Cognitive and motor skills in achondroplastic infants: Neurologic and respiratory correlates

Thirteen infants with achondroplasia underwent psychometric testing as part of a comprehensive neurologic assessment. As a group, mental development was average and motor development was delayed, although a wide range of scores was obtained. Foramen magnum measurements were correlated with respiratory dysfunction, abnormal so-matosensory evoked potentials, and delayed motor development. Abnormal polysomno-gram outcome was associated with reduced mental capacity. In light of the reported increased frequency of respiratory dysfunction in achondroplasia, these findings warrant careful attention and further study.     

Fine-needle aspiration cytology of juvenile papillomatosis of breast: A case report

The cytologic findings of juvenile papillomatosis (JP) have been rarely described. The clinical and cytologic findings were suggestive of a fibroadenoma, but due to the presence of 2 cc of clear fluid during the aspiration, fibrocystic change was in the differential diagnosis. Operation and subsequent examination of the mass identified a case of JP (so-called Swiss cheese disease of the breast). Because JP is a marker for breast carcinoma for the patients' families, and the patients may themselves be at increase risk for malignancy, it is important that this entity be considered in the differential diagnosis. The observations in this case indicate that it is difficult to diagnose JP only by cytology, but the combination of clinical findings—a well-circumscribed mass in a young patient with cystic fluid, but with a residual mass after aspiration due to the multicystic nature of JP—with the cytologic findings—sheets of hyperplatic breast epithelium with areas resembling fibroadenoma, macrophages, and apocrine cells—that appear to be sufficiently characteristic to suggest the diagnosis of JP.     

Histologic and immunohistochemical characteristics of neoplastic and nonneoplastic subgroups of atypical squamous lesions of the uterine cervix

Atypical squamous lesion (ASL), a histologic diagnosis of unclear significance in the uterine cervix, can be divided into neoplastic and nonneoplastic groups. We aimed to determine the morphologic characteristics of these 2 groups. Histologic and immunohistochemical features were evaluated on the original biopsy specimen from 37 ASL cases, and the results were compared between neoplastic (19 cases) and nonneoplastic (18 cases) groups, which were determined based on the follow-up histopathologic findings. Mitosis, vertical nuclear growth pattern, no perinuclear halo, indistinct cytoplasmic border, primitive cells in the upper third of the squamous layer, p16+ cells in the upper two thirds of the squamous layer, and Ki-67+ cells in the upper two thirds of the squamous layer were significant indicators for neoplastic ASLs. Of the 19 neoplastic ASLs, 16 (84%) had 5 or more of these 7 indicators. The majority (16/18 [89%]) of the nonneoplastic ASLs had 2 or fewer indicators. Determination of the histologic and immunohistochemical characteristics is useful for distinguishing neoplastic and nonneoplastic ASLs.     

Morphine Stimulates Mesangial Cell TNF-α and Nitrite Production

Background: Intravenous opiate abusers are susceptible to develop heroin and HIV-associated nephropathies; however, the role of opiates in the development of these kidney lesions is not clear. Patients with opiate addiction are prone to recurrent infections. Methods: The effect of morphine was studied on the generation of TNF- with or without LPS (lipopolysaccharide) by cultured mouse mesangial cells. In addition, the effect of morphine was evaluated on mesangial cell nitrite production. To evaluate the role of opiate receptors, we studied the effect of naloxone and naltrexone on mesangial cell TNF- and nitrite production. To determine the role of TNF- on mesangial cell nitrite production, we examined the effect of anti-TNF- antibody on morphine-induced nitrite production. Assay of TNF- and nitrite production was carried by ELISA and Griess method respectively. Results: Morphine alone did not enhance the generation of TNF- by mesangial cells, however, an enhanced (P < 0.001) TNF- production was observed when mesangial cells were first treated with morphine for 18 h and then activated further with LPS. Maximum release of TNF- was seen at a concentration of 10^–12 M of morphine. Opiate receptor antagonists (naloxone and naltrexone) inhibited the effect of morphine. Morphine also amplified (P < 0.0002) the effect of LPS on mesangial cell nitrite production. Anti-TNF- antibody attenuated morphine induced nitrite generation. Conclusion: We conclude that morphine stimulates the generation of TNF- by LPS-activated mesangial cells. This effect of morphine seems to be opiate receptor mediated and has a downstream effect in the form of mesangial cell nitrite generation. The present in vitro study provides the basis for a hypothesis that morphine may be playing a role in the development of heroin and HIV-associated nephropathies.     

Scaffold protein harmonin (USH1C) provides molecular links between Usher syndrome type 1 and type 2

Usher syndrome (USH) is the most frequent cause of combined deaf-blindness in man. USH is clinically and genetically heterogeneous with at least 11 chromosomal loci assigned to the three USH types (USH1A-G, USH2A-C, USH3A). Although the different USH types exhibit almost the same phenotype in human, the identified USH genes encode for proteins which belong to very different protein classes and families. We and others recently reported that the scaffold protein harmonin (USH1C-gene product) integrates all identified USH1 molecules in a USH1-protein network. Here, we investigated the relationship between the USH2 molecules and this USH1-protein network. We show a molecular interaction between the scaffold protein harmonin (USH1C) and the USH2A protein, VLGR1 (USH2C) and the candidate for USH2B, NBC3. We pinpoint these interactions to interactions between the PDZ1 domain of harmonin and the PDZ-binding motifs at the C-termini of the USH2 proteins and NBC3. We demonstrate that USH2A, VLGR1 and NBC3 are co-expressed with the USH1-protein harmonin in the synaptic terminals of both retinal photoreceptors and inner ear hair cells. In hair cells, these USH proteins are also localized in the signal uptaking stereocilia. Our data indicate that the USH2 proteins and NBC3 are further partners in the supramolecular USH-protein network in the retina and inner ear which shed new light on the function of USH2 proteins and the entire USH-protein network. These findings provide first evidence for a molecular linkage between the pathophysiology in USH1 and USH2. The organization of USH molecules in a mutual 'interactome' related to the disease can explain the common phenotype in USH.     

Patient follow-up is a major problem at genetics clinics

Children with genetic diseases must be followed for long periods of time to seek new findings. Other patients require further check-ups and studies to be diagnosed. Some patients never return for medical care after the first consultation, which may have serious consequences. We reviewed 400 medical charts of patients with genetic disease to analyze overall attendance to the genetics clinic, investigate some of the causes of failure to seek medical advice, and determine the differences between those first seen as outpatients or as inpatients. The mean follow-up period was 8.3 months (range 0-79), and the average number of visits was 2.8 (range 1-16). Forty eight percent of the cases first seen as inpatients were evaluated only once and 14% twice; while 22 and 21% of the 300 cases first seen as outpatients attended once and twice, respectively (P = 0.0). Appointment keeping was apparently not affected by the presence or absence of diagnosis. Overall, 97 patients were discharged, 7 died, 55 continued on follow-up, 62 attended other hospital services-but not genetics-and 179 were completely lost to follow-up. Diagnosed patients were counseled more frequently than undiagnosed patients (62 vs. 5%); and 71% of the diagnosed patients first seen as outpatients but only 36% of undiagnosed cases first seen as inpatients were counseled, differences between these two groups were significant (P = 0.005). We conclude that keeping the patient with genetic disease on follow-up is a difficult task. New educational strategies must be planned to improve this worrisome situation.     

NPHS2 gene, nephrotic syndrome and focal segmental glomerulosclerosis: a HuGE review.

Nephrotic syndrome, characterized by edema, proteinuria, hyperlipidemia and low serum albumin, is a manifestation of kidney disease involving the glomeruli. Nephrotic syndrome may be caused by primary kidney disease such as focal segmental glomerulosclerosis. Mutations in the podocin gene, NPHS2, have been shown in familial and sporadic forms of steroid-resistant nephrotic syndrome, including focal segmental glomerulosclerosis. Podocin is an integral membrane protein located at the slit diaphragm of the glomerular permeability barrier. Complete information is lacking for the population frequency of some NPHS2 variants for all racial and ethnic groups. The most frequently reported variant, R229Q, is more common among European-derived populations than African-derived populations. We calculated crude odds ratios and 95% confidence intervals of childhood nephrotic syndrome and focal segmental glomerulosclerosis associated with R229Q heterozygosity using data from five studies. The R229Q variant is not associated with focal segmental glomerulosclerosis in the US population of African descent. In contrast, the R229Q variant is associated with a trend toward increased focal segmental glomerulosclerosis risk in European-derived populations, with an estimated increased risk of 20-40%. Our insight into the association between NPHS2 variants and nephrotic disease is hampered by the limitations of the existing studies, including small numbers of affected individuals and suboptimal control groups. Nevertheless, the available data suggest that large epidemiological case-control studies to examine the association between NPHS2 variants and nephrotic syndrome are warranted.     

A flow cytometric assay for the detection of antiphospholipid antibodies

The data and the results obtained at the above symposium show that the flow cytometric method closely correlates with the standardized aCL bench ELISA and with the APhL ELISA kit. The aCL/aPS FACS kit is comparable in sensitivity to the APhL ELISA kit and standard aCL bench ELISA, but the aCL/aPS FACS kit is more specific than the standard anticardiolipin assay (particularly for the determination of aPS). In summary, the aCL/aPS FACS kit enables rapid (total run time < or = 1 hr) and simultaneous determination of aCL (aCL) and anti-PS antibodies of the IgG and IgM classes and combines good sensitivity and specificity in a single assay. The method is reproducible (intraassay variations < 5%). Furthermore, it is easy to transform into a partially or fully mechanized process and is well suited for laboratories that test large numbers of samples daily. The assay promises to be useful not only for detecting positive APS sera, but also in evaluating the significance of phospholipid specificity and antibody isotypes in patients with APS.     

Coxsackievirus-mediated hyperglycemia is enhanced by reinfection and this occurs independent of T cells

The induction of autoimmunity by viruses has been hypothesized to occur by a number of mechanisms. Coxsackievirus B4 (CB4) induces hyperglycemia in SJL mice resembling diabetes in humans. While virus is effectively cleared within 2 weeks, hyperglycemia does not appear until about 8-12 weeks postinfection at a time when replicative virus is no longer detectable. In SJL mice, reinfection with CB4 enhanced the development of hyperglycemia. As predicted, the immune system responded more rapidly to the second infection and virus was cleared more swiftly. However, while infiltrating T cells were found within the pancreas, depletion of the CD4 T cell population prior to secondary infection or use of CD8 knock-out mice had no effect on the development of virus-mediated hyperglycemia. In conclusion, enhanced hyperglycemia induced by CB4 occurs independent of the T cell response.