The ecology of cutaneous leishmaniasis in Nizzana, Israel: infection patterns in the reservoir host, and epidemiological implications.

We conducted an extensive interdisciplinary study in an emerging focus of cutaneous leishmaniasis in the Western Negev Desert of Israel between July 1998 and February 2000. The aims of the this study were to determine (1) the reservoir hosts, (2) the distribution of the pathogen within the host range, (3) the associations of host, vector, and pathogen within defined habitats, (4) the demographic distribution of the pathogen within the host populations, and (5) to apply the newly acquired epizootiological data to explain morbidity patterns in humans. Fourteen square (60 m width) sampling plots were delimited in three types of habitats each with a different kind of substrate: loess, sand, and sand-loess ecotone. Rodents and sand flies were trapped and several environmental variables were measured. Leishmania infections in rodents were detected microscopically in stained smears of ear tissue and by a Leishmania-specific polymerase chain reaction. Results indicate that, contrary to previous reports, Psammomys obesus and not Meriones crassus is the main reservoir host in the region. Additional rodents (12 Gerbillus dasyurus and two M. crassus) were also found positive for Leishmania DNA. Prevalence of Leishmania infections amongst P. obesus was highest in loess habitats (65%), intermediate in the sandy-loess ecotone (20%), and 0% in the sandy habitats. Psammomys obesus individuals in the loess habitat of the Nizzana ruins were larger, on average (probably older), than those in the sandy habitat of the Mt. Keren junction. Sand fly density was positively correlated to soil moisture being higher in the relatively humid plots of Nizzana ruins and much lower in the drier sandy soil of Mt. Keren. Elucidation of fundamental ecological factors affecting this disease has helped explain an apparent discrepancy between the distribution of the disease in the zoonotic system and among humans.     

hVps15, but not Ca2+/CaM, is required for the activity and regulation of hVps34 in mammalian cells

The mammalian Class III PI3K (phosphoinositide 3-kinase), hVps34 [mammalian Vps (vacuolar protein sorting) 34 homologue], is an important regulator of vesicular trafficking, autophagy and nutrient sensing. In yeast, Vps34 is associated with a putative serine/threonine protein kinase, Vps15, which is required for Vps34p activity. The mammalian homologue of Vps15p, hVps15 (formerly called p150), also binds to hVps34, but its role in hVps34 signalling has not been evaluated. In the present study we have therefore compared the activity and regulation of hVps34 expressed without or with hVps15. We find that hVps34 has low specific activity when expressed alone; co-expression with hVps15 leads to a marked increase in activity. Notably, beclin-1/UVRAG (UV radiation resistance-associated gene) activation of hVps34 requires co-expression with hVps15; this may be explained by the observation that beclin-1/UVRAG expression increases hVps34/hVps15 binding. Regulation of hVps34 activity by nutrients also requires co-expression with hVps15. Finally, given a recent report that hVps34 activity requires Ca2+/CaM (calmodulin), we considered whether hVps15 might be involved in this regulation. Although hVps34 does bind CaM, we find its activity is not affected by treatment of cells with BAPTA/AM [1,2-bis-(o-aminophenoxy)ethane-N,N,N',N'-tetra-acetic acid tetrakis(acetoxymethyl ester)] or W7. Removal of CaM by EDTA or EGTA washes has no effect on hVps34 activity, and hVps34 activity in vitro is unaffected by Ca2+ chelation. The results of the present study show that, in mammalian cells, hVps34 activity is regulated through its interactions with hVps15, but is independent of Ca2+/CaM.     

EMPIRICAL COMPARISON OF G MATRIX TEST STATISTICS: FINDING BIOLOGICALLY RELEVANT CHANGE

A central assumption of quantitative genetic theory is that the breeder's equation ( R = GP ⁻¹ S ) accurately predicts the evolutionary response to selection. Recent studies highlight the fact that the additive genetic variance–covariance matrix ( G ) may change over time, rendering the breeder's equation incapable of predicting evolutionary change over more than a few generations. Although some consensus on whether G changes over time has been reached, multiple, often-incompatible methods for comparing G matrices are currently used. A major challenge of G matrix comparison is determining the biological relevance of observed change. Here, we develop a "selection skewers" G matrix comparison statistic that uses the breeder's equation to compare the response to selection given two G matrices while holding selection intensity constant. We present a bootstrap algorithm that determines the significance of G matrix differences using the selection skewers method, random skewers, Mantel's and Bartlett's tests, and eigenanalysis. We then compare these methods by applying the bootstrap to a dataset of laboratory populations of Tribolium castaneum . We find that the results of matrix comparison statistics are inconsistent based on differing a priori goals of each test, and that the selection skewers method is useful for identifying biologically relevant G matrix differences.     

Capsular contracture: a prospective study of the effect of local antibacterial agents

In a prospective, random, double-blind, and concurrently controlled clinical study of 124 patients having augmentation mammaplasty, using multiple independent subjective judges as well as objective compressibility measurements, the use of a variety of local antibacterials in or around inflatable retromammary prosthetic implants reduced the early postoperative onset of class III to IV capsular contracture by sevenfold (85 percent) and the final incidence by more than half (50 percent) (p less than 0.01). We believe this study provides the most unequivocal evidence to date that the cause of capsular contracture in retromammary augmentation is periprosthetic bacterial contamination. Irrigation with a 5 percent povidone-iodine (50 percent Betadine) solution was as effective as other techniques and is currently our procedure of choice.     

Evidence for an underlying opponent process during morphine elicited hyperactivity in the hamster

Two experiments investigated the effects of naloxone on morphine elicited hyperactivity in the hamster. In Experiment 1, naloxone (0.4 mg/kg) administered two hours after morphine (15 mg/kg) produced sedation in animals running at high rates under the influence of morphine. Saline control animals running at comparable rates were unaffected by naloxone. In Experiment 2, naloxone administered two hours after morphine converted morphine elicited hyperactivity into sedation. These results are discussed in terms of a modified dual-action hypothesis which holds that morphine elicited hyperactivity masks an underlying opponent process.     

Phenotypic variability in X-linked ocular albinism: relationship to linkage genotypes.

One hundred nineteen individuals from 11 families with X-linked ocular albinism (OA1) were studied with respect to both their clinical phenotypes and their linkage genotypes. In a four-generation Australian family, two affected males and an obligatory carrier lacked cutaneous melanin macroglobules (MMGs); ocular features were identical to those of Nettleship-Falls OA1. Four other families had more unusual phenotypic features in addition to OA1. All OA1 families were genotyped at DXS16, DXS85, DXS143, STS, and DXS452 and for a CA-repeat polymorphism at the Kallmann syndrome locus (KAL). Separate two-point linkage analyses were performed for the following: group A, six families with biopsy-proved MMGs in at least one affected male; group B, four families whose biopsy status was not known; and group C, OA-9 only (16 samples), the family without MMGs. At the set of loci closest to OA1, there is no clear evidence in our data set for locus heterogeneity between groups A and C or among the four other families with complex phenotypes. Combined multipoint analysis (LINKMAP) in the 11 families and analysis of individual recombination events confirms that the major locus for OA1 resides within the DXS85-DXS143 interval. We suggest that more detailed clinical evaluations of OA1 individuals and families should be performed for future correlation with specific mutations in candidate OA1 genes.     

OA1 mutations and deletions in X-linked ocular albinism.

X-linked ocular albinism (OA1), Nettleship-Falls type, is characterized by decreased ocular pigmentation, foveal hypoplasia, nystagmus, photodysphoria, and reduced visual acuity. Affected males usually demonstrate melanin macroglobules on skin biopsy. We now report results of deletion and mutation screening of the full-length OA1 gene in 29 unrelated North American and Australian X-linked ocular albinism (OA) probands, including five with additional, nonocular phenotypic abnormalities (Schnur et al. 1994). We detected 13 intragenic gene deletions, including 3 of exon 1, 2 of exon 2, 2 of exon 4, and 6 others, which span exons 2-8. Eight new missense mutations were identified, which cluster within exons 1, 2, 3, and 6 in conserved and/or putative transmembrane domains of the protein. There was also a splice acceptor-site mutation, a nonsense mutation, a single base deletion, and a previously reported 17-bp exon 1 deletion. All patients with nonocular phenotypic abnormalities had detectable mutations. In summary, 26 (approximately 90%) of 29 probands had detectable alterations of OA1, thus confirming that OA1 is the major locus for X-linked OA.     

Mosaic loss of 15q11q13 in a patient with hypomelanosis of Ito: is there a role for the P gene?

We report a patient with mental retardation, behavioral disturbances, and pigmentary anomalies, consistent with the phenotype of hypomelanosis of Ito (HMI), and in whom cytogenetic analysis revealed mosaicism for an unbalanced translocation. His karyotype is 45, XY,–7, –15,+der(7)(7;15)t(q34;ql3)/46, XY. He is therefore monosomic for 7q34 to qter and 15pter to q13 in the cells containing the translocation. The human homolog (P) of the p gene (the product of the mouse pink-eyed dilution locus) maps to 15q11q13. Loss of this locus is believed to be associated with abnormalities of pigmentation, such as the hypopigmentation seen in patients with deletions of 15q11q13, and the Prader-Willi and Angelman syndromes. Mutations within the P gene have also been associated with tyrosinase-positive (type II) oculocutaneous albinism. Using fluorescence in situ hybridization, we confirmed that our patient is deleted for one copy of a P gene probe in the cells with the unbalanced translocation, and for loci within the region critical for the Prader-Willi/Angelman syndromes. Although hypomelanosis of Ito is a heterogeneous disorder, we postulate that, in our case and potentially in others, this phenotype may result directly from the loss of specific pigmentation genes.     

Metastasizing keratoacanthomas? The difficulties in differentiating keratoacanthomas from squamous cell carcinomas

The problem in diagnosis of keratoacanthoma versus squamous cell carcinoma has been reviewed, and 13 patients are presented to illustrate the difficulties in differentiating between these two lesions. If the pathologist is in doubt, the lesion should be called "probable keratoacanthoma, but squamous cell carcinoma cannot be ruled out." We should all be aware that even the most careful pathologist, using all the information and material available, may still erroneously diagnose a lesion as a benign keratoacanthoma--one which, if inadequately treated, may metastasize or recur as a squamous cell carcinoma. Therefore, it is important for the clinician to treat most keratoacanthomas by adequate removal and close follow-up.