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The structure of heparin and heparan sulfate (Hep/HS) oligosaccharides, as determined by the length and the pattern of sulfation, acetylation, and uronic acid epimerization, dictates their biological function through modulating interactions with protein targets. But fine structural determination is a very challenging task due to the lability of the sulfate modifications and difficulties in separating isomeric HS chains. Previously, we reported a strategy for chemical derivatization involving permethylation, desulfation, and trideuteroperacetylation, combined with standard reverse phase LC-MS/MS that enables the structural sequencing for heparin/HS oligosaccharides of sizes up to dodecasaccharide by positionally replacing all sulfates with more stable trideuteroacetyl groups, allowing for robust MS/MS sequencing. However, isomeric oligosaccharides that contain both N-sulfation and N-acetylation become isotopomers after labeling, differing only in the sites of deuteration. This prevents chromatographic separation of these different mixed domain sequences post-derivatization, and makes sequencing by MS/MS difficult due to co-fragmentation of the isotopomers leading to chimeric product ion spectra. In order to improve chromatographic separation of mixed domain oligosaccharides, we have introduced a propionylation step in place of trideuteroacetylation for labeling of sites of sulfation. HS standard disaccharides have been used to evaluate the efficiency of this improved chemical derivatization. The results show that we can quantitatively replace sulfation with propionyl groups with the same high efficiency as the previously reported trideuteroacetylation. After derivatization, we demonstrate the ability to chromatographically separate two mixed domain tetrasaccharide isomers differing solely by the order of N-sulfation and N-acetylation, allowing for full sequencing of each by MS/MS. These results represent a marked improvement in the ability of our previously reported derivatization strategy to analyze complex mixtures of Hep/HS oligosaccharides without a decrease in sensitivity., (Copyright © 2018. Published by Elsevier Ltd.)

Among dissociation methods, negative electron transfer dissociation (NETD) has been proven the most useful for glycosaminoglycan (GAG) sequencing because it produces informative fragmentation, a low degree of sulfate losses, high sensitivity, and translatability to multiple instrument types. The challenge, however, is to distinguish positional sulfation. In particular, NETD has been reported to fail to differentiate 4-O- versus 6-O-sulfation in chondroitin sulfate decasaccharide. This raised the concern of whether NETD is able to differentiate the rare 3-O-sulfation from predominant 6-O-sulfation in heparan sulfate (HS) oligosaccharides. Here, we report that NETD generates highly informative spectra that differentiate sites of O-sulfation on glucosamine residues, enabling structural characterizations of synthetic HS isomers containing 3-O-sulfation. Further, lyase-resistant 3-O-sulfated tetrasaccharides from natural sources were successfully sequenced. Notably, for all of the oligosaccharides in this study, the successful sequencing is based on NETD tandem mass spectra of commonly observed deprotonated precursor ions without derivatization or metal cation adduction, simplifying the experimental workflow and data interpretation. These results demonstrate the potential of NETD as a sensitive analytical tool for detailed, high-throughput structural analysis of highly sulfated GAGs. Graphical Abstract.

A chemoenzymatic approach has been developed for the preparation of diverse libraries of heparan sulfate (HS) oligosaccharides. It employs chemically synthesized oligosaccharides having a chemical entity at a GlcN residue, which in unanticipated manners influences the site of modification by NST, C5-Epi/2-OST and 6-OST 1 /6-OST 3 , thus resulting in oligosaccharides differing in N/O-sulfation and epimerization pattern. The enzymatic transformations defined fine substrate requirements of NST, C5-Epi, 2-OST, and 6-OST., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: We explored the potential relationship between steady state serum bilirubin levels and the incidence of cholelithiasis in the context of UGT1A1 gene A(TA)nTAA promoter polymorphism in Omani sickle cell anemia (SCA) patients, homozygotes for African (Benin and Bantu) and Arab-Indian β(S) haplotypes, but sharing the same microgeographical environment and comparable life style factors., Methods: 136 SCA patients were retrospectively studied in whom imaging data including abdominal CT scan, MRI or Ultrasonography were routinely available. Available data on the mean steady state hematological/biochemical parameters (n=136), β(s) haplotypes(n=136), α globin gene status (n=105) and UGT1A1 genotypes (n=133) were reviewed from the respective medical records., Results: The mean serum total bilirubin level was significantly higher in the homozygous UGT1A1(AT)7 group as compared to UGT1A1(AT)6 group. Thus, not cholelithiasis but total serum bilirubin was influenced by UGT1A1 polymorphism in this SCA cohort., Conclusion: As observed in other population groups, the UGT1A1 (AT)7 homozygosity was significantly associated with raised serum total bilirubin level, but the prevalence of gallstones in the Omani SCA patients was not associated with α thalassaemia, UGT1A1 polymorphism, or β(s) haplotypes.

Complex Regional Pain Syndrome (CRPS) is a neuropathic pain syndrome, which involves glial activation and central sensitization in the central nervous system. Here, we describe positive outcomes of two CRPS patients, after they were treated with low-dose naltrexone (a glial attenuator), in combination with other CRPS therapies. Prominent CRPS symptoms remitted in these two patients, including dystonic spasms and fixed dystonia (respectively), following treatment with low-dose naltrexone (LDN). LDN, which is known to antagonize the Toll-like Receptor 4 pathway and attenuate activated microglia, was utilized in these patients after conventional CRPS pharmacotherapy failed to suppress their recalcitrant CRPS symptoms.

Schwannomas are benign, encapsulated and slow-growing nerve sheath tumours arising from Schwann cells. The schwannoma arising from the cervical sympathetic chain (SCSC) is a very rare tumour. It usually presents as a slow growing, painless and asymptomatic neck mass, hence preoperative clinical diagnosis is difficult. Radiological investigation and fine needle aspiration cytology make only a small contribution to its preoperative diagnosis, histopathological examination being much more useful. We report here the first case report of SCSC from Oman. It occurred in a 45 year-old female and was successfully excised.

Context: Duodenal gastrointestinal stromal tumors (GISTs) are uncommon and constitute a relatively small subset of GISTs which presents a unique dilemma having various surgical options. A case of a large ulcerating duodenal GIST arising from the second and third parts of the duodenum and involving the pancreas which was managed by a Whipple resection is presented. The literature is also reviewed to present the current status on surgical options, outcome, prognostic indicators and the role of imatinib mesylate in its management., Case Report: A 58-year-old patient presented with acute gastrointestinal bleeding which was diagnosed to be due to a duodenal GIST following CT scan and endoscopic biopsy. The mass which measured about 10x9 cm originated from the 2nd part and extended into the 3rd part of the duodenum. He underwent a Whipple resection, and histopathology confirmed a duodenal GIST having a greater than 10 mitotic count per fifty high power field and areas of necrosis. Postoperatively, he received imatinib mesylate 400 mg bid; however, 4 months later, he presented with multiple disseminated peritoneal metastases and succumbed to the disease 2 months later., Conclusion: GISTs of the duodenum which are small in size and do not involve the papilla of Vater are better resolved using a limited resection of the duodenum since the outcome in terms of operative risk or disease recurrence is not influenced in these cases. However, large tumors with more extensive involvement would require a pancreaticoduodenectomy to achieve adequate tumor clearance. Even though duodenal GISTs have a relatively better prognosis as compared to GISTs at other sites, their aggressiveness ranges from small indolent tumors to aggressive sarcomas. Following tumor resection, a recurrence rate of about 40% has been reported. A more favorable prognosis in duodenal GISTs is attributed to a lower prevalence of P53 loss, the duodenal location of the tumor, a smaller size of the lesion and a low mitotic count. Imatinib mesylate is reported to play a role in neoadjuvant therapy as well as in the management of metastatic and recurrent disease, although some of these tumors may fail to respond.

Context: Pancreatic metastasis from colorectal malignancy is rare and accounts for less than 2% of all pancreatic metastases. A case of colonic metastasis to the pancreas is reported and the literature is reviewed to assess the role and outcome of pancreatic resection for metastatic tumors from colorectal malignancy., Case Report: A 58-year-old female underwent an emergency left hemicolectomy for an obstructing descending colon growth. The lesion was reported to be adenocarcinoma, Dukes C, with involvement of the serosa and 3 lymph nodes. A postoperative staging CT scan showed no other metastases and she received 6 cycles of FOLFOX chemotherapy (folinic acid, 5-flurouracil and oxaliplatin). Nine years after the colectomy during a routine follow-up, there was a sudden rise in her CEA levels. A CT scan revealed a 6.8x4.8 cm mixed consistency lesion in the tail of the pancreas which, on fine needle aspiration cytology, was confirmed to be adenocarcinoma. She underwent a distal pancreatectomy, and histopathology of the resected specimen confirmed a metastatic tumor from colon cancer. She then received 5 cycles of adjuvant chemotherapy. She was symptom free for nine months and subsequently succumbed to recurrent disease., Conclusion: Pancreatic metastasis from colorectal malignancy is rare. These patients could be asymptomatic in 17% of cases. The time-interval between the diagnosis of colorectal cancer and the detection of pancreatic metastasis varies widely but is approximately 24 months. The median survival time for post-pancreatic resection is 16 months. Pancreatic resection appears to offer good palliation until recurrence of the disease occurs and the possibility of long term cure is rare.

Papillary carcinoma of thyroid usually presents as a palpable thyroid mass. This could be associated with pain, hoarseness, stridor or dysphagia. Rarely, it presents solely as cervical lympadenopthy in the presence of an otherwise grossly normal thyroid gland. This could pose management problems. We report here a middle-aged lady who presented with cervical lymphadenopathy which on fine needle aspiration cytology was confirmed as metastatic papillary thyroid carcinoma. The thyroid gland was, however, normal on clinical examination and radiological investigations. Neck exploration confirmed a grossly normal thyroid gland; however, the cervical lymph node was found to invade the internal jugular vein. She underwent a total thyroidectomy and unilateral functional block dissection with resection of the involved segment of the internal jugular vein. Histopathology confirmed metastasis in the lymph node and a 2mm sized microcarcinoma in the resected thyroid gland. A radioactive iodine scan in the postoperative period revealed no other metastasis. The patient was prescribed lifelong thyroxine. She is on regular follow-up and 4 years following surgery continues to do well.

Context: Metastatic cancer to the pancreas is rare and accounts for less than 2% of all pancreatic malignancies, metastasis from renal cell carcinoma being predominant. While symptomatic patients present with obstructive jaundice, abdominal pain, or GI bleeding, the diagnosis is often made in asymptomatic patients during follow-up for renal cell carcinoma. Hence, a high index of clinical suspicion is required in a patient who presents with a pancreatic tumor following a nephrectomy for renal cell carcinoma., Case Report: We report the case of a patient in whom a lesion was detected in the head of the pancreas, following a nephrectomy performed 5 years previously for renal cell carcinoma. A magnetic resonance scan revealed a well-defined lesion in the head of the pancreas. The patient underwent a pancreaticoduodenectomy and histopathology confirmed a metastatic renal cell carcinoma. Two years after the surgery, the patient is doing well. The literature is reviewed for pancreatic metastasis from renal cell carcinoma, for metastatic pattern, surgical management and outcome., Conclusion: Pancreatic metastases are usually detected during the follow-up of patients having undergone a previous nephrectomy for renal cell carcinoma. Typically, the interval between a nephrectomy and pancreatic metastasis is long. The literature contained more than 250 cases of pancreatic resection for metastatic renal cell carcinoma. The median duration of presentation was 10.5+/-6.5 years following a nephrectomy. The lesions are multifocal (3.2+/-1.5) in about 39% of patients and resectable in 80%. A high resectability rate is characteristic of metastasis from renal cell carcinoma as compared to primary pancreatic cancer. The five year survival rate is between 43 and 88%.

Volvulus of the splenic flexure is very rare cause of colonic obstruction constituting 2% of cases of colonic segmental volvulus. Primary splenic flexure volvulus (SFV) is due to congenital absence or laxity of the phrenocolic, gastro colic, and splenocolic ligaments while secondary volvulus is due to other causes including some prior surgery releasing these ligaments. A preoperative diagnosis can be established based on the characteristic radiological findings on plain x-ray abdomen and CT scan. We present a case of SFV in a young man who presented with acute abdominal pain, and distension, and illustrate the usefulness of CT scan, and plain x-ray of the abdomen in making a preoperative diagnosis. Laparotomy revealed a gangrenous SFV, which was resected and primary anastomosis was carried out. Literature is reviewed with regards to predisposing factors, presentation, investigation, and management among the more than 32 cases reported so far.

Spigelian hernias are rare and generally difficult to diagnose because of their location and vague non-specific symptoms. They are situated between the muscular layers of the abdominal wall and can be easily overlooked because of abdominal obesity. The diagnosis has been considerably aided by the introduction of ultrasonography and computed tomography (CT). These hernias require surgical treatment. We report a 31 years old patient from the Sultan Qaboos University Hospital who presented with colicky lower abdominal pain associated with a tender swelling above and lateral to the inguinal canal. A diagnosis of Spigelian hernia was made and confirmed on exploration. The hernia was reduced and the defect repaired. Her recovery was uneventful.

Situs inversus is a rare anomaly characterized by transposition of organs to the opposite side of the body. In patients with this anomaly, cholelithiasis is observed with a frequency similar to that in the normal population. Herein, we report on a patient with situs inversus totalis who underwent laparoscopic cholecystectomy for mucocele of the gallbladder. Diagnostic pitfalls and technical difficulties of the operation with technical options are discussed in the context of the available literature. Difficulty is encountered particularly in skeletonizing the structures in Calot's triangle, which consumes extra time and is more demanding than in patients with a normally located gallbladder. A summary of an additional 32 similar cases reported in the medical literature is also presented.

Appendiceal tumours are rare and often discovered unexpectedly in an acute situation in which decision-making is difficult. We report the spectrum of appendiuar tumours seen in our institution over a period of more than 10 years, and discuss the clinicopathological behaviour, investigations, surgical procedures and outcomes in these patients. We have also reviewed the literature with regard to appendiceal tumours. Appendicular tumours were identified from the database of 1646 appendictomies (18% in children) performed in single centre and case notes were reviewed. Clinical presentation, investigations, histopathology, surgical procedures and outcome were analysed. Twelve patients with appendiceal tumours were identified (0.72%): 8 carcinoid, 2 mucinous (mucocele) and 2 adenocarcinoma. All the patients with a carcinoid tumour presented with features suggestive of acute appendicitis and were diagnosed postoperatively following appendicectomy and formal histology. No further surgical intervention was required as these lesions were less than 1cm away from the base of the appendix. One of the patient with mucinous cystadenoma presented acutely and underwent an appendicectomy; in the other patient with chronic pain, apreoperative MRI suggested the diagnosis leading to a planned hemicolectomy as the lesion was close to the base of the appendix. While one of the patient with an adenocarcinoma localized to the appendix did well following a right hemicolectomy, the other patient with disseminated disease succumbed within a year. Carcinoid tumours are the commonest appendiceal tumours, which present often as acute appendicitis. While appendicectomy would be adequate in most of these patients, in patients with a cystadenoma close to the base of the appendix or in case of a carcinoma, a right hemicolectomy is the appropriate option. While the prognosis is good in patients with carcinoid tumour and cystadenoma, it remains dismal in patients with disseminated malignant disease.

We report a rare case of agenesis of the gallbladder, which was misdiagnosed as cholecystitis. This is the first reported case from the Middle East. Despite advances in biliary imaging, the diagnosis is usually made at surgery. Like most patients, our patient became asymptomatic after the surgery. Extensive dissection to exclude the presence of gallbladder in an ectopic site is discouraged.