To tell or not to tell – what to do about p.C282Y heterozygotes identified by HFE screening

Hereditary hemochromatosis (HH) is a common preventable disorder of iron overload that can result in liver cirrhosis and reduced lifespan. Most HH is due to homozygosity for the HFE p.C282Y substitution. We conducted a study of screening for p.C282Y in high schools where p.C282Y heterozygotes (CY) individuals were informed of their genotype by letter. We studied whether these individuals understood the implications of their genotype, whether this resulted in anxiety or reduced health perception and whether cascade testing was higher in families of CY than wild‐type homozygous (CC) individuals. We found 586 of 5757 (1 in 10) screened individuals were CY. One month after receiving their result, 83% correctly answered that they have one copy of p.C282Y. There was no adverse change in anxiety or health perception from prior to screening to 1 month after receiving results. Significantly more family members of CY individuals than CC individuals were informed about HH and had testing for HH. In conclusion, we found that informing CY individuals of their genotype does not increase anxiety and the implications are generally well understood. This leads to cascade testing in a minority of families. CY individuals should be informed of their genetic status when identified by population screening.     

Spinal epidural abscesses – The role for non-operative management: A systematic review

BackgroundSpinal Epidural Abscesses (SEAs) are traditionally seen as a surgical emergency. However, SEAs can be discovered in entirely asymptomatic patients. This presents a dilemma for the attending clinician as to whether to subject these patients to significant surgery. This systematic review updates the evidence surrounding the efficacy of non-operative SEA management by means of intravenous antibiotics ± radiologically-guided aspiration.Aims1. To assess failure rates of medical therapy for SEA. The absolute definition of ‘failure’ used by the study was recorded, and comparisons made. 2. To review of risk factors for success/failure of medical treatment for SEA.MethodsA database search with the MESH term ‘epidural abscess’ and keywords [‘treatment’ OR ‘management’] were used.Results14 studies were included. The number of SEA patients managed non-operatively ranged from 19 to 142. There was significant heterogeneity across the studies. Pooled Failure of Medical Therapy (FMT) (defined as any poor outcome) was 29.40%. When FMT = mortality the pooled rate was 11.49%. Commonly cited risk factors for FMT included acute neurological compromise, diabetes mellitus, increasing age and Staphylococcus aureus.ConclusionSEA will always be a condition mostly managed surgically. Despite this, there is growing evidence that non-operative management can be possible in the correct patients. The key is in patient selection – patients with any of the above-mentioned risk factors have the potential to deteriorate further on medical treatment and have a worse outcome than if they had undergone emergency surgery straight away. Ongoing research will hopefully further investigate this crucial step.     

Characterization of membrane potential-dependent uptake of the novel PET tracer <Superscript>18</Superscript>F-fluorobenzyl triphenylphosphonium cation

Purpose Mitochondrial dysfunction has been attributed a critical role in the etiology and pathogenesis of numerous diseases, and is manifested by alterations of the organelle’s membrane potential (Δψ_m). This suggests that Δψ_m measurement can be highly useful for diagnostic purposes. In the current study, we characterized the capability of the novel PET agent ¹⁸F-fluorobenzyl triphenylphosphonium (¹⁸F-FBnTP) to assess Δψ_m, compared with the well-established voltage sensor ³H-tetraphenylphosphonium (³H-TPP). Methods ¹⁸F-FBnTP and ³H-TPP uptake under conditions known to alter Δψ_m and plasma membrane potential (Δψ_p) was assayed in the H345 lung carcinoma cell line. ¹⁸F-FBnTP biodistribution was assessed in CD1 mice using dynamic PET and ex vivo gamma well counting. Results ¹⁸F-FBnTP and ³H-TPP demonstrated similar uptake kinetics and plateau concentrations in H345 cells. Stepwise membrane depolarization resulted in a linear decrease in ¹⁸F-FBnTP cellular uptake, with a slope (−0.58±0.06) and correlation coefficient (0.94±0.07) similar (p>0.17) to those measured for ³H-TPP (−0.63±0.06 and 0.96±0.05, respectively). Selective collapse of Δψ_m caused a substantial decrease in cellular uptake for ¹⁸F-FBnTP (81.6±8.1%) and ³H-TPP (85.4±6.7%), compared with control. Exposure to the proapoptotic staurosporine, known to collapse Δψ_m, resulted in a decrease of 68.7±10.1% and 71.5±8.4% in ¹⁸F-FBnTP and ³H-TPP cellular uptake, respectively. ¹⁸F-FBnTP accumulated mainly in kidney, heart and liver. Conclusion ¹⁸F-FBnTP is a mitochondria-targeting PET radiopharmaceutical responsive to alterations in membrane potential with voltage-dependent performance similar to that of ³H-TPP. ¹⁸F-FBnTP is a promising new voltage sensor for detection of physiological and pathological processes associated with mitochondrial dysfunction, such as apoptosis, using PET.     

Time interval from a brain insult to the onset of infantile spasms

The temporal latency between an encephalopathic event and the onset of infantile spasms cannot be determined in the majority of symptomatic cases (e.g. genetic conditions, cerebral malformations). However, we can measure this interval when a previously normal infant sustains brain injury followed by infantile spasms. This information has implications for understanding the underlying pathophysiologic basis for infantile spasms and, also, is germane to allegations that a close temporal relationship between vaccination and the onset of this seizure disorder establishes causation. We identified 19 published cases with sufficient information. The interval between brain injury and the onset of infantile spasms ranged from 6 weeks to 11 months (mean = 5.1 months). A similar temporal latency occurs in children with perinatal cerebral infarction and infantile spasms. We conclude that infantile spasms do not occur acutely following an encephalopathic event. This interval of weeks to months is consistent with prior studies indicating temporal latency between brain injury and the onset of other types of epilepsy, as well as with the previously proposed developmental desynchronization hypothesis. The findings refute claims that a close temporal association between an immunization and the onset of infantile spasms establishes causation.     

Comparison of twice-daily ranitidine with standard cimetidine treatment of duodenal ulcer.

One hundred and three outpatients with endoscopically diagnosed duodenal ulcer were randomly allocated to treatment with either cimetidine 200 mg tds and 400 mg nocte, or ranitidine 150 mg bd for four weeks. The endoscopists were not aware of the treatment and took no part in the clinical management. On completion of treatment ulcers had healed in 43 of 51 (84%) patients given cimetidine and in 40 of 52 (77%) patients given ranitidine. There were no serious unwanted effects in either treatment group. The results show no significant difference between healing rates after four weeks of standard cimetidine therapy or ranitidine 150 mg bd.     

The kidneys in paroxysmal nocturnal hemoglobinuria

Long-term study of 21 PNH patients revealed an unexpectedly high incidence of functional and anatomic renal abnormalities. Most patients demonstrated varying degrees of hematuria and proteinuria distinct from hemoglobinuria. Evaluation of renal function revealed hyposthenuria, abnormal tubular function, and declining creatinine clearance. Radiologically these patients had enlarged kidneys, cortical infarcts, cortical thinning, and papillary necrosis which were confirmed by autopsy studies. Hypertension developed in eight patients. Urinary tract infection was uncommon. The renal findings bear striking similarity to those of sickle cell anemia. Contrary to the usual opinion, out studies clearly showed evidence of widespread renal pathology in PNH most likely due to repeated microvascular thrombosis similar to the venous thrombosis involving other organs in this disorder.     

Serum levels of CA 125 during the first trimester of normal outcome, ectopic and anembryonic pregnancies

Single serum samples were obtained during the first trimester of pregnancies with a retrospectively normal outcome (n = 150), ectopic pregnancies (n = 38) and anembryonic pregnancies (n = 78). Serial samples during the first trimester were also obtained from 43 women achieving pregnancy following successful treatment for infertility and with a retrospectively defined normal outcome. Significant variation in serum CA 125 levels in relation to gestational age was observed in pregnancies with a normal outcome (P less than 0.0001). Peak serum CA 125 levels were observed at 6-7 weeks, the mean level at this gestation being 40.1 U/ml (range 31.7-50.7 U/ml) in the normal conception/normal outcome group and 36.5 U/ml (range 25.6-52.0 U/ml) in the assisted conception/normal outcome group. A rise and fall in serum CA 125 levels during the first trimester was observed in 42 of 43 assisted conceptions monitored serially, with peak levels ranging from 7 to 1398 U/ml (median 48.8 U/ml) occurring at 28-61 days (median 45 days) gestation. Mean serum CA 125 levels were higher in the anembryonic pregnancy group at 4-5 and 6-7 weeks gestation than in both normal pregnancy outcome groups (P less than 0.01).