression of both adipocyte determination and differentiation factor 1 (ADD1) and peroxisome proliferator activated receptor gamma(PPARgamma) was induced in preadipocytes during differentiation. In the presence of GH, which markedly inhibited triglyceride accumulation, no reduction in the expression level of ADD1 was observed in response to GH, whereas there was a 50% reduction in the expression of PPARgamma. The DNA binding activity of the PPARgamma/retinoid X receptor-alpha(RXRalpha) to the ARE7 element from the aP2 gene was also reduced by approximately 50% in response to GH. GH inhibited the expression of late markers of adipocyte differentiation, fatty acid synthase, aP2, and hormone-sensitive lipase by 70-80%. The antiadipogenic effect of GH was not affected by the mitogen-activated protein (MAP) kinase/ extracellular-regulated protein (ERK) kinase inhibitor PD 98059, indicating that the mitogen-activated protein kinase pathway was not involved in GH inhibition of preadipocyte differentiation. The expression of preadipocyte factor-1/fetal antigen 1 was decreased during differentiation, and GH treatment prevented this down-regulation of Pref1/FA1. A possible role for Pref-1/FA1 in mediating the antiadipogenic effect of GH was indicated by the observation that FA1 inhibited differentiation as effectively as GH. These data suggest that GH exerts its inhibitory activity in adipocyte differentiation at a step after the induction of ADD1 but before the induction of genes required for terminal differentiation.

Modulatory action of PACAP27 on NMDA receptor channel activity in cultured chick cortical neurons.

The modulatory effect of PACAP27 on NMDA receptor channel activity in cultured chick cortical neurons was investigated using the outside-out recording mode of the patch clamp technique. Channel opening frequency elicited by 20 microM NMDA, or 20 microM NMDA plus 1 microM glycine, was potentiated in the presence of 100 nM PACAP27 and inhibited with 1000 nM PACAP27. These effects were reversible on washout and reduced when glycine concentration was increased to 10 microM, but were not affected by the PACAP antagonist PACAP6-27 (1 microM) or the GTP inhibitor GDP-beta-S (100 microM). It is suggested that PACAP27 may exert its modulatory action on NMDA receptor channel activity through the glycine site(s).

Long-term survival and quality of life in patients treated with a national all protocol 15-20 years earlier: IDM/HDM and late effects?

In a follow-up matched control study the 93 (70.5%) survivors of 132 children treated with a national protocol for acute lymphoblastic leukemia (ALL) and 5 survivors of the other 21 cases of ALL in childhood diagnosed in the same period were evaluated. Thus it was also a population-based study. The national treatment protocol was used in the period 1975-1980. Methotrexate (MTX) infusions combined with intrathecal MTX were used as prophylaxis against neuroleukemia instead of irradiation. Neither doxorubicin (Adriamycin) nor cyclophosphamide was used in the protocol. A questionnaire covering demographic data, number of offspring, learning problems, level of athletic performance, education, and work status as well as medical information was used. Forms were received from 94 (96%) of the 98 adult surviving cases and corresponding controls in the family. Interviews were performed in the remaining four cases (4%). There were no statistical differences between the two groups with respect to physical and mental health and quality of life. Hospital records of all patients were also checked for possible late effects. There was no definite case of secondary malignant neoplasm; however, there was one case of prolactinoma and only one case of serious sequelae (hemiparesis during therapy), probably due to intrathecal and intravenous MTX.

PACAP38 modulates activity of NMDA receptors in cultured chick cortical neurons.

The outside-out recording mode of the patch-clamp technique was used to study modulatory effects of pituitary adenylate cyclase-activating polypeptide (PACAP38) on N-methyl--aspartate (NMDA) receptor activity in cultured chick cortical neurons. Biphasic concentration-dependent effects of PACAP38 on channel opening frequency induced by NMDA (20 microM) and glycine (1 microM) were found, with low concentrations (0.5-2 nM) of PACAP38 increasing activity and higher concentrations (10-1,000 nM) causing inhibition. These effects were reversible, reduced with higher concentrations of glycine (2-10 microM) but not by 200 microM NMDA, and inhibited by 10 microM 7-chlorokynurenic acid. In addition, 1 microM PACAP6-38 (a PACAP antagonist) inhibited channel activity due to 20 microM NMDA and 1 microM glycine by 66%, and this inhibition was reduced to 13% in the additional presence of 2 nM PACAP38. These observations suggest that PACAP38 has a direct modulatory effect on the NMDA receptor that is independent of intracellular second messengers and probably mediated through the glycine coagonist site(s).

Sustained-release metoclopramide plus methylprednisolone versus placebo plus methylprednisolone as antiemetic prophylaxis during non-cisplatin chemotherapy. A randomized double-blind cross-over trial.

In a randomized double-blind cross-over trial, sustained-release metoclopramide (S) plus methylprednisolone (M) was compared with placebo (P) plus methylprednisolone as antiemetic prophylaxis during two cycles of non-cisplatin chemotherapy. S was administered as 60 mg every 12 h commencing on the evening before chemotherapy up to total of 300 mg metoclopramide in 2.5 days. Evaluation of nausea and vomiting was done by self-assessment schemes and visual analog scales. Fifty patients were included and 36 fulfilled both cycles. Mild nausea and vomiting were experienced by 81% and 83% in the S + M and P + M groups, respectively, while 42% and 39% showed complete control of nausea and vomiting during the first day of treatment. Moderate-dose S did not add to the antiemetic efficacy of M in non-cisplatin chemotherapeutic regimens.