Mutations in 3 genes (MKS3, CC2D2A and RPGRIP1L) cause COACH syndrome (Joubert syndrome with congenital hepatic fibrosis).

OBJECTIVE: To identify genetic causes of COACH syndrome BACKGROUND: COACH syndrome is a rare autosomal recessive disorder characterised by Cerebellar vermis hypoplasia, Oligophrenia (developmental delay/mental retardation), Ataxia, Coloboma, and Hepatic fibrosis. The vermis hypoplasia falls in a spectrum of mid-hindbrain malformation called the molar tooth sign (MTS), making COACH a Joubert syndrome related disorder (JSRD). METHODS: In a cohort of 251 families with JSRD, 26 subjects in 23 families met criteria for COACH syndrome, defined as JSRD plus clinically apparent liver disease. Diagnostic criteria for JSRD were clinical findings (intellectual impairment, hypotonia, ataxia) plus supportive brain imaging findings (MTS or cerebellar vermis hypoplasia). MKS3/TMEM67 was sequenced in all subjects for whom DNA was available. In COACH subjects without MKS3 mutations, CC2D2A, RPGRIP1L and CEP290 were also sequenced. RESULTS: 19/23 families (83%) with COACH syndrome carried MKS3 mutations, compared to 2/209 (1%) with JSRD but no liver disease. Two other families with COACH carried CC2D2A mutations, one family carried RPGRIP1L mutations, and one lacked mutations in MKS3, CC2D2A, RPGRIP1L and CEP290. Liver biopsies from three subjects, each with mutations in one of the three genes, revealed changes within the congenital hepatic fibrosis/ductal plate malformation spectrum. In JSRD with and without liver disease, MKS3 mutations account for 21/232 families (9%). CONCLUSIONS: Mutations in MKS3 are responsible for the majority of COACH syndrome, with minor contributions from CC2D2A and RPGRIP1L; therefore, MKS3 should be the first gene tested in patients with JSRD plus liver disease and/or coloboma, followed by CC2D2A and RPGRIP1L.

Metabolite differentiation and discovery lab (MeDDL): a new tool for biomarker discovery and mass spectral visualization.

The goal of this work was to design and implement a prototype software tool for the visualization and analysis of small molecule metabolite GC-MS and LC-MS data for biomarker discovery. The key features of the Metabolite Differentiation and Discovery Lab (MeDDL) software platform include support for the manipulation of large data sets, tools to provide a multifaceted view of the individual experimental results, and a software architecture amenable to modification and addition of new algorithms and software components. The MeDDL tool, through its emphasis on visualization, provides unique opportunities by combining the following: easy use of both GC-MS and LC-MS data; use of both manufacturer specific data files as well as netCDF (network Common Data Form); preprocessing (peak registration and alignment in both time and mass); powerful visualization tools; and built in data analysis functionality.

Encephalitis lethargica-like illness in a girl with mycoplasma infection.

We describe a patient with mycoplasma infection and clinical manifestations of encephalitis lethargica. The patient was brought to our attention after acute neurologic deterioration followed by a prolonged sleep-like state and the emergence of extrapyramidal features. MRI of the brain disclosed a striking pattern of subcortical involvement by the inflammatory process, corroborating the clinical picture.

Changes in volatile compounds of mouse urine as it ages: their interactions with water and urinary proteins.

Mice release a variety of chemical signals, particularly through urine, which mediate social interactions and endocrine function. Studies have been conducted to investigate the stability of urinary chemosignals in mice. Neuroendocrine and behavioral responses of mice to urine samples of male and female conspecifics which have aged for different amounts of time have been examined, demonstrating that the quality and intensity of signaling molecules in urine change over time. In this study, we monitored changes in volatile organic compounds (VOCs) released from male and female mouse urine following aging the urine samples. Substantial amounts of some VOCs were lost during the aging process of urine, whereas other VOCs increased. Considerable portions of the VOCs which exhibited the increased release were shown to have previously been dissolved in water and subsequently released as the urine dried. We also demonstrated that some VOCs decreased slightly due to their binding with the major urinary proteins (MUPs) and identified MUP ligands whose headspace concentrations increased as the urine aged. Our results underscore the important role of MUPs and the hydration status in the release of VOCs in urine, which may largely account for the changes in the quality and intensity of urinary signals over time.

Changes in volatile compounds of human urine as it ages: their interaction with water.

The urinary odors are commonly perceived as unpleasant. While numerous studies have identified the volatile organic compounds (VOCs) released from urine, the odorants responsible for the urine odor are not well characterized. Furthermore, anecdotal reports suggest that the odor of aged urine is different from that of fresh urine. However, no study has yet to investigate the specific VOCs released from aged urine. In this study, we analyzed and compared the VOCs released from fresh and aged urine samples, investigating the changes in the urinary VOCs as urine aged. We found an overall decrease in concentration of many urinary VOCs, and concluded this was due to the urine evaporating as it aged. On the contrary, some highly water-soluble compounds such as short and branched-chain organic acids and trimethylamine, increased. Their increased release is most likely due to the loss of water and the subsequent release of water-soluble VOCs as urine ages. We suggest that these VOCs may contribute to the odor of the aged urine.

Differential binding between volatile ligands and major urinary proteins due to genetic variation in mice.

Two different structural classes of chemical signals in mouse urine, i.e., volatile organic compounds (VOCs) and the major urinary proteins (MUPs), interact closely because MUPs sequester VOCs. Although qualitative and/or quantitative differences in each chemical class have been reported, previous studies have examined only one of the classes at a time. No study has analyzed these two sets simultaneously, and consequently binding interactions between volatile ligands and proteins in urines of different strains have not been compared. Here, we compared the release of VOCs in male urines of three different inbred strains (C57BL/6J, BALB/b and AKR) before and after denaturation of urinary proteins, mainly MUPs. Both MUP and VOC profiles were distinctive in the intact urine of each strain. Upon denaturation, each of the VOC profiles changed due to the release of ligands previously bound to MUPs. The results indicate that large amounts of numerous ligands are bound to MUPs and that these ligands represent a variety of different structural classes of VOCs. Furthermore, the degree of release in each ligand was different in each strain, indicating that different ligands are differentially bound to proteins in the urines of different strains. Therefore, these data suggest that binding interactions in ligands and MUPs differ between strains, adding yet another layer of complexity to chemical communication in mice.

Sentinel lymph node biopsy in the Sultanate of Oman.

OBJECTIVE: To establish the feasibility of newly started sentinel lymph node (SLN) biopsy in our center at the Royal Hospital in the Sultanate of Oman. METHODS: Twenty five patients with Breast cancer and melanoma were staged with sentinel lymph node (SLN) biopsy, followed by Axillary lymph Node Dissection (ALND). Axillary SLN were detected by injection of blue dye alone or with radioisotope. Intraoperatively, a gamma probe detector identified the isotope-labeled SLN. Two patients underwent preoperative lymphoscintigraphy. The SLNs were examined histologically by hematoxylin-eosin staining and, if negative by this method an immunohistochemical staining (IHC) was done. RESULTS: The only failure to detect inguinal SLN was one case after neoadjuvant chemotherapy. Total detection rate of SLN was of 96%. Metastatic spread occurred in 11 patients of these 9 had other lymph node (LN) involved. Nine patients had no SLN involvement and no other LNs involved. CONCLUSIONS: Ethically, according to the international recommendations and looking to the statistics of the Sultanate all clinical NO should have the choise of SLN biopsy prior to ALND.

Hook wire localization procedure in biopsy and diagnosis of early breast cancers: Oman experience.

INTRODUCTION: Between January 2000 and December 2005, a total of 30 cases of impalpable suspicious breast lesions (microcalcifications or impalpable lumps classified as BRADS IV and above) were biopsied after hook wire localization. This is a retrospective review of these cases. RESULTS: One third of the suspicious lesions were malignant or pre-malignant. All these had further oncological treatment and follow up. CONCLUSIONS: Hook wire localization biopsy remains an important tool for the diagnosis of impalpable lesions of the breast. The incidence of malignancy in our series was similar to the published international levels. Our series is small, so there is a need to review the data with bigger number.

Ultrasound in the diagnosis of typhoid fever.

OBJECTIVES: To establish the efficacy of ultrasound (US) of the abdomen as a diagnostic test in Typhoid. To determine the ultrasound diagnostic criteria in cases of Typhoid. METHODS: The Widal test is the most commonly used method of detecting Typhoid fever, but does not provide results until a week after onset of fever due to the need for enough antibodies to develop to render a positive result. Abdominal Ultrasound was performed within three days of the onset of fever in 80 cases suspected to be having Typhoid fever. Subsequent follow-up scans were performed at five days, ten days and fifteen days. Subsequently, all 80 cases were found to be Widal positive and Salmonella culture was positive in 32 cases. We present our findings in 26 patients in the age group between 4 to 20 years in whom both Widal test and Salmonella culture was subsequently positive. RESULTS: The US findings were as follows: splenomegaly (n-26, 100%); Bowel wall thickening (n-22, 85%); mesenteric lymphadenopathy(n-20,77%); hepatomegaly with normal parenchymal echotexture (n-8, 31%); thickened gall bladder (n-16, 62%); biliary sludge (n-6, 23%); positive US Murphy's sign (n-7, 27%); pericholecystic edema with increased vascularity (n-6, 23%); mucosal ulceration in the wall of the gall bladder (n-1, 3.8%). CONCLUSION: In endemic areas like India, ultrasound findings of hepatomegaly, splenomegaly, ileal and cecal thickening, mesenteric lymphadenopathy and thick-walled gallbladder are diagnostic features of typhoid. Ultrasound can be a non-invasive, economical and a reasonably sensitive tool for diagnosing typhoid when serology is equivocal and cultures are negative.

Transient small bowel intussusceptions: ultrasound findings and clinical significance.

PURPOSE: To study the ultrasound (US) findings and clinical significance of transient small bowel intussusceptions (TSBI) in adults and children. METHODS: Clinical records and US findings of 108 consecutive patients of intestinal intussusception diagnosed on US between August 1995 and August 2004 were reviewed. In all cases, the length, diameter, wall thickness and color Doppler study of the bowel segment involved in intussusception were evaluated. Subsequent follow-up scans were performed at 30 min, 3 days and 2 weeks. Patients were clinically followed up for 6 months. RESULTS: Forty-one patients were diagnosed as TSBI. Thirty-six intussusceptions were incidentally detected during US performed for some unrelated disease or vague abdominal symptom. Five patients presented with signs of obstruction at the time of the initial US diagnosis; however, the intussusceptions resolved without any treatment and were not detected on follow-up scans. Sixty-seven symptomatic patients required surgical intervention. CONCLUSION: Incidentally detected, small bowel intussusceptions without an identifiable pathological lead point, with a normal wall thickness, a length of less than 3.5 cm, normal nondilated proximal bowel and normal vascularity on color Doppler reduce spontaneously and are of no clinical significance.