Total synthesis of the L-hexoses.

Enantiomerically pure polyhydroxylated natural products are synthesized by using a reiterative two-carbon extension cycle consisting of four steps. The generality and efficiency of this methodology are demonstrated in the total synthesis of all eight L-hexoses.

The neuropathology of a chromosome 17-linked autosomal dominant parkinsonism and dementia ("pallido-ponto-nigral degeneration").

A group of similar autosomal dominant hereditary neurodegenerative disorders have been linked to chromosome 17 in thirteen kindreds. One of these disorders, known as pallido-ponto-nigral degeneration (PPND), is characterized by extensive degeneration of the globus pallidus and substantia nigra as well as accumulation of abnormally phosphorylated tau proteins. The authors now present comprehensive data on the cellular and molecular pathology of PPND, allowing its classification among chromosome 17-linked neurodegenerative disorders as well as its classification among sporadic and other familial tauopathies. First, we showed that PPND is characterized by abundant ballooned neurons in neocortical and subcortical regions as well as by tau-rich inclusions in the cytoplasm of neurons and oligodendroglia morphologically similar to those seen in corticobasal degeneration (CBD), but in a distribution pattern resembling progressive supranuclear palsy (PSP). Second, we demonstrated that antibodies to phosphorylation-independent (Alz50, 133, 304, Tau-2, T-46) as well as phosphorylation-dependent (AT8, PHF-6, 12E8, PHF-1, T3P, pS422) epitopes in human tau proteins stain these glial and neuronal inclusions as intensely as they stain CBD or PSP inclusions. Third, we probed PPND brain by Western blots using some of the same anti-tau antibodies to reveal 2 tau immunobands with molecular weights of 69 kD and 64 kD in gray and white matter extracts, as reported for both PSP and CBD. Finally, electron microscopy showed that these abnormal tau proteins formed flat twisted ribbons with a maximum diameter of 20 nanometers (nm) and a periodicity of about 200 nm, resembling those reported in CBD. Based on this, we conclude that PPND is a hereditary neurodegenerative disorder characterized by neuronal and glial tau-rich inclusions formed from aggregated filaments and hyperphosphorylated tau proteins and, hence, can be subcategorized into the tauopathy group of chromosome 17-linked neurodegenerative disorders. Further, since the morphologic and biochemical lesions of PPND overlap with those seen in sporadic CBD and PSP, we speculate that these disorders share common pathogenetic mechanisms.

Phenotypic correlations in FTDP-17.

Frontotemporal dementias with parkinsonism linked to chromosome 17 (FTDP-17) are hereditary tauopathies affecting at least 50 known kindred worldwide. Most kindred present with severe behavioral or psychiatric manifestations progressing to dementia, while some kindred first manifest a parkinsonian-plus syndrome. Nine missense mutations, one deletion mutation, and two transition mutations not altering the encoded amino acid, have been described in or near the microtubule-binding domains within exons 9, 10, 12, and 13. In addition, five different intronic mutations have been reported in the 5' splice-site of the alternatively spliced exon 10. Missense mutations affecting constitutively expressed exons affect all six major tau isoforms and result in neurofibrillary tangles similar to those present in secondary tauopathies, such as Alzheimer's disease. In contrast, mutations that affect the alternatively spliced exon 10 or its 5' splice regulatory region alter the ratio of the tau isoforms incorporated into the tangles and result in filamentous inclusions resembling those seen in the primary tauopathies, such as progressive supranuclear palsy, corticobasal degeneration, and Pick's disease. The severity and heterogeneity of the clinicomorphologic phenotype may, in part, reflect the diversity in the primary molecular mechanisms of disease in FTDP-17.

Albumin and labile-protein serum concentrations during very-low-calorie diets with different compositions.

Circulating concentrations of albumin and the labile proteins prealbumin (PA) and retinol-binding protein (RBP) were evaluated over 20 d in five groups of obese patients. The patients were given four types of very-low-calorie diets (VLCDs) (less than 500 kcal/d) that provided different amounts of protein or carbohydrate (CHO) plus protein and a conventional 1200-kcal/d hypocaloric diet. Serum albumin concentrations did not vary significantly during any of the diets whereas PA and RBP remained unchanged only during the conventional 1200-kcal/d diet. Similar and significant decreases of serum PA and RBP were observed during the VLCDs studied. The molar ratio of RBP to PA did not vary during dieting. Thus, when less than 500 kcal/d are given, changes of serum short-half-life visceral proteins are not affected by either the addition of CHO to protein or the changes in protein intake. Moreover, serum albumin concentration and RBP/PA do not vary during VLCDs.

Nasal dimple as part of the 22q11.2 deletion syndrome.

The phenotype of the 22q11.2 microdeletion syndrome is quite variable. We describe 2 patients with a 22q11.2 deletion and a dimpled nasal tip, which, we suggest can be the extreme of the broad or bulbous nose commonly found in the 22q11.2 deletion syndrome, and should not be confused with the more severe nasal abnormalities seen in frontonasal dysplasia.

Giant cell arteritis in association with cerebral amyloid angiopathy: immunohistochemical and molecular studies.

Giant cell arteritis (GCA) usually manifests as a transmural vascular infiltrate of mononuclear and multinucleated giant cells (MNGC). We describe six patients with GCA associated with severe cerebral amyloid angiopathy (CAA), all with cerebral hemorrhage or varying degrees of cerebral infarct, and histological evidence of Alzheimer's disease (cortical CAA often predominating over senile plaques and neurofibrillary tangles). One case showed mostly cortical involvement (with old microhemorrhages), and the others were primarily leptomeningeal (with involvement of the underlying cortex and extensive encephalomalacia of adjacent brain). Many vessels with CAA exhibited a pronounced adventitial and perivascular infiltrate of lymphocytes, histiocytes, and MNGC. Immunohistochemical staining showed deposition of beta/A4 peptide primarily in the thickened media of CAA vessels, and within the cytoplasm of MNGC--suggesting phagocytosis of insoluble peptide. Cystatin C antibody stained vascular amyloid and diffusely highlighted astrocytic and MNGC cytoplasm. HAM56-positive macrophages were frequently seen around amyloid-laden vessels. Anti-smooth muscle actin immunohistochemistry suggests the occurrence of medial destruction by amyloid, with relative preservation of intimal cells. Ultrastructural studies performed in one case confirmed the presence of intracytoplasmic amyloid in MNGC. The GCA seen in these cases of CAA most likely represents a foreign body response to amyloid proteins, causing secondary destruction of the vessel wall. DNA from brain tissues of five affected patients was examined to assess whether mutations were present in exon 17 of the APP gene or exon 2 of the cystatin C gene, a finding that might explain the foreign body giant cell response to amyloid proteins in these cases. However, restriction fragment mapping of amplified gene segments showed that previously described mutations were not present in these cases.

Cardiovascular risk factors and age of onset of obesity in severely obese patients.

Aim of this study was to evaluate whether the age of onset of obesity might affect the prevalence of CV risk factors in severely obese patients. Five hundred forty-five (385 F aged 42.3 +/- 7.1 yrs, BMI 47.3 +/- 5.1 w/h2 and 160 M of 39.0 +/- 1.1 yrs and BMI of 41.8 +/- 5.3 w/h2) severely obese patients hospitalized in the Metabolic Unit between 1972 and 1985 were subdivided in four classes according to the age of onset of obesity. Severely obese women with maturity onset obesity (i.e. onset greater than or equal to 20 yrs) (MOO) had higher (p less than or equal to .01) serum glucose (118 vs 103 mg/dl) and triglyceride (167 vs 126 mg/dl) than those with early onset obesity (EOO) (i.e. onset less than or equal to 3 yrs) with the same age, BMI and smoking habits. Similar trend was also found in men. In males arterial blood pressure was found to be higher (p less than or equal to .01) in EOO than in MOO (SBP = 152 vs 133 mmHg and DBP = 92 vs 83 mmHg). Similar trend was found in females. In conclusion age of onset of obesity may, at least in part, affect the prevalence of cardiovascular risk factors in severe obesity.

Occurrence of pesticide residues in four streams draining different land-use areas in Pennsylvania, 1969-71.

Samples of water, streambed material, fish, and soil were collected in four small drainage basins in Pennsylvania in 1969-71 and analyzed to determine the concentrations of chlorinated hydrocarbon insecticides. Water samples were also analyzed for phenoxy-acid herbicides. Each basin studied represents a predominant land use: forest, general farms, residential areas, and orchards. All water and fish samples showed pesticide concentrations less than the maximum level recommended by the Public Health Service, U.S. Department of Health, Education, and Welfare. However, no fish were found in the orchard stream. DDT or one of its metabolites was the most frequently occurring insecticide and was detected in all media sampled except the forest soil. The highest combined concentration of DDT and its metabolites in storm-runoff samples was 11.4 mug/liter in a sample collected from the residential area stream, but the median was higher (0.12 mug/liter) in the orchard than in the residential area (0.02 mug/liter). A sample of the top 0.5 inch (13 mm) of orchard soil contained 40,000 mug/kg DDT and its metabolites, even though DDT had not been used in the orchards for several years prior to this study. Maximum concentrations detected in other orchard media are 330 mug/kg in streambed material and 3.45 mug/kg in storm runoff. Dieldrin was the second most frequently occurring insecticide. Other insecticides detected were chlordane, heptachlor epoxide, lindane, and a trace of aldrin in one fish sample. Each stream contained at least one of the following herbicides: 2,4-D, silvex, or 2,4,5-T.

Pictorial cues and enhancement of patient recall of instructions or information.

Optometrists utilize handouts and pamphlets to facilitate information and instruction recall by their patients. A study was conducted to determine the effect of using pictorial cues. Thirty-six college students learned fifteen nouns in numerical order. In one condition subjects perceived the nouns alone, in another they perceived the nouns with illustrations. Half of the subjects in each condition were tested immediately after stimuli presentation; the remaining subjects were tested after a one-hour delay. It was determined that a picture-word association occurred, and decreased memory decay (longer memory) occurred for compound stimuli. This indicated that visual stimuli can facilitate word memory and pictorial cues would, therefore, be beneficial.

A unique autosomal dominant disorder with indifference to pain: clinicopathologic correlation of indifference to pain and thalamic gliosis.

We present updated information on a previously reported kindred with an autosomal dominant disorder variably expressed as indifference to pain, dementia, and ataxia. Additional clinical and radiological information is presented, as are autopsy results form the index case. In addition to evidence of Alzheimer's disease, the autopsy revealed bilateral thalamic gliosis, which may be a neuroanatomic substrate for the indifference to pain seen in this patient. To our knowledge, this is the first reported association of thalamic gliosis and indifference to pain.

Diarrheal condition in dogs associated with viruses antigenically related to feline herpesvirus.

Viruses with properties consistent with herpesvirus were isolated from dogs with diarrhea. The viruses were shown to be antigenically related to feline herpesvirus-1 (FHV-1) by virus neutralization tests. It was also observed that a canine herpesvirus (CHV) prototype, D004, and two field isolates from fatal CHV infections in 2-week-old and 6-week-old puppies were neutralized at a low level by antiserum to FHV-1. Reciprocal neutralization tests with CHV antiserum against FHV-1 were negative. These results indicated that viruses related to FHV-1 can infect the dog and that there appears to be uni-directional virus neutralization of CHV by FHV-1 antibody.

Cryptosporidiosis outbreak in a day-care center.

An outbreak of diarrhea occurred in a day-care center in San Marcos, Tex, in August 1984. At the time of this study, the center was caring for 81 children aged 2 months through 5 years. A single stool specimen was collected from each of 50 children (62%). Cryptosporidium oocysts and Giardia lamblia cysts were each identified in stool specimens from 18 children. Three children had both parasites present in the same stool specimen. Echovirus 30 was identified in 19 of 25 stools cultured. Although three pathogens were circulating simultaneously in this group of children, only the presence of Cryptosporidium oocysts was associated with the occurrence of a diarrheal illness. Cryptosporidium may be a common cause of diarrhea in children who attend day-care centers.

Autosomal dominant dementia with widespread neurofibrillary tangles.

Several familial dementing conditions with atypical features have been characterized, but only rarely is the neuropathology dominated solely by neurofibrillary lesions. We present a Midwestern American pedigree spanning four generations in which 15 individuals were affected by early-onset dementia with long disease duration, with an autosomal dominant inheritance pattern, and with tau-rich neurofibrillary pathology found in the brain post mortem. The average age at presentation was 55 years with gradual onset and progression of memory loss and personality change. After 30 years' disease duration, the proband's neuropathologic examination demonstrated abundant intraneuronal neurofibrillary tangles (NFTs) involving the hippocampus, pallidum, subthalamic nucleus, substantia nigra, pons, and medulla. Only sparse neocortical tangles were present and amyloid plaques were absent. The tangles were recognized by antibodies specific for phosphorylation-independent (Tau-2, T46, 133, and Alz-50) and phosphorylation-dependent epitopes (AT8, T3P, PHF-1, 12E8, AT6, AT18, AT30) in tau proteins. Electron microscopy of NFTs in the dentate gyrus and midbrain demonstrated paired helical filaments. Although the clinical phenotype resembles Alzheimer's disease, and the neuropathologic phenotype resembles progressive supranuclear palsy, an alternative consideration is that this familial disorder may be a new or distinct disease entity.

Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17.

Thirteen families have been described with an autosomal dominantly inherited dementia named frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), historically termed Pick's disease. Most FTDP-17 cases show neuronal and/or glial inclusions that stain positively with antibodies raised against the microtubule-associated protein Tau, although the Tau pathology varies considerably in both its quantity (or severity) and characteristics. Previous studies have mapped the FTDP-17 locus to a 2-centimorgan region on chromosome 17q21.11; the tau gene also lies within this region. We have now sequenced tau in FTDP-17 families and identified three missense mutations (G272V, P301L and R406W) and three mutations in the 5' splice site of exon 10. The splice-site mutations all destabilize a potential stem-loop structure which is probably involved in regulating the alternative splicing of exon10. This causes more frequent usage of the 5' splice site and an increased proportion of tau transcripts that include exon 10. The increase in exon 10+ messenger RNA will increase the proportion of Tau containing four microtubule-binding repeats, which is consistent with the neuropathology described in several families with FTDP-17.