Hemiarthroplasty for irreparable distal humeral fractures: medium-term follow-up of 42 patients.

We report our experience of performing an elbow hemiarthroplasty in the treatment of comminuted distal humeral fractures in the elderly patients. A cohort of 42 patients (three men and 39 women, mean age 72; 56 to 84) were reviewed at a mean of 34.3 months (24 to 61) after surgery. Functional outcome was measured with the Mayo Elbow Performance Score (MEPS) and range of movement. The disabilities of the arm, shoulder and hand questionnaire (DASH) was used as a patient rated evaluation. Complications and ulnar nerve function were recorded. Plain radiographs were obtained to assess prosthetic loosening, olecranon wear and heterotopic bone formation. The mean extension deficit was 23.5° (0° to 60°) and mean flexion was 126.8° (90° to 145°) giving a mean arc of 105.5° (60° to 145°). The mean MEPS was 90 (50 to 100) and a mean DASH score of 20 (0 to 63). Four patients had additional surgery for limited range of movement and one for partial instability. One elbow was revised due to loosening, two patients had sensory ulnar nerve symptoms, and radiographic signs of mild olecranon wear was noted in five patients. Elbow hemiarthroplasty for comminuted intra-articular distal humeral fractures produces reliable medium-term results with functional outcome and complication rates, comparable with open reduction and internal fixation and total elbow arthroplasty.

The novel tyrosine kinase inhibitor AKN-028 has significant antileukemic activity in cell lines and primary cultures of acute myeloid leukemia.

Aberrantly expressed tyrosine kinases have emerged as promising targets for drug development in acute myeloid leukemia (AML). We report that AKN-028, a novel tyrosine kinase inhibitor (TKI), is a potent FMS-like receptor tyrosine kinase 3 (FLT3) inhibitor (IC(50)=6 nM), causing dose-dependent inhibition of FLT3 autophosphorylation. Inhibition of KIT autophosphorylation was shown in a human megakaryoblastic leukemia cell line overexpressing KIT. In a panel of 17 cell lines, AKN-028 showed cytotoxic activity in all five AML cell lines included. AKN-028 triggered apoptosis in MV4-11 by activation of caspase 3. In primary AML samples (n=15), AKN-028 induced a clear dose-dependent cytotoxic response (mean IC(50) 1 µM). However, no correlation between antileukemic activity and FLT3 mutation status, or to the quantitative expression of FLT3, was observed. Combination studies showed synergistic activity when cytarabine or daunorubicin was added simultaneously or 24 h before AKN-028. In mice, AKN-028 demonstrated high oral bioavailability and antileukemic effect in primary AML and MV4-11 cells, with no major toxicity observed in the experiment. In conclusion, AKN-028 is a novel TKI with significant preclinical antileukemic activity in AML. Possible sequence-dependent synergy with standard AML drugs and good oral bioavailability has made it a candidate drug for clinical trials (ongoing).

Pore diameter of more than 100 microm is not requisite for bone ingrowth in rabbits.

The optimal pore size for bone ingrowth is claimed to be 100-400 microm. With the use of a highly standardized experimental model, the present study reevaluated whether a pore size of 100 microm is the threshold value for bone ingrowth into porous structures under non-load-bearing conditions. Titanium triangle-shaped plates 250 or 500 microm thick were perforated with the use of a laser in order to create standard-sized holes ( 50, 75, 100, and 125 microm) in multiple rows. The amount of bone ingrowth through the implant holes was studied in the cancellous bone of the distal rabbit femur. Twelve weeks after implantation, detailed analysis of bone ingrowth was performed with computerized image analysis of backscattered electron imaging techniques of scanning electron microscopy. The results showed that the amount of ingrown new bone was independent of the pore size and implant thickness. The median value for bone ingrowth varied between 64 and 78%. A striking feature was the formation of secondary osteonal structures even in the smallest holes. Based on these results, there is no threshold value for new bone ingrowth in pore sizes ranging from 50 to 125 microm under non-load-bearing conditions.

[Malpractice in connection with radius fractures must be reduced. Clear guidelines for treatment and follow-up are required]. / Antalet felbehandlingar av radiusfraktur måste minskas. Klara riktlinjer för behandling och uppföljning efterlyses.

PSR handles the vast majority of malpractice injuries in Sweden. PSR is a claims handling company which settles claims for malpractice on behalf of the insurance company owned by the Swedish county councils: the County Councils Mutual Insurance Company. A central issue in the law regulating patient injuries in Swedish health care is to define injuries that could have been avoided if a certain therapeutic/diagnostic procedure or a more appropriate method had been utilized. PSR arranged a multiprofessional conference regarding guidelines to decrease the number of malpractice injuries in the treatment of distal radius fractures. Among the most important issues defined were: To improve and standardize diagnostic imaging Patient information Early decision making in surgery and physical/occupational therapy A more well-defined indication for surgery, in which type of trauma, biological age and functional demands are considered in addition to radiographs Less stereotyped thinking in follow-up Controlled randomized trials.

Hand function in children with cerebral palsy after upper-limb tendon transfer and muscle release.

Thirty-two children with hand dysfunction due to cerebral palsy were examined before tendon transfer and muscle release, and 9 months postoperatively. All children improved their performance regardless of the degree of impaired hand function. The main advantage of surgery was a more functional position of the hand with increased wrist extension and forearm supination. There were also increased functionality of handgrips, grip strength, and dexterity. Impaired sensibility before surgery did not influence the outcome. Individual goals were set preoperatively. Individual functional goals outlined before surgery were met by most children. Children identified as having mild impairments gained new functional skills related to everyday activity (self-care and leisure), while children with severely impaired hand function demonstrated enhanced grasping ability, as well as a better cosmetic appearance.

Stimulation and inhibition of rat oocyte meiosis by forskolin.

The adenylate cyclase activator forskolin was used to study the role of cAMP for oocyte meiosis and follicular steroid secretion. Follicular and cumulus cAMP production was stimulated dose-dependently by forskolin, as was the follicular secretion of progesterone, testosterone and estradiol. Forskolin induced meiosis in follicle-enclosed oocytes with a maximal effect at 1 microM, with lower and higher concentrations being less effective. The spontaneous resumption of meiosis in isolated cumulus-enclosed oocytes was dose-dependently retarded by forskolin. Meiosis of cumulus-free oocytes was also retarded but only slightly. These data support the earlier hypothesis that a limited increase in follicular cAMP levels triggers meiosis, whereas sustained levels of cAMP in the oocyte itself prevent meiosis.

Effect of gonadotrophin releasing hormone upon the pattern of steroidogenesis in isolated preovulatory rat follicles.

The effects of GnRH and a potent GnRH analogue (D-Ala6-des-gly-NH2-GnRH-ethylamide) on steroidogenesis in isolated preovulatory follicles of PMSG-treated immature rats were examined in short-term incubations and compared to the effect of LH. Steroids were analyzed by RIA. GnRH stimulated the accumulation of pregnenolone (2-fold), progesterone (4-fold), 20 alpha-OH-progesterone (38-fold), androstenedione (4-fold), testosterone (3-fold), and oestradiol-17 beta (2-fold) during a 6 h incubation. The time-course of stimulation was the same for each of the steroids analyzed, with a significant effect at 4 and 6 h, but not at 2 h of incubation. Dose-response curves were similar for each steroid, and the GnRH analogue and GnRH gave parallel curves with minimal effective concentrations being 1 and 10 ng/ml, respectively. The stimulatory effect of LH was more pronounced and rapid (2 h) than that of GnRH. During prolonged incubation (6-8 h) with GnRH or LH there was evidence for an inhibition of testosterone production, probably due to suppression of the C21-side chain cleavage enzyme. Thus, the qualitative response to GnRH on follicular steroidogenesis resembled that of LH in some but not all respects. The differences in time-course and maximal steroid secretion between GnRH and LH are compatible with different mechanisms of action in the follicle.

Effect of a GnRH analogue on rat granulosa cell lactate production in vitro.

The effect of a GnRH analogue [D-Ala6, des-Gly10-NH2)-GnRH-ethylamide,GnRHa) on granulosa and cumulus cell glycolysis in presence or absence of FSH was studied. Cumulus complexes and granulosa cells from PMSG-treated rats were cultured in Eagle's minimal essential medium (MEM) for a period of 72 h. Media were changed at 24 and 48 h and lactate content was assayed by fluorimetry. GnRHa alone stimulated lactate production in granulosa cells. GnRH combined with FSH increased lactate production in granulosa cells during the 0-24 h period and decreased it during the 48-72 h period as compared to FSH alone. GnRHa did not stimulate lactate production in cumulus complexes during 72 h culture in MEM, while FSH did. In a less complex culture medium, BMOC, GnRHa caused a small increase in lactate production and slightly enhanced the FSH effect. In conclusion, GnRHa has a direct stimulatory effect on granulosa cell glycolysis. GnRHa also modulates the FSH stimulation of granulosa cells biphasically, i.e. early enhancement (0-24 h) and late inhibition (48-72 h). GnRHa has no consistent direct effects on cumulus cell glycolysis.

Dose-related effects of luteinizing hormone on the pattern of steroidogenesis and cyclic adenosine monophosphate release in superfused preovulatory rat follicles.

The secretion of steroids and the release of cAMP in response to repeated luteinizing hormone (LH) stimulation were examined during superfusion of isolated preovulatory rat follicles. A high dose of ovine LH (1 microgram/ml for 20 min) caused a prolonged increase in the secretion of progesterone (P) and 20 alpha-dihydroprogesterone (20 alpha-OHP) and a transient increase in the secretion of testosterone (T) and estradiol-17 beta (E2), and was accompanied by a peak of cAMP release. A single pulse of LH at a low dose level (10 mg/ml for 20 min) gave a limited increase in T secretion, but no clear change in P, 20 alpha-OHP and E2 secretion or cAMP release. When the follicles were challenged with a second pulse of LH (at 1 microgram/ml), the response varied according to the dose of LH delivered in the preceding pulse. Following exposure to the high dose of LH, the follicles were partially refractory to the second LH challenge in terms of cAMP and P and the secretion of T and E2 remained low. The low dose of LH, however, had a conditioning effect on the follicles since the response to the second LH challenge was amplified in terms of P, 20 alpha-OHP and cAMP. In this case a secondary increase in T and E2 secretion was found. The differential response to varying doses of LH are likely to reflect the physiological control of steroidogenesis during final follicular maturation.

The acute effect of oestrogens on testosterone production appears not to be mediated by testicular oestrogen receptors.

Scatchard binding analysis was performed to measure the cytoplasmic oestrogen receptor in the testis of rats. After treatment of rats with the antioestrogen tamoxifen no oestrogen receptor binding was found in testicular low speed supernatant between 12 and 96 h after treatment. Such tamoxifen-treated rats were used to study the acute effect of oestrogens on testosterone secretion, both in vivo and in vitro. Injection of oestradiol benzoate (50 microgram, 24 h prior to experiment) resulted in a significant depression of basal and LH-stimulated plasma testosterone levels in control rats and this effect was unchanged in tamoxifen-pretreated rats. In vitro, oestradiol-17 beta also inhibited the LH-induced rise in testosterone secretion by isolated testicular interstitial cells. This inhibition was not affected if the rats had been pretreated with tamoxifen. These results indicate that the inhibitory effects of exogenous oestrogens on testicular testosterone production are probably not mediated by the oestrogen receptor.

Biphasic effect of gonadotropin releasing hormone on progestin secretion by rat granulosa cells.

The effect of an agonistic gonadotropin releasing hormone (GnRH)-analog (D-Ala6, des-Gly10-NH2-GnRH-ethylamide, GnRHa) on granulosa cell steroidogenesis in the presence or absence of follicle-stimulating hormone (FSH) or luteinizing hormone (LH) was studied. Granulosa cells, isolated from preovulatory follicles of pregnant mare's serum gonadotropin (PMSG)-treated immature rats or from the less mature follicles of untreated immature rats, were cultured for a period of 72 h with daily changes of medium, and progesterone and its metabolite, 20 alpha-dihydro-progesterone (20 alpha-OHP), were assayed in the medium. In granulosa cells from preovulatory follicles, LH and FSH caused a much greater stimulation of steroidogenesis than did GnRHa. There appeared to be no interaction between GnRHa and FSH during the first 10 h, but at 24 h and later the presence of GnRHa clearly inhibited the steroidogenic response to LH and FSH. Steroidogenesis in granulosa cells from immature rats was considerably lower and the effects of GnRHa and FSH alone less pronounced. In these cells, FSH-stimulated progesterone secretion was inhibited by GnRHa only at 72 h. In contrast, 20 alpha-OHP secretion in the same cultures was potentiated by the combined presence of FSH and GnRHa. In conclusion, it seems as though the effects of GnRHa on granulosa cell steroidogenesis varies with exposure time, the initial response being stimulatory and the later inhibitory. Furthermore, the response is also to some extent determined by the maturational stage of the granulosa cells.

A microcomputer program for bibliographic reference handling with emphasis on flexible formatting of the reference printout.

A program for handling of bibliographic references on a microcomputer is described. The program offers full capabilities of searching, editing and rearranging reference lists. Also, the program has the feature of a fully formatted output when printing hardcopies, i.e. the user may exactly describe the format of the output in order to get a proof-quality hardcopy of references which may be used when writing manuscripts.

Importance of molecular charge for the passage of endogenous macromolecules across continuous capillary walls, studied by serum clearance of lactate dehydrogenase (LDH) isoenzymes.

Electrostatic capillary barrier characteristics was studied in the isolated maximally vasodilated rat hindquarter by use of a modified "tissue uptake" technique (Rippe et al. 1979). The hindquarters were artificially perfused with oxygenated horse serum at isogravimetry. As tracers two isoenzymes of lactate dehydrogenase (LDH) were used, having identical size (41 A, Mw approximately 140 000) but with differing molecular charge and labelled with two separable isotopes. LDH-H4 (125I) is negatively charged and LDH-M4 (131I) slightly positive, at physiological pH. The negatively charged protein LDH-H4 was more retarded in its transcapillary passage than LDH-M4. Net clearance of H4 was 0.0242 +/- 0.0045 ml/min X 100 g and that of M4 was 0.0748 +/- 0.0092 ml/min X 100 g (n = 11, p less than 0.001). This difference is suggested to be due to an interaction of the polyanionic tracer with a barrier of negative molecular charge, most effective at the small pore equivalent. Clearance data for H4 and for albumin (Rippe et al. 1979) are compatible with an equivalent large pore radius of 520 A. Neither vesicular transport (Palade 1953) nor the impact of fibre pore matrix (Michel 1980) is considered to be involved in the transcapillary passage of proteins. Negatively charged proteins probably pass through the large pore equivalent exclusively, while neutral macromolecules also utilize part of the small pore equivalent, for their transcapillary passage.

A gonadotrophin-releasing hormone (GnRH) antagonist inhibits GnRH- but not LH-induced meiosis in follicle-enclosed rat oocytes in vitro.

Previous studies have shown that gonadotrophin-releasing hormone (GnRH) can induce resumption of meiosis in follicle-enclosed rat oocytes. In the present study a GnRH antagonistic analogue ([D-pGlul,D-Phe2,-D-Trp3,6]LRF) was found to effectively abolish the stimulatory effect of a GnRH agonist upon resumption of meiosis and lactate accumulation in isolated pre-ovulatory rat follicles but the have no effect on LH stimulation of these parameters. It is concluded that although LH and GnRH can evoke a similar response they act through separate receptor sites and that it is unlikely that GnRH mediates the effect of LH on meiosis or glycolysis.

LH-induced inhibition of follicular androgen formation requires intact steroidogenesis.

LH exerts a biphasic effect on rat pre-ovulatory follicular steroidogenesis: an initial (1-4h) overall stimulation followed by a later (4-6 h) occurring inhibition of androgen synthesis. Because exogenous steroids may inhibit androgen formation, we investigated whether the steroids produced initially in response to LH are involved in the late inhibition of androgen synthesis. Isolated pre-ovulatory rat follicles were incubated for 6 h with and without ovine LH and 1 of 3 inhibitors of steroidogenesis (aminoglutethimide, cyanoketone, Su 10603). Accumulation of androstenedione and testosterone in a subsequent 2-h incubation in the presence of exogenous 17-hydroxyprogesterone was measured. LH treatment alone caused inhibition of apparent 17,20-lyase activity. The inhibitors had no effect on basal 17,20-lyase activity but were able to prevent the LH-induced inhibition of this enzyme activity. The results suggest that the physiological decline in pre-ovulatory androgen formation may in part be mediated by local action of follicular steroids.

Ovulation induced by a gonadotropin releasing hormone analog in hypophysectomized rats involves prostaglandins.

A potent analogue of gonadotropin releasing hormone [D-Ala6- Des-Gly10-NH2]-GnRH ethylamide (GnRHa) caused oocyte maturation and ovulation when injected in the afternoon of proestrus in immature PMSG-treated female rats, hypophysectomized on the morning of proestrus. This action of GnRHa was accompanied by a marked increase in ovarian PGE levels. Furthermore, the pretreatment of the animals with a prostaglandin synthetase inhibitor (indomethacin) completely inhibited this PGE increase and ovulation. These data suggest a role for prostaglandins in GnRHa induced ovulation.