Primary Dislocation of the Patella : A Clinical Study

A total of 177 patients with primary dislocation of the patella (PDP) were admitted to two trauma centers in Helsinki, Finland during 1991 to 1992. The inclusion criteria were: 1. Acute (≤14 days old) first-time lateral dislocation of the patella. 2. No previous knee operations or major knee injuries. 3. No ligament injuries to be repaired. 4. No osteochondral fractures requiring fixation. 50 patients were excluded. 30 of these excluded patients would have met the inclusion criteria, 19 patients received treatment by consultants not involved in the study, 7 refused to participate and 4 had an erroneous randomization. 127 patients including, 82 females, were then randomized to have either tailor-made operative procedure (group O) or conservative treatment (group C). The aftercare was similar for both groups. The mean age of the patients was 20 (9-47) years. All patients were subjected to analysis of trauma history (starting position and knee movement during the dislocation), examination under anesthesia (EUA) and arthroscopy. 70 patients (52 females) were randomized by their odd year of birth to operative group O and 57 patients (30 females) by their even year of birth to conservative group C. The diagnosis of PDP was based on locked dislocation in 68 patients, on dislocatability in EUA in 47 patients, and on subluxation in EUA combined with typical intra-articular lesions in 12 patients. In group O, 63 patients had exploration of the injuries on the medial side of the knee and tailor made reconstruction added with lateral release in 54 cases. The medial injury was operated by suturing in 39 patients, by duplication in 18 patients and by additional augmentation of the medial patellofemoral ligament (MPFL) with adductor magnus tenodesis in 6 patients. 7 patients, without locking in trauma history and only subluxation in EUA had only lateral release for realignment. In adductor magnus tenodesis the proximal end of the distal tendinous part was rerouted to the upper medial border of the patella. In the conservative group C, the treatment was adjusted to the extent of patellar displacement in EUA. Patients with dislocation in EUA had 3 weeks’ immobilization with the knee in slight flexion. Mobilization was started with a soft patellar stabilizing orthosis (PSO) used for additional three weeks. The patients with subluxation in EUA wore an orthosis for six weeks. The aftercare was similar in group O. The outcome was similar in both groups. After an average of 25 (20-45) months´ follow-up, the subjective result was better in group C in respect of the mean Hughston VAS knee score (87 for group O and 90 for group C, p=0.04, visual analog scale), but similar in terms of the patient’s own overall opinion and the mean Lysholm II knee score. Recurrent instability episodes occurred in 18 patients in group O and in 20 patients in group C. After an average of 7 (6-9) years´ follow-up, the groups did not show statistical difference either in respect of the patient’s own overall opinion, or the mean Hughston VAS and Kujala knee scores. The proportions of stable patellae was 25/70 (36%) in group O and 17/57 (30%) in group O (p=0.5). In a multivariate risk analysis, there was a correlation between low Kujala score (<90) as dependent parameter and female gender (OR: 3.5; 95% CI: 1.4-9.0), and loose body on primary radiographs (OR: 4.1; 95% CI: 1.2-15). Recurrent instability correlated with young age at the time of PDP (OR: 0.9; 95% CI: 0.8-1.0/year). Girls with open tibial apophysis had the worst prognosis for instability (88%; 95% CI: 77-98). The most common mechanisms in trauma history of the patients were movement to flexion from a straight start (78%) and movement to extension from a well-bent start (8%). Spontaneous relocation of the patella had taken place in 13/39 of girls, in 11/21 of boys, in 26/42 of women and in 17/24 of men with skeletal maturity of the tibia. The dislocation in EUA was non-rotating in 96/126 patients followed by outward rotating dislocation in 14/126 patients. Operative treatment policy in PDP is not recommended. Locking tendency of the patella in PDP depended on the skeletal maturation. Recurrence rate after PDP was higher than expected.

Pharmacogenetics of SLCO1B1: Population genetics and effect on statins

Kohonneiden kolesterolipitoisuuksien alentamisessa käytettävien statiinien hyödyt sydän- ja verisuonisairauksien estossa on vahvasti osoitettu ja niiden käyttö on niin Suomessa kuin muuallakin maailmassa kasvanut voimakkaasti – Suomessa statiininkäyttäjiä on noin 600 000. Statiinilääkitys on pitkäaikaisessakin käytössä melko hyvin siedetty, mutta yleisimpinä haittavaikutuksina voi ilmetä lihasheikkoutta, -kipua ja -kramppeja, jotka voivat edetä jopa henkeä uhkaavaksi lihasvaurioksi. Lihashaittariski suurenee suhteessa statiiniannokseen ja plasman statiinipitoisuuksiin. Statiinien plasmapitoisuuksissa, tehossa ja haittavaikutusten ilmenemisessä on suuria potilaskohtaisia eroja. SLCO1B1-geenin koodaama OATP1B1-kuljetusproteiini kuljettaa monia elimistön omia aineita ja lääkeaineita verenkierrosta solukalvon läpi maksasoluun, mm. statiineja, joiden kolesterolia alentava vaikutus ja poistuminen elimistöstä tapahtuvat pääosin maksassa. Erään SLCO1B1-geenin nukleotidimuutoksen (c.521T>C) tiedetään heikentävän OATP1B1:n kuljetustehoa. Tässä väitöskirjatyössä selvitettiin SLCO1B1-geenin perinnöllistä muuntelua suomalaisilla ja eri väestöissä maailmanlaajuisesti. Lisäksi selvitettiin SLCO1B1:n muunnosten vaikutusta eri statiinien pitoisuuksiin (farmakokinetiikka) ja vaikutuksiin (farmakodynamiikka) sekä kolesteroliaineenvaihduntaan. Näihin tutkimuksiin valittiin SLCO1B1-genotyypin perusteella terveitä vapaaehtoisia koehenkilöitä, joille annettiin eri päivinä kerta-annos kutakin tutkittavaa statiinia: fluvastatiinia, pravastatiinia, simvastatiinia, rosuvastatiinia ja atorvastatiinia. Verinäytteistä määritettiin plasman statiinien ja niiden aineenvaihduntatuotteiden sekä kolesterolin ja sen muodostumista ja imeytymistä kuvaavien merkkiaineiden pitoisuuksia. Toiminnallisesti merkittävien SLCO1B1-geenimuunnosten esiintyvyydessä todettiin suuria eroja eri väestöjen välillä. Suomalaisilla SLCO1B1 c.521TC-genotyypin (geenimuunnos toisessa vastinkromosomissa) esiintyvyys oli noin 32 % ja SLCO1B1 c.521CC-genotyypin (geenimuunnos molemmissa vastinkromosomeissa) esiintyvyys noin 4 %. Globaalisti geenimuunnosten esiintyvyys korreloi maapallon leveyspiirien kanssa siten, että matalaan transportteriaktiivisuuteen johtavat muunnokset olivat yleisimpiä pohjoisessa ja korkeaan aktiivisuuteen johtavat päiväntasaajan lähellä asuvilla väestöillä. SLCO1B1-genotyypillä oli merkittävä vaikutus statiinien plasmapitoisuksiin lukuun ottamatta fluvastatiinia. Simvastatiinihapon plasmapitoisuudet olivat keskimäärin 220 %, atorvastatiinin 140 %, pravastatiinin 90 % ja rosuvastatiinin 70 % suuremmat c.521CC-genotyypin omaavilla koehenkilöillä verrattuna normaalin c.521TT-genotyypin omaaviin. Genotyypillä ei ollut merkittävää vaikutusta minkään statiinin tehoon tässä kerta-annostutkimuksessa, mutta geenimuunnoksen kantajilla perustason kolesterolisynteesinopeus oli suurempi. Tulokset osoittavat, että SLCO1B1 c.521T>C geenimuunnos on varsin yleinen suomalaisilla ja muilla ei-afrikkalaisilla väestöillä. Tämä geenimuunnos voi altistaa erityisesti simvastatiinin, mutta myös atorvastatiinin, pravastatiinin ja rosuvastatiinin, aiheuttamille lihashaitoille suurentamalla niiden plasmapitoisuuksia. SLCO1B1:n geenimuunnoksen testaamista voidaan tulevaisuudessa käyttää apuna valittaessa sopivaa statiinilääkitystä ja -annosta potilaalle, ja näin parantaa sekä statiinihoidon turvallisuutta että tehoa.

Relationship between annual rainfall and tree mortality in a tropical dry forest: Results of a 19-year study at Mudumalai, southern India

Variability in rainfall is known to be a major influence on the dynamics of tropical forests, especially rates and patterns of tree mortality. In tropical dry forests a number of contributing factors to tree mortality, including dry season fire and herbivory by large herbivorous mammals, could be related to rainfall patterns, while loss of water potential in trees during the dry season or a wet season drought could also result in enhanced rates of death. While tree mortality as influenced by severe drought has been examined in tropical wet forests there is insufficient understanding of this process in tropical dry forests. We examined these causal factors in relation to inter-annual differences in rainfall in causing tree mortality within a 50-ha Forest Dynamics Plot located in the tropical dry deciduous forests of Mudumalai, southern India, that has been monitored annually since 1988. Over a 19-year period (1988-2007) mean annual mortality rate of all stems >1 cm dbh was 6.9 +/- 4.6% (range = 1.5-17.5%); mortality rates broadly declined from the smaller to the larger size classes with the rates in stems >30 cm dbh being among the lowest recorded in tropical forest globally. Fire was the main agent of mortality in stems 1-5 cm dbh, elephant-herbivory in stems 5-10 cm dbh, and other natural causes in stems > 10 cm dbh. Elephant-related mortality did not show any relationship to rainfall. On the other hand, fire-related mortality was significantly negatively correlated to quantity of rainfall during the preceding year. Mortality due to other causes in the larger stem sizes was significantly negatively correlated to rainfall with a 2-3-year lag, suggesting that water deficit from mild or prolonged drought enhanced the risk of death but only with a time lag that was greater than similar lags in tree mortality observed in other forest types. In this respect, tropical dry forests growing in regions of high rainfall variability may have evolved greater resistance to rainfall deficit as compared to tropical moist or temperate forests but are still vulnerable to drought-related mortality.

Heat-shock protein 70-2 (HSP70-2) expression in bladder urothelial carcinoma is associated with tumour progression and promotes migration and invasion

Purpose: Testis specific heat-shock protein 70-2 (HSP70-2), a member of HSP70 chaperone family, is essential for the growth of spermatocytes and cancer cells. We investigated the association of HSP70-2 expression with clinical behaviour and progression of urothelial carcinoma of bladder. Experimental design: We assessed the HSP70-2 expression by RT-PCR and HSP70-2 protein expression by immunofluorescence, flow cytometry, immunohistochemistry and Western blotting in urothelial carcinoma patient specimens and HTB-1, UMUC-3, HTB-9, HTB-2 and normal human urothelial cell lines. Further, to investigate the role of HSP70-2 in bladder tumour development, HSP70-2 was silenced in the high-grade invasive HTB-1 and UMUC-3 cells. The malignant properties of urothelial carcinoma cells were examined using colony formation, migration assay, invasion assay in vitro and tumour growth in vivo. Results: Our RT-PCR analysis and immunohistochemistry analysis revealed that HSP70-2 was expressed in both moderate to well-differentiated and high-grade invasive urothelial carcinoma cell lines studied and not in normal human urothelial cells. In consistence with these results, HSP70-2 expression was also observed in superficially invasive (70%) and muscle-invasive (90%) patient's tumours. Furthermore, HSP70-2 knockdown significantly suppressed cellular motility and invasion ability. An in vivo xenograft study showed that inhibition of HSP70-2 significantly suppressed tumour growth. Conclusions: In conclusion, our data suggest that the HSP70-2 expression is associated with early spread and progression of urothelial carcinoma of bladder cancer and that HSP70-2 can be the potential therapeutic target for bladder urothelial carcinoma. (C) 2009 Elsevier Ltd. All rights reserved.

Vitamin E may affect the life expectancy of men, depending on dietary vitamin C intake and smoking

Background: Antioxidants might protect against oxidative stress, which has been suggested as a cause of aging. Methods: The ATBC Study recruited males aged 50-69 years who smoked at least 5 cigarettes per day at the baseline. The current study was restricted to participants who were followed up past the age of 65. Deaths were identified in the National Death Registry (1445 deaths). We constructed Kaplan-Meier survival curves for all participants, and for four subgroups defined by dietary vitamin C intake and level of smoking. We also constructed Cox regression models allowing a different vitamin E effect for low and high age ranges. Results: Among all 10,837 participants, vitamin E had no effect on those who were 65 to 70 years old, but reduced mortality by 24% when participants were 71 or older. Among 2284 men with dietary vitamin C intakes above the median who smoked less than a pack of cigarettes per day, vitamin E extended life-span by two years at the upper limit of the follow-up age span. In this subgroup, the survival curves of vitamin E and no-vitamin E participants diverged at 71 years. In the other three subgroups covering 80% of the participants, vitamin E did not affect mortality. Conclusions: This is the first study to strongly indicate that protection against oxidative stress can increase the life expectancy of some initially healthy population groups. Nevertheless, the lack of effect in 80% of this male cohort shows that vitamin E is no panacea for extending life expectancy.

The Proto-Lucianic Problem in 1 Samuel

The Lucianic text of the Septuagint of the Historical Books witnessed primarily by the manuscript group L (19, 82, 93, 108, and 127) consists of at least two strata: the recensional elements, which date back to about 300 C.E., and the substratum under these recensional elements, the proto-Lucianic text. Some distinctive readings in L seem to be supported by witnesses that antedate the supposed time of the recension. These witnesses include the biblical quotations of Josephus, Hippolytus, Irenaeus, Tertullian, and Cyprian, and the Old Latin translation of the Septuagint. It has also been posited that some Lucianic readings might go back to Hebrew readings that are not found in the Masoretic text but appear in the Qumran biblical texts. This phenomenon constitutes the proto-Lucianic problem. In chapter 1 the proto-Lucianic problem and its research history are introduced. Josephus references to 1 Samuel are analyzed in chapter 2. His agreements with L are few and are mostly only apparent or, at best, coincidental. In chapters 3 6 the quotations by four early Church Fathers are analyzed. Hippolytus Septuagint text is extremely hard to establish since his quotations from 1 Samuel have only been preserved in Armenian and Georgian translations. Most of the suggested agreements between Hippolytus and L are only apparent or coincidental. Irenaeus is the most trustworthy textual witness of the four early Church Fathers. His quotations from 1 Samuel agree with L several times against codex Vaticanus (B) and all or most of the other witnesses in preserving the original text. Tertullian and Cyprian agree with L in attesting some Hebraizing approximations that do not seem to be of Hexaplaric origin. The question is more likely of early Hebraizing readings of the same tradition as the kaige recension. In chapter 7 it is noted that Origen, although a pre-Lucianic Father, does not qualify as a proto-Lucianic witness. General observations about the Old Latin witnesses as well as an analysis of the manuscript La115 are given in chapter 8. In chapter 9 the theory of the proto-Lucianic recension is discussed. In order to demonstrate the existence of the proto-Lucianic recension one should find instances of indisputable agreement between the Qumran biblical manuscripts and L in readings that are secondary in Greek. No such case can be found in the Qumran material in 1 Samuel. In the text-historical conclusions (chapter 10) it is noted that of all the suggested proto-Lucianic agreements in 1 Samuel (about 75 plus 70 in La115) more than half are only apparent or, at best, coincidental. Of the indisputable agreements, however, 26 are agreements in the original reading. In about 20 instances the agreement is in a secondary reading. These agreements are early variants; mostly minor changes that happen all the time in the course of transmission. Four of the agreements, however, are in a pre-Hexaplaric Hebraizing approximation that has found its way independently into the pre-Lucianic witnesses and the Lucianic recension. The study aims at demonstrating the value of the Lucianic text as a textual witness: under the recensional layer(s) there is an ancient text that preserves very old, even original readings which have not been preserved in B and most of the other witnesses. The study also confirms the value of the early Church Fathers as textual witnesses.

Boundary regularity of correspondences in C-n

Let M, M' be smooth, real analytic hypersurfaces of finite type in C-n and f a holomorphic correspondence (not necessarily proper) that is defined on one side of M, extends continuously up to M and maps M to M-t. It is shown that f must extend across M as a locally proper holonnorphic correspondence. This is a version for correspondences of the Diederich-Pinchuk extension result for CR maps.

Crystal structure of the charge-transfer complex promethazine picrate

Promethazine picrate (C23H23N5O7S) crystallises in the triclinic space group P[unk] with a = 8.137(1), b = 8.144(3), c = 19.224(6) Å, α = 87.78(3), β = 79.97(2), γ = 70.57(2)° and two molecules per unit cell. The structure was solved by direct methods (MULTAN 80) using 2438 observed reflections [I > 2.5 σ(I)]. Refinement was carried out by block-diagonal least-squares methods to a final R = 0.052. The picrate group is planar and is almost perpendicular to the promethazine plane. The two groups are joined by a hydrogen bond. The pairs of molecules related by a centre of symmetry make a molecular arrangement where promethazine and picrate groups are packed in sheets in three dimensions.

Protein Kinase C and Anaplastic Lymphoma Kinase Targeted Compounds

The protein kinases (PKs) belong to the largest single family of enzymes, phosphotransferases, which catalyze the phosphorylation of other enzymes and proteins and function primarily in signal transduction. Consequently, PKs regulate cell mechanisms such as growth, differentiation, and proliferation. Dysfunction of these cellular mechanisms may lead to cancer, a major predicament in health care. Even though there is a range of clinically available cancer-fighting drugs, increasing number of cancer cases and setbacks such as drug resistance, constantly keep cancer research active. At the commencement of this study an isophthalic acid derivative had been suggested to bind to the regulatory domain of protein kinase C (PKC). In order to investigate the biological effects and structure-activity relationships (SARs) of this new chemical entity, a library of compounds was synthesized. The best compounds induced apoptosis in human leukemia HL-60 cells and were not cytotoxic in Swiss 3T3 fibroblasts. In addition, the best apoptosis inducers were neither cytotoxic nor mutagenic. Furthermore, results from binding affinity assays of PKC isoforms revealed the pharmacophores of these isophthalic acid derivatives. The best inhibition constants of the tested compounds were measured to 210 nM for PKCα and to 530 nM for PKCδ. Among natural compounds targeting the regulatory domain of PKC, the target of bistramide A has been a matter of debate. It was initially found to activate PKCδ; however, actin was recently reported as the main target. In order to clarify and to further study the biological effects of bistramide A, the total syntheses of the natural compound and two isomers were performed. Biological assays of the compounds revealed accumulation of 4n polyploid cells as the primary mode of action and the compounds showed similar overall antiproliferative activities. However, each compound showed a distinct distribution of antimitotic effect presumably via actin binding, proapoptotic effect presumably via PKCδ, and pro-differentiation effect as evidenced by CD11b expression. Furthermore, it was shown that the antimitotic and proapoptotic effects of bistramide A were not secondary effects of actin binding but independent effects. The third aim in this study was to synthesize a library of a new class of urea-based type II inhibitors targeted at the kinase domain of anaplastic lymphoma kinase (ALK). The best compounds in this library showed IC50 values as low as 390 nM for ALK while the initial low cellular activities were successfully increased even by more than 70 times for NPM-ALK- positive BaF3 cells. More importantly, selective antiproliferative activity on ALK-positive cell lines was achieved; while the best compound affected the BaF3 and SU-DHL-1 cells with IC50 values of 0.5 and 0.8 μM, respectively, they were less toxic to the NPM-ALK-negative human leukemic cells U937 (IC50 = 3.2 μM) and BaF3 parental cells (IC50 = 5.4 μM). Furthermore, SAR studies of the synthesized compounds revealed functional groups and positions of the scaffold, which enhanced the enzymatic and cellular activities.

Campylobacter jejuni and C. coli in Finnish poultry production

Campylobacter, mainly Campylobacter jejuni and C. coli, are worldwide recognized as a major cause of bacterial food-borne gastroenteritis. Epidemiological studies have shown handling or eating of poultry to be significant risk factors for human infections. Campylobacter contamination can occur at all stages of a poultry meat production cycle. The aim of this thesis was to study the occurrence and diversity of Campylobacter in broiler and turkey production in Finland. In summer 1999, 2.9 % of slaughtered broiler flocks were Campylobacter-positive. From the isolated strains 94 % were C. jejuni and 6% were C. coli. During years 2005-2006 one turkey parent flock, the hatchery, six different commercial turkey farms and different stages of the slaughterhouse were monitored during one and the half year. No Campylobacter were detected in either of the samples from the turkey parent flock or from the hatchery using the culture method. Instead PCR detected DNA of Campylobacter from the turkey parent flock and samples from the hatchery. Six out of 12 commercial turkey flocks were found negative at the farm level but only two of those were negative at slaughter. Campylobacter-positive samples within the flock at slaughter were detected between 0% and 94% with evisceration and chilling water being the most critical stages for contamination. All of Campylobacter isolates were shown to be C. jejuni. Campylobacter-positive turkey flocks were colonized by a limited number of Campylobacter genotypes both at the farm and slaughter level. In conclusion, in our first study in 1999 a low prevalence of Campylobacter in Finnish broiler flocks was detected and it has remained at a low level during the study period until the present. In the turkey meat production, we found that flocks which were negative at the farm became contaminated with Campylobacter at the slaughter process. These results suggest that proper and efficient cleaning and disinfection of slaughter and processing premises are needed to avoid cross-contamination. Prevention of colonization at the farm by a high level of biosecurity control and hygiene may be one of the most efficient ways to reduce the amount of Campylobacter-positive poultry meat in Finland. With a persistent low level of Campylobacter-positive flocks, it could be speculated that the use of logistic slaughtering, according to Campylobacter status at farm, might have be advantageous in reducing Campylobacter contamination of retail poultry products. However, the significance of the domestic poultry meat for human campylobacteriosis in Finland should be evaluated.

Treatment of illicit opioid and γ-hydroxybutyrate overdose by Helsinki emergency medical services

Aims: To examine the characteristics, incidence, treatment and outcome of presumed opioid, γ-hydroxybutyrate (GHB) and γ-butyrolactone (GBL) overdoses involving users of illicit drugs in Helsinki. GHB/GBL were included in this study, despite not being opioids, due to the relative ease with which they can cause potentially fatal respiratory depression. The incidence and time interval of recurrent opioid toxicity after prehospital administration of naloxone, an opioid antagonist, was studied in presumed heroin overdose patients. Naloxone has been reported to have many adverse effects and the effects of naloxone administered during an opioid overdose on the cardiovascular system and catecholamine levels in piglets were studied. Materials and methods: Patients included in these published retrospective studies were from the following time periods: Study I: 1995-2002, II: 1997-2000, III: 1995-2000, V: 2006-2007. Presumed opioid overdose patients were examined in studies I, II and III. GHB/GBL overdoses among injecting drug users was examined in study V. Recurrent opioid toxicity after prehospital naloxone administration in heroin overdose patients was examined in study III. The effects of naloxone (80 μg/kg i.v.) on the cardiovascular system and catecholamine levels administered during morphine overdose (8mg/kg i.v.) and under propofol anesthesia with spontaneous breathing were studied in eight piglets (IV). In this thesis, previously unpublished data on the incidence of opioid overdose between 2001-2007 and comparison of the characteristics of buprenorphine and heroin overdose patients encountered in 1995-2005 are also included. Results: Helsinki Emergency Medical Service (EMS) ambulances were dispatched annually to 34,153- 45,118 calls from 1995 to 2007. Of them, 7-8% were coded as intoxications or overdoses. During this time, 436 patients were treated by the EMS for presumed opioid overdose. The peak incidence of opioid overdoses was in the year 2000 (113 cases), after which they declined to 6-26 cases annually. The annual incidence of buprenorphine related overdoses increased from 4 (4% of opioid overdoses) in the year 2000 to 8 (30% of opioid overdoses) in 2007. The annual number of GHB related overdose patients treated by Helsinki EMS increased from 21 to 73 between 2004-2007. There appeared to be a peak in the incidence of both GHB/GBL and opioid related overdoses on Saturdays. Characteristics of opioid overdose patients The median age of opioid overdose patients was 28 years (22;33, 25- and 75-percentiles), and 84% were male. Buprenorphine overdose patients had more polydrug, such as alcohol and/or benzodiazepines, use in comparison with heroin overdose patients, 70% versus 33%, respectively. Severe respiratory depression was reported less often with buprenorphine overdoses compared to heroin overdoses, in 67.0% versus 85.4%, respectively. Outcome of heroin overdose patients with cardiac arrest Ninety four patients suffered cardiac arrest due to acute drug poisoning/overdose and were thus considered for resuscitation. Resuscitation was attempted in 72 cases. Cardiac arrest was caused by heroin overdose for 19 patients of which three (16%) were discharged alive. Other agents also induced cardiac arrest in 53 patients, of which six (11%) were discharged alive. The arrest was either EMS witnessed or occurring after the emergency call for all survivors of heroin induced cardiac arrest. Characteristics of GHB/GBL overdose patients The records of 100 GHB/GBL related overdose patients from 2006-2007 were retrieved. The median age of GHB/GBL overdose patients encountered on weekend nights was 24 years (22;27, 25- and 75-percentiles) and 49% were male. Polydrug use was reported in 62-80% of the cases. Thirty nine patients were encountered on Friday-Saturday or Saturday-Sunday night between 11 pm-6 am. The remaining sixty one patients were outside this time frame. There was a statistically significant difference between these two groups in history of chronic injecting drug use (33% vs. 59%, respectively, p=0.012). Recurrent heroin toxicity after prehospital naloxone administration Study III included 145 presumed heroin overdose patients. After prehospital care, 84 patients refused further care and were not transported to an Emergency Department (ED). Seventy one (85%) of them were administered naloxone by the EMS. During a 12-h follow up period, none of these patients developed severe recurrent opioid toxicity. The remaining 61 patients were transported to an ED. Prior to transportation, 52 (85%) patients were administered naloxone by the EMS. Fifteen of them were administered naloxone also in the ED and recurrent opioid toxicity was evident either on arrival at the ED or shortly thereafter. Prehospital naloxone was administered either intravenously, intramuscularly (i.m.) or subcutaneously (s.c.). There was a tendency for more frequent recurrent heroin toxicity among the patients with only intravenous administration of prehospital naloxone (13/36) compared with the patients with intramuscular or subcutaneous prehospital naloxone (2/16), p=0.106. The effects of naloxone on the cardiovascular system and catecholamine levels in piglets The administration of morphine to piglets resulted in an obvious respiratory depression, which was reversed by naloxone. Two severely hypoxemic piglets developed cardiac arrest after naloxone administration. In the other six animals, the administration of naloxone did not provoke arrhythmias, cardiac ischemia or visible evidence of pulmonary edema. There was a statistically significant (p=0.012) increase in norepinephrine levels after morphine administration and before naloxone administration: from 1.9 (1.3-2.3) ng/ml at baseline, to 31.7 (8.3-83.0) ng/ml (median, 25 and 75 percentiles parentheses) after morphine administration. After the administration of naloxone, the catecholamine levels continued to increase in only one of the animals. Conclusions: The incidence of buprenorphine related overdoses increased during the study period, but was still lower in comparison to those involving heroin. Injecting drug users have also started to use GHB/GBL. While recreational drug users use GHB/GBL during weekend nights, a GHB/GBL overdose patient encounter during weekdays has a more probable history of injecting drug use. Patients with cardiac arrest after heroin overdose have a poor prognosis. It appears to be safe to leave heroin overdose patients on scene after prehospital treatment with naloxone. Although no statistically significant difference was observed, it seems prudent to administer part of the total naloxone dose s.c. or i.m. to reduce the risk of recurrent respiratory depression. If transported to an ED, an observation period of one to two hours after the last naloxone dose seems adequate. The treating physician must be vigilant, however, due to the high prevalence of polydrug use and high morbidity after non fatal heroin overdose. Furthermore, care should be taken regarding possible chronic disorders and drug rehabilitation should be addressed. In the experimental animal study, two animals developed cardiac arrest after receiving naloxone while in hypoxemia and bradycardia. Further studies are required to assess the effect of naloxone during opioid-induced hypercapnia and hypoxemia in animals addicted to opioids.

HDL subspecies : association with low HDL-C, obesity, and metabolic syndrome

AIMS An independent, powerful coronary heart disease (CHD) predictor is a low level of high-density lipoprotein cholesterol (HDL-C). Discoidal preβ-HDL particles and large HDL2 particles are the primary cholesterol acceptors in reverse cholesterol transport, a key anti-atherogenic HDL mechanism. The quality of HDL subspecies may provide better markers of HDL functionality than does HDL-C alone. We aimed I) to study whether alterations in the HDL subspecies profile exist in low-HDL-C subjects II) to explore the relationship of any changes in HDL subspecies profile in relation to atherosclerosis and metabolic syndrome; III) to elucidate the impact of genetics and acquired obesity on HDL subspecies distribution. SUBJECTS The study consisted of 3 cohorts: A) Finnish families with low HDL-C and premature CHD (Study I: 67 subjects with familial low HDL-C and 64 controls; Study II: 83 subjects with familial low HDL-C, 65 family members with normal HDL-C, and 133 controls); B) a cohort of 113 low- and 133 high-HDL-C subjects from the Health 2000 Health Examination Survey carried out in Finland (Study III); and C) a Finnish cohort of healthy young adult twins (52 monozygotic and 89 dizygotic pairs) (Study IV). RESULTS AND CONCLUSIONS The subjects with familial low HDL-C had a lower preβ-HDL concentration than did controls, and the low-HDL-C subjects displayed a dramatic reduction (50-70%) in the proportion of large HDL2b particles. The subjects with familial low HDL-C had increased carotid atherosclerosis measured as intima-media-thickness (IMT), and HDL2b particles correlated negatively with IMT. The reduction in both key cholesterol acceptors, preβ-HDL and HDL2 particles, supports the concept of impaired reverse cholesterol transport contributing to the higher CHD risk in low-HDL-C subjects. The family members with normal HDL-C and the young adult twins with acquired obesity showed a reduction in large HDL2 particles and an increase in small HDL3 particles, which may be the first changes leading to the lowering of HDL-C. The low-HDL-C subjects had a higher serum apolipoprotein E (apoE) concentration, which correlated positively with the metabolic syndrome components (waist circumference, TG, and glucose), highlighting the need for a better understanding of apoE metabolism in human atherosclerosis. In the twin study, the increase in small HDL3b particles was associated with obesity independent of genetic effects. The heritability estimate, of 73% for HDL-C and 46 to 63% for HDL subspecies, however, demonstrated a strong genetic influence. These results suggest that the relationship between obesity and lipoproteins depends on different elements in each subject. Finally, instead of merely elevating HDL-C, large HDL2 particles and discoidal preβ-HDL particles may provide beneficial targets for HDL-targeted therapy.

Visualization of enantiomers and determination of homo- and hetero-nuclear residual dipolar and scalar couplings: The natural abundant C-13 edited J/D-resolved NMR techniques

The simple two dimensional C-13-satellite J/D-resolved experiments have been proposed for the visualization of enantiomers, extraction of homo- and hetero-nuclear residual dipolar couplings and also H-1 chemical shift differences between the enantiomers in the anisotropic medium. The significant advantages of the techniques are in the determination of scalar couplings of bigger organic molecules. The scalar couplings specific to a second abundant spin such as F-19 can be selectively extracted from the severely overlapped spectrum. The methodologies are demonstrated on a chiral molecule aligned in the chiral liquid crystal medium and two different organic molecules in the isotropic solutions. (C) 2010 Elsevier B.V. All rights reserved.

Role of neutral metabolites in microbial conversion of 3beta-acetoxy-19-hydroxycholest-5-ene into estrone

Biotransformation of 3 beta-acetoxy-19-hydroxycholest-5-ene (19-HCA, 6 g) by Moraxella sp. was studied. Estrone (712 mg) was the major metabolite formed. Minor metabolites identified were 5 alpha-androst-1-en-19-ol-3,17-dione (33 mg), androst-4-en-19-ol-3,17-dione (58 mg), androst-4-en-9 alpha,19-diol-3,17-dione (12 mg), and androstan-19-ol-3,17-dione (1 mg). Acidic metabolites were not formed. Time course experiments on the fermentation of 19-HCA indicated that androst-4-en-19-ol-3,17-dione was the major metabolite formed during the early stages of incubation. However with continuing fermentation its level dropped, with a concomitant increase in estrone. Fermentation of 19-HCA in the presence of specific inhibitors or performing the fermentation for a shorter period (48 h) did not result in the formation of acidic metabolites. Resting-cell experiments carried out with 19-HCA (200 mg) in the presence of alpha,alpha'-bipyridyl led to the isolation of three additional metabolites, viz., cholestan-19-ol-3-one (2 mg), cholest-4-en-19-ol-3-one (10 mg), and cholest-5-en-3 beta,19-diol (12 mg). Similar results were also obtained when n-propanol was used instead of alpha,alpha'-bipyridyl. Resting cells grown on 19-HCA readily converted both 5 alpha-androst-1-en-19-ol-3,17-dione and androst-4-en-19-ol-3,17-dione into estrone. Partially purified 1,2-dehydrogenase from steroid-induced Moraxella cells transformed androst-4-en-19-ol-3,17-dione into estrone and formaldehyde in the presence of phenazine methosulfate, an artificial electron acceptor. These results suggest that the degradation of the hydrocarbon side chain of 19-HCA does not proceed via C-22 phenolic acid intermediates and complete removal of the C-17 side chain takes place prior to the aromatization of the A ring in estrone. The mode of degradation of the sterol side chain appears to be through the fission of the C-17-C-20 bond. On the basis of these observations, a new pathway for the formation of estrone from 19-HCA in Moraxella sp. has been proposed.