Characterizing multiple sclerosis disease progression using a combined structural and functional connectivity metric.

PURPOSE: A combined resting state functional connectivity MRI (fcMRI) and diffusion tensor imaging (DTI) metric called structural and functional connectivity index (SFCI) was recently proposed for tracking disease status and progression in multiple sclerosis (MS). The metric combines fcMRI and transverse diffusivity (TD) along different functional pathways involved in principle symptomatic domains of MS. In a longitudinal study of patients with MS receiving the same MS therapy, initial worsening of transcallosal (TC) motor and frontoparietal (FP) cognitive networks, as measured by fcMRI and DTI over the first year was followed by stabilization in the second year of follow-up. In this study we have (i) probed relationships between individual and composite neurological measures of MS with SFCI and its individual components along TC motor and FP cognitive pathways and (ii) compared sensitivity of SFCI to treatment-induced longitudinal changes with each individual imaging measure. METHODS: Twenty five patients with MS (15 female, age 42 ± 8 y) participated in this study and were scanned at 3 T whole body MRI scanner with diffusion tensor imaging (DTI) and resting-state functional connectivity MRI (fcMRI) scan protocol at baseline and 6, 12, 18 and 24 months after starting fingolimod. fcMRI and TD along TC and FP pathways were combined to form structural and functional connectivity index (SFCI) at each time point. Correlations between individual/combined neurological measures and individual imaging components/SFCI at baseline and were evaluated and compared. In addition, efficacies of individual and combined imaging metrics in tracking network integrity were compared. RESULTS: Individual TD along the TC pathway was significantly inversely correlated with all individual/composite neurological scores. There were moderate correlations of TC and FP components of SFCI with most of the neurological scores, and the pathway-combined SFCI was significantly correlated with all neurological scores. Trend-level increases of both TC and FP fcMRI were observed during the second year of follow-up, both TC and FP TD increased significantly in the first year and then stabilized during the second year. A trend toward a decrease in combined imaging metrics along TC and FP were observed during the first year, followed by a trend toward an increase in these metrics during the second year, while a significant decrease in SFCI during the first year followed by a significant increase during the second year was observed. CONCLUSIONS: SFCI was more effective in tracking network integrity/disease progression than individual pathway-specific components, which supports its use as an imaging marker for MS disease status and progression.

Changes in structural and functional connectivity during two years of fingolimod therapy for multiple sclerosis.

BACKGROUND: Fingolimod, an oral drug, has been reported to reduce relapse rate in multiple sclerosis (MS). However disease progression may still occur in spite of control of inflammation. Functional imbalances within and between cerebral networks associated with disruption of structural and functional network integrity, have been reported in MS. An effective therapy is expected to stabilize such functional network integrity. OBJECTIVE: The purpose of this study was to investigate changes in structural and resting-state functional connectivity of motor and cognitive networks, and associated changes in neurologic scores in MS, during 2 years of fingolimod therapy. METHODS: Twenty five subjects with MS were recruited for this study. Subjects were scanned with diffusion tensor imaging (DTI) and resting-state functional connectivity MRI (fcMRI) scan protocol at 3 T with 6-month interval over a period of 2 years. Neurologic performance scores of motor and cognitive performances were also obtained. RESULTS: DTI measures worsened during the 1st year and then stabilized; any trend of stabilization of fcMRI was delayed until the 2nd year. While motor performance did not change, cognitive performance showed improvement. Several baseline DTI measures correlated with relevant neurologic scores. CONCLUSION: Initial worsening of motor and cognitive network was reported after 1 year of treatment, but seems DTI and fcMRI measures seem to stabilize after around one year fingolimod therapy.

Unusual case of simultaneous presentation of plasma cell myeloma, chronic myelogenous leukemia, and a jak2 positive myeloproliferative disorder.

Background. Multiple articles discuss the rare incidence and potential causes of second hematologic disorders arising after treatment of Chronic Myelogenous Leukemia (CML), leading to the theory of imatinib, the current treatment regimen for CML, as a possible trigger for the development of secondary neoplasms. Our case eliminates the possibility of imatinib as the sole cause since our patient received a diagnosis of simultaneous plasma cell myeloma, CML, and a Jak2 mutation positive myeloproliferative disorder (MPD) arising de novo, prior to any treatment. We will further investigate into alternative theories as potential causes for multiple hematopathologic disorders. Case Report. There are currently no reported cases with the diagnosis of simultaneous plasma cell myeloma, chronic myelogenous leukemia, and Jak2 positive myeloproliferative disorder. We present a case of a 77-year-old male who was discovered to have these three concurring hematopathologic diagnoses. Our review of the literature includes a look at potential associations linking the three coexisting hematologic entities. Conclusion. The mechanism resulting in simultaneous malignancies is most likely multifactorial and potentially includes factors specific to the host, continuous stimulation of the immune system, previous chemotherapy or radiation, a potential common pluripotent stem cell, or, lastly, preexisting myeloma which may increase the susceptibility of additional malignancies.

Sensorimotor cortex gamma-aminobutyric acid concentration correlates with impaired performance in patients with MS.

BACKGROUND AND PURPOSE: Abnormalities in GABA concentration [GABA] have been associated with several neuropsychiatric disorders, and research has suggested that GABA may play a role in sensorimotor cortex function. We sought to determine whether identifying a change in [GABA] within the sensorimotor cortex of patients with MS has any effect on motor function and would provide information about the adaptive/compensatory mechanisms involved in the attempt to maintain motor function during disease progression. MATERIALS AND METHODS: In 19 healthy controls and 30 patients with MS, we assessed task performance with the MS Functional Composite scale and its components (T25FW test, 9HPT, and PASAT). With in vivo MR spectroscopy, we measured [GABA] in the sensorimotor cortex and determined correlations between [GABA] and task performance. We also assessed the association between [GABA] and cortical activation volume after a bilateral finger-tapping task. RESULTS: [GABA] was inversely correlated with 9HPT scores in patients with MS, indicating a worsening of performance with increased [GABA]. No significant correlation was observed between [GABA] and T25FW or PASAT scores. [GABA] was directly correlated with primary motor cortex activation volume after the finger-tapping task in patients with MS. CONCLUSIONS: These results suggest that cortical [GABA] may be a marker of function and reorganization/adaptation of cortical gray matter in MS.

Spectral quality control in motion-corrupted single-voxel J-difference editing scans: an interleaved navigator approach.

Motion has an adverse effect on spectral quality and needs to be properly identified in MR spectroscopy (MRS) scans. Spectral subtraction-based techniques like J-difference editing are prone to be affected more by subject motion where motion can result in false peaks or inefficient subtraction of peaks. Introducing a water signal-based interleaved navigator scan in the MEGA point-resolved spectroscopy (MEGA-PRESS) sequence and acquiring data on a shot-by-shot basis, subject motion inside a scanner was tracked and motion-corrupted data were identified and excluded from the dataset. Performing a gamma-aminobutyric acid (GABA) editing scan at the occipital cortex, it was possible to retrieve a properly edited GABA spectrum from a dataset otherwise to be discarded due to motion. This study demonstrates the importance of independent motion assessment in J-difference editing.

Orbital mucosa-associated lymphoid tissue (MALT)-type lymphoma in a patient with relapsing polychondritis.

Relapsing polychondritis is characterized by recurrent inflammation of the cartilaginous tissues of the ears, nose, peripheral joints, and the tracheobronchial tree. The eye is also a frequent target organ in relapsing polychondritis, and proptosis is a well-recognized manifestation of eye involvement. Similar to other rheumatologic diseases, an association of relapsing polychondritis with malignancy has been reported. We describe a patient with relapsing polychondritis who presented with exophthalmos. When treatment directed toward control of her underlying disease was only partially effective, further investigation revealed that she had an orbital mucosa-associated lymphoid tissue (MALT)-type B cell lymphoma. We hypothesize that the lymphoma resulted from malignant transformation of the relapsing polychondritis-induced inflammatory pseudotumor and emphasize that neoplastic disease should be considered in the differential diagnosis in patients with relapsing polychondritis presenting with exophthalmos.

Pancreatic beta cell function in normoglycaemic offspring of diabetic parents.

The aim of the study was to look for any time-realted fluctuation in the pancreatic beta cell function in normal offspring of diabetic parents, over a period of three years. Serum insulin (IRI) and C-peptide (CP) responses to oral glucose were reevaluated three years after the initial study in 25 normoglycaemic offspring of conjugal Type 2 diabetic parents. The mean area under the curve of IRI (AUC IRI) response was higher than normal control value in the offspring at both time points (P < 0.01) and the two values did not differ much. The 2 hr IRI was also significantly higher (P < 0.05) than the control value. CP responses at both time points in the offspring did not differ from the mean control value. Wide fluctuations in the individual IRI were noted on follow-up despite similar plasma glucose response. Follow-up IRI was higher in 6, lower in 5 (+/- 25% of the initial) and remained unaltered in the other 4 offspring. The corresponding CP showed increased values in 3, decreased values in 5 and no change in 7 offspring. The fluctuations were nonuniform in nature among the individuals studied. Disparity between the IRI and CP responses were present in 5 offspring during the follow-up. This study thus shows that wide fluctuations in insulin responses occur even in the normoglycaemic offspring of diabetic parents.

Glucagon response to glucose load in offspring of conjugal type 2 diabetic parents in south India.

Immunoreactive glucagon responses were measured in 21 normoglycaemic adult offspring of non-insulin dependent (Type 2) diabetic parents, in the fasting state and during an oral glucose tolerance test. In 7 of the 21 offspring, the mean fasting immunoreactive glucagon value was significantly lower than the control value (p < 0.001). In this group, glucose stimulation did not produce inhibition of immunoreactive glucagon secretion. The insulin response in this group was not significantly different from the values in the other study groups. In the other 14 offspring, the pattern of glucagon response to glucose stimulation was similar to controls. It is likely that this non-suppressive effect of glucose on immunoreactive glucagon in some of the "prediabetic" individuals is an early change in the alpha cell function during the natural history of non-insulin dependent diabetes in Asian Indian subjects.

Synthesis and lysis of formate by immobilized cells of Escherichia coli.

Formate hydrogenlyase (FHL) activity was induced in a strain of Escherichia coli S13 during anaerobic growth in yeast extract-tryptone medium containing 100 mM formate. The cells obtained at the optimum growth phase were immobilized in 2.5% (w/v) agar gel when 50-60% of the whole cell FHL activity was retained. The immobilized FHL system had good storage stability and recycling efficiency. In the lysis of formate, an increase of formate concentration to 1.18 M increased QH(2) (initial) value of the immobilized cell, and subsequently cells, hydrogen evolution, in general, ceased after 6 to 8 of incubation, resulting in incomplete lysis of formate. Presence of small amount of glucose (28 mM) was more or less quantitatively lysed with concomitant disappearance of glucose from the medium. Synthesis of formate from hydrogen and bicarbonate solution by the immobilized cells was also characterized. Presence of glucose (10 mM) in 50 mM bicarbonate solution stimulated formate synthesis by immobilized cells. The pH optimum range, K(m), and specific activity of the immobilized cells for the lysis of formate were 6.8-7.2 0.4M, and 66 mL/g cell-h, respectively. The cells could fix hydrogen to the extent of 24.4% (w/w) of its own wet cell mass in a 72-h reaction cycle. Potentiality of the immobilized FHL system for biotechnological exploitation was discussed.

Aftermaths of surgical sterilisation with special reference to menstrual disturbances.

With the increasing use of a variety of surgical methods for sterilisation, certain pitfalls of these surgical decisions are emerging. In the present study 216 cases who underwent sterilisation at least 2 years prior to coming for consultation with various problems have been analysed. Menstrual disturbances like menorrhagia (59.2%), dysmenorrhoea (29.6%) and metrorrhagia (5.56%) are the leading symptoms ascribable to a large extent to the operation if not the fullest extent in some cases. The physical and psychological disturbances that have evolved from sterilisation include pain abdomen (25%), vague abdominal discomfort and backache (14.8%), leucorrhoea (12.03%), obesity (8.34%), insomnia (4.17%), irritability (2.78%), depression (2.78%) and regret (1.39%).

PIP: Physicians examined 216 women who presented at Chittaranjan Seva Sadan College of Obstetrics, Gynaecology, and Child Health in Calcutta, India, and had undergone surgical sterilization at least 2 years earlier. Endometrial biopsies during the late secretory phase in the 32 cases with excessive bleeding during the late menstrual period found proliferative changes: dilated glands in 28 cases and poor secretory phase in 4 cases. The 12 ovarian biopsies revealed cortical stromal hyperplasia in 1 case. None of the control cases (i.e., those with no menorrhagia) had any ovarian changes. Observed pelvic pathologies included in the order of frequency: cystic ovaries, hydrosalpinx, uterine fibroids, pelvic endometriosis, uterine prolapse, chronic cervicitis, and scar endometriosis. Most of the 216 women were 25 to 35 years old and the youngest was 22 years old. Menorrhagia was the most common complaint (59.2%) and 30 to 35 year old women suffered from it the most. Among women who had no pelvic pathology, dysfunctional uterine bleeding was responsible for menorrhagia. Dysmenorrhea was the next most frequent complaint (29.6%). Intermenstrual bleeding, abnormally infrequent menstruation, and secondary amenorrhea were other menstrual disturbances (5.56%, 4.17%, and 1.39%, respectively). Other relatively common symptoms associated with surgical sterilization were abdominal pain (25%), abdominal discomfort and backache (14.8%), and whitish, viscid vaginal or uterine discharge (12.03%). Less frequent symptoms were obesity, painful scar, insomnia, irritability, depression, and regret. Proper preoperative and postoperative counseling would have prevented many of the complications.

Clinical and biochemical studies in the prediabetic phase of tropical calcific pancreatitis.

The frequency of diabetes is much higher in tropical calcific pancreatitis (TCP) as compared with alcoholic chronic pancreatitis. We report 97 patients with tropical calcific pancreatitis and compare the profile of 21 patients without diabetes (called TCP for the purpose of this report) with that of 76 patients with diabetes, called fibrocalculous pancreatic diabetes (FCPD) according to the World Health Organization (WHO) study group classification of diabetes. TCP patients were a decade younger and had marginally higher body mass indices (BMIs) as compared with the FCPD group. Of the TCP patients, 13 had abnormal glucose tolerance tests (GTT) and the others had normal GTT. Immunoreactive insulin (IRI) responses to glucose load in the TCP group did not differ significantly from that of the control group. This study shows the existence of early stages of glucose intolerance in TCP.

Microalbuminuria in NIDDM patients in south India.

Urinary albumin excretion (UAE) was estimated by radioimmunoassay in 316 non-insulin dependent diabetic patients (NIDDM), with diabetes for 10 or more years and proteinuria less than 150 mg/24 h. Albuminuria was determined in 24 h collection of urine in 259 patients but in the other 57, a random sample was used. The mean UAE was 23 +/- 45.3 (SD) micrograms/mg creatinine in the patients against 4.4 +/- 2.7 micrograms/mg in the controls (30). Ninety patients (28.5%) had microalbuminuria i.e., the UAE exceeded, 20 micrograms/mg creatinine. A higher percentage (31.7%) of men had microalbuminuria than women (23.6%). The presence of microalbuminuria was similar in the insulin-treated and in oral drug-treated patients (29.6% and 26.5% respectively). Stepwise multiple regression analysis using albumin/creatinine ratio as the dependent variable showed that factors such as blood pressure, blood glucose, HbA1, body mass index, sex, age, duration of diabetes and the association of vascular complications of diabetes did not have significant correlation to microalbuminuria. Creatinine clearance showed a significant inverse correlation to the albumin/creatinine ratio. Although the prevalence of microalbuminuria in NIDDM in this study is not significantly different from those reported from other countries, the morbidity index due to kidney disease could be high due to the large absolute number involved in our country. This underscores the need for early detection of the disease and institution of preventive measures to arrest its progression.

Nutritional profile of fibrocalculous pancreatic diabetes and primary forms of diabetes seen in southern India.

Plasma levels of retinol binding protein (RBP), prealbumin, total protein, albumin, transferrin and ferritin were estimated in three groups of diabetic patients seen at a diabetes centre in S. India. The groups consisted of patients with fibrocalculous pancreatic diabetes (FCPD), non-insulin-dependent diabetes mellitus (NIDDM) and insulin-dependent diabetes mellitus (IDDM). Mean RBP levels were lower in FCPD and IDDM patients compared to controls but this did not reach statistical significance. Prealbumin levels were normal in FCPD patients, but low in IDDM compared to controls (P less than 0.005) and NIDDM (P less than 0.05). FCPD patients had lower transferrin levels compared to controls (P less than 0.05). There were no differences in the levels of total protein, albumin and ferritin in any of the study groups. The study shows that biochemical evidence of undernutrition is seen in FCPD and IDDM patients while NIDDM patients are not significantly different from non-diabetic control subjects.

Decreased insulin sensitivity in offspring whose parents both have type 2 diabetes.

Offspring of two Type 2 diabetic parents have a high prevalence of diabetes and impaired glucose tolerance. Studies in normoglycaemic offspring have shown abnormal insulin responses. Twenty-four non-obese offspring having normal oral glucose tolerance were investigated by the insulin tolerance test for abnormalities of insulin sensitivity. Plasma insulin responses were measured during an oral glucose tolerance test. Although the plasma glucose responses during the OGTT were similar to the control values, the corresponding insulin responses were higher. The mean area under the insulin curve was 121 +/- 29 (+/- SD) mU l-1 h in the control subjects and 203 +/- 73 mU l-1 h in the offspring (p less than 0.001). The mean KITT value in the offspring was 4.3 +/- 1.9 min-1 x 100 which was significantly lower (p less than 0.01) than the value of 6.2 +/- 2.0 min-1 x 100 in the control subjects. The results suggest that some offspring of two Type 2 diabetic parents have low insulin sensitivity and the presence of hyperinsulinism may be a compensatory phenomenon.

Protein components of a cytochrome P-450 linalool 8-methyl hydroxylase.

The cytochrome P-450 heme-thiolate monooxygenases that hydroxylate monoterpene hydrocarbon groups are effective models for the cytochrome P-450 family. We have purified and characterized the three proteins from a P-450-dependent linalool 8-methyl hydroxylase in Pseudomonas putida (incognita) strain PpG777. The proteins resemble the camphor 5-exohydroxylase components in chemical and physical properties; however, they show neither immunological cross-reactivity nor catalytic activity in heterogenous recombination. These two systems provide an excellent model to probe more deeply the heme-thiolate reaction center, molecular domains of substrate specificity, redox-pair interactions, and the regulation of the reaction cycle.