A reconstruction of the Vienna skull of Hadropithecus stenognathus.

Franz Sikora found the first specimen and type of the recently extinct Hadropithecus stenognathus in Madagascar in 1899 and sent it to Ludwig Lorenz von Liburnau of the Austrian Imperial Academy of Sciences. Later, he sent several more specimens including a subadult skull that was described by Lorenz von Liburnau in 1902. In 2003, some of us excavated at the locality and found more specimens belonging to this species, including much of a subadult skeleton. Two frontal fragments were found, and these, together with most of the postcranial bones, belong to the skull. CT scans of the skull and other jaw fragments were made in Vienna and those of the frontal fragments at Penn State University. The two fragments have been reunited with the skull in silico, and broken parts from one side of the skull have been replaced virtually by mirror-imaged complete parts from the other side. The parts of the jaw of another individual of a slightly younger dental age have also been reconstructed virtually from CT scans with mirror imaging and by using the maxillary teeth and temporomandibular joints as a guide to finish the reconstruction. Apart from forming a virtual skull for biomechanical and systematic analysis, we were also able to make a virtual endocast. Missing anterior pieces were reconstructed by using part of an endocast of the related Archaeolemur majori. The volume is 115 ml. Hadropithecus and Archaeolemur seem to have had relatively large brains compared with the other large-bodied subfossil lemurs.

Knockout-transgenic mouse model of sickle cell disease.

When transgenic mice that expressed human sickle hemoglobin were mated with mice having knockout mutations of the mouse alpha- and beta-globin genes, animals were produced that synthesized only human hemoglobin in adult red blood cells. Similar to many human patients with sickle cell disease, the mice developed a severe hemolytic anemia and extensive organ pathology. Numerous sickled erythrocytes were observed in peripheral blood. Although chronically anemic, most animals survived for 2 to 9 months and were fertile. Drug and genetic therapies can now be tested in this mouse model of sickle cell disease.

Human sickle hemoglobin in transgenic mice.

DNA molecules that contain the human alpha- and beta s-globin genes inserted downstream of erythroid-specific, deoxyribonuclease I super-hypersensitive sites were coinjected into fertilized mouse eggs and a transgenic mouse line was established that synthesizes human sickle hemoglobin (Hb S). These animals were bred to beta-thalassemic mice to reduce endogenous mouse globin levels. When erythrocytes from these mice were deoxygenated, greater than 90 percent of the cells displayed the same characteristic sickled shapes as erythrocytes from humans with sickle cell disease. Compared to controls the mice have decreased hematocrits, elevated reticulocyte counts, lower hemoglobin concentrations, and splenomegaly, which are all indications of the anemia associated with human sickle cell disease.

Synthesis of functional human hemoglobin in transgenic mice.

Human alpha- and beta-globin genes were separately fused downstream of two erythroid-specific deoxyribonuclease (DNase) I super-hypersensitive sites that are normally located 50 kilobases upstream of the human beta-globin gene. These two constructs were coinjected into fertilized mouse eggs, and expression was analyzed in transgenic animals that developed. Mice that had intact copies of the transgenes expressed high levels of correctly initiated human alpha- and beta-globin messenger RNA specifically in erythroid tissue. An authentic human hemoglobin was formed in adult erythrocytes that when purified had an oxygen equilibrium curve identical to the curve of native human hemoglobin A (Hb A). Thus, functional human hemoglobin can be synthesized in transgenic mice. This provides a foundation for production of mouse models of human hemoglobinopathies such as sickle cell disease.

Detection of spinal cord compression in dogs with cervical intervertebral disc disease by magnetic resonance imaging.

The medical records and magnetic resonance images of 33 dogs with surgically confirmed Hansen type I cervical intervertebral disc disease were reviewed. Fourteen of the dogs were chondrodystrophic and 19 were not chondrodystrophic. The most common clinical sign was neck pain, which affected 28 of the dogs, and 23 of the dogs were able to walk. Fifteen of the dogs had developed clinical signs acutely, within the previous 24 hours. On cross-sectional images the median area of spinal cord compression was 26 per cent (range 11 to 71 per cent) of the normal spinal cord area. The degree of spinal cord compression was significantly associated with the dogs' presurgical neurological status but not with their postsurgical neurological status. The dogs with an acute onset of clinical signs had more severe neurological dysfunction before surgery, but their condition improved more as a result of surgery.

Human gamma-globin gene promoter element regulates human beta-globin gene developmental specificity.

The persistence of fetal hemoglobin in many patients with deletion type beta thalassemias and the expression patterns of human globin genes in transgenic mice suggest that gamma- to beta-globin gene switching results primarily from competition of gamma- and beta-globin genes for interaction with the beta-globin locus control region (LCR). To define regulatory sequences that are essential for the competitive advantage of the gamma gene at early developmental stages, stable transgenic mouse lines were produced with LCR gamma-beta constructs containing deletions of gamma 5'-flanking DNA. All constructs contained the full 22 kb LCR, a 4.1 kb beta-globin gene and a gamma-globin gene with 1348, 383, 202, 130, 72 or 52 bp of 5'-flanking sequence. Primer extension analysis of yolk sac, fetal liver and blood RNA from these lines demonstrated that a region between -202 and -130 of the human gamma-globin gene promoter was required to suppress beta-globin gene expression at early developmental stages. Four transcription factor binding sites within this region [GATA(p), Oct1, GATA(d) and CACCC] were mutated independently in LCR gamma-beta constructs and transgenic mouse lines were produced. Only the gamma CACCC box mutation resulted in high levels of beta-globin gene expression in early embryos. These results demonstrate that the CACCC box of the human gamma-globin gene plays a critical role in human beta-globin gene developmental specificity. The data also suggest that gamma CACCC box binding factors mediate LCR-gamma interactions which normally enhance gamma-globin and suppress beta-globin gene expression in fetal erythroid cells.

Redescription of Pseudotropheus livingstonii and Pseudotropheus elegans from Lake Malawi, Africa.

Pseudotropheus livingstonii and P. elegans are two sand-dwelling cichlid species that belong to the so-called mbuna, a group of predominantly rock-dwelling haplochromines of Lake Malawi. The identity of these two species has confused taxonomists for almost a century until a recent rediscovery of representatives of P. elegans close to its type locality. New diagnoses for both species are provided.

Clinical Applications of Barbed Suture in Aesthetic Breast Surgery.

The breadth of literature regarding barbed suture applications in plastic surgical procedures and of importance to this article, barbed suture applications in breast surgery, is growing dramatically as surgical practitioners are becoming more familiar with the advantages of this new suture technology. Barbed suture devices were first implemented by plastic surgeons for the use in various minimally invasive techniques for facial rejuvenation, but have now surpassed these applications and are now much more commonly used in Breast and Body closures.

Plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) and clinical symptoms in Alzheimer's disease.

Postmortem findings point to significant abnormalities in central noradrenergic function in Alzheimer's disease (AD) which may be associated with changes in peripheral markers. In this study, the relationship between the peripheral noradrenergic marker, plasma 3-methoxy-4-hydroxyphenylglycol (MHPG), and clinical symptoms was examined in 23 patients with probable AD. Basal MHPG levels correlated significantly with increased cognitive impairment (r = .58, p = .005), controlling for age, age at onset, gender, and time interval between plasma MHPG determination and cognitive testing. These results suggest that plasma MHPG increases as cognitive function in AD deteriorates, further supporting preliminary evidence for increases in noradrenergic indices in association with disease severity in AD.

Clinical symptoms associated with age at onset in Alzheimer's disease.

OBJECTIVE: The aim of the study was to examine the relationship between age at onset of Alzheimer's disease and demographic and clinical characteristics in a large cohort of patients with Alzheimer's disease. METHOD: The subjects were 104 patients meeting the criteria for Alzheimer's disease of the National Institute of Neurological and Communicative Disorders and Stroke. The relationships of age at disease onset to cognitive and noncognitive variables and to rate of progression were explored by using multiple regression analysis. RESULTS: Earlier disease onset was associated with the presence of greater language and praxis difficulties and with the development of higher depression scores during the follow-up study period but not with faster disease progression. CONCLUSIONS: These findings suggest that in Alzheimer's disease, which is a clinically heterogeneous illness, younger age at onset may be related to the presence of more prominent language and praxis impairment and to development of greater depression during the disease course.

Lack of association between cortisol hypersecretion and nonsuppression on the DST in patients with Alzheimer's disease.

Among 23 patients with Alzheimer's disease, 11 (48%) exhibited cortisol hypersecretion (> or = 11.8 micrograms/dl) and nine (39%) displayed cortisol nonsuppression on the dexamethasone suppression test. Only four patients exhibited both neuroendocrine abnormalities, demonstrating a lack of association between these two neuroendocrine disturbances of over 50%. Twenty-two of the 23 patients were studied for 4 1/2 years, and 14 died during that period. Six of the eight surviving patients exhibited cortisol hypersecretion without cortisol nonsuppression.

Resistance exercise training increases muscle strength, endurance, and blood flow in patients with chronic heart failure.

Resistance exercise training was well tolerated in patients with stable, chronic heart failure, resulting in increased strength and endurance, and lower oxygen consumption at submaximum workloads but no improvement in VO2peak. There was also a significant increase in basal forearm blood flow following this form of exercise training.

Noncognitive disturbances in Alzheimer's disease: frequency, longitudinal course, and relationship to cognitive symptoms.

OBJECTIVE: To investigate the frequency and longitudinal course of symptoms of depression, agitation, and psychosis in a longitudinally studied sample of patients with Alzheimer's disease (AD). DESIGN: Longitudinal study of AD patients with follow-up assessments at 6-month intervals for an average of more than 3 years. SETTING: Alzheimer's Disease Research Center of the Mount Sinai Medical Center and the Bronx VA Medical Center, New York. PARTICIPANTS: A total of 153 AD patients. MEASUREMENTS: Blessed Test of Information, Memory and Concentration (BIMC) and the Alzheimer's Disease Assessment Scale cognitive (ADAS-Cog) and noncognitive (ADAS-NC) subscales. RESULTS: At entry into the study, more than 90% of patients had a behavioral disturbance that was rated as mild or worse on one of the 10 ADAS noncognitive items; and 40% had at least one rating that was moderate or severe. Correlational analyses indicated that, with the exception of the two mood-related items, noncognitive symptoms on the ADAS were not highly correlated with one another. Only one of the noncognitive items, concentration, was strongly correlated with the severity of cognitive impairment. On average, patients showed progressively worse cognitive functioning over time as measured both by the ADAS-Cog and the BIMC. The mean severity of noncognitive symptoms did not change during the course of a 5-year follow up. The severity of behavioral disturbance at any one evaluation was negatively correlated with change in behavior during the next 6 months and was not correlated with cognitive decline. CONCLUSION: Mild behavioral disturbances are common, whereas moderate to severe behavioral symptoms are less frequent in this population of AD patients. Disturbances in mood and manifestations of agitation and psychotic symptoms are not closely related to one another and show little progressive worsening over time. Rather, they tend to be episodic such that increasing severity at one time is usually followed by improvement later. Concentration problems are a manifestation of cognitive dysfunction rather than behavioral disturbance in AD. Implications of these results for treatment of noncognitive disturbances in AD are discussed.

L-deprenyl and physostigmine for the treatment of Alzheimer's disease.

The present study evaluated the safety of and obtained preliminary data on the cognitive effects of L-deprenyl and physostigmine in patients with Alzheimer's Disease. Seventeen outpatients with Alzheimer's Disease participated in a double-blind crossover study in which they received 4 weeks of L-deprenyl at a dose of 10 mg p.o., q.d., and 4 weeks of placebo in random order. During both the L-deprenyl and placebo periods, patients received cognitive assessments during physostigmine (0.5 mg) and placebo infusions separated by 2 days. The cognitive effects of these agents alone and in combination were measured with digit span, verbal fluency, list learning, praxis, delayed recall, and delayed recognition tasks. Fifteen patients completed the study. The two drugs, used alone or in combination, were safe and well tolerated. Analyses of variance demonstrated that neither physostigmine nor L-deprenyl, whether given alone or in combination, significantly improved cognition, when compared with the double placebo condition.

Post-mortem examination of dopaminergic parameters in Alzheimer's disease: relationship to noncognitive symptoms.

Dopaminergic mechanisms have been implicated in depression, agitation, and psychosis--symptoms that are frequently observed in patients with Alzheimer's disease (AD). In a longitudinal study, 23 prospectively assessed AD patients underwent autopsies in which concentrations of dopamine, homovanillic acid, and dihydroxyphenylacetic acid were assayed in the temporal lobe (Brodmann areas 20 and 21). Data-reduction techniques were used to minimize the number of relationships tested. For this series of AD patients, no significant correlation was found between indices of dopaminergic neurotransmission and maximal severity of psychosis, depression, or agitation.

Consequences and costs of shutting off methadone.

In the face of rising fiscal conservatism, many states and localities with sizable addict populations have reduced or eliminated public funding for methadone maintenance (MM) programs and permitted private-fee-for-service programs to replace them. The social and economic costs of these changed funding policies with reference to the California experience were analyzed. A two-and-a-half year follow-up of a sample of San Diego MM clients (195 men, 129 women) terminated from a public subsidized program compared outcome results to clients from publicly funded MM programs in Orange, Riverside and San Bernardino counties (129 men, 131 women). In a secondary analysis, San Diego clients who transferred into private (fee-for-service) treatment programs were compared with those who did not transfer. Major adverse consequences were found for clients unable or unwilling to transfer to private programs: higher crime and dealing rates, more contact with the criminal justice system, and higher rates of illicit drug use were demonstrated by nontransfer clients. Moreover, the savings resulting from a reduction of MM program costs were nearly offset by increased direct costs for incarceration, legal supervision, and other government-funded drug treatment. Indirect costs were not assessed.

Phenylephrine tumescence in split-thickness skin graft donor sites in surgery for burn injury- a concentration finding study.

The purpose of this study is to determine the lowest concentration of subcutaneous phenylephrine (neosynephrine) required for effective vasoconstriction in skin graft donor sites. Surgery for burn injury is associated with blood loss. Tourniquet use and tumescence with epinephrine have decreased blood loss. However, absorption of epinephrine has been reported with systemic effects. Phenylephrine, an α1-adrenergic receptor agonist, has vasoconstrictive properties similar to epinephrine's without other α-adrenergic or ß-adrenergic activity. The aim of this study is to determine the lowest effective concentration of phenylephrine that will provide vasoconstriction in split-thickness graft donor sites. By using intensive care unit equivalency tables, the authors estimated a concentration of phenylephrine on the basis of current epinephrine tumescence. This concentration was titrated up or down according to an algorithm established a priori, determining the minimum concentration that achieved vasoconstriction in three consecutive patients. The primary outcome was local vasoconstriction. Secondary outcomes measured were pre-, intra-, and postoperative mean arterial pressure, systolic pressure and heart rate, graft take, and donor site healing. The subjects were six otherwise healthy adult patients (five men and one woman) with a mean age of 36 years. The average TBSA was 737.5 cm². Vasoconstriction was achieved at 5 µg/ml. No significant alterations in hemodynamic measures were observed. The optimal concentration of phenylephrine for prevention of bleeding in donor sites appears to be 5 µg/ml. Participants will be able to identify the effects of phenylephrine and epinephrine tumescence. They will also identify the concentration at which phenylephrine will be effective in donor sites.