Engineering human immunodeficiency virus 1 protease heterodimers as macromolecular inhibitors of viral maturation.

Dimerization of human immunodeficiency virus type 1 protease (HIV-1 PR) monomers is an essential prerequisite for viral proteolytic activity and the subsequent generation of infectious virus particles. Disruption of the dimer interface inhibits this activity as does formation of heterodimers between wild-type and defective monomers. A structure-based approach was used to identify amino acid substitutions at the dimer interface of HIV-1 PR that facilitate preferential association of heterodimers and inhibit self-association of the defective monomers. Expression of the designed PR monomers inhibits activity of wild-type HIV-1 PR and viral infectivity when assayed in an ex vivo model system. These results show that it is possible to design PR monomers as macromolecular inhibitors that may provide an alternative to small molecule inhibitors for the treatment of HIV infection.     

Cognitive rehabilitation in the elderly: overview and future directions.

This study provides an overview of the papers emanating from the experimental trial that evaluated a new cognitive rehabilitation program in older adults who were experiencing normal cognitive decline. The main features of the design are summarized, along with evidence that the training produced long-lasting improvement in memory performance, goal management, and psychosocial status. The benefits were attributed to several factors, including the program's emphasis on techniques that promoted efficient strategic processing. Limitations of the program and directions for future research are discussed.     

Bilingualism and naming: implications for cognitive assessment.

The article by Gollan, Fennema-Notestine, Montoya, and Jernigan (2007, this issue) raises important issues about the, effects of bilingualism on naming test performance in older adults. In particular, proficiency in their two languages determines the ability with which older bilingual adults can name pictures in each of those languages. This observation is important if cognitive status is inferred from naming performance. In this commentary we largely endorse the arguments made by Gollan and colleagues, although we point to some limitations in their experimental design.     

Endometrial fluid collection in women with hydrosalpinx after human chorionic gonadotrophin administration: a report of two cases and implications for management

The impact of hydrosalpinx (HSPX) on in-vitro fertilization (IVF) outcome has recently been the subject of intense debate. Most, but not all, studies have reported decreased implantation and pregnancy rates and increased early pregnancy loss in HSPX patients. This has led to prophylactic salpingectomies prior to IVF in HSPX patients despite the lack of any prospective studies to suggest that any improvement will occur. Women with HSPX constitute a heterogeneous population because some conceive easily with IVF while others do not until after surgical correction. HSPX also increases in size with ovarian stimulation, and can cause implantation failure by fluid reflux into the uterine cavity. Careful assessment of the endometrial lining is mandatory in HSPX to rule out fluid reflux from the HSPX. We present two case reports of patients whose HSPX enlarged with ovarian stimulation, causing fluid reflux into the uterine cavity which was only noted after human chorionic gonadotrophin (HCG) administration.      

Two new classes of conopeptides inhibit the alpha1-adrenoceptor and noradrenaline transporter

Cone snails use venom containing a cocktail of peptides ('conopeptides') to capture their prey. Many of these peptides also target mammalian receptors, often with exquisite selectivity. Here we report the discovery of two new classes of conopeptides. One class targets alpha1-adrenoceptors (rho-TIA from the fish-hunting Conus tulipa), and the second class targets the neuronal noradrenaline transporter (chi-MrIA and chi-MrIB from the mollusk-hunting C. marmoreus). rho-TIA and chi-MrIA selectively modulate these important membrane-bound proteins. Both peptides act as reversible non-competitive inhibitors and provide alternative avenues for the identification of inhibitor drugs.     

The effects of age on the neural correlates of episodic encoding

Young and old adults underwent positron emission tomographic scans while encoding pictures of objects and words using three encoding strategies: deep processing (a semantic living/nonliving judgement), shallow processing (size judgement) and intentional learning. Picture memory exceeded word memory in both young and old groups, and there was an age-related decrement only in word recognition. During the encoding tasks three brain activity patterns were found that differentiated stimulus type and the different encoding strategies. The stimulus-specific pattern was characterized by greater activity in extrastriate and medial temporal cortices during picture encoding, and greater activity in left prefrontal and temporal cortices during encoding of words. The older adults showed this pattern to a significantly lesser degree. A pattern distinguishing deep processing from intentional learning of words and pictures was identified, characterized mainly by differences in prefrontal cortex, and this pattern also was of significantly lesser magnitude in the old group. A final pattern identified areas with increased activity during deep processing and intentional learning of pictures, including left prefrontal and bilateral medial temporal regions. There was no group difference in this pattern. These results indicate age-related dysfunction in several encoding networks, with sparing of one specifically involved in more elaborate encoding of pictures. These age-related changes appear to affect verbal memory more than picture memory.     

Novelty and Familiarity Activations in PET Studies of Memory Encoding and Retrieval

Nine young right-handed men viewed colored pictures of people,scenes, and landscapes. Then, 24 hr later while undergoing PETscanning, they viewed previously studied (OLD) pictures in onetype of scan, and previously not seen (NEW) pictures in another.The OLD-NEW subtraction of PET images indicates familiarity,and the NEW-OLD indicates novelty. Familiarity activations,signalling aspects of retrieval, were observed in the left andright frontal areas, and posterior regions bilaterally. Noveltyactivations were in the right limbic regions, and bilaterallyin temporal and parietal regions, including area 37. These latteractivations were located similarly to novelty activations inprevious PET studies using visual words and auditory sentences,suggesting the existence of brain regions specializing in transmodalnovelty assessment The effects of novelty are seen both be haviorallyand in replicable patterns of cortical and subcortical activation.We propose a "novelty/encoding hypothesis": (1) novelty assessmentrepresents an early stage of long-term memory encoding; (2)elaborate, meaning-based encoding processes operate on the incoming information to the extent of its novelty, and therefore(3) the probability of long-term storage of information vanesdirectly with the novelty of the information.     

Anthelmintic activity of cyclotides: In vitro studies with canine and human hookworms

Hookworm infection is a leading cause of maternal and child morbidity in countries of the tropics and subtropics, as well as being an important parasite in companion-animal medicine. The cyclotides are a novel family of cyclic cystine knot containing peptides from plants that have been shown to possess anthelmintic activity against Haemonchus contortus and Trichostrongylus colubriformis, two important gastrointestinal nematodes of sheep. In the current study we demonstrated the in vitro effects of three representative cyclotides, kalata B1, kalata B6 and cycloviolacin O14, on the viability of larval and adult life stages of the dog hookworm Ancylostoma caninum, and larvae of the human hookworm Necator americanus. The cyclotides showed significant anthelmintic activity towards both hookworm species. The different cyclotides showed similar patterns of relative activity as that seen previously with the livestock nematode species. This study demonstrates that cyclotides have promising activity in vitro against important parasites of companion animals and humans.     

In Vivo Efficacy of Anuran Trypsin Inhibitory Peptides against Staphylococcal Skin Infection and the Impact of Peptide Cyclization

Staphylococcus aureus is a virulent pathogen that is responsible for a wide range of superficial and invasive infections. Its resistance to existing antimicrobial drugs is a global problem, and the development of novel antimicrobial agents is crucial. Antimicrobial peptides from natural resources offer potential as new treatments against staphylococcal infections. In the current study, we have examined the antimicrobial properties of peptides isolated from anuran skin secretions and cyclized synthetic analogues of these peptides. The structures of the peptides were elucidated by nuclear magnetic resonance (NMR) spectroscopy, revealing high structural and sequence similarity with each other and with sunflower trypsin inhibitor 1 (SFTI-1). SFTI-1 is an ultrastable cyclic peptide isolated from sunflower seeds that has subnanomolar trypsin inhibitory activity, and this scaffold offers pharmaceutically relevant characteristics. The five anuran peptides were nonhemolytic and noncytotoxic and had trypsin inhibitory activities similar to that of SFTI-1. They demonstrated weak in vitro inhibitory activities against S. aureus, but several had strong antibacterial activities against S. aureus in an in vivo murine wound infection model. pYR, an immunomodulatory peptide from Rana sevosa, was the most potent, with complete bacterial clearance at 3 mg · kg⁻¹. Cyclization of the peptides improved their stability but was associated with a concomitant decrease in antimicrobial activity. In summary, these anuran peptides are promising as novel therapeutic agents for treating infections from a clinically resistant pathogen.     

Human evolution and tears of the rotator cuff

Purpose

Humans differ from other great ape species in their propensity to develop tears of the rotator cuff. The aim of this study was to compare the anatomical risk factors for subacromial impingement and rotator cuff tears amongst the great apes and to determine which features may be accentuated in humans and therefore play a more significant role in disease aetiology.

Methods

Orthogonal digital photographs of 22 human, 17 gorilla, 13 chimpanzee and 12 orangutan dry bone scapula specimens oriented in the glenoid plane were taken. Anatomical measurements were preformed using a calibrated digital image technique and the results scaled according to scapula vertebral border length.

Results

Of the ten anatomical features associated with subacromial impingement and rotator cuff tears in humans, none were shown to be accentuated and significantly different to the other species studied. However the human supraspinatus fossa was shown to be significantly smaller.

Conclusions

These results indicate that an alternative primary aetiological factor for rotator cuff tears must exist. A reduction in the size of the supraspinatus fossa in human scapulae suggests that structural insufficiency of the supraspinatus or a change in rotator cuff force vectors could play a role.