Extensive loss of cell-cycle and DNA repair genes in an ancient lineage of bipolar budding yeasts.

Cell-cycle checkpoints and DNA repair processes protect organisms from potentially lethal mutational damage. Compared to other budding yeasts in the subphylum Saccharomycotina, we noticed that a lineage in the genus Hanseniaspora exhibited very high evolutionary rates, low Guanine-Cytosine (GC) content, small genome sizes, and lower gene numbers. To better understand Hanseniaspora evolution, we analyzed 25 genomes, including 11 newly sequenced, representing 18/21 known species in the genus. Our phylogenomic analyses identify two Hanseniaspora lineages, a faster-evolving lineage (FEL), which began diversifying approximately 87 million years ago (mya), and a slower-evolving lineage (SEL), which began diversifying approximately 54 mya. Remarkably, both lineages lost genes associated with the cell cycle and genome integrity, but these losses were greater in the FEL. E.g., all species lost the cell-cycle regulator WHIskey 5 (WHI5), and the FEL lost components of the spindle checkpoint pathway (e.g., Mitotic Arrest-Deficient 1 [MAD1], Mitotic Arrest-Deficient 2 [MAD2]) and DNA-damage-checkpoint pathway (e.g., Mitosis Entry Checkpoint 3 [MEC3], RADiation sensitive 9 [RAD9]). Similarly, both lineages lost genes involved in DNA repair pathways, including the DNA glycosylase gene 3-MethylAdenine DNA Glycosylase 1 (MAG1), which is part of the base-excision repair pathway, and the DNA photolyase gene PHotoreactivation Repair deficient 1 (PHR1), which is involved in pyrimidine dimer repair. Strikingly, the FEL lost 33 additional genes, including polymerases (i.e., POLymerase 4 [POL4] and POL32) and telomere-associated genes (e.g., Repressor/activator site binding protein-Interacting Factor 1 [RIF1], Replication Factor A 3 [RFA3], Cell Division Cycle 13 [CDC13], Pbp1p Binding Protein [PBP2]). Echoing these losses, molecular evolutionary analyses reveal that, compared to the SEL, the FEL stem lineage underwent a burst of accelerated evolution, which resulted in greater mutational loads, homopolymer instabilities, and higher fractions of mutations associated with the common endogenously damaged base, 8-oxoguanine. We conclude that Hanseniaspora is an ancient lineage that has diversified and thrived, despite lacking many otherwise highly conserved cell-cycle and genome integrity genes and pathways, and may represent a novel, to our knowledge, system for studying cellular life without them.

A histological study of the eye lesions in 12 leprosy patients with tuberculoid lesion in 4 eyes.

The histological reactions in 12 eyes of 12 leprosy patients were studied (5 BT, 1 BB, 1 BL and 5 LL). Granuloma lesions composed of epithelioid cells, Langerhans giant cells, macrophages and lymphocytes were found in various intraocular tissues, e.g. cornea, sclera, iris, ciliary body or retina in 4 patients (1 BT and 3 LL). Of the 3 LL patients, according to the records, 2 were cured and in the other patient the outcome of the treatment was not mentioned. In view of the finding of the granulomatous lesions in the clinically cured patients and tuberculoid granuloma in the intraocular tissues in the LL patients, could there be some peculiarities in the intraocular sites? Or perhaps the tuberculoid reaction is just a manifestation of an upgrading reaction? More examinations on human leprosy eye specimens will be needed to answer these questions.

The pathology of the eye in armadillos experimentally infected with Mycobacterium leprae.

One hundred and twenty-seven eyes from 66 Mycobacterium leprae inoculated armadillos were studied histologically and some ultrastructurally. Inflammatory reactions were found in the following extraocular tissues: the eyelid, including the orbicularis muscle and the third eyelid, extraocular muscles, tear gland and Harder's gland. The early and slight changes of the intraocular tissues, small amounts of lymphocytes, plasma cells and macrophage infiltrations were confined to the area around the anterior angle specifically within the trabeculae and the adjacent ciliary body, the root of the iris and the limbus region of the cornea. But in the cases with severe lesions the whole uvea was densely infiltrated with large, foamy macrophages intermingled with small amounts of lymphocytes, plasma cells and frequently, neutrophils. No specific necrosis of the granulomas was seen. No explanation for the neutrophil infiltrations was given. The lesions in the cornea were significantly less severe than those in the uvea. Retinal lesions comprised of macrophage infiltrations were all obvious extensions of the adjacent uvea lesions. Acid-fast bacilla (AFB) were found within all tissues. The infection of the intraocular tissues in the armadillo eyes seemed to be mainly, if not solely, haematogenous.

Histopathological findings in the iris of dapsone treated leprosy patients.

From 43 Nepalese leprosy patients skin smear negative, and treated with dapsone (diamino diphenyl sulphone), and without any sign of active leprosy or iritis, specimens from iridectomy during cataract surgery were studied histopathologically. Of 49 iris specimens only six (12%) were found to be without any histopathological change. Atrophy of the iris stroma was seen in 63% and neovascularisation in 6% of all cases. In 16% in which the dilator muscle could be detected, it was atrophic, and in 11% the pigmented epithelium was thinned and atrophic. Cellular inflammatory infiltrations were seen in 88% of all specimens. They were mostly slight in eyes which before operation had been without posterior synechiae of the iris. In most of the eyes in which posterior synechiae had been present moderate or heavy inflammatory cell infiltrates composed of lymphocytes and plasma cells, often associated with macrophages, neutrophils, or eosinophils, were found. In five iris specimens acid fast bacilli were present. This raises the question whether these can survive systemically despite dapsone chemotherapy in the iris, thus leading to dapsone-resistant leprosy and to recurrent iritis.

[Lagophthalmos and posterior synechiae of the iris during treatment of leprosy with diaminodiphenylsulfone]. / Lagophthalmus und hintere Synechien der Iris bei der Behandlung der Lepra mit Diamino-diphenyl-sulfon.

Four years after controlled and standardized chemotherapy with diaminodiphenylsulfone (DDS), 316 patients in the leprosarium at Khokana, Nepal were re-examined for ophthalmological findings. Patients who, 4 years earlier, had not had lagophthalmos in either eye, nor posterior synechiae of the iris, had only developed these complications in the meantime if they were suffering from DDS-resistant leprosy. New posterior synechiae of the iris were only found in patients with inactive leprosy who had already had a posterior synechia in the fellow eye four years previously. In cases of inactive leprosy there was also a tendency for existing posterior synechiae to increase. It is emphasized that the development of lagophthalmos or posterior synechiae of the iris indicates that a previously inactive leprosy may have become reactivated in spite of treatment with DDS.

The incidence of lagophthalmus and posterior synechiae of the iris during chemotherapy of leprosy (morbus Hansen).

In the Green-Pastures-Leprosy-Hospital in Pikhara/Nepal 340 outpatients with leprosy were examined to evaluate the incidence of lagophthalmus and posterior synechiae of the iris. Patients who had already received chemotherapeutical treatment during the first 5 years following the onset of the disease developed fewer cases of lagophthalmus in both types of leprosy than patients who remained untreated for longer than 5 years. A comparable positive influence of early chemotherapy on the incidence of posterior synechiae of the iris could not be proven. The possible causes were discussed.

Blindness from cataract formation in leprosy.

Of 744 leprous patients, 61 (8.2%) had cataract-induced blindness; 46 patients (6.2%) were unilaterally blind and 15 (2.0%) were bilaterally blind. The mean age of patients with cataracts was 63.4 years in the tuberculoid-type leprosy and 56.4 years in the lepromatous type. The appearance of cataracts in lepromatous patients at an earlier age than in tuberculoid patients is significant (p less than 0.005). Of 41 cataractous eyes with posterior iris synechiae, 42.1% were observed in patients with tuberculoid-type leprosy and 59.1% in patients with the lepromatous type. Histopathological examination of 24 lenses showed that irregularities of the lens epithelium were present in 79.2%. Posterior iris synechiae were seen in 66.7% and fibrous pseudometaplasia in 41.7%. Posterior migration of the lens epithelium in the posterior subcapsular area was observed in 54.2%. In view of these clinical and histopathological findings, we discuss the probability that most cataracts in leprous patients are complicated in nature.

Influence of untreated chronic plastic iridocyclitis on intraocular pressure in leprous patients.

The intraocular pressures of a total of 1015 eyes of leprous patients who never had ophthalmological care or local eye treatment were measured. The patients were categorised according to the type of leprosy they had the eyes were categorised as without or with chronic plastic iridocyclitis. In patients with the tuberculoid and lepromatous types of leprosy the intraocular pressure was significantly lower in eyes with chronic plastic iridocyclitis than in unaffected eyes. It has been shown that chronic plastic iridocyclitis which remains untreated for many years results in significantly lower intraocular pressure.

Ocular findings in leprosy patients in an institution in Nepal (Khokana).

A total of 466 leprosy patients in Nepal, some advanced cases, were surveyed for ocular lesions. 74.2% were found with ocular features, and 12.7% of the eyes were blind. The patients were classified in tuberculoid, borderline-borderline, and lepromatous groups. Lepromatous leprosy is responsible for major ocular complications and blindness.

Ocular findings in leprous patients. A report of a survey in Malunga/Nepal.

A total of 116 patients in Nepal with advanced leprosy were examined in an ophthalmological survey. All patients were older than 20 years and none had suffered from leprosy for less than 10 years. Abnormal ocular findings occurred in 69.8% of all patients and 9.3% of the eyes were blind. The results are compared with those of other authors.

[Ocular findings in leprosy: results of a survey in the Green Pastures Leprosy Hospital, Nepal (author's transl)]. / Augenbefunde bei Lepra. Ergebnisse einer Studie im Green-Pastures-Leprosy-Hospital Pokhara/Nepal.

One hundred and seventy leprous patients underwent ophthalmic examination; of those with tuberculoid leprosy, 49.3% had ocular pathology; in patients with lepromatous leprosy the corresponding figure was 61.4%. 4.7 percent of all eyes examined were blind. Early chemotherapy prevents further complications in tuberculoid leprosy, but not in ;the lepromatous type. The results are compared with those of other authors.