PDE4 and PDE5 regulate cyclic nucleotides relaxing effects in human umbilical arteries

Cyclic nucleotides (cAMP and cGMP) are the main second messengers linked to vasodilatation. They are synthesized by cyclases and degraded by different types of phosphodiesterases (PDE). The effect of PDE inhibition and cyclases stimulation on 5-hydroxytryptamine (5-HT; 1 microM) and histamine (10 microM) contracted arteries was analysed. Stimulation of guanylate cyclase or adenylate cyclase relaxed the histamine- and 5-HT-induced contractions indicating that intracellular increase of cyclic nucleotides leads to vasodilatation of the human umbilical artery. We investigated the role of different PDE families in the regulation of this effect. The presence of the different PDE types in human umbilical artery smooth muscle was analysed by RT-PCR and the expression of PDE1B, PDE3A, PDE3B, PDE4C, PDE4D and PDE5A was detected. The unspecific PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX; 50 microM) relaxed histamine-contracted human umbilical artery on 47.4+/-7.2%. This effect seems to be due to PDE4 and PDE5 inhibition because among the selective PDE inhibitors used only the PDE4 inhibitor (rolipram; 1 microM) and the PDE5 inhibitors (dipyridamole and T0156; 3 microM and 1 microM respectively) induced significant relaxation (39.0+/-8.7, 30.4+/-6.0 and 36.3+/-2.8 respectively). IBMX, dipyridamole and T0156 produced similar relaxation on 5-HT-induced contraction. After forskolin, the addition of IBMX or rolipram increased the effect of the adenylate cyclase stimulator and almost completely relaxed the human umbilical artery contracted by histamine (92.5+/-4.9 and 90.9+/-4.7 respectively), suggesting a main role of PDE4. The data obtained with 5-HT contracted arteries confirmed this, because only rolipram and IBMX significantly increased the forskolin vasodilator effect. The administration of dipyridamole and T0156 after sodium nitroprusside (SNP) induced a significant increase of the SNP relaxant effect on histamine-contracted arteries, but PDE1 and PDE3 inhibition did not increase the effect of the guanylate cyclase stimulator. Similar effects were obtained in 5-HT contracted arteries, the SNP induced relaxation was increased by the PDE5 inhibition, but not by PDE1 or PDE3 inhibition. In summary, our results demonstrate that: 1) the increase of cAMP and/or cGMP levels induces relaxation of the human umbilical vascular smooth muscle; 2) four families of PDE are expressed in this smooth muscle: PDE1, PDE3, PDE4 and PDE5; 3) between these families, PDE4 and PDE5 are the key enzymes involved in the regulation of the relaxation associated to cAMP and cGMP, respectively.     

Survival analysis of the cemented SPII stem

The aim of this study was to evaluate the survivorship of cemented stems for hip replacement. From March 1989 to October 1991, 98 patients underwent total hip arthroplasty using the Lubinus SPII stem. The preoperative diagnoses included 73 cases of osteoarthritis, 17 fractures of the femoral neck, and 8 cases of aseptic loosening. The adopted acetabular cups were: in 59 cases a screwed cup V-Thabe (Waldemar Link, Hamburg, Germany); in 5 cases the press-fit cup Mallory-head (Biomet, Inc., Warsaw, IN, USA); in 3 cases a Muller cemented cup; and in 2 cases a cemented cup (Waldemar Link). In the 17 cases of fracture, a hemispherical biarticular cup was employed. The SPII (Waldemar Link) stem is made of a chromecobalt alloy; it is smooth and 150-mm long. Its shape anatomically reproduces the curves of the femoral shaft. The neck had anatomical anteversion for the right and left femurs, and an inclination of 135°. Cementation was performed using CMW3 cement, mixed under vacuum, and injected with a needle after positioning an intramedullary plug. The survivorship of 98 implants, was evaluated after 10 years. The survival rate was 98%. The Lubinus SPII prosthetic stem shows a high rate of survival. The influencing factors of this good outcome are the prosthetic design, the improvement in cementation techniques, and after all a good surgical technique. Received: 5 June 2000/Accepted: 29 June 2000     

Effects of the Manufacturing Methods on the Mechanical Properties of a Medical-Grade Copolymer Poly(L-lactide-co-D,L-lactide) and Poly(L-lactide-co-ε-caprolactone) Blend

Biocompatible and biodegradable polymers represent the future in the manufacturing of medical implantable solutions. As of today, these are generally manufactured with metallic components which cannot be naturally absorbed within the human body. This requires performing an additional surgical procedure to remove the remnants after complete rehabilitation or to leave the devices in situ indefinitely. Nevertheless, the biomaterials used for this purpose must satisfy well-defined mechanical requirements. These are difficult to ascertain at the design phase since they depend not only on their physicochemical properties but also on the specific manufacturing methods used for the target application. Therefore, this research was focused on establishing the effects of the manufacturing methods on both the mechanical properties and the thermal behavior of a medical-grade copolymer blend. Specifically, Injection and Compression Molding were considered. A Poly(L-lactide-co-D,L-lactide)/Poly(L-lactide-co-ε-caprolactone) blend was considered for this investigation, with a ratio of 50/50 (w/w), aimed at the manufacturing of implantable devices for tendon repair. Interesting results were obtained.     

Synovial chondromatosis of the foot: Two case reports and literature review

BACKGROUND Primary synovial chondromatosis(PSC) is a rare arthropathy of the synovial joints characterized by the formation of cartilaginous nodules, which may detach and become loose bodies within the joint and may undergo secondary proliferation. PSC of the foot and ankle is exceedingly rare, with only a few cases reported in the literature. The diagnosis may be difficult and delayed until operative treatment, when it is confirmed by histological assessment. PSC may degenerate into chondrosarcoma. Operative treatment is the gold standard aiming to minimize pain, improve function, prevent or limit progression of arthritis. Surgical treatment consists in debridement by arthrotomic or arthroscopic management, but there is no consensus in the literature about timing of surgery and surgical technique. Thus, the aim of this study is to report the outcomes of the surgical treatment of two cases, together with a literature review.CASE SUMMARY We report two cases of patients affected by PSC of the foot in stage III, according to the Milgram classification: the former PSC localized in the ankle that underwent open surgery consisted of loose bodies removal; the latter in the subtalar joint, and the choice of treatment was the arthrotomy and debridement from loose bodies, in addition to the subtalar arthrodesis. Both patients returned to complete daily and working life after surgery.CONCLUSION Synovial chondromatosis is a rare benign pathology, even rarer in the ankle joint and especially in the foot. Surgery should be minimal in patients with ankle PSC,choosing the correct timing, waiting if possible until stage III. More aggressive and early surgery should be performed in patients with PSC of the foot,particularly the subtalar joint, due to the high risk of arthritic evolution.     

Decision-making cognition in neurodegenerative diseases

A large proportion of human social neuroscience research has focused on the issue of decision-making. Impaired decision-making is a symptomatic feature of a number of neurodegenerative diseases, but the nature of these decision-making deficits depends on the particular disease. Thus, examining the qualitative differences in decision-making impairments associated with different neurodegenerative diseases could provide valuable information regarding the underlying neural basis of decision-making. Nevertheless, few comparative reports of decision-making across patient groups exist. In this Review, we examine the neuroanatomical substrates of decision-making in relation to the neuropathological changes that occur in Alzheimer disease, frontotemporal dementia, Parkinson disease and Huntington disease. We then examine the main findings from studies of decision-making in these neurodegenerative diseases. Finally, we suggest a number of recommendations that future studies could adopt to aid our understanding of decision-making cognition.     

Overexpression of activated murine Notch1 and Notch3 in transgenic mice blocks mammary gland development and induces mammary tumors

The mouse mammary tumor virus (MMTV) provirus was found to target the Notch1 gene, producing insertional mutations in mammary tumors of MMTV/neu transgenic (Tg) mice. In these mammary tumors, the Notch1 gene is truncated upstream of the transmembrane domain, and the resulting Notch1 intracellular domain (Notch1(intra)), deleted of most extracellular sequences, is overexpressed. Although Notch1(intra) transforms mammary epithelial cells in vitro, its role in mammary gland tumor formation in vivo was not studied. Therefore, we generated MMTV/Notch1(intra) Tg mice that overexpress murine Notch1(intra) in the mammary glands. We observed that MMTV/Notch1(intra) Tg females were unable to feed their pups because of impaired ductal and lobulo-alveolar mammary gland development. This was associated with decreased proliferation of ductal and alveolar epithelial cells during rapid expansion at puberty and in early pregnancy, as well as decreased production of beta-casein. Notch1(intra) repressed expression of the beta-casein gene promoter, as assessed in vitro with a beta-casein/luciferase reporter construct. The MMTV/Notch1(intra) Tg females developed mammary gland tumors, confirming the oncogenic potential of Notch1(intra) in vivo. Furthermore, MMTV/Notch3(intra) Tg mice exhibited a very similar phenotype. Thus, these Tg mice represent novel models for studying the role of Notch1 or Notch3 in the development and transformation of the mammary gland.     

RHBDD2: a 5-fluorouracil responsive gene overexpressed in the advanced stages of colorectal cancer

In previous studies, we identified rhomboid domain containing 2 (RHBDD2) gene to be markedly overexpressed in breast cancer patients that developed recurrence of the disease. In this study, we evaluated for the first time RHBDD2 gene expression in colorectal cancer (CRC). Five public available DNA microarray studies were compiled in a homogeneous dataset of 906 colorectal samples. The statistical analysis of these data showed a significant increase of RHBDD2 expression in the advanced stages of CRC (p?<?0.01). We validated these findings by immunohistochemistry on 130 colorectal tissue samples; RHBDD2 protein overexpression was also observed in the advanced stages of the disease (p?<?0.001). In addition, we investigated RHBDD2 expression in response to the chemotherapy agent 5-fluorouracile (5FU). We detected a significant increase of RHBDD2 mRNA and protein after 5FU treatment (20?C40???M; p?<?0.001). Overall, these results showed that RHBDD2 overexpression might play a role in colorectal cancer progression.     

Estudio observacional,transversal, de una muestra representativa de las mujeres españolas en edad fértil,sobre los cuidados,hábitos y promoción de la salud previamente y durante el embarazo: Estudio GESTMUJER

Objective

To identify the use of folic acid and other vitamins in Spanish women of fertile age before and during pregnancy.

Material and method

A representative survey of 1020 Spanish women aged 15 to 49 years was carried out in March 2013.

Results

Only one quarter of Spanish women planned their pregnancies and,as a result, only 28.6% of women took folic acid before becoming pregnant.

Conclusions

There is a lack of information about the role and importance of folic acid to prevent neural tube defects. Institutional campaigns are needed to promote both pregnancy planningand the use of vitamin supplements before and during pregnancy.     

A multifaceted intervention to increase prophylactic oxytocin use during the third stage of labor and to reduce routine episiotomies in Nicaragua

Objective

To assess the effect of a multifaceted intervention among skilled birth attendants on the use of oxytocin during the third stage of labor, the active management of the third stage of labor (AMTSL), and the rate of routine episiotomy during vaginal births in two health districts in Nicaragua.

Methods

An uncontrolled before-and-after study design was used. The rates of oxytocin use in the third stage of labor, AMTSL, and episiotomy were measured for vaginal births occurring in eight hospitals and health centers during 2011–2012, before and after implementation of a multifaceted facility-based intervention. The intervention involved the use of opinion leaders, interactive workshops to develop and implement evidence-based guidelines, academic detailing, the use of reminders, and feedback on the rates of oxytocin use and episiotomy.

Results

Oxytocin use during the third stage of labor increased significantly from 95.3% to 97.4% (P = 0.003). The episiotomy rate dropped significantly from 31.2% to 21.2% overall, and from 59.6% to 40.5% in primiparous women (P < 0.001 for both comparisons).

Conclusion

The multifaceted intervention improved the targeted care practices during childbirth. However, a further decrease in the routine use of episiotomy would be desirable.