The diagnosis of the early infantile form of hypophosphatasia tarda.

The diagnostic characteristics of the early infantile form of hypophosphatasia tarda are demonstrated in a case of a first child of healthy, probably consanguineous, unmarried parents. The diagnosis of the disease is based on the clinical and radiographic findings. The absence of alkaline phosphatase activity in the blood serum and leukocytes, and the excretion of phosphorylethanolamine in urine confirm the diagnosis. The inheritance appears to be autosomal recessive.     

Hyperphosphatemia in infantile hypophosphatasia: implications for carrier diagnosis and screening.

Twenty obligate carriers of infantile hypophosphatasia (HOPS), a severe autosomal recessive metabolic bone disorder, were studied and compared with 36 controls. Decreased serum alkaline phosphatase activity and increased urinary phosphoethanolamine excretion were confirmed in the HOPS carriers. Relative hyperphosphatemia was documented for the first time in the carriers. Logistic regression analysis was used to develop models for the diagnosis of and screening for HOPS carriers in the high-risk population of Manitoba Mennonites. Models based on serum alkaline phosphatase activity and on serum phosphate levels with or without urinary phosphoethanolamine excretion were used for diagnostic purposes. A model based on serum alkaline phosphatase activity and on the serum phosphate level was the most suitable for screening.     

The early diagnosis of carcinoma of the stomach

The insidious nature of carcinoma of the stomach has induced a pessimistic attitude in the medical profession, for by the time the unmistakable signs of malignant disease become evident, the patient is doomed. Improvement in results of the surgical treatment of gastric carcinoma will come only with early diagnosis, which is in turn dependent upon appreciation of the gravity of recognizable epigastric distress and the application of the available diagnostic procedures to aid in the diagnosis of malignant lesions in the early, preinvasive stages. Recognition of the significant risk of malignant change in gastric ulcers is essential, for a high degree of suspicion in the presence of the symptoms of ulcer can lead to diagnosis of malignant lesions at a stage when resection can cure.     

Prenatal diagnosis of hypophosphatasia; genetic, biochemical, and clinical studies.

This report has considered three approaches to the prenatal diagnosis of the severe, early onset form of hypophosphatasia. Two of these approaches, ultrasonography and the determination of the bone/liver isozymes of alkaline phosphatase (ALP) in cultured amniotic fluid cells, have proven useful diagnostically. The third method, assay of the bone/liver isozyme activity or total activity in supernatant amniotic fluid, was not informative for the affected fetus we studies. Failure to visualize a well-defined fetal skull after 16 weeks of pregnancy when the level of alpha-fetoprotein in the amniotic fluid is normal should arouse the suspicion of hypophosphatasia. Because the disease is known to manifest clinical variabiltiy, studies to detect both the biochemical defect as well as the structural manifestations should be considered. The combined use of ultrasonography, analysis of amniotic fluid alpha-fetoprotein, and the measurement of the bone/liver ALP in cultured amniotic fluid cells would appear to be the best approach to the prenatal diagnosis.     

The allometry of leaf form in early plant ontogeny

A general allometric model between metabolic rate and body size has been derived for early plant ontogeny. The scaling exponent is (2 + N/6)/3, where N is the cell’s degree of freedom of motion. For early plant ontogeny N = 2, our prediction agrees well with Sack et al.’s observation [Sack, L., Maranon, T., Grubb, P.J., 2002. Science 295, 1923].     

On the origin of pattern and form in early Metazoans

The 'Cambrian explosion', about 540 million years ago, may have occurred within 10 to 50 million years. Almost all of the modern phyla, a very restricted group and many groups that may represent extinct phyla, suddenly appear near that time in the fossil record. Numerous extensive periods of mass extinction since that time led to no new phyla. This is taken as an impetus to examine a possible source, beyond Darwinian adaptation, of the apparently restricted number of phyla. Such a postulated constraint or restriction beyond adaptation is proposed to be based on a mutation or mutations allowing single celled or colonial precursors to begin forming into epithelial sheets and gene activation patterns of a particular kind, those giving rise to the very earliest metazoans. The interaction of signaling pathways in pairs, with different pairs acting sequentially are proposed as key to this earliest patterning, such patterning being extensively elaborated over the last approximately 550 million years. Restrictions on the very large set of possible forms and patterns on which adaptation acts are discussed.     

The molecular basis of X-linked spondyloepiphyseal dysplasia tarda

The X-linked form of spondyloepiphyseal dysplasia tarda (SEDL), a radiologically distinct skeletal dysplasia affecting the vertebrae and epiphyses, is caused by mutations in the SEDL gene. To characterize the molecular basis for SEDL, we have identified the spectrum of SEDL mutations in 30 of 36 unrelated cases of X-linked SEDL ascertained from different ethnic populations. Twenty-one different disease-associated mutations now have been identified throughout the SEDL gene. These include nonsense mutations in exons 4 and 5, missense mutations in exons 4 and 6, small (2-7 bp) and large (>1 kb) deletions, insertions, and putative splicing errors, with one splicing error due to a complex deletion/insertion mutation. Eight different frameshift mutations lead to a premature termination of translation and account for >43% (13/30) of SEDL cases, with half of these (7/13) being due to dinucleotide deletions. Altogether, deletions account for 57% (17/30) of all known SEDL mutations. Four recurrent mutations (IVS3+5G-->A, 157-158delAT, 191-192delTG, and 271-275delCAAGA) account for 43% (13/30) of confirmed SEDL cases. The results of haplotype analyses and the diverse ethnic origins of patients support recurrent mutations. Two patients with large deletions of SEDL exons were found, one with childhood onset of painful complications, the other relatively free of additional symptoms. However, we could not establish a clear genotype/phenotype correlation and therefore conclude that the complete unaltered SEDL-gene product is essential for normal bone growth. Molecular diagnosis can now be offered for presymptomatic testing of this disorder. Appropriate lifestyle decisions and, eventually, perhaps, specific SEDL therapies may ameliorate the prognosis of premature osteoarthritis and the need for hip arthroplasty.     

The early clinical features of dengue in adults: challenges for early clinical diagnosis

Background

The emergence of dengue throughout the tropical world is affecting an increasing proportion of adult cases. The clinical features of dengue in different age groups have not been well examined, especially in the context of early clinical diagnosis.

Methodology/Principal Findings

We structured a prospective study of adults (≥18 years of age) presenting with acute febrile illness within 72 hours from illness onset upon informed consent. Patients were followed up over a 3–4 week period to determine the clinical outcome. A total of 2,129 adults were enrolled in the study, of which 250 (11.7%) had dengue. Differences in the rates of dengue-associated symptoms resulted in high sensitivities when the WHO 1997 or 2009 classification schemes for probable dengue fever were applied to the cohort. However, when the cases were stratified into age groups, fewer older adults reported symptoms such as myalgia, arthralgia, retro-orbital pain and mucosal bleeding, resulting in reduced sensitivity of the WHO classification schemes. On the other hand, the risks of severe dengue and hospitalization were not diminshed in older adults, indicating that this group of patients can benefit from early diagnosis, especially when an antiviral drug becomes available. Our data also suggests that older adults who present with fever and leukopenia should be tested for dengue, even in the absence of other symptoms.

Conclusion

Early clinical diagnosis based on previously defined symptoms that are associated with dengue, even when used in the schematics of both the WHO 1997 and 2009 classifications, is difficult in older adults.     

Niemann Pick disease: presence of the magnesium-dependent sphingomyelinase in brain of the infantile form of the disease.

Abstract— Brain of a 14-month-old patient with the infantile form of Niemann Pick disease was found to be practically devoid of sphingomyelinase activity when assayed at pH 5. When assayed at pH 7.4, in the presence of magnesium ions considerable hydrolysis of sphingomyelin was obtained by brain preparations. The rate of hydrolis of a homogenate of grey matter was about 0.3 μmol. mg protein^?1. H^?1, corresponding to about 15 μmol of sphingomyelin hydrolysed perg brain in 1 h. The possibility is suggested that the presence of the extra-lysosomal, magnesium dependent sphingomyelinase in brain of Niemann Pick patients may be responsible, in part, for the lesser accumulation of sphingomyelin in this tissue relative to other organs, such as liver or spleen.