Propionyl-L-carnitine

Propionyl-L-carnitine stimulates energy production in ischaemic muscles by increasing citric acid cycle flux and stimulating pyruvate dehydrogenase activity. The free radical scavenging activity of the drug may also be beneficial. Propionyl-L-carnitine improves coagulative fibrinolytic homeostasis in vasal endothelium and positively affects blood viscosity. Improvements in maximum walking distance (MWD) correlated positively with increased mitochondrial oxidative adenosine triphosphate (ATP) synthesis in a study in patients with peripheral arterial disease. Oral propionyl-L-carnitine 1 to 3 g/day significantly improved mean MWD compared with placebo in patients with peripheral arterial obstructive disease (Fontaine Leriche stage II) in double-blind multicentre phase III studies (mean improvements ranged from 21 to 50% with placebo and from 33 to 73% with propionyl-L-carnitine). In one phase III study, propionyl-L-carnitine 1 to 3 g/day significantly improved mean MWD (measured by treadmill) compared with placebo (by 73 vs 46% after 24 weeks) in patients with intermittent claudication. Oral propionyl-L-carnitine therapy was associated with significant improvements in quality of life compared with placebo in patients with a baseline MWD < 250m. Propionyl-L-carnitine appears to be well tolerated, showing a similar incidence of adverse events to that reported in placebo recipients.     

Corticomotoneuronal contribution to the fractionation of muscle activity during precision grip in the monkey

1. During independent finger movements, the intrinsic muscles of the hand show a fractionated pattern of activity in which the timing and amplitude of electromyographic (EMG) activity varies considerably from one muscle to another. It has been suggested that, in the macaque monkey, corticomotoneuronal (CM) cells that produce postspike facilitation (PSF) of EMG in these muscles contribute to this fractionation. To test this hypothesis, we have investigated the relationship between the pattern of PSF exerted by a CM cell and the pattern of activity shown by the cell and by its target muscles. 2. The activity of 15 identified CM cells was recorded from two monkeys that performed a precision grip task. Spike-triggered averaging of rectified EMG during the hold period of this task showed that each cell produced PSF in at least two intrinsic hand muscles. 3. Segments of data were selected from the initial movement period of the task in which the EMG activity in one target muscle was substantially greater than that of the other, and the mean firing rate of each CM cell was determined for these periods. 4. CM cells showed bursts of activity in the movement period. Most of them (13/15) had a significantly (P < 0.001) higher firing rate when one of its target muscles was more active than the other. For nine of these cells (identified as set A), this muscle was the one receiving the larger PSF. In four cases (set B), the reverse was true. Two cells (set C), which produced PSF of equal size in their target muscles, showed no change in firing rate across the periods of fractionated EMG activity. 5. All set A and set B cells fired at significantly (P < 0.001) higher rates during the movement period, in association with fractionation of EMG activity, than in the hold period, in which a cocontracted pattern of muscle activity was observed. 6. There were pronounced differences in the strength of PSF exerted by the CM cells on their target muscles during the fractionation periods. One CM cell exerted PSF of a muscle during one period of fractionation, but postspike suppression of the same muscle during the other period. 7. It is suggested that changes in the firing rate of a CM cell and in the degree of facilitation it exerts could both contribute to the fractionation of activity in its target muscles. Cells of set A appear to be specifically recruited in a manner that directly reflects the pattern of facilitation they exert on the sampled target muscles. These results may explain why the CM system is so important for the performance of relatively independent finger movements.     

Distribution of iatrogenic retinal breaks in macular hole surgery

BACKGROUND: Intraoperative peripheral iatrogenic retinal breaks can be a serious complication of vitreous surgery. This study was undertaken to determine whether vitreous surgical techniques used for macular hole surgery were associated with a different incidence or distribution of retinal breaks. METHODS: The authors prospectively evaluated a series of 181 consecutive eyes undergoing macular hole surgery. Contemporaneous reporting of intraoperative and postoperative retinal breaks and postoperative retinal detachments was performed. Comparison was made to historic controls of two case series of patients undergoing vitreous surgery for other indications. RESULTS: Of 181 eyes, 10 (5.5%) had 15 intraoperative retinal breaks. Of the 15 breaks, 3 (20%) were in the quadrant near the surgeon's right-hand sclerotomy, 9 (60%) were in the two inferior quadrants, and 11 (73%) were in the two temporal quadrants. By comparison to previously reported case series, tears in our series were less likely to be near the right-hand sclerotomy (P = 0.00055) and more likely to occur in the two inferior retinal quadrants (P = 0.00015) and two temporal retinal quadrants (P = 0.0042). Two patients (1.1%) of 181 had postoperative retinal detachments. CONCLUSIONS: Patients undergoing vitreous surgery for macular hole have a similar incidence but different location of iatrogenic retinal breaks when compared with patients undergoing pars plana vitrectomy for other indications. These breaks are not distributed near sclerotomy sites and tend to be in the inferior and temporal retina. This establishes the need for greater intraoperative surveillance in these areas.     

Genetic analysis of Drosophila larval optic nerve development

To identify genes necessary for establishing connections in the Drosophila sensory nervous system, we designed a screen for mutations affecting development of the larval visual system. The larval visual system has a simple and stereotypic morphology, can be recognized histologically by a variety of techniques, and is unnecessary for viability. Therefore, it provides an opportunity to identify genes involved in all stages of development of a simple, specific neuronal connection. By direct observation of the larval visual system in mutant embryos, we identified 24 mutations affecting its development; 13 of these are larval visual system-specific. These 13 mutations can be grouped phenotypically into five classes based on their effects on location, path or morphology of the larval visual system nerves and organs. These mutants and phenotypic classifications provide a context for further analysis of neuronal development, pathfinding and target recognition.     

Transplanted neurons alter the course of neurodegenerative disease in Lurcher mutant mice

Embryonic cerebellar, neocortical, and striatal tissues derived from NSE-LacZ transgenic mice were transplanted into the right cerebellar hemisphere of 8- to 10-day-old Lurcher or wild-type mice. Host mice survived for 30-90 days and the transplanted tissue was examined by light microscopy using Nissl staining, X-gal histochemistry, and immunohistochemistry for calcium binding protein and glutamic acid decarboxylase. Transplantation of cerebellar tissue, but not neocortical or striatal progenitors, resulted in robust infiltration of the lurcher mutant host cerebellar cortex by transgenic Purkinje neurons. Deep to the infiltrated molecular layer, the host granular layer was thicker and denser than the mutant granular layer, but transgenic cells did not contribute to the spared granular layer. The host inferior olivary complex consistently exhibited a noticeable bilateral asymmetry in Nissl-stained sections. A quantitative analysis of the olivary complex was performed in 10 90-day-old host mice. The results indicate that the left inferior olivary complex of 90-day-old host mice contained more neurons than the right inferior olive of the host mice and contained more neurons than was observed in 90-day-old Lurcher control mice. Analysis by olivary subdivision indicates that increased neuron numbers were present in all subdivisions of the host left inferior olive. These studies confirm the specific attractive effect of the mutant cerebellar cortex on transplanted Purkinje neuron progenitors and indicate that neural transplants may survive the neurodegenerative period to interact with developing host neural systems. The unilateral rescue of Lurcher inferior olivary neurons in cerebellar transplant hosts indicates that transplanted neurons may interact with diseased host neural circuits to reduce transneuronal degeneration in the course of a neurodegenerative disease.     

Effect of hypohydration on gastric emptying and intestinal absorption during exercise

Dehydration and hyperthermia may impair gastric emptying (GE) during exercise; the effect of these alterations on intestinal water flux (WF) is unknown. Thus the purpose of this study was to determine the effect of hypohydration ( approximately 2.7% body weight) on GE and WF of a water placebo (WP) during cycling exercise (85 min, 65% maximal oxygen uptake) in a cool environment (22 degrees C) and to also compare GE and WF of three carbohydrate-electrolyte solutions (CES) while the subjects were hypohydrated. GE and WF were determined simultaneously by a nasogastric tube placed in the gastric antrum and via a multilumen tube that spanned the duodenum and the first 25 cm of jejunum. Hypohydration was attained 12-16 h before experiments by low-intensity exercise in a hot (45 degrees C), humid (relative humidity 50%) environment. Seven healthy subjects (age 26.7 +/- 1.7 yr, maximal oxygen uptake 55.9 +/- 8.2 ml . kg-1 . min-1) ingested either WP or a 6% (330 mosmol), 8% (400 mosmol), or a 9% (590 mosmol) CES the morning following hypohydration. For comparison, subjects ingested WP after a euhydration protocol. Solutions ( approximately 2.0 liters total) were ingested as a large bolus (4.6 ml/kg body wt) 5 min before exercise and as small serial feedings (2.3 ml/kg body wt) every 10 min of exercise. Average GE rates were not different among conditions (P > 0.05). Mean (+/-SE) values for WF were also similar (P > 0.05) for the euhydration (15.3 +/- 1.7 ml . cm-1 . h-1) and hypohydration (18.3 +/- 2.6 ml . cm-1 . h-1) experiments. During exercise after hypohydration, water absorption was greater (P < 0.05) with ingestion of WP (18.3 +/- 2. 6) and the 6% CES (16.5 +/- 3.7), compared with the 8% CES (6.9 +/- 1.5) and the 9% CES (1.8 +/- 1.7). Mean values for final core temperature (38.6 +/- 0.1 degrees C), heart rate (152 +/- 1 beats/min), and change in plasma volume (-5.7 +/- 0.7%) were similar among experimental trials. We conclude that 1) hypohydration to approximately 3% body weight does not impair GE or fluid absorption during moderate exercise when ingesting WP, and 2) hyperosmolality (>400 mosmol) reduced WF in the proximal intestine.     

Increased height gain of children fed a high-protein diet during convalescence from shigellosis: a six-month follow-Up study

The impact of dietary supplementation on catch-up growth was evaluated in 69 malnourished children ages 24-60 mo after recovery from shigellosis. They were fed either a high-protein (HP) diet with 15% of energy as protein, or a standard-protein (SP) diet with 7.5% energy as protein, for 3 wk in a metabolic study ward. Children were followed up bi-weekly for 6 mo by trained health assistants when anthropometric measurements and information of any illness were collected. Thirty-one children in the HP group and 28 children in the SP group completed 6-mo follow-up. The increase in height (mean +/- SD) was 5.3 +/- 1.0 cm vs. 4.1 +/- 1.1 cm for HP and SP groups, respectively (P < 0.001), whereas increase in body weight was 1.39 +/- 0.58 and 1.29 +/- 0.72 kg for children fed HP and SP, respectively (P = 0.59). The proportion of children who were severely stunted (< -2 SD height-for-age) decreased from 45 to 29% in the HP group compared to 50 to 46% in the SP group (P < 0.05) at 6-mo follow-up. The number of diarrheal episodes per child tended to be lower in the HP vs. SP than in the SP group (1.9 vs. 2.3, P = 0.41). These results demonstrate that feeding an HP diet to the malnourished children during recovery from shigellosis enhanced linear growth with a modest reduction in diarrheal morbidity during the 6-mo follow-up period.     

Selective inhibition of [D-Ala2, Glu4]deltorphin antinociception by supraspinal, but not spinal, administration of an antisense oligodeoxynucleotide to an opioid delta receptor

Evidence in vivo has suggested the existence of subtypes of the delta opioid receptor (DOR), which have been termed delta 1 and delta 2. These proposed DOR subtypes are thought to be activated by [D-Pen2, D-Pen5]enkephalin (DPDPE, delta 1) and [D-Ala2, Glu4]deltorphin (delta 2). Recent work in which an antisense oligodeoxynucleotide (oligo) to a cloned DOR was administered by the intrathecal (i.th.) route has demonstrated a reduction in the antinociceptive actions of both i.th. DPDPE and [D-Ala2, Glu4]deltorphin, but not of [D-Ala2, NMPhe4, Gly-ol]enkephalin (DAMGO, mu agonist) in mice. The present investigation has extended these observations by administering the same DOR antisense oligo sequence by the intracerebroventricular (i.c.v.) route and evaluating the antinociceptive actions of i.c.v. agonists selective for delta, mu and kappa receptors. I.th. treatment with DOR antisense oligo, but not mismatch oligo, significantly inhibited the antinociceptive actions of both i.th. DPDPE and [D-Ala2, Glu4]deltorphin but not of i.th. DAMGO or U69,593 (kappa agonist), confirming previous data. In contrast, i.c.v. DOR antisense oligo, but not mismatch oligo, selectively inhibited the antinociceptive response to i.c.v. [D-Ala2, Glu4]deltorphin without altering the antinociceptive actions of i.c.v. DPDPE, DAMGO or U69,593. The data suggest that the cloned DOR corresponds to that pharmacologically classified as delta 2 and further, suggest that this delta receptor subtype may play a major role in eliciting spinal delta-mediated antinociception.     

Tumour suppressor genes in the pathogenesis of human pituitary tumours

Abnormal cell proliferation is controlled by opposing actions of oncogene products (stimulatory) and tumour suppressor gene (TSG) products (inhibitory). The former are dominantly acting, i.e. only one copy needed for tumorigenesis, whilst for TSG both copies of the gene must be inactivated so these are recessive at a cellular level. For anterior pituitary tumours only one oncogene (Gsp) has been identified in a variable proportion (4-40%) of a single tumour subtype (somatotrophinomas). Contrariwise, allelic deletion studies, using a PCR-based microsatellite polymorphism analysis of DNA extracted from archival specimens, have shown significant loss of heterozygosity in 20-40% of all tumour subtypes at the locus of the putative MEN-1 gene (chr. 11q13); the retinoblastoma gene (chr. 13q 12-14), and 10q26. Moreover, these DNA microdeletions were concentrated in radiologically invasive tumours compared to noninvasive tumours (modified Hardy gdes 3 and 4 vs. 1 + 2). In addition, 50% of Cushing's adenomas showed presence of p53 immunopositivity, though no point mutations in exons 4-9 were found, by SSCP analysis, to account for this. These studies show that analysis of TSGs in pituitary adenomas may provide clues to their pathogenesis, and more importantly relate to clinical behaviour of the tumour, and hence aid decisions regarding management.