NMIHBA results from hypomorphic PRUNE1 variants that lack short-chain exopolyphosphatase activity.

Neurodevelopmental disorder with microcephaly, hypotonia and variable brain anomalies (NMIHBA) is an autosomal recessive neurodevelopmental and neurodegenerative disorder characterized by global developmental delay and severe intellectual disability. Microcephaly, progressive cortical atrophy, cerebellar hypoplasia and delayed myelination are neurological hallmarks in affected individuals. NMIHBA is caused by biallelic variants in PRUNE1 encoding prune exopolyphosphatase 1. We provide in-depth clinical description of two affected siblings harboring compound heterozygous variant alleles, c.383G > A (p.Arg128Gln), c.520G > T (p.Gly174*) in PRUNE1. To gain insights into disease biology, we biochemically characterized missense variants within the conserved N-terminal aspartic acid-histidine-histidine (DHH) motif and provide evidence that they result in the destabilization of protein structure and/or loss of exopolyphosphatase activity. Genetic ablation of Prune1 results in midgestational lethality in mice, associated with perturbations to embryonic growth and vascular development. Our findings suggest that NMIHBA results from hypomorphic variant alleles in humans and underscore the potential key role of PRUNE1 exopolyphoshatase activity in neurodevelopment.

Distinct Membrane Disruption Pathways Are Induced by 40-Residue ß-Amyloid Peptides.

Cellular membrane disruption induced by ß-amyloid (Aß) peptides has been considered one of the major pathological mechanisms for Alzheimer disease. Mechanistic studies of the membrane disruption process at a high-resolution level, on the other hand, are hindered by the co-existence of multiple possible pathways, even in simplified model systems such as the phospholipid liposome. Therefore, separation of these pathways is crucial to achieve an in-depth understanding of the Aß-induced membrane disruption process. This study, which utilized a combination of multiple biophysical techniques, shows that the peptide-to-lipid (P:L) molar ratio is an important factor that regulates the selection of dominant membrane disruption pathways in the presence of 40-residue Aß peptides in liposomes. Three distinct pathways (fibrillation with membrane content leakage, vesicle fusion, and lipid uptake through a temporarily stable ionic channel) become dominant in model liposome systems under specific conditions. These individual systems are characterized by both the initial states of Aß peptides and the P:L molar ratio. Our results demonstrated the possibility to generate simplified Aß-membrane model systems with a homogeneous membrane disruption pathway, which will benefit high-resolution mechanistic studies in the future. Fundamentally, the possibility of pathway selection controlled by P:L suggests that the driving forces for Aß aggregation and Aß-membrane interactions may be similar at the molecular level.

Cryptococcal osteomyelitis: a report of 5 cases and a review of the recent literature.

Cryptococcus neoformans is a fungal pathogen associated with advanced HIV disease and other disorders associated with immune dysfunction. The pulmonary and the central nervous system are the most common manifestations of the disease. Localised osteomyelitis as the sole manifestation of extrapulmonary disease is rare. Herein, we present five cases of Cryptococcus osteomyelitis as the only manifestation of extrapulmonary disease. We also identified 84 additional cases of isolated cryptococcal osteomyelitis in the literature. Using these data, we have made some general recommendations regarding an approach to treatment of this uncommon clinical entity.

Prosthetic valve endocarditis secondary to Tropheryma whipplei in a patient with chronic polyarthritis.

BACKGROUND: Whipple's disease is a chronic multisystemic infectious disease that rarely presents as culture-negative endocarditis. Most patients reported with Tropheryma whipplei endocarditis involve a native valve and few describe prosthetic valve disease. CASE PRESENTATION: A patient with chronic polyarthritis and previous mitral valve replacement developed decompensated heart failure without fever. Transesophageal echocardiography revealed a prosthetic mitral valve vegetation and he underwent prosthetic mitral valve replacement. Blood and prosthetic mitral valve cultures were unrevealing. Broad-range polymerase chain reaction (PCR) of the extracted valve and subsequent Periodic-acid-Schiff (PAS) staining established the diagnosis of T. whipplei prosthetic valve endocarditis. CONCLUSION: Whipple's disease may present as culture-negative infective endocarditis and affect prosthetic valves. Histopathology with PAS staining and broad-range PCR of excised valves are essential for the diagnosis. Greater clinical awareness and implementation of these diagnostic procedures should result in an increased reported incidence of this rare disease.

Concomitant cholecystoduodenal fistula and cholecystocholedochal fistula due to actinomyces.

This report describes a patient with a cholecystoduodenal fistula and cholecystocholedochal fistula who was found to have Actinomyces contained within the gallbladder upon pathologic examination. The cholecystocholedochal fistula was repaired using a flap of gallbladder over a T-tube, and the actinomycosis was successfully eradicated with 6 weeks of intravenous doxycycline followed by an additional 6 months of oral doxycycline.

A correlation between ovulatory phase and cytohormonal maturation index of women with affected disorders: a preliminary study

Difference in endocrine features between men and women supports a biological hypothesis in affective disorders among women. Studies done showed high probability that mood changes in associated with hormonal alterations, particularly that of estrogen and progesterone. There are cyclic morphological changes occurring in the female reproductive system in response to these hormones. The cytohormonal maturation index (CHMI) is used to evaluate the female hormonal milieu. A differential of the three types of cells is expressed as percentages of the parabasal (P), the intermediate (I), and the superficial (S) cells, in that order. Predominance of the intermediate cells reflect high levels of progesterone, and the superficial cells that of estrogen. This study aims to compare the correlation of CHMI with ovulatory phase between women of reproductive age with affective disorder and normal control; and to compare the CHMI of the two groups. Eight women of reproductive age (mean age = 29.62 +/- 7.95), diagnosed to have affective disorders and having an episode of mania/hypomania or depression, underwent Paps smear. Written consents were obtained. LMP and PMP were obtained to determine the current ovulatory phase. The control group is composed of seven women of same age group (mean age = 29.29 +/- 6.65) having no manifestations of any psychiatric illnesses. Paps smear was performed by a Gynecology Resident. A Pathology Resident blinded to the study reviewed the slides for CHMI. Fishers exact I test and Mann-Whitney U test were utilized. A p value of 0.05 was considered as statistically significant. There is a significant difference in the proportion of agreement between the ovulatory phase and the CHMI between the two groups (p=0.045). However, there is no difference in the percentages of progesterone and estrogen between the two groups (p=0.247 and 0.452, respectively).