Vitamin D: in the evolution of human skin colour.

The natural selection hypothesis suggests that lighter skin colour evolved to optimise vitamin D production. Some authors question if vitamin D deficiency leads to sufficient health problems to act as a selection pressure. This paper reviews the numerous effects of vitamin D deficiency on human health and argues that vitamin D deficiency is sufficient to pose as a potent selection pressure for lighter skin colour. Vitamin D deficiency manifesting as rickets and osteomalacia are sufficient to impair reproductive success, but additionally, animal studies and some clinical observations suggest that vitamin D may have more direct impact on human fertility. Vitamin D deficiency may lead to a whole host of clinical conditions which impair health and increase mortality rates: increase susceptibility to bacterial and viral infections; rickets, osteomalacia and osteoporosis, with increased risk of falls and fractures; increased risk of cancers; hypertension and cardiovascular disease; maturity onset diabetes; autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease and Type 1 diabetes; and gum disease. We submit that at higher latitudes, lighter skin colour evolved to facilitate vitamin D production under conditions of low ultra-violet B radiation in order to avoid a plethora of ill health, reproductive difficulties and early mortality.

A 31-phosphorus neurospectroscopy study of omega-3 long-chain polyunsaturated fatty acid intervention with eicosapentaenoic acid and docosahexaenoic acid in patients with chronic refractory epilepsy.

The aim of this study was to determine whether supplementation with the n-3 long-chain polyunsaturated fatty acids eicosapentaenoic acid and docosahexaenoic acid in patients with chronic refractory epilepsy is associated with beneficial changes in cerebral biochemistry. In a 3-month pilot randomized double-blind placebo-controlled study, three patients received eicosapentaenoic acid and docosahexaenoic acid daily and four received a placebo. 31-Phosphorus neurospectroscopy showed a decrease in phosphodiesters, an increase in gammaNTP and an increase in the broadband component in the active group over this period, while the opposite changes occurred in the placebo group. Therefore, in chronic refractory epilepsy, omega-3 supplementation may be associated with reduced membrane phospholipid breakdown in the brain, an improvement in brain energy metabolism, and an increased level of phospholipids in membranes and/or vesicle bilayers in cells in the brain. The unfavourable biochemical changes observed in the placebo group may be a feature of chronic intractable epilepsy.

The long term retention of levetiracetam in a large cohort of patients with epilepsy.

Levetiracetam (Lev) is a new antiepileptic drug with a distinct mechanism of action, shown in regulatory trials to be effective. These controlled trials do not always predict how useful a drug will be in day to day clinical practice. Retention rates can provide a better indication of efficacy and tolerability in everyday use. Patients attending a tertiary referral centre for epilepsy and who received Lev in the first 2 years of its marketing were assessed (n = 811) to determine continuation rates of treatment with this drug. At the last follow up, 65% of patients were still taking Lev, and the estimated 3 year retention rate was 58%. In total, 11% attained seizure freedom of at least 6 months. Patients taking greater numbers of concurrent antiepileptic drugs (AEDs) were more likely to discontinue Lev, and those reaching higher maximum daily dosages were less likely to discontinue Lev. The retention rate for Lev compares favourably with that of other new AEDs.

Laparoscopic surgery for common surgical emergencies: a population-based study.

BACKGROUND: Despite being controversial in the past, many reports on the safe use of laparoscopic surgery in emergency settings have been published. The aim of this study was to investigate the diffusion of laparoscopic surgery in three common surgical emergency operations, namely, appendectomy, cholecystectomy, and simple repair of perforated peptic ulcer (PPU), in a stable population. METHODS: This was a retrospective analysis of the central database of the Hospital Authority (HA) in Hong Kong. Data for patients managed in 14 HA hospitals from 1998 to 2002 were studied. The operation record and discharge record of each patient were also investigated to verify the data. RESULTS: A total of 12,708 patients underwent appendectomy, 2631 patients underwent cholecystectomy, and 2260 patients had simple repair of PPU performed. During the study period, 37.2% of appendectomies, 46.5% of cholecystectomies, and 23.1% of simple repairs of PPU were performed laparoscopically. More than a two-fold increase in the proportion of laparoscopic surgery was observed in each of these three operations. By the end of 2002, the percentage of laparoscopic surgery had increased to 53.5% for appendectomies, 61.3% for cholecystectomies, and 32.9% for simple repairs of PPU. Significantly lower hospital mortality rates and shorter postoperative hospital stay were consistenty observed in patients with laparoscopic surgery of the three emergencies. A wide variation in the use of laparoscopic surgery, ranging from 3.7% to 73.1%, was observed among the 14 HA hospitals. However, there was no correlation in the use of laparoscopic surgery with the volume of operation performed in each hospital (p = 0.933). CONCLUSION: A high diffusion rate on the use of laparoscopic surgery for common surgical emergency was observed in Hong Kong. However, there was also a wide variation in the diffusion rate among the 14 HA hospitals. Efforts to reduce hospital variation for the better dissemination of safe laparoscopic technique may be warranted.

Gallbladder cancer presenting with acute cholecystitis: a population-based study.

BACKGROUND: The role of laparoscopic cholecystectomy (LC) in acute cholecystitis remains controversial. The aim of the present study was to determine the incidence, clinicopathological characteristics, and outcome of patients with gallbladder cancer presenting with acute cholecystitis. METHODS: We performed a retrospective analysis of patients with gallbladder cancer who presented with acute cholecystitis and were treated at the public hospitals in Hong Kong between 1998 and 2002. RESULTS: Among 2,700 patients with acute cholecystitis managed with cholecystectomy (1,347 open and 1,353 LC), 63 patients (2.3%) were found to have gallbladder cancer. There were 44 women and 19 men with a mean age of 74.7 (+/-12.8) years. Adenocarcinoma (90.5%) was the most common cancer. The overall median survival was 5 months (95% CI = 2.6-7.4). The 5-year survival rate was 20.8%. Laparoscopic cholecystectomy was attempted in 11 patients and was completed successfully in six of them. There was no difference between the LC and open groups in the complication rate, hospital mortality rate, or survival rate. CONCLUSIONS: In the ethnic Chinese population of Hong Kong, the incidence of gallbladder cancer presenting with acute cholecystitis is higher than the same finding in patients undergoing elective cholecystectomy for cholelithiasis. Long-term survival is possible because such patients may be diagnosed at an early stage of the disease.

Validation of POSSUM scoring systems for audit of major hepatectomy.

BACKGROUND: The aim of the study was to validate the use of Physiological and Operative Severity Score in the enUmeration of Mortality and morbidity (POSSUM) and Portsmouth (P) POSSUM scoring systems to predict postoperative mortality in a group of Chinese patients who had a major hepatectomy for hepatocellular carcinoma. METHODS: A retrospective analysis was performed on data collected prospectively over a 6-year interval from January 1997 to December 2002. The mortality risks were calculated using both the POSSUM and the P-POSSUM equations. RESULTS: Two hundred and fifty-nine patients underwent major hepatectomy; there were 17 (6.6 per cent) postoperative deaths. Of 32 preoperative and intraoperative variables studied, age, smoking habit, serum creatinine concentration, American Society of Anesthesiologists grade, and physiological and operative severity scores were found to be significant factors predicting mortality. On multivariate analysis only the physiological and operative severity scores were independent variables. The POSSUM system overpredicted mortality risk (14.2 per cent) and there was a significant lack of fit in these patients (chi(2) = 14.1, 3 d.f., P = 0.003). The mortality rate predicted by P-POSSUM was 4.2 per cent and showed no significant lack of fit (chi(2) = 7.6, 3 d.f., P = 0.055), indicating that it predicted outcome effectively. A new logistic equation was derived from the present patient data set that requires testing prospectively. CONCLUSION: P-POSSUM significantly predicted outcome in Chinese patients who had major hepatectomy for hepatocellular carcinoma. A modified disease-specific equation requires further testing.

Lamotrigine versus placebo in the prophylaxis of migraine with and without aura.

Lamotrigine blocks voltage-sensitive sodium channels, leading to inhibition of neuronal release of glutamate. Release of glutamate may be essential in the propagation of spreading cortical depression, which some believe is central to the genesis of migraine attacks. This study compared safety and efficacy of lamotrigine and placebo in migraine prophylaxis in a double-blind randomized parallel-groups trial. A total of 110 patients entered; after a 1-month placebo run-in period, placebo-responders and non-compliers were excluded, leaving 77 to be treated with lamotrigine (n = 37) or placebo (n = 40) for up to 3 months. Initially, lamotrigine therapy was commenced at the full dose of 200 mg/day, but, following a high incidence of skin rashes, a slow dose-escalation was introduced: 25 mg/day for 2 weeks, 50 mg/day for 2 weeks, then 200 mg/day. Attack rates were reduced from baseline means of 3.6 per month on lamotrigine and 4.4 on placebo to 3.2 and 3.0 respectively during the last month of treatment. Improvements were greater on placebo and these changes, not statistically significant, indicate that lamotrigine is ineffective for migraine prophylaxis. There were more adverse events on lamotrigine than on placebo, most commonly rash. With slow dose-escalation their frequency was reduced and the rate of withdrawal for adverse events was similar in both treatment groups.

Lamotrigine substitution study: evidence for synergism with sodium valproate? 105 Study Group.

Three hundred and forty seven patients with epilepsy from 54 centres across Europe not fully controlled with sodium valproate (VPA, n = 117), carbamazepine (CBZ, n = 129), phenytoin (PHT, n = 92) or phenobarbital (PB, n = 9) monotherapy were recruited into a lamotrigine (LTG) substitution study. If 50% or more seizure reduction occurred (responders) on addition of LTG, an attempt was made to withdraw the original antiepileptic drug (AED). If successful, this was followed by a 12 week period of LTG monotherapy. Overall, 73% patients completed the add-on phase (47% responders), 41% attempted AED withdrawal and 23% achieved LTG monotherapy. In the 60 patients (17%) completing the trial by remaining on LTG monotherapy, median monthly seizure frequency was reduced from 6 during baseline to 1.7. Sixteen percent of patients were withdrawn due to adverse effects, mostly during the add-on phase. Dizziness and diplopia occurred most frequently in the CBZ group, nervousness and ataxia in the PHT group, and rash and tremor in the VPA group. Slower LTG dose escalation resulted in fewer withdrawals due to rash in the VPA-treated patients (38% to 8%, P < 0.01). The responder rate was higher (P < 0.01) in patients with idiopathic tonic-clonic seizures (61%) than in those with partial seizures (43%). The addition of LTG to VPA (64% responders) produced a significantly better response (P < 0.001) than adding it to CBZ (41% responders) or PHT (38% responders). This effect was seen for partial (VPA, 57%; CBZ, 39%; PHT, 39%; P < 0.02) as well as tonic-clonic seizures (VPA, 70%; CBZ, 53%; PHT, 50%; NS). These data lend credence to the suggestion of therapeutic synergy between LTG and VPA.

A randomised open multicentre comparative trial of lamotrigine and carbamazepine as monotherapy in patients with newly diagnosed or recurrent epilepsy.

The efficacy and safety of lamotrigine and carbamazepine as monotherapy in patients with untreated, newly diagnosed or recurrent partial and/or generalised tonic-clonic seizures, were compared in a randomised, open, multicentre study. Patients received 24 weeks' treatment with oral lamotrigine 100 mg (LTG 100, n = 115) or 200 mg (LTG 200, n = 111) or carbamazepine 600 mg (CBZ 600, n = 117). Efficacy measurements were comparable between the three treatment groups, although the higher lamotrigine dose was possibly most effective, with 60.4% completing seizure free compared with 51.3% (LTG 100) and 54.7% (CBZ 600). Both dosage regimens of lamotrigine were well tolerated. More patients on CBZ 600 reported adverse experiences, 66% versus 53% (LTG 100) and 58% (LTG 200), and of these a greater proportion were attributed to CBZ 600 treatment, 53% versus 23% (LTG 100) and 28% (LTG 200). Similarly, a greater proportion of the CBZ 600 group required a change in dose, 47% versus 20% (LTG 100) and 17% (LTG 200) or withdrew completely due to adverse experiences, 10.3% versus 4.3% (LTG 100) and 4.5% (LTG 200). The most common adverse experience leading to withdrawal was rash, with approximately double the proportion of reports occurring in patients on CBZ 600 (5.1%) compared with lamotrigine (1.7% on LTG 100 and 2.7% on LTG 200). Overall lamotrigine appeared equally effective but better tolerated compared with carbamazepine.

Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy. UK Lamotrigine/Carbamazepine Monotherapy Trial Group.

Lamotrigine has been licensed widely as adjunctive therapy for partial and secondary generalised seizures. Use of the drug as monotherapy was investigated in a double-blind, randomised, parallel-group comparison with carbamazepine in newly diagnosed epilepsy. After 4 weeks of planned, fixed dose escalation, doses were adjusted according to efficacy, adverse events, and plasma concentrations. 151 of 260 patients (131 lamotrigine, 129 carbamazepine) in eight UK centres completed the 48-week trial. No differences in efficacy between the drugs were found for partial seizures with or without secondary generalisation or for primary generalised tonic-clonic seizures. The proportion of patients maintained seizure-free during the last 24 weeks of treatment was almost the same in both groups (39% lamotrigine, 38% carbamazepine). More patients with primary generalised tonic-clonic seizures (47% both groups) than those presenting with a focal onset (35%, 37%) were fully controlled. Overall, fewer patients on lamotrigine than on carbamazepine withdrew because of adverse events (15 vs 27%). The commonest side-effect leading to withdrawal with either drug was rash (9%, 13%). Sleepiness was less common in lamotrigine than in carbamazepine recipients (12 vs 22%, p < 0.05). More lamotrigine than carbamazepine recipients (65 vs 51%, p = 0.018) completed the study (hazard ratio 1.57 [95% CI 1.07-2.31]). Lamotrigine and carbamazepine showed similar efficacy against partial onset seizures and primary generalised tonic-clonic seizures in newly diagnosed epilepsy. Lamotrigine, however, was better tolerated.

Lamotrigine: a review of antiepileptic efficacy.

Lamotrigine (LTG) is a chemically novel antiepileptic drug (AED) that blocks voltage-sensitive sodium channels, leading to inhibition of neurotransmitter release, principally glutamate. LTG is active in a wide range of pharmacologic models of epilepsy, demonstrating a potency and duration of action generally superior to currently available AEDs. Preliminary evidence of efficacy was provided by single-dose studies showing effects on reducing interictal spike activity and photoconvulsive response. A total of eight randomized, double-blind, placebo-controlled, crossover trials have established the efficacy of LTG in patients with refractory partial epilepsy. Literature reports suggest LTG also is effective in patients with idiopathic generalized epilepsy, including absence seizures, and in patients with Lennox-Gastaut syndrome. Other reports suggest that LTG is useful in the pediatric population, and an interim report of an open monotherapy trial suggests that the efficacy of LTG was comparable to that of carbamazepine (CBZ) but the adverse experiences leading to discontinuation were less frequent.

Carbamazepine and lamotrigine in healthy volunteers: relevance to early tolerance and clinical trial dosage.

This study was conducted to examine the effects of acute doses of lamotrigine (LTG) and carbamazepine (CBZ) in healthy subjects and determine whether the low tendency to impairment with LTG observed in animals applied to humans. Twelve healthy men participated in a placebo-controlled, balanced, double-blind comparison of the drugs on a series of psychomotor, autonomic, sensory, and subjective variables. Variables were analyzed by analysis of variance, and p < 0.05 was considered significant. Adaptive tracking and body sway were impaired by CBZ 600 mg. CBZ 400 and 600 mg impaired smooth pursuit eye movements and also reduced mean peak saccadic velocity. No differences from placebo occurred after LTG. CBZ 600 mg increased heart rate (HR), but no drug-related changes were noted in pupil size, salivary secretion, visual near point, or subjective effects. During the controlled study, mean plasma CBZ concentrations at 2 and 6.5 h after the 600-mg dose were 5.28 and 5.36 micrograms/ml; after LTG 300 mg, they were 3.16 and 3.00 micrograms/ml. Increased CBZ saliva concentrations were significantly associated (p < 0.01) with impaired adaptive tracking, smooth and saccadic eye movements and increased HR, and plasma concentrations were associated with impaired eye movements and body sway.

Sodium valproate acutely inhibits lamotrigine metabolism.

Concomitant administration of sodium valproate (VPA) reduced lamotrigine (LTG) total clearance by approximately 21% and increased elimination half-life and AUC. Reduced elimination occurred acutely within the first hour. Renal elimination of LTG was not impaired. The most probable explanation for this effect is hepatic competition between VPA and LTG for glucuronidation. Volume of distribution and parameters related to absorption, Cmax and tmax were unchanged.

Overview of the clinical efficacy of lamotrigine.

Testing the efficacy of lamotrigine (LTG) in epileptic patients has been approached in several ways. The first pilot study examined the effect of a single dose of LTG in patients with frequent interictal spikes, and a reduction in spike frequency was observed. Subsequently, single doses reduced photosensitivity in appropriate patients. Single-blind administration of LTG for 1 week in addition to the patients' regular antiepileptic drugs (AEDs), in patients with refractory seizures, reduced seizures despite the short duration of therapy. This regimen was continued using a placebo-controlled crossover study with 1-week duration of treatment. Efficacy in partial and tonic-clonic seizures was subsequently confirmed in four double-blind crossover studies; a meta-analysis of these four studies showed a 30% reduction in partial seizures despite the intractable nature of the seizures in the patients included. Current studies aim at evaluating the drug as monotherapy and in different seizure types.

Human safety of lamotrigine.

The clinical safety of lamotrigine (LTG), assessed in four completed randomized, double-blind, placebo-controlled crossover trials and an interim analysis of 27 12-month open studies, is discussed. LTG was added to existing antiepileptic drugs (AEDs) of adult patients with refractory epilepsy, using a twice-daily regimen. In the pooled data from the four double-blind studies (n = 92), the incidence of adverse experiences with LTG and placebo did not differ significantly. Two patients were withdrawn on LTG due to adverse experiences (one rash, one nausea and vomiting). In the open studies (pooled data; n = 572) the most commonly reported adverse experiences were dizziness, diplopia, somnolence, headache, ataxia, and asthenia (10-14% incidence). Forty-nine patients (8.6%) were withdrawn with adverse events, most commonly for rash (2.3%). No patients were withdrawn from any of the studies with physical, neurological, or ECG abnormalities thought attributable to LTG treatment. Laboratory measures, vital signs, and weight did not show any consistent changes of clinical significance, and no significant changes in plasma concentrations of concomitant AEDs after the addition of LTG were observed.

A randomised double-blind placebo-controlled crossover add-on trial of lamotrigine in patients with treatment-resistant partial seizures.

Efficacy and safety of lamotrigine (LTG) as add-on therapy was assessed in a randomised double-blind placebo-controlled trial of this drug in 23 adult patients with refractory partial seizures. Fifteen patients showed an improvement on LTG treatment, with a greater than 50% decrease in total seizure count in 7 patients. Fourteen patients experienced fewer simple and complex partial seizures, with 8 patients benefitting by more than a 50% decrease in seizure frequency. The drug was well tolerated over the 2 month treatment period. The plasma concentration of concomitant antiepileptic drugs remained unchanged. No haematological or chemical abnormalities were noted.

Response of skin thickness and metacarpal index to estradiol therapy in postmenopausal women.

A radiologic method for measuring skin thickness and metacarpal index was used to investigate 41 postmenopausal women treated with estradiol (100-mg) subcutaneous implants (Organon, UK). All the women completed the first six months of the study, and 33 completed one year. Both skin thickness and metacarpal index increased to a statistically significant degree over the one-year period, with most of the increase occurring in the first six months of therapy. Skin thickness showed the largest increases, from a mean of 0.86 mm at the start of the study to 0.97 mm at six months and 1 mm at one year. The metacarpal index increased from a mean of 0.77 at the start of the study to a mean of 0.799 and 0.8 at six months and one year, respectively.