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This review presents principles of glycosylation, describes the relevant glycosylation pathways and their related disorders, and highlights some of the neurological aspects and issues that continue to challenge researchers. More than 100 rare human genetic disorders that result from deficiencies in the different glycosylation pathways are known today. Most of these disorders impact the central and/or peripheral nervous systems. Patients typically have developmental delays/intellectual disabilities, hypotonia, seizures, neuropathy, and metabolic abnormalities in multiple organ systems. Among these disorders there is great clinical diversity because all cell types differentially glycosylate proteins and lipids. The patients have hundreds of misglycosylated products, which afflict a myriad of processes, including cell signaling, cell-cell interaction, and cell migration. This vast complexity in glycan composition and function, along with the limited availability of analytic tools, has impeded the identification of key glycosylated molecules that cause pathologies. To date, few critical target proteins have been pinpointed.

Dynamic loading on articular joints is essential for the evaluation of the risk of the articulation degeneration associated with occupational activities. In the current study, we analyzed the dynamic constraint loading for the thumb during pipetting. The constraint loading is considered as the loading that has to be carried by the connective tissues of the joints (i.e., the cartilage layer and the ligaments) to maintain the kinematic constraints of the system. The joint loadings are solved using a classic free-body approach, using the external loading and muscle forces, which were obtained in an inverse dynamic approach combined with an optimization procedure in anybody. The constraint forces in the thumb joint obtained in the current study are compared with those obtained in the pinch and grasp tests in a previous study (Cooney and Chao, 1977, “Biomechanical Analysis of Static Forces in the Thumb During Hand Function,” J. Bone Joint Surg. Am., 59(1), pp. 27–36). The maximal compression force during pipetting is approximately 83% and 60% greater than those obtained in the tip pinch and key pinch, respectively, while substantially smaller than that obtained during grasping. The maximal lateral shear force is approximately six times, 32 times, and 90% greater than those obtained in the tip pinch, key pinch, and grasp, respectively. The maximal dorsal shear force during pipetting is approximately 3.2 and 1.4 times greater than those obtained in the tip pinch and key pinch, respectively, while substantially smaller than that obtained during grasping. Our analysis indicated that the thumb joints are subjected to repetitive, intensive loading during pipetting, compared to other daily activities.

Summary A persistently positive positron emission tomography ( PET ) scan during therapy for diffuse large B‐cell lymphoma ( DLBCL ) is predictive of treatment failure. A response‐adapted strategy consisting of an early treatment change to four cycles of R‐ ICE (rituximab, ifosfamide, carboplatin, etoposide) was studied in the Eastern Cooperative Oncology Group E3404 trial. Previously untreated patients with DLBCL stage III, IV, or bulky II, were eligible. PET scan was performed after three cycles of R‐ CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) and scored as positive or negative by central review during the fourth cycle. PET ‐positive patients received four cycles of R‐ ICE , PET ‐negative patients received two more cycles of R‐ CHOP . A ≥45% 2‐year progression‐free survival ( PFS ) for mid‐treatment PET ‐positive patients was viewed as promising. Of 74 patients, 16% were PET positive, 79% negative. The PET positivity rate was much lower than the 33% expected. Two‐year PFS was 70%; 42% [90% confidence interval (CI), 19–63%] for PET ‐positives and 76% (90% CI 65–84%) for PET ‐negatives. Three‐year overall survival ( OS ) was 69% (90% CI 43–85%) and 93% (90% CI 86–97%) for PET ‐positive and ‐negative cases, respectively. The 2‐year PFS for mid‐treatment PET ‐positive patients intensified to R‐ ICE was 42%, with a wide confidence interval due to the low proportion of positive mid‐treatment PET scans. Treatment modification based on early PET scanning should remain confined to clinical trials.

SummaryBackgroundThe relationships between primary sclerosing cholangitis (PSC) and the environment are largely unknown.AimTo validate associations reported in previous studies and to identify novel environmental exposures among PSC patients.MethodsWe performed a multicenter, case–control analysis utilising self‐administered questionnaires. Responses between cases (n = 1000) and controls (n = 663) were compared using multivariable logistic regression adjusted for age and gender. The model was further stratified based on inflammatory bowel disease (IBD) status (with IBD n = 741 without IBD n = 259).ResultsSmoking was associated with PSC only when IBD was present (OR, 0.5; 95% CI 0.4–0.7) but not among those PSC patients without IBD (OR, 0.9; 95% CI 0.7–1.2). Compared to controls, women with PSC (irrespective of the presence of IBD) were less likely to have received hormone replacement therapy (HRT; OR, 0.5; 95% CI 0.4–0.7) and were more likely to have recurrent urinary tract infections (OR, 1.6; 95% CI 1.2–2.3). PSC patients regardless of gender or IBD status were less likely to eat fish (OR, 0.4; 95% CI 0.3–0.6) and grilled/barbecued meat (OR, 0.8; 95% CI 0.7–0.9). In contrast, PSC patients with and without IBD were more likely to consume steak/burgers that were more well done (OR, 1.3; 95% CI 1.2–1.5).ConclusionsIBD (rather than PSC) is associated with smoking. Women with PSC are more likely to have recurrent urinary tract infections and less likely to receive HRT. Dietary intake and methods of food preparation differ in PSC patients when compared to controls.

Appropriate nephron function is dependent on the intrarenal arrangement of blood vessels. The preferred and primary means to study the architecture of intrarenal circulation has been by filling it with opaque substances such as india ink, radio-opaque contrast material, or various polymers for study by light or scanning electron microscopy. With such methodologies, superficial vessels may obscure deep vessels and little quantitative information may be obtained. Serial-section microtomy has not been practical because of problems relating to alignment and registration of adjacent sections, lost sections, and preparation time and effort. Microcomputed tomography (micro-CT) overcomes such limitations and provides a means to study the three-dimensional architecture of filled vessels within an intact rodent kidney and to obtain more quantitative information. As an example of micro-CT's capabilities, we review the use of micro-CT to study the alterations in renal microvasculature caused by the development of liver cirrhosis after chronic bile duct ligation. In this example, micro-CT evidence shows a selective decrease in cortical vascular filling in the kidney, with a maintenance of medullary vascular filling. These changes may contribute to the salt and water retention that accompanies cirrhosis. These results indicate that micro-CT is a promising method to evaluate renal vascular architecture in the intact rodent kidney relative to physiological and pathological function.

Currarino syndrome (OMIM 175450) presents with sacral, anorectal, and intraspinal anomalies and presacral meningocele or teratoma. Autosomal dominant loss‐of‐function mutations in the MNX1 gene cause nearly all familial and 30% of sporadic cases. Less frequently, a complex phenotype of Currarino syndrome can be caused by microdeletions of 7q containing MNX1. Here, we report one familial and three sporadic cases of Currarino syndrome. To determine the most efficient genetic testing approach for these patients, we have compared results from MNX1 sequencing, chromosomal microarray, and performed a literature search with analysis of genotype–phenotype correlation. Based on the relationship between the type of mutation (intragenic MNX1 mutations vs 7q microdeletion) and the presence of intellectual disability, growth retardation, facial dysmorphism, and associated malformations, we propose a testing algorithm. Patients with the classic Currarino triad of malformations but normal growth, intellect, and facial appearance should have MNX1 sequencing first, and only in the event of a normal result should the clinician proceed with chromosomal microarray testing. In contrast, if growth delay and/or facial dysmorphy and/or intellectual disability are present, chromosomal microarray should be the first method of choice for genetic testing.

Instability in flexion after total knee replacement (TKR) typically occurs as a result of mismatched flexion and extension gaps. The goals of this study were to identify factors leading to instability in flexion, the degree of correction, determined radiologically, required at revision surgery, and the subsequent clinical outcomes. Between 2000 and 2010, 60 TKRs in 60 patients underwent revision for instability in flexion associated with well-fixed components. There were 33 women (55%) and 27 men (45%); their mean age was 65 years (43 to 82). Radiological measurements and the Knee Society score (KSS) were used to assess outcome after revision surgery. The mean follow-up was 3.6 years (2 to 9.8). Decreased condylar offset (p < 0.001), distalisation of the joint line (p < 0.001) and increased posterior tibial slope (p < 0.001) contributed to instability in flexion and required correction at revision to regain stability. The combined mean correction of posterior condylar offset and joint line resection was 9.5 mm, and a mean of 5° of posterior tibial slope was removed. At the most recent follow-up, there was a significant improvement in the mean KSS for the knee and function (both p < 0.001), no patient reported instability and no patient underwent further surgery for instability.The following step-wise approach is recommended: reduction of tibial slope, correction of malalignment, and improvement of condylar offset. Additional joint line elevation is needed if the above steps do not equalise the flexion and extension gaps.Cite this article: Bone Joint J 2014;96-B:1644–8.