Homocystinuria diagnosis and management: it is not all classical.

Homocystinuria (HCU) refers to a group of inherited disorders of homocysteine metabolism associated with high blood homocysteine concentration, thromboembolic tendency and neurocognitive symptoms. The most common causes of a high blood homocysteine relate to underlying vitamin B12 or folate deficiency which must be excluded first. Thereafter, an inherited metabolic condition can be considered.The most prevalent inherited disorder of homocysteine metabolism is classical HCU caused by deficiency of the pyridoxine-dependent enzyme, cystathione beta-synthase, which converts homocysteine to cystathionine in the transsulphuration pathway. An alternative route for homocysteine metabolism is its remethylation to methionine by the cobalamin-dependent enzyme, methionine synthase, using the folate derivative, methyltetrahydrofolate, as a methyl donor. Remethylation defects are caused by impaired activity of methionine synthase itself, of an enzyme required to generate its methylcobalamin cofactor from dietary vitamin B12, or of the enzyme methyltetrahydrofolate reductase (MTHFR), which generates the methyl donor.The correct diagnosis can be inferred from additional laboratory investigations including a complete blood count and quantitation of methionine and methylmalonic acid. Methionine is high/normal in HCU and low in the remethylation disorders. In the latter, cobalamin defects are readily distinguished from MTHFR by a coexisting macrocytic anaemia and further delineated by presence or absence of methylmalonic acid in urine or plasma.Lowering homocysteine reverses thromboembolic risk. In HCU, this may be achieved with pyridoxine alone or with betaine as an alternative methyl donor. Some patients additionally follow a methionine-restricted diet. Betaine is the primary treatment for MTHFR and cobalamin disorders are managed with high-dose hydroxocobalamin.

Development of Preclinical Ultrasound Imaging Techniques to Identify and Image Sentinel Lymph Nodes in a Cancerous Animal Model.

Lymph nodes (LNs) are believed to be the first organs targeted by colorectal cancer cells detached from a primary solid tumor because of their role in draining interstitial fluids. Better detection and assessment of these organs have the potential to help clinicians in stratification and designing optimal design of oncological treatments for each patient. Whilst highly valuable for the detection of primary tumors, CT and MRI remain limited for the characterization of LNs. B-mode ultrasound (US) and contrast-enhanced ultrasound (CEUS) can improve the detection of LNs and could provide critical complementary information to MRI and CT scans; however, the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) guidelines advise that further evidence is required before US or CEUS can be recommended for clinical use. Moreover, knowledge of the lymphatic system and LNs is relatively limited, especially in preclinical models. In this pilot study, we have created a mouse model of metastatic cancer and utilized 3D high-frequency ultrasound to assess the volume, shape, and absence of hilum, along with CEUS to assess the flow dynamics of tumor-free and tumor-bearing LNs in vivo. The aforementioned parameters were used to create a scoring system to predict the likelihood of a disease-involved LN before establishing post-mortem diagnosis with histopathology. Preliminary results suggest that a sum score of parameters may provide a more accurate diagnosis than the LN size, the single parameter currently used to predict the involvement of an LN in disease.

Comparison of Acorn and Fluted Reamers on Tibial Tunnel Outer Aperture Dimensions in ACL Reconstruction.

The aim of this study was to determine if the type of reamer used in tibial tunnel creation during anterior cruciate ligament (ACL) reconstruction influences the dimensions of the tunnel's outer aperture. Tibial tunnels were created in tibial saw bones by reaming over a guidewire using an 8 mm acorn or fluted reamer in an antegrade manner. Reaming was aimed either in line with the guidewire, or with 10-degree inferior/superior deviation in relation to the wire. The shape and size of the outer aperture of the tibial tunnel were compared between the two reamers. When using the acorn reamer, a 10-degree deviation in relation to the guidewire resulted in minimal change in outer aperture length (mean 13.6 vs. 15.6 mm, p = 0.11) and width (11.6 vs. 11.1 mm, p = 0.51). However, when using the fluted reamer, although the aperture width showed no substantial change with reamer/guidewire deviation (11.4 vs. 11.2 mm, p = 0.71), the mean length almost doubled (14.7 vs. 28.1 mm, p = 0.002). The use of a fluted reamer when reaming the tibial tunnel creates a distal aperture which is inconsistently sized, larger, and of oblong shape compared with an acorn-shaped reamer. This should be taken in consideration when using a fluted reamer for creating the tibial tunnel in ACL reconstruction.

A case series of cerebral venous thrombosis as the first manifestation of homocystinuria.

Background: Cerebral venous thrombosis (CVT) is an important cause of stroke particularly in younger patients and potentially fatal if diagnosis is delayed. The presentation of symptoms is highly variable and consequently the diagnosis and underlying cause is often delayed or overlooked. Homocystinuria, a rare autosomal recessive disorder is an identified risk factor for CVT. Purpose: A timely diagnosis and treatment of the underlying cause of CVT could result in improved outcome and prevent further events. This case series describes the clinical course of six adults presented with unprovoked CVT, in whom the diagnosis of underlying homocystinuria was delayed with adverse consequences. We aim to highlight the importance of recognising homocystinuria as an underlying cause of CVT and offer a practical approach to the diagnosis and management. Methods: This is a retrospective case series of a cohort of 30 consecutive patients seen in a UK tertiary referral centre. Result: Six out of 30 patients presented with CVT prior to homocystinuria diagnosis. The mean and range of age at the time of the first CVT episode was 22.6 (range 11-31) years. The mean ±SD age at diagnosis of homocystinuria as the underlying cause was 26 ± 4.2 years. The time between first CVT and diagnosis of homocystinuria ranged from 1.6 to 11 years resulting in a delay to introduction of effective treatment and, in some cases, a further large vessels thrombotic event. Conclusion: Physician awareness of homocystinuria as an underlying cause for an unprovoked CVT will facilitate timely introduction of effective treatment to prevent a further event.

Inter-laboratory analytical improvement of succinylacetone and nitisinone quantification from dried blood spot samples.

BACKGROUND: Nitisinone is used to treat hereditary tyrosinemia type 1 (HT-1) by preventing accumulation of toxic metabolites, including succinylacetone (SA). Accurate quantification of SA during newborn screening is essential, as is quantification of both SA and nitisinone for disease monitoring and optimization of treatment. Analysis of dried blood spots (DBS) rather than plasma samples is a convenient method, but interlaboratory differences and comparability of DBS to serum/plasma may be issues to consider. METHODS: Eight laboratories with experience in newborn screening and/or monitoring of patients with HT-1 across Europe participated in this study to assess variability and improve SA and nitisinone concentration measurements from DBS by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Quantification of nitisinone from both DBS and plasma was performed to assess sample comparability. In addition, efforts to harmonize laboratory procedures of SA and nitisinone quantifications during 5 rounds of analysis are described. RESULTS: Nitisinone levels measured from DBS and plasma strongly correlated (R 2 = 0.93). Due to partitioning of nitisinone to the plasma, levels were higher in plasma by a factor of 2.34. In the initial assessment of laboratory performance, all had linear calibrations of SA and nitisinone although there was large inter-laboratory variability in actual concentration measurements. Subsequent analytical rounds demonstrated markedly improved spread and precision over previous rounds, an outcome confirmed in a final re-test round. CONCLUSION: The study provides guidance for the determination of nitisinone and SA from DBS and the interpretation of results in the clinic. Inter-laboratory analytical harmonization was demonstrated through calibration improvements.

Traumatic bruising of the hepatoduodenal ligament can conceal a catastrophic injury to the hepatic artery.

We present the case of a 22-year-old man transferred to the regional major trauma centre following a fall of ~15 m. He remained consistently haemodynamically stable for over 10 hours of observation until he deteriorated suddenly with major haemorrhagic shock requiring immediate trauma laparotomy. At laparotomy, 2 L of blood was drained from the abdomen but no source of active bleeding identified. 30 minutes after closure of the abdomen, 500 mL of fresh blood was noted in the drain so he was returned to the theatre where the bleeding source was found to be-after manual compression of a mildly bruised hepatoduodenal ligament-the proper hepatic artery (PHA). This case describes an unusual finding at relaparotomy and shows that even when there is no active bleeding from abdominal organs or classified vessels, it is possible to have isolated injury to PHA.

Surgeon-led Intraoperative Ultrasound Localization for Nonpalpable Breast Cancers: Results of 5 Years of Practice.

BACKGROUND: The uptake of breast screening has led to a rise in the number of nonpalpable breast cancer diagnoses. Breast conserving therapy (BCT) is the treatment of choice for early breast cancer, and this requires localization of the lesion. Commonly detection is achieved by wire-guided localization in the radiology department. This technique has complications and requires utilization of a radiologist. Intraoperative ultrasound (IOUS) has been shown to be a safe alternative, but there is little data on its use. The aim of this study is to report the use of surgeon-led IOUS over the past 5 years, assessing the ability to detect lesions and the re-excision rate for involved margins. PATIENTS AND METHODS: A retrospective observational study was performed on consecutive patients undergoing IOUS-marked BCT between 2014 and 2018. The technique is described, and patients' records were reviewed to assess the histologic specimen reports and need for subsequent re-excision. RESULTS: Ninety-five IOUS BCT operations were performed. Every cancer was identified by IOUS and removed. Fourteen margins were positive and required re-excision. Of these, only 2 contained residual tumor. CONCLUSION: This is the first data from the United Kingdom for IOUS skin marking without wire localization. IOUS is a safe method of localization in BCT. It offers advantages both to the patient and the unit as it reduces pressure on the radiology department.

Arthroscopic Excision of Medial Knee Plica: A Meta-Analysis of Outcomes.

PURPOSE: A meta-analysis was performed to assess the outcomes following surgical intervention for medial knee plica. MATERIALS AND METHODS: A literature search of Medline, EMBASE, CINAHL and Cochrane CENTRAL was performed using relevant key words. The primary outcome was patient-reported postoperative scores of "good" and "excellent". Meta-analyses were performed using a random effects model. RESULTS: The literature search identified 731 articles. After removing duplicates and those not meeting the inclusion criteria, 12 articles reporting on a total of 643 knees were included for analysis, and of these, 7 articles including 235 knees were used for meta-analysis. The overall rate of good and excellent outcomes following surgery was estimated at 84.2% (95% confidence interval [CI], 72.8-91.4). In those cases that had non-surgical therapy prior to surgery, the rate of good and excellent outcomes of surgery was estimated at 76.1% (95% CI, 60.1-87). CONCLUSIONS: Arthroscopic surgical management of symptomatic medial knee plica results in favourable outcomes. Our results suggest that arthroscopic surgical excision should be considered as a treatment modality in patients with pathological medial plica disease of the knee either as a first-line treatment or when symptoms have not responded to non-surgical interventions. LEVEL OF EVIDENCE: IV.

Primary Bile Duct Perforation Associated with Pancreatitis.

Primary bile duct perforation is rare in adults. It commonly results in biliary peritonitis and high morbidity and mortality. We present a 72-year-old man who was initially admitted with biochemically diagnosed pancreatitis who was found to have a bile duct perforation and bile collection limited to the lesser sac. This presented a diagnostic challenge and, due to its containment, did not result in generalized biliary peritonitis, which is usually associated with this condition. His condition was managed with stenting with endoscopic retrograde cholangiopancreatography.

[3-hydroxy-3-methylglutaryl-CoA lyase deficiency: a case report and literature review]. / Anorexia nerviosa como causa de fallo hepático agudo. A propósito de un caso.

INTRODUCTION: 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase deficiency is an autosomal recessive disorder that usually presents in the neonatal period with vomiting, metabolic acidosis, hypoglycemia and absent ketonuria. Few cases are reported in the literature, and optimal dietary management and long term outcome are not fully understood. CASE REPORT: We report a 2 year old girl with HMG-CoA-lyase deficiency who had limited fasting tolerance on a low protein diet, with several recurrent hospital admissions with severe hypoketotic hypoglycaemia and metabolic acidosis. We also review the dietary management and outcome of other reported cases in the literature. DISCUSSION: In order to define optimal dietary treatment, it is important to collect higher numbers of case studies with detailed dietary management, fasting times and outcome.

The safety of Lipistart, a medium-chain triglyceride based formula, in the dietary treatment of long-chain fatty acid disorders: a phase I study.

BACKGROUND: Children with long-chain fatty acid ß-oxidation disorders (LCFAOD) presenting with clinical symptoms are treated with a specialist infant formula, with medium chain triglyceride (MCT) mainly replacing long chain triglyceride (LCT). It is essential that the safety and efficacy of any new specialist formula designed for LCFAOD be tested in infants and children. METHODS: In an open-label, 21-day, phase I trial, we studied the safety of a new MCT-based formula (feed 1) in six well-controlled children (three male), aged 7-13 years (median 9 years) with LCFAOD (very long chain acyl CoA dehydrogenase deficiency [VLCADD], n=2; long chain 3-hydroxyacyl CoA dehydrogenase deficiency [LCHADD], n=2; carnitine acyl carnitine translocase deficiency [CACTD], n=2). Feed 1 (Lipistart; Vitaflo) contained 30% energy from MCT, 7.5% LCT and 3% linoleic acid and it was compared with a conventional MCT feed (Monogen; Nutricia) (feed 2) containing 17% energy from MCT, 3% LCT and 1.1% linoleic acid. Subjects consumed feed 2 for 7 days then feed 1 for 7 days and finally resumed feed 2 for 7 days. Vital signs, blood biochemistry, ECG, weight, height, food/feed intake and symptoms were monitored. RESULTS: Five subjects completed the study. Their median daily volume of both feeds was 720 mL (range 500-1900 mL/day). Feed 1 was associated with minimal changes in tolerance, free fatty acids (FFA), acylcarnitines, 3-hydroxybutyrate (3-HB), creatine kinase (CK), blood glucose, liver enzymes and no change in an electrocardiogram (ECG). No child complained of muscle pain or symptoms associated with LCFAOD on either feed. CONCLUSIONS: This is the first safety trial reported of an MCT formula specifically designed for infants and children with LCFAOD. In this short-term study, it appeared safe and well tolerated in this challenging group.

3-hydroxy-3-methylglutaryl-CoA lyase deficiency: a case report and literature review / Deficiencia de la 3-hidroxi-3-metilglutaril-CoA liasa: un caso clínico y revisión de la literatura

Introduction: 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase deficiency is an autosomal recessive disorder that usually presents in the neonatal period with vomiting, metabolic acidosis, hypoglycemia and absent ketonuria. Few cases are reported in the literature, and optimal dietary management and long term outcome are not fully understood. Case report: We report a 2 year old girl with HMG-CoA-lyase deficiency who had limited fasting tolerance on a low protein diet, with several recurrent hospital admissions with severe hypoketotic hypoglycaemia and metabolic acidosis. We also review the dietary management and outcome of other reported cases in the literature. Discussion: In order to define optimal dietary treatment, it is important to collect higher numbers of case studies with detailed dietary management, fasting times and outcome (AU)

Introducción: la deficiencia de la 3-hidroxi-3-metilglutaril-CoA (HMG-CoA) liasa es un desorden autosómico recesivo que normalmente se presenta en la infancia con vómitos, acidosis metabólica, hipoglicemia y sin cetonuria. Se han publicado pocos casos en la literatura científica sobre el mejor tratamiento dietético para el adecuado desarrollo de los pacientes a largo plazo, por lo que esta deficiencia no es bien conocida. Caso clínico: presentamos una niña de 2 años con deficiencia de la 3-hidroxi-3-metilglutaril-CoA (HMG-CoA) liasa. Recibiendo una dieta baja en proteína con una tolerancia de ayuno limitada con episodios recurrentes de admisión hospitalaria con hipoglicemia hipoketotica y acidosis metabólica. También hemos revisado el tratamiento dietético y el desarrollo de otros casos publicados en la literatura científica. Discusión: es importante recoger más casos clínicos describiendo el tratamiento dietético seguido, el tiempo máximo de ayuno y el desarrollo de los pacientes con el objetivo de definir el mejor tratamiento (AU)

Meta-analysis of epidural analgesia versus peripheral nerve blockade after total knee joint replacement.

BACKGROUND: Postoperative pain after major knee surgery can be severe. Our aim was to compare the outcomes of epidural analgesia and peripheral nerve blockade (PNB) in patients undergoing total knee joint replacement (TKR). Moreover, we aimed to compare outcomes of adductor canal block (ACB) with those of femoral nerve block (FNB) after TKR. METHODS: We conducted a systematic search of electronic information sources, including MEDLINE; EMBASE; CINAHL; and the Cochrane Central Register of Controlled Trials (CENTRAL). We applied a combination of free text and controlled vocabulary search adapted to thesaurus headings, search operators, and limits in each of the above databases. Pain intensity assessed on visual analogue scale (VAS), nausea and vomiting, systolic hypotension, and urinary retention was the reported outcome parameters. RESULTS: We identified 12 randomised controlled trials (RCTs) comparing outcomes of epidural analgesia and PNB reporting a total of 670 patients. There was no significant difference between two groups in VAS scores at 0-12 h (MD -0.48; 95 % CI -1.07-0.11, P = 0.11), 12-24 h (MD 0.04; 95 % CI -0.81-0.88, P = 0.93), and 24-48 h (MD 0.16; 95 % CI -0.08-0.40, P = 0.19). However, epidural analgesia was associated with significantly higher risk of postoperative nausea and vomiting (RR 1.65; 95 % CI, 1.20-2.28, P = 0.002), hypotension (RR 1.76; 95 % CI, 1.26-2.45, P = 0.0009), and urinary retention (RR 4.51; 95 % CI, 2.27-8.96, P < 0.0001) compared to PNB. Moreover, pooled analysis of data from 6 RCTs demonstrated no significant difference in VAS score between ACB and FNB at 24 h (MD -0.00; 95 % CI, -0.56-0.56, P = 0.99) and 48 h (MD -0.06; 95 % CI, -0.14-0.03, P = 0.23). CONCLUSIONS: PNB is as effective as epidural analgesia for postoperative pain management in patients undergoing TKR. Moreover, it is associated with significantly lower postoperative complications. ACB appears to be an effective PNB with similar analgesic effect to FNB after TKR. Future RCTs may provide better evidence regarding knee range of motion, length of hospital stay, and neurological complications.

Small bowel diaphragm disease mimicking malignancy.

Non-steroidal anti-inflammatory drugs (NSAIDs) can produce diaphragm disease where multiple strictures develop in the small bowel. This typically presents with anaemia and symptoms of small bowel obstruction. The strictures develop as a result of circumferential mucosal ulceration with subsequent contraction of rings of scar tissue. We report a case of a 47-year-old woman with a 6-month history of NSAIDs abuse who presented with subacute small bowel obstruction 1 year after stopping NSAIDs. CT and MRI showed multiple ileal strictures with florid locoregional lymphadenopathy. A malignant diagnosis such as lymphoma was considered likely as florid mesenteric lymphadenopathy has not been previously reported in diaphragm disease. Laparotomy with small bowel resection was therefore performed. Histology showed diaphragm disease with the enlarged mesenteric nodes having reactive features. Gross locoregional lymphadenopathy should not deter a diagnosis of diaphragm disease in cases of multiple small bowel strictures where there is a strong history of NSAIDs use.